In re: Acetaminophen - ASD-ADHD Products Liability Litigation
Filing
99
OPINION AND ORDER: The defendants' motions of September 19, 2023 to exclude plaintiffs' general causation experts' opinions regarding Autism Spectrum Disorder, Attention Deficit Hyperactivity Disorder, and biological plausibility are granted. (Signed by Judge Denise L. Cote on 12/18/2023) (vfr)
UNITED STATES DISTRICT COURT
SOUTHERN DISTRICT OF NEW YORK
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IN RE: Acetaminophen – ASD-ADHD
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Products Liability Litigation
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APPEARANCES:
For plaintiffs:
Keller Postman LLC
Ashley C. Keller
Ashley Barriere
Amanda Hunt
John James Snidow
150 N. Riverside Plaza, Ste. 4100
Chicago, IL 60606
Watts Guerra LLC
Mikal C. Watts
Millennium Park Plaza RFO
Ste. 410, C112
Guaynabo, PR 00966
The Lanier Law Firm
W. Mark Lanier
Evan Janush
535 Madison Avenue, 12th Fl.
New York, NY 10022
Tracey & Fox Law Firm
Sean Tracey
Lawrence Tracey
440 Louisiana Street, Ste. 1901
Houston, TX 77002
Holland Law Firm
Eric Holland
Ann Callis
211 North Broadway, Ste. 2625
St. Louis, MO 63102
22MD3043 (DLC)
22MC3043 (DLC)
OPINION AND
ORDER
Beasley Allen Law Firm
W. Roger Smith, III
218 Commerce Street
Montgomery, AL 36104
Littlepage Booth
Zoe Littlepage
1912 W. Main St.
Houston, TX 77098
Holwell Shuster & Goldberg
Daniel Sullivan
425 Lexington Avenue
New York, NY 10017
Dovel & Luner
Julien Adams
201 Santa Monica Blvd, Ste. 600
Santa Monica, CA 90401
Cooper Law Partners
Charles Cooper
1717 Pennsylvania Avenue N.W., Ste. 1025
Washington, DC 20006
Krause & Kinsman
Tricia Cambell
4717 Grand Avenue, Ste. 300
Kansas City, MO 64112
Torhoerman Law
Eric Cracken
227 West Monroe, Ste. 2650
Chicago, IL 60606
Matthews and Associates
David Matthews
2905 Sackett St.
Houston, TX 77098
Danzinger & Dellano
Paul Danzinger
440 Louisiana St.
Houston, TX 77002
Luff Law Firm, PLLC
2
Patrick Luff
10440 N. Central Expressway, Ste. 950
Dallas, TX 75231
Moskow Law Group, LLC
Neal Moskow
425 Kings Highway East, 2nd Fl.
Fairfield, CT 06825
Paul, LLP
Richard M. Paul, III
Ashlea Schwarz
601 Walnut St, Ste. 300
Kansas City, MO 64106
Carlson Law
Ruth Rizkalla
1500 Rosecrans Avenue, Ste. 500
Manhattan Beach, CA 90266
Wagstaff & Cartmell, LLP
Lindsey Scarcello
4740 Grand Avenue, Ste 300
Kansas City, MO 64112
For defendants:
Barnes & Thornburg LLP
Kristin L. Richer
Sarah E. Johnston
James F. Murdica
2029 Century Park East, Suite 300
Los Angeles, CA 90067
Skadden, Arps, Slate, Meagher & Flom LLP
Allison M. Brown
Jessica Davidson
One Manhattan West
New York, NY 10001
King & Spalding LLP
Kristen R. Fournier
1185 Avenue of the Americas, 34th Floor
New York, New York 10036
Arnold & Porter Kaye Scholer LLP
Lori B. Leskin
3
250 W. 55th St.
New York, NY 10019
Contents
Procedural Background.......................................... 6
I.
II.
Prior Opinions in this Case ............................. 6
Proposed Label Change & FDA Involvement ................ 7
III.
IV.
V.
VI.
General Causation Discovery ............................ 8
Acetaminophen and Regulation .......................... 10
ASD and ADHD ........................................... 12
Epidemiology .......................................... 16
A.
Interpreting Observational Study Results .............. 17
B.
Animal Studies ........................................ 22
C.
Causation ............................................. 22
VII.
Types of Evidence at Issue Here ....................... 23
A.
Published Studies ..................................... 24
B. Statements by Governmental Bodies, Medical Societies, and
other Associations ........................................ 38
Discussion.................................................... 46
VIII.
IX.
X.
A.
XI.
A.
B.
XII.
A.
XIII.
XIV.
Epidemiology Cases .................................... 53
Dr. Baccarelli ......................................... 58
B.
B.
Standard: Daubert and Rule 702 ...................... 49
Bradford Hill ......................................... 62
Navigation Guide ..................................... 101
Dr. Cabrera .......................................... 107
Bradford Hill ........................................ 109
Adverse Outcome Pathway .............................. 113
Dr. Hollander ........................................ 122
Transdiagnostic Approach ............................. 127
Bradford Hill Analysis ............................... 133
Dr. Pearson ........................................ 135
Dr. Louie ............................................ 141
Conclusion................................................... 148
4
DENISE COTE, District Judge:
This Opinion addresses the Rule 702 motions filed by the
parties in this multidistrict products liability litigation
(“MDL”).
The plaintiffs in this MDL assert that the defendants
violated their state law duties to warn consumers of the risk
that children may develop autism spectrum disorder (“ASD”)
and/or attention-deficit/hyperactivity disorder (“ADHD”) as a
result of in utero exposure to acetaminophen.
The defendants
include a manufacturer as well as several retailers of
acetaminophen products.
The parties have completed discovery on
the issue of general causation -- that is, whether prenatal
exposure to acetaminophen causes ASD and ADHD.
Plaintiffs have put forward five expert witnesses on
general causation.
Defendants have put forward six experts.
Each of the parties’ experts is eminently qualified.
For the following reasons, the defendants’ motions to
preclude the testimony of plaintiffs’ general causation experts
are granted.
With these rulings, the plaintiffs do not have
admissible evidence to demonstrate that prenatal exposure to
acetaminophen causes either ASD or ADHD in offspring.
The Court
denies as moot plaintiffs’ motions to preclude the testimony of
defendants’ experts.
5
Procedural Background
In 2022, plaintiffs -- children, parents, and guardians who
allege injuries from the development in children of ASD and ADHD
due to a mother’s prenatal use of acetaminophen -- began to file
products liability lawsuits in federal courts.
These lawsuits
allege that defendants’ labeling practices for acetaminophen
were deficient under various state laws.
Plaintiffs have sued
the manufacturer of Tylenol (Johnson & Johnson Consumer Inc.
(“JJCI”)) and retailers of store-branded acetaminophen products
(“Retailer Defendants”).
Plaintiffs assert several state law
causes of action: strict liability for failure to warn, strict
liability for design defect due to inadequate warnings and
precautions, negligence, negligent misrepresentation by
omission, and breach of implied warranty.
On October 5, 2022, the Judicial Panel on Multidistrict
Litigation (“JPML”) consolidated eighteen of plaintiffs’ cases
(filed in seven districts) and transferred the cases to this
Court under 28 U.S.C. § 1407.
This MDL now includes around 600
member cases.
I.
Prior Opinions in this Case
Two defendants (Wal-Mart Stores, Inc. (“Walmart”) and JJCI)
separately moved to dismiss a total of three actions on the
6
ground of preemption.
Walmart’s motion to dismiss two lawsuits
filed in the Western District of Arkansas was denied on November
14, 2022.
In re Acetaminophen – ASD-ADHD Prods. Liab. Litig.,
No 22md3043 (DLC), 2022 WL 17348351 (S.D.N.Y. Nov. 14, 2022).
JJCI’s motion to dismiss an action filed in the District of
Nevada was denied on April 20, 2023.
In re Acetaminophen – ASD-
ADHD Pros. Liab. Litig., No 22md3043 (DLC), 2023 WL 3026412
(S.D.N.Y. Apr. 20, 2023).
In April and May of 2023, motions to
dismiss addressed to individual actions in this MDL were
addressed. 1
The plaintiffs subsequently agreed to drop all
strict liability misrepresentation claims, consumer protection
claims, and standalone apparent manufacturer liability claims
from all of the individual actions.
II.
22md3043: ECF No. 772.
Proposed Label Change & FDA Involvement
On April 7, 2023, in response to a request from the Court,
the plaintiffs submitted proposed language for a label change
for the acetaminophen products at issue in this litigation
(“Plaintiffs’ Proposed Warning”).
The Plaintiffs’ Proposed
Warning is:
Autism/ADHD: Some studies show that frequent use of
this product during pregnancy may increase your
In re Acetaminophen – ASD-ADHD Prods. Liab. Litig., No.
22md3043 (DLC), 2023 WL 3126589 (S.D.N.Y. Apr. 27, 2023); 2023
WL 3045802 (S.D.N.Y. Apr. 21, 2023); 2023 WL 3126636 (S.D.N.Y.
Apr. 27, 2023); 2023 WL 3162623 (S.D.N.Y. Apr. 28, 2023); 2023
WL 3467057 (S.D.N.Y. May 15, 2023).
1
7
child’s risk of autism and attention deficit
hyperactivity disorder. If you use this product
during pregnancy to treat your pain and/or fever, use
the lowest effective dose for the shortest possible
time and at the lowest possible frequency.
Because this MDL raises important issues related to public
health and drug safety for pregnant women and their offspring,
the Court invited the United States, including the Food and Drug
Administration (“FDA”), to submit its views on the Plaintiffs’
Proposed Warning.
On September 8, as the parties were about to
file their Rule 702 motions, the United States responded to the
invitation.
The Government declined to submit a Statement of
Interest but noted in its letter the FDA’s independent 2023
conclusion (discussed in more detail infra) that the scientific
evidence on this topic is as of yet “unable to support a
determination of causality.”
III. General Causation Discovery
All fifty states require some evidence of general causation
in products liability cases involving complex products liability
or medical issues.
See In re Mirena IUS Levonorgestrel-Related
Products Liability Litigation, 982 F.3d 113, 124 (2d. Cir. 2020)
(“Mirena II”).
At a pretrial conference on December 2, 2022,
the Court proposed, and the parties agreed, to conduct discovery
related to general causation first; if the plaintiffs’ experts
on the issue of general causation survived Rule 702 motions, the
8
remainder of discovery would proceed.
After additional
conferences, an Order of February 1, 2023 set a schedule for
fact and expert discovery and Rule 702 proceedings on the issue
of general causation.
All general causation fact discovery was
to be completed on June 2.
Plaintiffs served their expert reports on June 16.
Plaintiffs’ experts are: Andrea Baccarelli, M.D., Ph.D. (“Dr.
Baccarelli”), Brandon Pearson, Ph.D. (“Dr. Pearson”), Robert
Cabrera, Ph.D. (“Dr. Cabrera”), Stan Louie, Pharm.D. (“Dr.
Louie”), and Eric Hollander, M.D. (“Dr. Hollander”).
Dr.
Baccarelli is an epidemiologist, Dr. Pearson a toxicologist, Dr.
Cabrera a teratologist and geneticist, Dr. Louie a
pharmacologist, and Dr. Hollander a psychiatrist.
One week
later, plaintiffs emailed defendants with a link to amended
reports for all five of plaintiffs’ experts.
Defendants’ expert
designation and report deadline was thus moved one week.
The defendants’ experts are: Dr. Jennifer Pinto-Martin,
Ph.D., M.P.H. (“Dr. Pinto-Martin”), Dr. Wendy Chung, M.D., Ph.D.
(“Dr. Chung”), Dr. Craig Powell, M.D., Ph.D. (“Dr. Powell”), Dr.
Mitchell McGill, M.D., Ph.D. (“Dr. McGill”), Dr. Stephen
Faraone, Ph.D. (“Dr. Faraone”), and Dr. Alexander Kolevzon, M.D.
(“Dr. Kolevzon”).
Dr. Pinto-Martin is an epidemiologist, Dr.
Chung a geneticist, Dr. Powell a neuroscientist, Dr. McGill a
9
toxicologist, Dr. Faraone a psychologist, and Dr. Kolevzon a
psychiatrist.
Plaintiffs’ rebuttal expert reports were served
on July 28, and all experts were deposed as of September 8.
The Rule 702 motions were fully submitted on October 20,
2023.
Oral argument on the defendants’ motions to strike the
plaintiffs’ expert reports was held on December 7, 2023. 2
Factual Background
Before addressing the individual Rule 702 motions, this
Opinion sets out background information relevant to the motions.
This background information describes 1) acetaminophen and its
regulation; 2) ASD and ADHD and their characteristics; 3) the
basics of epidemiological evidence; 4) the types of the
scientific research and many of the studies on which the
parties’ experts have relied; and 4) the assessments, statements
and conclusions of various medical and governmental bodies on
the issue at stake in these motions.
IV.
Acetaminophen and Regulation
Acetaminophen (sometimes referred to as “APAP” in the
literature) is the active ingredient marketed for the relief of
The Court advised the parties on November 7, 2023 that it did
not require testimony from any of the expert witnesses. See
Kumho Tire Company, Ltd. v. Carmichael, 526 U.S. 137, 152 (1999)
(noting trial court has “latitude in deciding how to test an
expert’s reliability, and to decide whether or when special
briefing or other proceedings are needed to investigate
reliability”).
2
10
fever and pain in Tylenol and other over-the-counter pain
relievers.
Untreated fever during pregnancy is associated with
poor pregnancy outcomes, and untreated pain can result in
depression, anxiety, and high blood pressure in the mother.
See
FDA 2022 3 at 33; see U.S. Food and Drug Administration, FDA has
reviewed possible risks of pain medicine use during pregnancy
(Jan. 9, 2015), at perma.cc/4JY6-CN6V.
Acetaminophen is
considered the only pain reliever and fever reducer indicated
for use during pregnancy because of the risks of miscarriage or
birth defects associated with other analgesics like NSAIDS.
About 60% of pregnant women in the U.S. are estimated to use
acetaminophen.
FDA 2022 at 5.
Acetaminophen can cross the
As will be discussed in detail infra, the FDA has reviewed
scientific literature pertinent to this litigation several
times. The FDA’s internal reviews include: Taylor & Wang,
Review of Study of Acetaminophen Use in Pregnancy and Risks of
ADHD in Offspring, U.S. Food and Drug Administration (May 15,
2014) (“FDA 2014”); Mosholder et al., Acetaminophen Use in
Pregnancy and ADHD in Offspring, U.S. Food and Drug
Administration (March 18, 2015) (“FDA 2015”); Mosholder,
Neurodevelopmental Outcomes Following Prenatal Acetaminophen
Exposure, U.S. Food and Drug Administration (October 14,
2016)(“FDA 2016”); Nguyen & Gassman, Memorandum of Consultation:
Public Communication About In Utero Acetaminophen Exposure And
The Potential For Adverse Neurodevelopmental Outcomes, U.S. Food
and Drug Administration (Feb 10, 2017) (“FDA 2017”); Abraham et
al., Functional Neurobehavioral Outcomes and Urogenital Outcomes
Associated with Prenatal Acetaminophen Exposure, U.S. Food and
Drug Administration July 15, 2022) (“FDA 2022”); Abraham et al.,
Updated Literature Review of Studies that Examine the
Association Between Acetaminophen Exposure During Pregnancy and
Neurobehavioral or Urogenital Outcomes, U.S. Food and Drug
Administration (March 10, 2023) (“FDA 2023”).
3
11
placental barrier and can thus enter fetal circulation.
Ricci
et al., In Utero Acetaminophen Exposure and Child
Neurodevelopmental Outcomes: Systematic Review and MetaAnalysis, 37 Paediatr. Perinat. Epidemiol. 473, 474 (2023)
(“Ricci 2023”).
Since 1982, all over-the-counter drugs intended for
systemic absorption must include a general pregnancy warning:
“If pregnant or breast-feeding, ask a health professional before
use.”
21 C.F.R. § 201.63; see In re Acetaminophen – ASD-ADHD
Prods. Liab. Litig., 2022 WL 17348351, at *6 (noting requirement
that first four words be in bold type).
Acetaminophen, which is
systemically absorbed, is among the drugs whose labelling must
include this warning.
The governing regulations require no
additional warning related to pregnancy for acetaminophen
products.
See U.S. Food and Drug Administration, Over-the-
Counter (OTC) Monograph M013: Internal Analgesic, Antipyretic,
and Antirheumatic Drug Products for Over-the-Counter Human Use
(Oct. 14, 2022).
V.
ASD and ADHD
The essential features of ASD are persistent impairment in
reciprocal social communication and social interaction and
restricted, repetitive patterns of behavior, interests, or
activities.
American Psychiatric Association, Diagnostic and
12
Statistical Manual of Mental Disorders (5th ed., Text Revision,
2022) (“DSM”) at 60.
These symptoms are present from early
childhood and limit or impair everyday functioning.
Id.
Estimates of prevalence range from about 1% to 2% of children in
the United States, and a little under 1% globally.
63.
Id. at 62-
ASD is about three times as prevalent in males as in
females, although there are concerns about under-recognition of
ASD in women and girls.
Id. at 63.
The precise cause of ASD is unknown.
Heritability, a
measure of how much variation in a trait at the population level
is due to genetic influence, rather than environmental factors,
is estimated to be about 80%.
Id. at 64.
About 15% of ASD
cases appear to be associated with a known genetic mutation.
Id.
Even when a known genetic mutation is associated with ASD,
not all individuals with that genetic mutation will have ASD.
Id.
Risk for the majority of cases appears to be polygenic
(i.e., many genes each making relatively small contributions).
Id.
The DSM notes that “[a] variety of risk factors for
neurodevelopmental disorders, such as advanced parental age,
extreme prematurity, or in utero exposures to certain drugs or
teratogens like valproic acid, may broadly contribute to risk of
[ASD].”
Id.
13
Like ASD, ADHD is a neurodevelopmental disorder (“NDD”).
Its essential feature is a persistent pattern of inattention
and/or hyperactivity-impulsivity that interferes with
functioning or development.
Id. at 70.
Inattention typically
manifests as wandering off task, failing to follow through on
instructions or finishing work or chores, having difficulty
sustaining focus, and being disorganized.
Id.
Hyperactivity
refers to excessive motor activity when it is not appropriate.
Id.
Impulsivity refers to hasty actions that occur in the
moment without forethought; impulsive behaviors may manifest as
social intrusiveness or making decisions without consideration
of long-term consequences.
Id.
ADHD begins in childhood, and several symptoms must be
present by age 12 for diagnosis.
Id. at 70.
Further, children
must show symptoms in more than one setting (e.g., home and
school or home and work), and confirmation of substantial
symptoms across settings typically cannot be done accurately
without consulting informants who have seen the individual in
those settings.
Id.
The prevalence of ADHD is estimated to be about 7.2% of
children worldwide, although prevalence ranges widely from
country to country (from 0.1% to 10.2%).
no biological marker for diagnosing ADHD.
14
Id. at 71.
Id. at 72.
There is
While
some neuroimaging studies have shown differences in children
with ADHD compared with control subjects, meta-analysis of all
neuroimaging studies do not show differences, likely due to
differences in diagnostic criteria as well as technical aspects
of the neuroimaging technique.
ADHD.
71.
Id.
There is no single gene for
Heritability is estimated at approximately 74%.
Id. at
As with ASD, studies have identified a number of genes that
may be associated with ADHD, as well as several environmental
risk factors, including low birthweight, prenatal exposure to
smoking, and possibly diet.
Id.
ADHD is one of the most common comorbidities with ASD,
along with depression and anxiety.
Id. at 66.
Both disorders
include symptoms in the domains of social communication and
abnormal attention; however, the DSM notes that “[t]he social
dysfunction and peer rejection seen in individuals with ADHD
must be distinguished from the social disengagement, isolation
and indifference to facial and tonal communication cues” seen in
individuals with ASD.
Id. at 74.
While children with ASD may
display tantrums because of an inability to tolerate a change
from their expected course of events, children with ADHD may
misbehave or have tantrums during transitions because of
impulsivity or poor self-control.
Id.
Further, “the
developmental course and absence of restricted, repetitive
15
behaviors and unusual interests [in ADHD]” differentiate the two
disorders.
VI.
Id.
Epidemiology
Epidemiology is the study of the causes, incidence, and
distribution of diseases.
Epidemiological studies attempt to
determine whether an agent is related to the risk of developing
a certain disease.
Reference Manual on Scientific Evidence (3d
ed. 2011) (“RMSE”) at 555.
Due to ethical constraints, most
epidemiological studies are observational, rather than
experimental.
In an observational study, the authors compare
the rate of disease among a group of subjects who have been
exposed to the agent of interest and compare that rate with that
of an unexposed control group.
Id. at 556.
Two major types of observational studies are cohort studies
and case control studies.
In cohort studies, researchers define
a study population without regard to the participants’ disease
status, then classify the study participants into groups based
on whether they were exposed to the agent of interest.
557.
Id. at
Cohort studies can be prospective (the cohort is defined
in the present and followed forward into the future, and the
proportions of individuals in each group who develop the disease
of interest are compared) or retrospective (the researcher
determines the proportion of individuals in the exposed group
16
who developed the disease from available records or evidence and
compares that proportion with the proportion of another group
that was not exposed).
Id.
In case-control studies, the researcher begins with a group
of individuals who have a disease (“cases”) and then selects a
similar group of individuals who do not have the disease
(“controls”).
Id. at 559.
The researcher then compares the
groups in terms of past exposures.
A.
Interpreting Observational Study Results
Because observational studies do not control for exposure
to other risk factors for disease, their results must be
interpreted with some caution.
“[T]he first question an
epidemiologist addresses is whether an association exists
between exposure to the agent and disease.”
Id. at 566.
If an
association is found, its strength can be stated in several
ways, including risk ratios (“RR”), which represent the ratio of
the incidence rate of disease in exposed individuals to the
incidence rate in unexposed individuals.
If the risk ratio
equals 1.0, the risk in exposed individuals is the same as the
risk in unexposed individuals.
Id. at 567.
If it is greater
than 1.0, the risk in exposed individuals is greater than the
risk in unexposed individuals; in other words, there is a
positive association between exposure to the agent and the
17
disease, which may or may not be causal.
Id.
If it is less
than 1.0, there is a negative association between exposure and
disease, which may or may not reflect a protective effect of the
agent on risk of disease.
Id.
An association (negative or
positive), without more, should be interpreted with caution;
further analysis must be conducted to assess whether the
association is real or is instead a result of chance,
confounding, or bias.
1.
Id. at 567-568.
Chance
Chance, or random error, is evaluated through measures of
statistical significance, which is usually reported using a
range of values referred to as the “95% confidence interval”
(“CI”).
The CI encompasses the results we would expect 95% of
the time if samples for new studies were repeatedly drawn from
the same population.
All other things being equal, the larger
the sample size, the narrower the confidence interval.
581.
Id. at
The narrower the CI, the more statistically stable the
results of the study.
Id. at 580.
For example, if a study
found a risk ratio of 1.5 with a 95% CI of .08-3.4, the result
is not statistically significant because the CI includes 1.0.
Id. at 581.
If a study found a risk ratio of 1.5 with a 95% CI
of 1.1-2.2, the results are statistically significant because
the CI does not include an RR of 1.0.
18
Id.
2.
Bias
Bias is a systematic, non-random error.
Two types of
relevant bias are selection bias (where the population of the
study is not representative of the general population), and
information bias (where inaccurate information about either the
disease or the exposure status of the study participants is
recorded).
Id. at 583.
Many studies have shown that
individuals who participate in studies differ significantly from
those who do not; thus, if a significant number of subjects drop
out of a study before completion, the remaining subjects may not
be representative of the original study population.
Id. at 584.
Research has also shown that individuals with diseases tend to
recall past exposures more readily than individuals with no
disease, which creates a potential for recall bias in studies
that rely on retroactive interviews of subjects to determine
exposure, such as retroactive case control studies.
3.
Id. at 585.
Confounding
Confounding, which occurs when another causal factor (the
confounder) confuses the relationship between the agent of
interest and outcome of interest, is another major cause for
error in epidemiological studies.
Id. at 591.
For example,
researchers may conduct a study that finds individuals with gray
hair have a higher rate of death than those with hair of another
19
color.
Instead of hair color having an impact on rate of death,
the results are probably explained by the confounding factor of
age.
Id.
Two major potential confounders are at issue in this
litigation: confounding by indication and confounding by
genetics.
Confounding by indication may be at issue if the
reason a pregnant person takes acetaminophen itself causes ASD
or ADHD.
If, for example, fever during pregnancy is associated
with development of ADHD or ASD, and fever is also related to
whether a pregnant person takes acetaminophen, it will be
critical to determine whether an association between prenatal
exposure to acetaminophen and ASD or ADHD is causal or the
result of confounding.
As for genetic confounding, there could
be genetic factors that make pregnant people more likely to take
acetaminophen during pregnancy, and also make it more likely
that their offspring will have ADHD or ASD.
Although there is always a chance that an unknown
confounder contributes to a study’s finding, there are choices
researchers can make in designing a study that prevent, limit,
or account for confounding.
For confounding by indication, a
study design could track both the potential confounder (e.g.,
fever) and the exposure of interest (prenatal use of
acetaminophen), and then control for fever in the data analysis.
20
Researchers can attempt to control for genetic confounders
by gathering data on parental ASD or ADHD diagnoses, using
negative control exposures, or conducting sibling control
studies.
Negative control exposures should be time-invariant
and should not be expected to have a causal relationship to the
outcome of interest.
For example, there is no reason to expect
that paternal use of acetaminophen during pregnancy varies
compared to paternal use of acetaminophen before pregnancy
(time-invariance), or that it could cause a neurodevelopmental
disorder in offspring (because conception has already occurred). 4
In sibling control studies, researchers compare the rate of
the outcome in siblings who were exposed to the agent to that of
siblings who were not exposed.
If the association is causal,
the exposed sibling is expected to have a higher risk of the
outcome than the non-exposed sibling.
Gustavson et al.,
Acetaminophen Use During Pregnancy and Offspring Attention
Deficit Hyperactivity Disorder -- A Longitudinal Sibling Control
Study, 1(2) JCPP Advances 1, 2 (2021) (“Gustavson 2021”).
If
the association is mainly explained by familial confounding
See, e.g., Sanderson et al., Negative Control Exposure Studies
in the Presence of Measurement Error: Implications for Attempted
Effect Estimate Calibration, 47(2) Int. J. Epidemiol. 587
(2018); Brew & Gong, Modelling Paternal Exposure as a Negative
Control, 49(3) Int. J. Epidemiol. 1053 (2020).
4
21
factors, such as genetics or shared environmental factors, the
risk should be similar for the two siblings.
B.
Id.
Animal Studies
In addition to observational studies, scientists use
toxicology models based on live animal studies to determine
toxicity in humans.
RMSE at 563.
The advantage of animal
studies is that they can be conducted as true controlled
experiments and thus can avoid the problem of confounding.
On
the other hand, a significant disadvantage of animal studies is
that the results must be extrapolated to human beings, and
differences in absorption, metabolism, and other factors may
result in interspecies variation in responses –- that is, some
agents cause birth defects or disease in rodents but not humans,
and vice versa.
Id.
Another disadvantage is that the high
doses customarily used in animal studies require consideration
of the dose-response relationship and whether a threshold noeffect dose exists.
Id.
In this case, an additional concern is
analogizing observed changes in animal behaviors to ASD and
ADHD, neurodevelopmental disorders that consist of complex
behavioral symptoms in humans.
C.
Causation
Once an association has been found between exposure to an
agent and development of a disease, researchers then consider
22
whether the association reflects a true cause-effect
relationship.
It is important to note that epidemiology cannot
prove causation; rather, causation is a judgment to be made by
epidemiologists and others interpreting the epidemiological
data.
RMSE at 598.
There is no objective formula or algorithm
that can be used to determine whether a causal inference can be
made.
Thus, although the drawing of causal inferences is
informed by scientific expertise, courts must scrutinize
proposed expert opinions on causation to ensure the experts
conducted a review of available studies using a reliable
methodology.
Id.
Pertinent to this MDL is whether it is
reliable to draw a causal inference from the associations that
researchers have observed between prenatal acetaminophen
exposure, ASD, and ADHD.
VII. Types of Evidence at Issue Here
Since at least 1987, 5 scientists have been examining whether
the prenatal use of acetaminophen may be associated with adverse
neurodevelopmental outcomes.
To date, however, no medical
organization or regulatory body has concluded that prenatal
exposure to acetaminophen causes ADHD or ASD.
Before reviewing
the relevant literature from medical organizations and
Streissguth et al., Aspirin and acetaminophen use by pregnant
women and subsequent child IQ and attention decrements, 35
Teratology 211 (1987).
5
23
regulatory bodies, a description of the types of studies that
have been undertaken and of some of the individual studies will
be helpful.
A.
Published Studies
1.
Exposure Measurement Methods
Because acetaminophen is available without a prescription
and used widely by both non-pregnant and pregnant individuals,
it is particularly hard for researchers to come by objective and
precise data about its use.
As Laue 2019 6 recognized, studies
that rely on “parental report of behavior . . . may be
inaccurate or biased.” 7
Thus, before discussing individual
studies, it is important to note that, while a few studies have
assessed acetaminophen exposure using biomarkers, which are
objective measures, and one study used prescription data from
maternal medical records, the majority of the studies have
assessed exposure using maternal self-reports at varying times
during or after pregnancy.
For example, mothers in the Norwegian Mother and Child
Cohort Study (“MoBa”), the data from which has been the basis of
Laue et al., Association Between Meconium Acetaminophen and
Childhood Neurocognitive Development in GESTE, a Canadian Cohort
Study, 167(1) Toxicol. Sci. 138, 142 (2019).
6
Plaintiffs’ expert Dr. Baccarelli was one of the authors of
Laue 2019.
7
24
several studies, completed questionnaires at weeks 17 and 30 of
gestation and 6 months after giving birth.
The mothers reported
fever and medication use per month leading up to each
questionnaire.
Mothers in the Danish National Birth Cohort
(“DNBC”), another large cohort, were interviewed over the
telephone at weeks 12 and 30 of gestation and 6 months after
giving birth.
They were asked if they had ever taken
painkillers during the preceding period; if they said yes, they
were given a list of the 44 most common pain medications and
were asked to report the number of weeks during which they had
taken such medication in the preceding period.
One study used
biennial questionnaires (Nurses Health Study II) and inferred
exposure from use reported the year of the pregnancy; another
used interviews ranging from a few days to up to 10 years after
birth.
Some studies asked mothers to remember how many days
they had used acetaminophen in a given period, others asked
simply whether the mother had ever used acetaminophen during the
pregnancy, and others asked for weeks of use without
discriminating between, e.g., daily use during that week or use
just once.
The studies discussed below should thus be
interpreted with this heterogeneity in mind.
25
2.
ASD
There are two studies examining the connection between
prenatal acetaminophen exposure and an ASD diagnosis: Liew 2016a 8
and Saunders 2019. 9
Liew 2016a is a large cohort study analyzing
64,322 children from the DNBC that measured acetaminophen
exposure using maternal self-report at 12 and 30 weeks
gestation.
It found that acetaminophen exposure was associated
with ASD co-occuring with hyperkinetic disorder (“HKD”) 10 (1.51;
95% CI 1.19-1.92) but not ASD without HKD (1.07; 95% CI 0.921.24).
Saunders 2019, a small case-control study of 141 cases
and 199 controls recruited by public campaign and medical
records, found no association.
Saunders 2019 measured exposure
by maternal-self report at 0-10 years post-partum.
Liew et al., Maternal Use of Acetaminophen During Pregnancy and
Risk of Autism Spectrum Disorders in Childhood: A Danish
National Birth Cohort Study, 9 Autism Research 951 (2016) (“Liew
2016a”). There are three Liew articles published in 2016. To
distinguish among them, this Opinion uses the suffix “a” to
describe the article addressed to ASD, “b” for the child IQ
study, and “c” for the attention and executive function article.
8
Saunders, A Comparison of Prenatal Exposures in Children with
and without a Diagnosis of Autism Spectrum Disorder, 11(7)
Cureus I (2019).
9
HKD is the analogue for ADHD used by the International
Statistical Classification of Diseases and Related Health
Problems, 10th Revision (“ICD-10”), a medical classification
list published by the World Health Organization.
10
26
Two studies, Ji 2018 11 and Ji 2020 12, used objective measures
of biomarkers to assess acetaminophen exposure during the
postpartum (Ji 2018) and peripartum (Ji 2020) periods.
studies used data from the Boston Birth Cohort.
Both
Ji 2018
measured acetaminophen metabolites in maternal blood plasma from
1,180 samples taken 1-3 days postpartum and found no association
with a child’s ASD diagnosis.
Because the blood samples were
taken post-partum and the half-life of acetaminophen is only
1.5-3 hours, the samples do not reflect prenatal use of
acetaminophen.
Ji 2020 measured acetaminophen metabolites in umbilical
cord plasma.
The authors found an association between those
samples with the highest level of acetaminophen and a child’s
ASD diagnosis (3.65; 95% CI 1.62-8.60), and no association for
comorbid ADHD and ASD.
Again, because of the short half-life of
acetaminophen, the samples only reflected use during the period
shortly before, during, and immediately after giving birth,
Ji et al., Maternal Biomarkers of Acetaminophen Use and
Offspring Attention Deficit Hyperactivity Disorder, 8(127) Brain
Sci. 1 (2018).
11
Ji et al., Association of Cord
Acetaminophen Exposure With Risk
Deficit/Hyperactivity Disorder &
Childhood, 77(2) JAMA Psychiatry
12
Plasma Biomarkers of In Utero
of AttentionAutism Spectrum Disorder in
180 (2020).
27
rather than the entire prenatal period.
The relevance of these
studies to this litigation is disputed by the parties.
3.
ADHD
There are several original studies, reflecting data from
five cohorts, examining the connection between prenatal
acetaminophen exposure and an ADHD diagnosis.
One study, Liew 2014, 13 drew data from the DNBC, which
assessed exposure using maternal interviews at weeks 12 and 30
of gestation.
This study had a sample size of 64,322 children.
The authors found statistically significant associations between
a diagnosis of HKD and first trimester use (1.35; 95% CI 1.071.72), use in both the first and third trimesters (1.41; 95% CI
1.07-1.84), and use in all three trimesters (1.61; 1.30-2.01),
id. at 318, but no such associations for second or third
trimester use, for use in both the first and second trimesters,
or for use in both the second and third trimesters.
Id.
The
authors cautioned that “the possibility of unmeasured residual
confounding by indication for drug use, ADHD-related genetic
factors, or co-exposures to other medications cannot be
dismissed.”
Id. at 319.
Liew et al., Acetaminophen Use During Pregnancy, Behavioral
Problems, and Hyperkinetic Disorders, 168(4) JAMA Pediatrics 313
(2014).
13
28
Liew 2019 14 gathered data from 8,856 children born to women
enrolled in the Nurses’ Health Study II cohort.
Data was
collected in biennial questionnaires that asked women whether
they had regularly used a variety of medications in the past two
years. 15
Regular maternal use during the year of the child’s
birth was analyzed as the exposure variable.
The authors also
attempted to perform a negative control exposure analysis using
the mother’s responses from four years before and four years
after the child’s birth.
They found that ADHD was associated
with regular use during the child’s birth year (1.35; 95% CI
1.07-1.71), but not with use four years before (1.12; 95% CI
0.91-1.38) or after (1.05; 95% CI 0.88-1.26).
Id. at 773.
In
the subset of women who indicated they were pregnant at the time
they completed the questionnaire, there was a statistically
Liew et al., Use of Negative Control Exposure Analysis to
Evaluate Confounding: An Example of Acetaminophen Exposure and
Attention-Deficit/Hyperactivity Disorder in Nurses’ Health Study
II, 188(4) Am. J. Epidemiol. 768 (2019).
14
In 1993, women were asked to “mark if used regularly” the box
next to acetaminophen if they used it 2+ times per week in a
section titled “Current Medication”. In 1995, the
questionnaires asked recipients how many days each month, on
average, they took acetaminophen, with 0, 1-4, 5-14, 15-21, and
22+ days as options. The 1996 study instructed women to “mark
if used regularly in past 2 years” acetaminophen if use was 2+
times per week. In 2001, they were directed to “mark if used
regularly in past 2 years” both days per week (1, 2-3, 4-5, 6+)
and total tabs per week (1-2, 3-5, 6-14, 15+). See
https://nurseshealthstudy.org/participants/questionnaires.
15
29
insignificant association (1.39; 95% CI 0.99-1.95), although in
the model with acetaminophen use in all exposure periods
included together, the association was statistically significant
(1.46; 95% CI 1.01-2.09).
Id.
The authors concluded that their
results provided evidence that the association is “unlikely to
be explained by [] time-invariant factors” such as genetics.
Id. at 774.
Baker 2020, 16 a study of 345 children, is the only study
that showed an association between an objective biological
measure of prenatal exposure and a child’s ADHD diagnosis.
The
authors found that detection of acetaminophen in meconium -- an
infant’s first feces, which may reflect exposure during the
final two-thirds of pregnancy -- was associated with ADHD (2.43;
95% CI 1.41-4.21).
Id. at 1077.
The authors conducted a
sensitivity analysis to determine whether the results would be
different if they excluded mothers who were given acetaminophen
during delivery, and the association persisted (2.38; 95% CI
1.35-4.21).
Id.
The authors concluded that the association
between prenatal acetaminophen and ADHD may be even stronger
than previously estimated because prior studies may have been
Baker et al., Association of Prenatal Acetaminophen Exposure
Measured in Meconium with Risk of AttentionDeficit/Hyperactivity Disorder Mediated by Frontoparietal
Network Brain Connectivity, 174(11) JAMA Pediatrics 1073 (2020).
16
30
biased toward the null by inaccurate maternal recall, and that
the FDA and SMFM should “consider re-evaluating the evidence
regarding the safety of fetal acetaminophen exposure.”
Id. at
1080.
Ji 2020 and Ji 2018, discussed above, both reported
associations between biomarkers and an ADHD diagnosis.
As noted
above, however, the biomarkers reflected at most peripartum (Ji
2020) and postpartum (Ji 2018) exposure.
Chen 2019, 17 a case-control study with 950 mother-and-child
case pairs and 3800 control pairs, found an association between
prenatal acetaminophen prescriptions in Taiwan and a child’s
ADHD diagnosis.
Finally, two studies -- Ystrom 2017 18 and Gustavson 2021 -used data from the MoBa cohort.
Ystrom 2017 found associations
between two trimesters of use (1.22; 95% CI 1.07-1.38) and use
for greater than 29 days (2.20; 95% CI 1.50-3.24) and an HKD
diagnosis.
The authors cautioned that they “d[id] not provide
definitive evidence for or against a causal relation between
maternal use of acetaminophen and ADHD.”
Chen et al., Prenatal Exposure to Acetaminophen and the Risk
of Attention-Deficit/Hyperactivity Disorder: A Nationwide Study
in Taiwan, 80(5) J. Clin. Psychiatry (2019).
17
Ystrom et al., Prenatal Exposure to Acetaminophen and Risk of
ADHD, 140(5) Pediatrics 1 (2017).
18
31
Gustavson 2021 used more recent data from the same cohort
to conduct a sibling-control analysis with the goal of assessing
the role of familial confounding.
The authors found no
association between use for less than 29 days and HKD but did
initially find an association between HKD and use for more than
29 days over the course of the pregnancy (2.02; 95% CI 1.173.25).
Id. at 7.
That association was attenuated to non-
significance using the sibling-control analysis (1.06; 95% CI
0.51-2.05).
Id.
The authors concluded that the association
between acetaminophen use and ADHD “may at least partly be due
to familial confounding.”
4.
Id. at 8.
Studies Examining Possible Confounders: Fever and
Genetics
A few studies have examined the associations between
possible confounders and ASD or ADHD.
One, Hornig 2018, 19
examined the association between maternal fever and ASD risk in
children.
The study used data from the MoBa cohort and had a
sample size of 95,754.
The authors found associations between
second trimester fever and ASD (1.40; 95% CI 1.11-1.77), id. at
762, and three or more fevers after 12 weeks and ASD (3.12; 95%
CI 1.28-7.63).
Id. at 764.
When the authors conducted a
Hornig et al., Prenatal Fever and Autism Risk, 23 Molecular
Psychiatry 759 (2018).
19
32
stratified analysis based on acetaminophen use, they found that
acetaminophen use attenuated the risk.
Id. at 762.
Another study, Brynge 2022, 20 had a sample size of 549,967
and initially found an association between prenatal maternal
infection and autism (1.16; 95% CI 1.09-1.23), id. at 786, that
was attenuated after a sibling analysis (0.94; 95% CI 0.821.08).
Id. at 787.
Leppert 2019 21 examined associations between maternal
polygenic risk scores (a measure of genetic variations
associated with disease risk) for neurodevelopmental disorders
and early-life exposures previously linked to the disorders.
The study included 7,921 mothers with genotype data from the
Avon Longitudinal Study of Parents and Children (“ALSPAC”).
The
authors found no associations between maternal risk scores for
ASD and prenatal acetaminophen use or infection.
Id. at 838.
They found a slight association between maternal risk scores for
ADHD and prenatal acetaminophen use in both the first (1.09; 95%
Brynge et al., Maternal Infection During Pregnancy and
Likelihood of Autism and Intellectual Disability in Children in
Sweden: a Negative Control and Sibling Comparison Cohort Study,
9(10) Lancet Psychiatry 782 (2022).
20
Leppert et al., Association of Maternal Neurodevelopmental
Risk Alleles With Early-Life Expsoures, 76(8) JAMA Psychiatry
834 (2019).
21
33
CI 1.02-1.17) and second (1.11; 95% CI 1.04-1.18) halves of
pregnancy.
Id.
5.
Questionnaire Studies
Several other studies used the results of screening
questionnaires as outcome measurements as opposed to diagnoses
for specific disorders.
These screening questionnaires
included, inter alia, the Strength and Difficulties
Questionnaire (“SDQ”), the Ages and Stages Questionnaire
(“ASQ”), the Child Behavior Checklist (“CBCL”), the Childhood
Autism Spectrum Test (“CAST”), and the Emotionality, Activity,
and Sociability Temperament Questionnaire (“EAS”).
relevance of these questionnaires is disputed.
The clinical
For example, the
authors of Russell 2013 22 note that they “do not currently
recommend using the SDQ as a screening tool for either disorder
[ASD or ADHD] in clinical practice due to the high number of
false positives.”
Id. at 7.
Most studies using screening data included several
questionnaires, resulting in up to dozens of endpoints measured
per study.
Some studies used questionnaires administered by
parents, others by teachers, and others by clinicians or
Russell et al., The Strengths and Difficulties Questionnaire
as a Predictor of Parent-Reported Diagnosis of Autism Spectrum
Disorder and Attention Deficit Hyperactivity Disorder, 8(12)
PLoS One e80247 (2013).
22
34
research professionals.
A few studies used questionnaires
completed by the child.
Many studies used multiple informants
(i.e., the individual completing or administering the
questionnaire); the results of the study often differed by
informant.
The studies varied widely as to the child’s age when
the questionnaire was administered.
In addition to
heterogeneity of outcome measures, these studies reflect the
same heterogeneity of exposure measures discussed supra.
6.
Meta-Analyses
Finally, there have been at least five meta-analyses
attempting to pool data from existing studies.
The most recent
meta-analysis, Ricci 2023, is the only meta-analysis that
conducted a subgroup analysis limited to studies with diagnostic
outcome measurements.
Ricci 2023 found that there “was an
insufficient number of comparable studies due to heterogeneity
and methodology to calculate pooled effect estimates for ASD.”
Id. at 482.
The study did conduct an ADHD subgroup analysis
using data from Baker 2020, Ji 2020, Liew 2019, and Ystrom 2017,
which found an association (1.47; 95% CI 1.12-1.92); however,
the authors were not able to adjust for confounding by
indication or parental ADHD in this analysis.
The Ricci 2023 authors noted that their findings “should be
interpreted in the context of the limitations of the included
35
studies[;] [o]ne-third of the studies included in the review
were rated as having low or very low quality” based on concerns
about caregiver self-report of exposures and outcomes,
“incomplete control for confounding by indication and
considerable variability across studies in terms of what
indications were measured.”
Id. at 482.
Further, “very few
studies measured parental ADHD, which may also be an important
covariate.”
Id.
These limitations “increased the probability
that findings could be explained by measurement error or
confounding.”
Id.
Finally, “[s]tudies were also fairly
heterogenous with respect to their conceptualizations of child
neuro-developmental outcomes and the ranges of tools used to
assess these outcomes.”
Id.
The authors thus concluded that their findings “suggest a
small increase in risk of child ADHD associated with in utero
acetaminophen exposure,” but noted that “[t]he certainty of the
evidence on this topic is low,” and their findings “should be
further explored in future high-quality research on a range of
neurodevelopmental outcomes, with adequate control for
confounding by indication.”
7.
Id. at 483.
Animal Studies
Animal studies, principally on mice and rats, have been
conducted examining the effect of acetaminophen on a variety of
36
biological and behavioral outcomes.
The outcomes measured in
these studies will be discussed in more detail infra in relation
to the reports of Drs. Cabrera and Pearson.
Briefly, they tend
to measure biomarkers of acetaminophen’s proposed molecular and
cellular impacts, as well as changes in behavioral
characteristics proposed as analogues to hyperactivity,
inattention, impulsiveness, and repetitive behaviors.
As in In re Mirena Ius Levonorgestrel-Related Products
Liability Litigation (No. II), 341 F. Supp. 3d 213, 229
(S.D.N.Y. 2018), aff’d, 982 F.3d 113 (2d Cir. 2020) (“Mirena
II”), the animal studies do not, and cannot, assess whether
acetaminophen causes ADHD or ASD, although in this case some of
the animal studies purport to measure ASD- or ADHD-like
behaviors in animals.
Instead, these studies “relate to
discrete steps in longer biological chains of causation posited
by individual experts who opine as to possible mechanisms by
which” acetaminophen might cause ASD or ADHD.
Id.
Notably, “in
order for animal studies to be admissible to prove causation in
humans, there must be good grounds to extrapolate from animals
to humans, just as the methodology of the studies must
constitute good grounds to reach conclusions about the animals
themselves.”
In re Paoli R.R. Yard PCB Litig., 35 F.3d 717, 743
(3d Cir. 1994).
Where the animal studies on which experts
37
purport to rely are far-removed or too dissimilar from the facts
of a case, they may not provide a proper foundation for the
expert’s opinion.
See General Elec. Co. v. Joiner, 522 U.S.
136, 144 (1997).
B.
Statements by Governmental Bodies, Medical Societies,
and other Associations
1.
FDA Oversight
Following the publication of Liew 2014, the FDA opened a
Tracked Safety Issue (“TSI”) for prenatal acetaminophen exposure
on May 15, 2014; it has been conducting periodic reviews of the
evidence ever since.
The 2014 review recommended that “no
regulatory action be taken at this time based on available data”
but that, given the TSI, “DEPI [the Division of Epidemiology]
and DNDP [the Division of Nonprescription Drug Products] stay
current on the published safety literature related to
[acetaminophen] use in pregnancy.”
FDA 2014 at 3.
The 2015
review concluded that “[w]hether the association is causal in
nature remains uncertain.”
FDA 2015 at 3.
In 2016, the FDA
noted that “in utero exposure to APAP was associated with a
spectrum of adverse neurodevelopmental outcomes, though findings
with respect to specific outcomes varied somewhat across
studies, and positive findings were generally modest.”
at 15.
FDA 2016
It further stated that “a causal relationship is not
certain because of the possibility of confounding, particularly
38
by conditions such as maternal fever and infection that may
prompt pregnant women to take APAP but which may also be risk
factors for neurocognitive problems.”
Id.
In 2015, the FDA issued a public Drug Safety Communication
about prenatal use of NSAIDs, opioids, and acetaminophen.
See
FDA, FDA has reviewed possible risks of pain medicine use during
pregnancy (Jan. 9, 2015), at perma.cc/4JY6-CN6V.
The safety
announcement noted the recent reports questioning the safety of
pain medications when used during pregnancy, but stated that the
FDA had evaluated the scientific literature and determined it
was too limited to make any recommendations.
Id. at 1.
Regarding ADHD specifically, the announcement noted that the
“weight of evidence is inconclusive regarding a possible
connection between acetaminophen use in pregnancy and ADHD in
children.”
Id. at 5.
In 2016, the FDA reviewed published preclinical literature
(i.e., animal studies).
It concluded that the animal studies
were not adequately designed to address the question of
causation, and that behavioral responses in animals predictive
of ADHD in humans are uncertain.
FDA 2017 at 2.
A 2017 review noted that all of the observational studies
reviewed “had significant limitations that question the causal
effect of [acetaminophen] on adverse neurodevelopmental
39
outcomes.”
FDA 2017 at 10.
Thus, the FDA was “unable to draw
any conclusion about the causal association between prenatal
[acetaminophen] exposure and the different adverse
neurodevelopmental outcomes, based on the available evidence.”
Id. at 12.
That review recommended informing the public that
the FDA had evaluated additional studies but retaining the 2015
conclusion about the inability to draw causality conclusions.
Id.
The FDA conducted further reviews in 2022 and 2023.
2022 review looked at 24 additional studies.
The
FDA 2022 at 7.
It
concluded that “there are still study limitations and
inconsistent study findings that prohibit causal interpretations
of the association between APAP exposure and functional
neurobehavioral outcomes.”
Id. at 33.
The 2023 review looked
at three additional studies, only one of which assessed
attention, and concluded that “findings on the associations
between APAP use during pregnancy and neurobehavioral . . .
outcomes remain mixed.”
FDA 2023 at 17.
It noted that the
three studies reviewed “do not change DEPI-I’s conclusions from
its most recent review -- the limitations and inconsistent
findings of current observational studies of APAP and
neurobehavioral and urogenital outcomes are unable to support a
determination of causality.”
Id. at 17-18.
40
2.
Other Organizations
The FDA’s conclusions were in line with the conclusions
reached by medical societies both in this country and in Europe.
For example, the U.S.-based Society for Maternal-Fetal Medicine
(“SMFM”) examined studies on acetaminophen and
neurodevelopmental outcomes in 2017.
SMFM found that “the
weight of the evidence is inconclusive regarding the possible
causal relationship between acetaminophen use and
neurobehavioral disorders in the [children]” and that
acetaminophen use during pregnancy is “reasonable and
appropriate.”
SMFM, SMFM Statement: Prenatal Acetaminophen Use
and Outcomes in Children (Mar. 2017). 23
The Royal College of
Obstetricians and Gynaecologists, a professional association
based in the United Kingdom, noted in 2018 that “[c]urrent
advice is that [acetaminophen] remains safe for use during
pregnancy and breastfeeding.”
Bisson, Antenatal and postnatal
analgesia: Scientific Impact Paper No. 59, BJOG (2018), at e117118.
The first major statement suggesting that pregnant women
receive a more specific warning about the risk of developmental
disorders in their offspring came just two years ago.
In 2021,
https://www.smfm.org/publications/234-smfm-statement-prenatalacetaminophen-and-outcomes-in-children.
23
41
a group of 13 authors (joined by 78 signees) -- consisting of
scientists, clinicians, and epidemiologists -- published a
“Consensus Statement” reviewing literature concerning prenatal
acetaminophen use and fetal development.
Bauer et al.,
Consensus Statement: Paracetamol Use During Pregnancy — A Call
for Precautionary Action, 17 Nature Revs. Endocrinology 757, 758
(2021) (“Consensus Statement”).
The Consensus Statement called
for the prioritization of research initiatives and evidencebased medical guidance for acetaminophen use by pregnant women.
The authors of the Consensus Statement stated that “the combined
weight of animal and human scientific evidence is strong enough
for pregnant women to be cautioned by health professionals
against its indiscriminate use . . . .
We recommend that APAP
should be used by pregnant women cautiously at the lowest
effective does for the shortest possible time.”
Id. at 764.
The Consensus Statement prompted a “Consensus
Counterstatement” by another group of 60 scientists and
clinicians (comprising 10 authors and 50 signees) affiliated
with the Organization of Teratology Information Specialists
(“OTIS”).
See Alwan et al., Paracetamol Use In Pregnancy --
Caution Over Causal Inference From Available Data, 18 Nature
Revs. Endocrinology 190 (2022) (“Counterstatement”).
The
authors of the Counterstatement reviewed literature and
42
concluded that the studies were “limited by serious
methodological problems, including failure to account for
confounding, and elements of bias that make interpretation of
the data challenging.”
Id.
Although the authors agreed with
the Consensus Statement’s call for further investigation, they
“urge[d] against recommending [] precautionary measures for
[acetaminophen] use in pregnancy and against the dissemination
of information based on inconclusive and insufficient evidence.”
Id.
In a reply, the authors of the Consensus Statement pointed
out that “we avoided any inference of causality in our Consensus
Statement.”
Bauer et al., Reply to ‘Paracetamol Use In
Pregnancy –- Caution Over Causal Inference from Available Data’;
‘Handle With Care -- Interpretation, Synthesis and Dissemination
of Data on Paracetamol in Pregnancy’, 18 Nature Rev.
Endocrinology 192 (2022).
They reiterated, however, their
belief that “available data provide sufficient evidence for
concern and a recommendation of precautionary action.”
They
also noted that “[o]ur recommendations should not increase
maternal anxiety, as they only suggest adherence to current
guidelines.”
Id.
Another response to the initial Consensus Statement, signed
by 63 researchers and clinicians and 16 organizations, “argue[d]
43
that the available evidence supports neither a change in
clinical practice (minimal use when necessary), restricting APAP
availabilities to pharmacies, nor additional warning labels on
packaging.”
O’Sullivan 2022. 24
The authors of the O’Sullivan
2022 statement noted that “[t]he overarching societal message
that has been drawn from [the] Consensus Statement is that APAP
use in pregnancy is unsafe and should be restricted in both use
and access.”
Id.
The authors stated that “[w]e, and others,
believe this interpretation is exaggerated.”
Id.
The
organizations that signed this letter included, inter alia, the
International Federation of Obstetrics and Gynaecology, the
European Association of Perinatal Medicine, the British Maternal
and Fetal Medicine Society, the U.K. Teratology Information
Service, as well as American, Angolan, Brazilian, Canadian,
Finnish, and Portuguese obstetric and gynecological
associations.
Medical bodies also responded to the Consensus Statement.
The American College of Obstetricians and Gynecologists (“ACOG”)
reviewed the literature and noted that the studies “show no
clear evidence that proves a direct relationship between the
prudent use of acetaminophen during any trimester and fetal
O’Sullivan et al., Paracetamol Use in Pregnancy -- Neglecting
Context Promotes Misinterpretation, 18 Nat. Rev. Endocrinology
385 (2022).
24
44
developmental issues.”
ACOG, ACOG Response to Consensus
Statement on Paracetamol Use During Pregnancy (Sept. 29, 2021). 25
The European Network of Teratology Information Services
(“ENTIS”) issued a position statement that the Consensus
Statement “reflects the views of the authors and is not endorsed
by regulatory authorities or medical specialty organizations.”
European Network of Teratology Information Services, Position
Statement on Acetaminophen (Paracetamol) in Pregnancy, at 1
(Oct. 3, 2021).
It noted several problems with the underlying
studies, including the use of unvalidated outcome measurements,
which “are neither developed nor validated for the purpose and
context in which they are used.”
Id.
It specifically pointed
to Ji 2020, which it stated has “severe issues with external and
internal validity.”
Id. at 2.
ENTIS noted that the Consensus
Statement “and the ensuing reaction w[ould] promote unwarranted
uncertainty, fear, and guilt among pregnant women” and would
“also likely result in use of less safe alternatives during
pregnancy.”
Id.
Finally, the Society of Obstetricians and Gynaecologists of
Canada (“SOGC”) weighed in.
It noted that “[t]he position of
the SOGC, and a number of other international societies, is that
https://www.acog.org/news/news-articles/2021/09/response-toconsensus-statement-on-paracetamol-use-during-pregnancy.
25
45
the evidence for causality for this claim is weak and has many
fundamental flaws.”
SOGC, Statement on the Use of Acetaminophen
for Analgesia and Fever in Pregnancy (Nov. 8, 2021). 26
Discussion
As in all tort cases, plaintiffs in this MDL must prove by
a preponderance of the evidence that defendants’ breach of a
duty it owed plaintiffs caused plaintiffs’ injuries.
Causation
in pharmaceutical products liability cases such as those in this
litigation has two components, general and specific.
Daniels-
Feasel v. Forest Pharmaceuticals, Inc., 2021 WL 4037820, at *5
(S.D.N.Y. 2021), aff’d, 2023 WL 4837521 (2d Cir. 2023) (citation
omitted).
“General causation is whether a substance is capable
of causing a particular injury or condition in the general
population, while specific causation is whether a substance
caused a particular individual’s injury.”
Id.
As the above discussion reflects, the state of scientific
evidence on prenatal use of acetaminophen presents a challenge
for any expert witness offering the opinion that such use causes
ADHD and ASD.
The epidemiological evidence is highly
heterogenous, and major medical organizations and regulators
have cautioned against drawing causal inferences from the
https://sogc.org/en/en/content/featurednews/Statement_on_the_use_of_acetaminophen.aspx.
26
46
existing body of scientific literature.
Nevertheless, three of
plaintiffs’ experts draw such an inference.
Plaintiffs proffer the testimony of five experts: Drs.
Andrea Baccarelli, Robert Cabrera, Eric Hollander, Brandon
Pearson, and Stan Louie.
Drs. Baccarelli, Cabrera, and
Hollander reviewed epidemiological, animal, and cell studies and
undertook Bradford Hill analyses, each reaching the conclusion
that acetaminophen causes ASD and ADHD.
Dr. Louie offers the
opinion that the children of pregnant women who take therapeutic
doses of acetaminophen for at least 28 days have twice the risk
of developing ASD or ADHD than the children of pregnant women
who do not.
Dr. Pearson conducted a “weight of the evidence”
review of animal studies and opines that the literature shows
that prenatal acetaminophen exposure can cause ASD and ADHD by
disturbing normal neurodevelopmental processes through several
mechanisms.
Defendants argue that plaintiffs’ experts’ opinions
regarding general causation, dose-response, and biological
plausibility are inadmissible under the Federal Rules of
Evidence and the standards set by the Supreme Court in Daubert
v. Merrell Dow Pharmaceuticals, Inc., 509 U.S. 579 (1993), and
its progeny.
For the following reasons, the Court agrees.
Before setting forth the legal standards that this Opinion
applies in addressing the defendants’ motions, a few
47
observations are appropriate.
Each of the plaintiffs’ experts
is well qualified to render an opinion in the areas addressed by
their reports.
The defendants do not contend otherwise.
None
of the plaintiffs’ experts, however, has published research that
expresses the ultimate opinions they offer here.
Indeed, the
plaintiffs’ lead expert on causation, Dr. Baccarelli, as
recently as 2022, co-authored a study on the prenatal effects of
acetaminophen that cautioned against any change in clinical
practice.
To prepare their reports, the plaintiffs’ experts have,
appropriately, reviewed the body of scientific literature
regarding in utero exposure to acetaminophen and its possible
impact on neurodevelopment.
As explained infra, however, they
have not used that literature to render discrete opinions
regarding that exposure and the risk of ASD and the risk of
ADHD.
Instead, they have applied a “transdiagnostic” analysis
that sweeps into their analyses (and conclusions) ASD, ADHD and
other neurodevelopmental disorders.
They have failed to show
that their methodology in doing so is generally accepted by the
scientific community.
In any event, here, their analyses have
not served to enlighten but to obfuscate the weakness of the
evidence on which they purport to rely and the contradictions in
the research.
As performed by the plaintiffs’ experts, their
48
transdiagnostic analysis has obscured instead of informing the
inquiry on causation.
The issues explored by this litigation have great public
health significance.
It matters to get this right.
It matters
to parents, their children, and their health care providers.
ASD and ADHD are neurological disorders that can have profound
consequences for families and communities.
Scientists have worked with great skill and dedication to
explore many hypotheses that may lead us to better understand
the etiology of these two disorders.
This research has focused
as well on acetaminophen -- a pharmaceutical that is critical to
the treatment of an expecting mother’s pain or fever and the
protection of the health of her pregnancy.
The FDA has been
following this research closely for almost a decade.
Internationally, medical associations have weighed in.
As just
described, there is no generally accepted scientific conclusion
that in utero exposure to acetaminophen causes either ASD or
ADHD.
As explained below, the plaintiffs’ experts have not
reliably opined so either.
VIII.
Standard: Daubert and Rule 702
Federal Rule of Evidence 702 (“Rule 702”) governs the
admission of expert testimony in federal court.
The Supreme
Court has made clear that the district court has a “gatekeeping”
49
function under Rule 702: it is charged with the “task of
ensuring that an expert’s testimony both rests on a reliable
foundation and is relevant to the task at hand.”
Daubert, 509
U.S. at 597.
Testimony is relevant where it has “any tendency to make
the existence of any fact that is of consequence to the
determination of the action more probable or less probable than
it would be without the evidence.”
Amorgianos v. Nat’l R.R.
Passenger Corp., 303 F.3d 256, 265 (2d Cir. 2002) (citation
omitted).
Next, to determine whether testimony has a
sufficiently reliable foundation to be admissible at trial, a
court must consider the “indicia of reliability identified in
[Rule] 702.”
Clerveaux v. East Ramapo Central School District,
984 F.3d 213, 233 (2d Cir. 2021) (citation omitted).
Rule 702 allows a “witness who is qualified as an expert by
knowledge, skill, experience, training, or education” to
testify, “in the form of an opinion or otherwise if the
proponent demonstrates to the court that it is more likely than
not that”:
(a) the expert's scientific, technical, or other
specialized knowledge will help the trier of fact to
understand the evidence or to determine a fact in issue;
(b) the testimony is based on sufficient facts or data;
(c) the testimony is the product of reliable principles and
methods; and
(d) the expert’s opinion reflects a reliable application of
the principles and methods to the facts of the case.
50
Fed. R. Evid. 702. 27
Further, in addition to the indicia of reliability
identified in Rule 702, a trial court may consider the criteria
enumerated in Daubert, “some or all of which might prove helpful
in determining the reliability of a particular scientific theory
or technique.”
Clerveaux, 984 F.3d at 233 (citation omitted).
The Daubert factors are: (1) whether the methodology or theory
has been or can be tested; (2) whether the methodology or theory
has been subjected to peer review and publication; (3) the
methodology’s error rate and the existence and maintenance of
standards controlling the technique’s operation; and (4) whether
the methodology or technique has gained general acceptance in
the relevant scientific community.
Daubert, 509 U.S. at 593-94.
“[W]hile a court need not consider the Daubert factors, it does
Rule 702 was amended effective December 1, 2023. “Nothing in
the amendment imposes any new, specific procedures.” Fed. R.
Evid. 702, Advisory Committee Notes, 2023 Amendments. Instead,
one purpose of the amendment was to emphasize that
[j]udicial gatekeeping is essential because just as
jurors may be unable, due to lack of specialized
knowledge, to evaluate meaningfully the reliability of
scientific and other methods underlying expert
opinion, jurors may also lack the specialized
knowledge to determine whether the conclusions of an
expert go beyond what the expert’s basis and
methodology may reliably support.
Id.
27
51
not abuse its discretion in doing so.”
Mirena II, 982 F.3d at
124.
Although “Rule 702 sets forth specific criteria for the
district court’s consideration, the Daubert inquiry is fluid and
will necessarily vary from case to case.”
omitted).
Id. at 123 (citation
The Daubert factors do not constitute a definitive
checklist or test.
Proffered expert testimony can fail all four
Daubert factors and still be admitted; however, in those
circumstances, a court must “carefully scrutinize, pause, and
take a hard look at the expert’s methodology.”
F. Supp. 3d at 240.
So long as an expert’s analysis is reliable
“at every step,” it is admissible.
(citation omitted).
Mirena II, 341
Mirena II, 982 F.3d at 123
But “any step that renders the analysis
unreliable ... renders the expert's testimony inadmissible.”
Amorgianos v. National R.R. Passenger Corp., 303 F.3d 256, 267
(2d Cir. 2002) (citation omitted).
Thus, it may not only be
appropriate for a district court “to take a hard look at
plaintiffs’ experts’ reports,” it may be “required to do so to
ensure reliability.”
Mirena II, 982 F.3d at 123.
“[I]n deciding whether a step in an expert’s analysis is
unreliable, the district court should undertake a rigorous
examination of the facts on which the expert relies, the method
by which the expert draws an opinion from those facts, and how
52
the expert applies the facts and methods to the case at hand.”
Id. (citation omitted).
Ultimately, a court must “make certain
that an expert, whether basing testimony upon professional
studies or personal experience, employs in the courtroom the
same level of intellectual rigor that characterizes the practice
of an expert in the relevant field.”
Kumho Tire Co., 526 U.S.
at 152.
Although the Supreme Court in Daubert emphasized that the
court’s inquiry under Rule 702 must focus “solely on principles
and methodology, not on the conclusions they generate,” 509 U.S.
at 595, it later clarified that “conclusions and methodology are
not entirely distinct from one another.”
General Electric
Company v. Joiner, 522 U.S. 136, 146 (1997).
Thus, although
“[t]rained experts commonly extrapolate from existing
data[,] nothing in either Daubert or the Federal Rules
of Evidence requires a district court to admit opinion
evidence that is connected to existing data only by
the ipse dixit of the expert. A court may conclude
that there is simply too great an analytical gap
between the data and the opinion proffered.”
Id.
IX.
Epidemiology Cases
Several additional considerations are important when
experts offer general causation opinions in pharmaceutical
cases.
For instance, “if an expert applies certain techniques
to a subset of the body of evidence and other techniques to
53
another subset without explanation, this raises an inference of
unreliable application of methodology.”
In re Zoloft
(Sertraline Hydrochloride) Products Liability Litigation, 858
F.3d 787, 797 (3d Cir. 2017) (“Zoloft”).
Additionally, when
experts, such as those in this litigation, rely on the studies
of others, they must not exceed the limitations the authors
themselves place on the study.
Daniels-Feasel, 2021 WL 4037820,
at *4.
Further, “an expert must not cherry-pick from the
scientific landscape and present the Court with what he believes
the final picture looks like.”
Id. at *5 (citation omitted).
Instead, “[s]ound scientific methodology in assessing general
causation requires an expert to evaluate all of the scientific
evidence when making causation determinations.”
omitted).
Id. (citation
Cherry-picking is a form of “result-driven analysis
which undermines principles of the scientific method by applying
methodologies (valid or otherwise) in an unreliable fashion.”
Id. (citing In re Lipitor (Atorvastatin Calcium) Mktg., Sales
Practices & Prod. Liab. Litig. (No II) MDL 2502, 892 F.3d 624,
634 (4th Cir. 2018)).
“Therefore, exclusion of the proffered
testimony is warranted where the expert fails to address
evidence that is highly relevant to his or her conclusion.”
54
Id.
Courts have previously addressed some of the methodologies
used by plaintiffs’ experts here.
One generally accepted
methodology for determining causation among epidemiologists is a
consideration of the “Bradford Hill” criteria.
See Zoloft, 858
F.3d at 795; see also RMSE at 599-606; Daniels-Feasel, 2021 WL
4037820, at *6-*7.
The Bradford Hill criteria are “metrics that
epidemiologists use to distinguish a causal connection from a
mere association.”
Zoloft, 858 F.3d at 795.
The “weight of the
evidence analysis,” also used by several of plaintiffs’ experts,
“involves a series of logical steps used to infer to the best
explanation.”
Zoloft, 858 F.3d at 795 (citation omitted).
The nine Bradford Hill criteria are:
1) Strength of Association.
This criterion is represented by
the risk ratio discussed above.
The higher the relative
risk, the higher the likelihood that the relationship is
causal.
Lower relative risks can also reflect causality,
but such associations should be scrutinized more carefully
because there is a greater chance that they are the result
of uncontrolled confounding or biases.
2) Consistency.
RMSE at 602.
Because no single study can prove causation,
it is important to replicate study results before drawing
an inference of causation.
Consistent findings observed in
55
multiple studies across different populations tend to
support causation.
3) Dose-Response.
Id. at 604.
A dose-response relationship exists where
studies show that the greater the exposure, the greater the
risk of disease.
Id. at 603.
Generally, higher exposures
should increase the incidence or severity of disease;
however, some causal agents do not exhibit a dose-response
relationship.
Id.
For example, some agents do not cause
disease until the exposure exceeds a certain threshold
dose.
Id.
Thus, a dose-response relationship is strong
but not essential evidence of causation.
4) Biological Plausibility.
Causal relationships should be
consistent with existing knowledge about the mechanism by
which the outcome develops.
The importance of this factor
depends on the degree of existing knowledge about how a
disease develops.
5) Temporality.
6) Coherence.
Causes must precede effects.
A causal relationship should be consistent with
other information and knowledge about the disease or harm.
7) Specificity.
When the exposure is only associated with a
single disease or type of disease, such specificity
strengthens the case for a causal inference.
Lack of
specificity does not undermine causal inferences where
56
there is a good explanation for its absence.
Id. at 605-
606.
8) Analogy.
A causal inference is supported where
relationships similar to the putative causal relationships
have been substantiated.
9) Experimental Evidence.
Causation is more likely if there
is experimental evidence showing that removing the exposure
results in a decrease of the occurrence of a disease.
No single Bradford Hill factor is required to infer
causation; the criteria “are neither an exhaustive nor a
necessary list.”
Zoloft, 858 F.3d at 796.
Both the Bradford
Hill analysis and weight of the evidence approach have been
found to be “generally reliable” as methodologies.
Id.
Rule 702 requires, however, that an expert not only use
“reliable principles and methods” but also that “the expert’s
opinion reflects a reliable application of the principles and
methods to the facts of the case.”
Fed. R. Evid. 702.
“Flexible methodologies, such as the ‘weight of the evidence,’
can be implemented in multiple ways; despite the fact that the
methodology is generally reliable, each application is distinct
and should be analyzed for reliability.”
795.
Zoloft, 858 F.3d at
Experts must “rigorously explain how they have weighted
57
the criteria considered.”
Daniels-Feasel, 2021 WL 4037820, at
*6.
Likewise, because the Bradford Hill factors are “neither an
exhaustive nor a necessary list[,] [a]n expert can theoretically
assign the most weight to only a few factors, or draw
conclusions about one factor based on a particular combination
of evidence.”
Zoloft, 858 F.3d at 796.
“No algorithm exists
for applying the [Bradford] Hill guidelines to determine whether
an association truly reflects a causal relationship or is
spurious.”
Milward v. Acuity Specialty Prods. Grp., Inc., 639
F.3d 11, 18 (1st Cir. 2011) (citation omitted).
Thus, district
courts must ensure that “[t]he specific way an expert conducts
such an analysis [is] reliable.”
Zoloft, 858 F.3d at 796.
“In
discussing the conclusions produced by such techniques in light
of the Bradford Hill criteria, an expert must explain 1) how
conclusions are drawn for each Bradford Hill criterion and 2)
how the criteria are weighed relative to one another.”
X.
Id.
Dr. Baccarelli
Dr. Andrea Baccarelli has provided an amended expert report
of June 23, 2023, and a rebuttal report of July 28.
He was
deposed on August 14.
Dr. Baccarelli is an epidemiologist, toxicologist, and
physician whose research focuses on molecular mechanisms that
58
link environmental exposures to human disease.
He is the Chair
of the Department of Environmental Health Sciences and
Epidemiology at the Columbia Mailman School of Public Health,
and will become Dean of the Harvard T.H. Chan School of Public
Health in 2024.
He holds a Ph.D. in Toxicology and Occupational
Health from the University of Milan, an M.S. in Epidemiology
from the University of Turin, and an M.D. from the University of
Perugia.
He has published over 600 peer-reviewed papers, many
of which investigate the effects of environmental toxins on
neurodevelopment.
Of particular significance to this litigation, Dr.
Baccarelli co-authored three studies that examined the impact of
the use of acetaminophen during pregnancy on children’s
neurodevelopment by measuring levels of acetaminophen in fetal
meconium.
The studies, which used the same cohort, began with
Laue 2019, which did not detect a statistically significant
association between acetaminophen levels in meconium and
intelligence scores of 118 children who were six to eight years
old.
The second study, Baker 2020 (discussed supra), which had
a sample size of 345, found an association between acetaminophen
levels in meconium and a child’s ADHD diagnosis.
Baker 2022 28
Baker et al., Association of Prenatal Acetaminophen Exposure
Measured in Meconium with Adverse Birth Outcomes in a Canadian
Birth Cohort, 10 Frontiers in Pediatrics 1 (2022).
28
59
examined the associations between meconium acetaminophen levels,
with a sample size of 393, and a variety of outcomes including
birthweight, gestational age, gestational diabetes,
preeclampsia, and high blood pressure.
The authors noted that
“[w]hile this study may add evidence in support of questioning
the safety of acetaminophen use during pregnancy, more work is
needed to rule out confounding by indication and to assess
generalizability before a change in clinical practice is
recommended.”
Id. at 7.
Dr. Baccarelli was asked by plaintiffs’ counsel to review
the current state of the epidemiological scientific literature
to determine whether the prenatal use of acetaminophen “causes
NDDs, including ADHD, ASD, and/or symptoms consistent with those
disorders in the child.”
Dr. Baccarelli began with a systematic
search of the literature to identify original papers on the
relationship between ADHD, ASD, and NDDs and prenatal exposure
to acetaminophen.
He located 6 original, non-duplicative
studies in humans related to ASD, 14 related to ADHD, and 15
related to other neurodevelopmental deficits and disorders.
He
also examined meta-analyses and other studies and reviews.
Having identified relevant literature, Dr. Baccarelli
offers the opinion that “there is a causal relationship between
prenatal acetaminophen use and the NDDs of ADHD and ASD and the
60
related symptomology.” 29
To reach this opinion, Dr. Baccarelli
states that he used two methods, either of which would, in his
view, be sufficient to determine a “causal association.”
The
first, called the Navigation Guide, Dr. Baccarelli states was
created to “assess causal relationships for toxic substances,”
and involves “a systematic rating and review of each identified
study for bias, strength of evidence, and other indicia of study
quality.” 30
Using the Navigation Guide, Dr. Baccarelli concluded
in three separate opinions that acetaminophen use during
pregnancy is “known to be toxic” because of its ability to cause
1) ADHD, 2) ASD, and 3) other NDDs in children.
Second, Dr.
In his reports, Dr. Baccarelli uses various formulations in
expressing his ultimate opinion. He opines that there “is
likely a causal link between exposure to acetaminophen during
pregnancy and offspring suffering from a NDD, including ASD and
ADHD, and the related symptomology.” Later, he opines that
“prenatal use of acetaminophen exposure can cause the offspring
to develop NDDs such as ADHD and ASD, as well as symptoms
consistent with those diagnoses.”
29
Dr. Baccarelli explains that the Navigation Guide is
recommended by the Committee to Review EPA’s Toxic Substances
Control Act as an approach the EPA should use in evaluating
Toxic Substances Control Act risks. In fact, the document cited
by Dr. Baccarelli explains that “there is no consensus on the
best tool for risk-of-bias analysis,” and lists the Navigation
Guide as one of several tools; it recommends the Navigation
Guide as a tool for assessing risk of bias and study quality,
not for coming to a causal conclusion. Committee to Review
EPA’s TSCA Systematic Review Guidance Document, Board on
Environmental Studies and Toxicology, The Use of Systematic
Review in EPA’s Toxic Substances Control Act Risk Evaluations at
35 (2021).
30
61
Baccarelli “weigh[ed] and assess[ed] the Bradford Hill factors,”
with respect to NDDs as a group.
He determined that each of the
Bradford Hill factors except specificity was satisfied.
Defendants argue that Dr. Baccarelli’s opinions are
unreliable for several reasons.
They contend that he improperly
applied a “transdiagnostic” approach to neurodevelopmental
disorders that elides meaningful differences between ADHD and
ASD.
They contend as well that he did not conduct a reliable
Bradford Hill or Navigation Guide analysis for several reasons,
including that he cherry-picked and misrepresented study results
and refused to acknowledge the role of genetics in the etiology
of either ASD or ADHD.
They are correct.
After addressing the
reliability of his Bradford Hill analysis, his findings from his
Navigation Guide analysis will be addressed.
A.
Bradford Hill
1.
Transdiagnostic Evaluation
“The Bradford Hill factors form the generally accepted set
of criteria by which, when reliably applied, modern practicing
epidemiologists assign causality to an association.”
Feasel, 2021 WL 4037820, at *6 (emphasis added).
Daniels-
It is not
clear, therefore, that conducting a Bradford Hill analysis on
multiple associations at once is informative or reliable.
Moreover, his transdiagnostic approach raises a question of
62
relevance.
After all, this litigation is brought to obtain
recovery on behalf of those who have been diagnosed with ASD or
ADHD, not on behalf of anyone with, for example, a deficit in
communication or self-regulation.
Another consequence of his examination of a potpourri of
evidence is that he has obscured limitations in the scientific
literature.
For example, there are only a limited number of
studies associated with a population that is diagnosed as having
either ASD or ADHD.
If the studies for either ASD or ADHD were
subjected to their own individual Bradford Hill analysis, it
would be easier to discern whether there was actual support for
a finding that prenatal exposure to acetaminophen causes either
ASD or ADHD.
And, as importantly, if the analysis were focused
on a single disorder, the tensions among the studies and any
contradictory conclusions would be more evident and more easily
weighed by an epidemiologist.
And, consequently, the
reliability of any such expert analysis would be more easily
assessed by other experts and ultimately by a court conducting a
Rule 702 inquiry.
To make this concrete, Dr. Baccarelli reports that his
survey of the scientific literature identified just six
original, non-duplicative studies in humans of the relationship
63
between ASD and prenatal exposure to acetaminophen. 31
As
discussed above, just two of these studies examined the
connection between prenatal exposure and a diagnosis of ASD:
Saunders 2019 and Liew 2016a.
And, only one of them, Liew
2016a, found an association, although the association only
existed for ASD with hyperkinetic disorder.
The other studies
include a peripartum exposure study (Ji 2020), and two studies
examining possible confounding (Hornig 2018 finding an
association with fever, and Leppert 2019, finding no association
with a polygenic risk score).
Finally, Avella-Garcia 2016 32
found an increase in CAST symptom scores for boys but not girls.
Its authors identified several limitations of the study,
including an inability to evaluate the dosage taken, confounding
by genetics, and possible misclassification of exposure.
Id. at
1994.
Dr. Baccarelli does not identify the six studies to which he
is referring. They are not listed in either of his reports or
in the tables accompanying his Navigation Guide. From context,
he appears to be referring to the six identified supra. At oral
argument, plaintiffs’ counsel identified Alemany 2021 as one of
the six and omitted Hornig 2018 for the list recited supra.
Alemany 2021, however, is a metanalysis and not an original,
non-duplicative study.
31
Avella-Garcia et al., Acetaminophen Use in Pregnancy and
Neurodevelopment: Attention Function and Autism Spectrum
Symptoms, 45(6) Int. J. Epiemiol. 1987 (2016).
32
64
Dr. Baccarelli claims that a shared Bradford Hill analysis
is “appropriate” because the symptoms associated with deficits
in cognition, communication, motor skills, self-regulation or
social-emotional function “transcend diagnostic boundaries” and
because ASD and ADHD are both categorized as NDDs in the DSM.
But the diagnostic criteria of the two disorders are undeniably
distinct.
A child may suffer from both disorders, from only
one, or from neither, despite being described as having the
neurological deficits that Dr. Baccarelli lists as relevant.
The fact that ASD and ADHD are both categorized as NDDs does not
suffice to explain the use of a transdiagnostic Bradford Hill
analysis.
After all, Dr. Baccarelli’s analysis did not focus on
the other NDDs categorized in the same section of the DSM, such
as motor disorders, tic disorders, certain learning disorders,
communication disorders, or intellectual disorders.
Equally troubling, Dr. Baccarelli’s assessment of a study’s
use of a non-ADHD, non-ASD endpoint seems to depend on whether
the study’s result supports his ultimate opinion about a causal
connection with prenatal exposure to acetaminophen.
The
following examples illustrate this point.
Dr. Baccarelli describes as a limitation on the reliability
of Laue 2019, its use of “an outcome -- intelligence score -that does not directly bear on ADHD or ASD.”
65
He makes that
assessment even though he lists cognition as a relevant deficit
justifying his transdiagnostic analysis and even though
intelligence scores “directly bear” on other neurodevelopmental
disorders such as Intellectual Development Disorder.
41.
See DSM at
Notably, Laue 2019 found no statistically significant
association between acetaminophen in meconium and a child’s
intelligence scores.
Indeed, its conclusion was much broader.
It stated, “we did not find evidence of neurodevelopmental harm
from prenatal exposure to acetaminophen measured in meconium.”
Id. at 143.
Dr. Baccarelli was one of the authors of Laue 2019.
Similarly, Dr. Baccarelli found Trønnes 2020 33 unpersuasive
in part because it “did not have ADHD as an endpoint and was
forced to rely on less clearly defined child outcomes.”
Trønnes
2020 found “a moderate increased risk of internalizing behaviors
and a borderline [statistically insignificant] increased risk of
externalizing behavior,” but emphasized that “unmeasured
confounding plays an important role and we cannot rule out
chance or unmeasured confounding as possible explanations for
our findings.”
Id. at 252.
Trønnes et al., Prenatal Paracetamol Exposure and
Neurodevelopmental Outcomes in Preschool-Aged Children, 34 (3)
Peadtr. Perinat. Epidemiol. 247 (2020).
33
66
Trønnes 2020 used MoBa data to study the association
between prenatal exposure to acetaminophen and a set of
neurodevelopmental outcomes, such as language competence and
dimensions of temperament, for children at age five.
The
outcomes were taken from responses to three questionnaires. 34
Yet the use of outcome measures from responses to the same
questionnaires in Brandlistuen 2013, 35 which studied same-sex
sibling pairs aged three in the MoBa cohort, did not trigger Dr.
Baccarelli’s concern.
Brandlistuen 2013 concluded that children
exposed to long-term use of acetaminophen during pregnancy had
substantially adverse development outcomes at three years of
age.
Likewise, his summary of Liew 2016b, 36 which found an
association between maternal acetaminophen use and lower IQ in
5-year-olds, does not list the non-ADHD, non-ASD outcome as a
limitation.
This list of the inconsistencies in Dr.
Baccarelli’s treatment of studies that did not use an ASD or
ADHD endpoint could go on and on.
34
The three questionnaires were the ASQ, the CBCL, and the EAS.
Brandlistuen et al., Prenatal Paracetamol Exposure and Child
Neurodevelopment: A Sibling-Controlled Cohort Study, 42(6) Int’l
J. Epidemiol. 1702 (2013).
35
Liew et al., Prenatal Use of Acetaminophen and Child IQ: A
Danish Cohort Study, 27(6) Epidemiology 912 (2016).
36
67
There is yet another reason to question Dr. Baccarelli’s
use of a transdiagnostic approach for his Bradford Hill
analysis.
Dr. Baccarelli does not explain why he did not apply
the transdiagnostic approach to his Navigation Guide
assessments.
In conducting that assessment, he separated his
evaluation of ASD, ADHD and other NDD studies.
“[I]f an expert
applies certain techniques to a subset of the body of evidence
and other techniques to another subset without explanation, this
raises an inference of unreliable application of methodology.”
Zoloft, 858 F.3d at 797.
At oral argument, plaintiffs’ counsel suggested that any
failure by Dr. Baccarelli to conduct separate Bradford Hill
analyses for ASD and ADHD could be excused by his having done
separate literature reviews and separate analyses in connection
with the Navigation Guide.
Not so.
The Navigation Guide is not
designed to distinguish a causal connection from a mere
association.
At no point have plaintiffs suggested that their
experts could have satisfied their burden to offer reliable
testimony of general causation without performing a reliable
Bradford Hill analysis.
To Dr. Baccarelli’s cursory explanation for conducting a
single Bradford Hill analysis, he adds that he has relied on Dr.
Hollander in concluding that it is appropriate to consider not
68
only studies that assess ADHD and ASD specifically, but also
those studies that “assess symptoms of NDDs that are consistent
with ADHD and ASD”.
As explained below, Dr. Hollander’s report
does not fill this analytical gap.
While a transdiagnostic
Bradford Hill analysis may be appropriate if the basis for doing
so is properly supported, that basis has not been supplied here.
At oral argument, plaintiffs’ counsel referred to one metaanalysis, Alemany 2021, 37 as evidence that it was appropriate to
conduct a transdiagnostic Bradford Hill analysis.
This meta-
analysis does not provide sufficient support for the
admissibility of Dr. Baccarelli’s own transdiagnostic Bradford
Hill analysis.
Alemany 2021 is a meta-analysis of questionnaire
responses regarding use of acetaminophen during pregnancy and
ASD and ADHD symptoms in six European birth/child cohorts with
70,000 children. 38
Alemany 2021 concluded from its meta-analysis
that children prenatally exposed to acetaminophen were 19% and
21% more likely to subsequently have ASD and ADHD symptoms
within the borderline/clinical range than non-exposed children.
Id. at 999-1,000.
It is true that Alemany 2021 briefly
Alemany et al., Prenatal and Postnatal Exposure to
Acetaminophen in Relation to Autism Spectrum and AttentionDeficit and Hyperactivity Symptoms in Childhood: Meta-Analysis
in Six European Population-Based Cohorts, 36 Euro. J. Epidemiol.
993 (2021).
37
38
Hospital diagnoses were available for one cohort, the DNBC.
69
mentioned Bradford Hill factors (biological plausibility,
coherence, consistency, temporality, and dose response), but it
did so by citing to other research.
It did not conduct its own
Bradford Hill analysis.
For each of these reasons, Dr. Baccarelli’s use of a
transdiagnostic Bradford Hill analysis fails to meet the
requirements for admissibility on the issue of causation for
either ASD or ADHD.
But, even if it were appropriate to conduct
a transdiagnostic Bradford Hill analysis, Dr. Baccarelli’s
analysis would nonetheless be excluded as unreliable.
2.
Consistency/Replication
Beginning with a discussion of the Bradford Hill factor of
consistency will place in context many of the deficiencies that
appear in Dr. Baccarelli’s application of the other Bradford
Hill factors.
The consistency factor arises from the insight
that, to effectively demonstrate a causal relationship, it is
important that a study be replicated in different populations
and by different investigators.
“Although inconsistent results
do not necessarily rule out a causal nexus, any inconsistencies
signal a need to explore whether different results can be
reconciled with causality.”
RMSE at 604.
Dr. Baccarelli assigned the most weight in his Bradford
Hill analysis to three factors: consistency, strength of
70
association, and dose-response.
Dr. Baccarelli opines that the
consistency element of the Bradford Hill test is “strongly”
satisfied.
He judges that there are at least ten studies
showing an association between prenatal acetaminophen use and
ADHD, three showing an association with ASD, and five showing an
association with symptoms of NDDs.
He acknowledges that there
are studies that did not show such associations, but considers
them to be in the “extreme minority.”
He adds that a set of
studies can still be consistent even if some of their results
are not statistically significant.
He finds support for his
finding of association in two meta-analyses:
Gou 2019 39 and
Alemany 2021.
Plaintiffs have failed to carry their burden to show that
Dr. Baccarelli’s analysis of this Bradford Hill factor is
reliable.
To begin with, it is cursory.
It fails to engage
meaningfully with the inconsistencies among the studies,
inconsistencies which exist to a remarkable degree.
He fails to
address meta-analyses and scientific literature which do not
find consistency among the study results.
His failure to engage
Gou et al., Association of Maternal Prenatal Acetaminophen Use
with the Risk of Attention Deficit/Hyperactivity Disorder in
Offspring: A Meta-Analysis, 53(3) Australian & New Zealand J.
Psych. 195 (2019).
39
71
seriously with the complexity of the relevant studies’ outcomes
is well illustrated by his assertion regarding ASD.
It is difficult to understand where Dr. Baccarelli was
looking when he found that the research regarding ASD was
consistent and that there were three studies to support his
conclusion.
Of the six studies publishing risk ratios for
prenatal, peripartum, or postpartum exposure and an ASD
diagnosis, three found no association (Ji 2018, Leppert 2019,
and Saunders 2019), one found an association only for ASD cooccurring with HKD (Liew 2016a), and one found a protective
association among febrile women (Hornig 2018).
While Ji 2020
did find an association, it has significant limitations.
Ji 2020 broke down the total level of acetaminophen
detected in umbilical cord blood into thirds.
It found a
statistically significant increase in a diagnosis of ASD for
mothers whose total level of acetaminophen (unchanged
acetaminophen and its metabolites) was in the third tertile
compared to the first.
Among the study’s limitations, however,
the authors listed their inability to exclude genetic
confounding and that they had only measured peripartum use of
acetaminophen.
Id. at 188.
Since the half-life of
acetaminophen is less than three hours, this study has limited
relevance to use of acetaminophen during the pregnancy itself.
72
Although Dr. Baccarelli’s report does not list which three
studies he is counting as consistent with his thesis about ASD,
Dr. Baccarelli’s Navigation Guide chart suggests that he is
counting the largely irrelevant Ji 2020 along with Liew 2016a
and Avella-Garcia 2016.
Consideration of these studies doesn’t
help him get to three or support a finding of consistency.
Avella-Garcia 2016 did not rest on a diagnosis of ASD.
Instead, it examined a child’s score on the CAST questionnaire,
and found that there was an increase in CAST symptom scores
among boys and decrease among girls.
Independent of that
difference, the authors “did not use cut-off points to evaluate
the outcomes” and thus examined “symptoms in a manner that goes
beyond examining only disorders, to include milder
dysfunctions.”
Id. at 1993.
In other words, the clinical
significance of the results in Avella-Garcia 2016, and thus
their consistency or lack thereof with other ASD studies is not
clear.
And, as discussed supra, Liew 2016a found no association
between in utero use of acetaminophen and a diagnosis of ASD
unless the diagnosis was for ASD with HKD.
The authors observed
that, if those two disorders are considered to be different,
then their results “can be interpreted as acetaminophen only
having an impact of hyperkinetic disorder but not ASD.”
73
Id. at
954.
Thus, considering the different outcome measurements and
the authors’ limitations, an expert assessing consistency
between Avella-Garcia 2016 and Liew2016a should have explained
the “analytical gap between the data and the opinion proffered.”
Joiner, 522 U.S. at 146.
Dr. Baccarelli did not do so.
Further, while Liew 2016a found an association between
acetaminophen and ASD with HKD, but not for ASD without
hyperkinetic disorder, Ji 2020 found no significant association
for ASD with ADHD, but did find a statistically significant
association for ASD without ADHD. 40
Dr. Baccarelli does not
mention, let alone address, the possibility that Liew 2016a is
evidence only of ADHD.
Nor does Dr. Baccarelli mention that the
authors of Ricci 2023 -- the most recent meta-analysis and one
that he has praised elsewhere in his report -- determined that
Liew 2016a has another important complication that merits
careful consideration when addressing consistency of results.
The study measured exposure during each of a pregnancy’s three
trimesters. The associations between those exposures and the
ASD diagnosis did not appear to be consistent with plaintiffs’
other experts’ opinions on when the critical window for
acetaminophen exposure falls during a pregnancy. Dr. Louie
opines that exposure for at least 28 days during pregnancy can
cause ASD and ADHD no matter how those 28 days are spread out
during the course of the pregnancy, Dr. Cabrera states that the
second trimester is the critical window, and Dr. Hollander
states that the second and third trimesters are the critical
periods. But Liew 2016a found significant associations for use
in all three trimesters, and the first and second trimester
combined, but not the second and third trimester combined or the
first and third trimester combined. Id. at 955.
40
74
studies examining ASD “were either too few or too heterogeneous
in their measures to pool.”
Id. at 481.
In sum, Dr. Baccarelli’s conclusory opinion about
consistency does not adequately address the many conflicting
study results.
As the FDA’s reviews of these studies have
recorded time and again, the literature remains mixed.
See,
e.g., FDA 2022 at 33 (“[T]here are still study limitations and
inconsistent study findings that prohibit causal interpretations
of the association between [acetaminophen] exposure and
functional neurobehavioral outcomes”); FDA 2023 at 17
(“[F]indings on the associations between [acetaminophen] use
during pregnancy and neurobehavioral and urogenital outcomes
remain mixed”).
Another example of how Dr. Baccarelli’s analysis of
consistency fell far short can be found in his discussion of
those studies that relied on questionnaires instead of diagnoses
of either ASD or ADHD.
Of course, the challenge in assessing
consistency is particularly pronounced in studies that rely on
questionnaires.
If the multiple endpoints in these studies
provide valuable evidence of a causal relationship, an
assessment of consistency in a Bradford Hill analysis purporting
to consider all NDDs should acknowledge and address inconsistent
75
questionnaire-based results within each study and also between
such studies.
For example, in Trønnes 2020 (a study addressing nondiagnostic outcomes in the MoBa cohort), the authors found no
statistically significant results at all for communication
problems assessed by the ASQ or externalizing problems assessed
by the CBCL and three trimesters of acetaminophen exposure.
The
authors did find a positive, statistically significant
association between three trimesters of acetaminophen exposure
and internalizing problems as measured by the CBCL (1.36; 95% CI
1.02-1.80).
Id. at 252.
Yet Brandlistuen 2013 found the
inverse: a statistically significant, positive association
between exposure for greater than 28 days and externalizing
problems measured by the CBCL, and no significant association
for internalizing problems.
Id. at 1709.
Other inconsistencies for studies using questionnaires
abound.
Vlenterie 2016 41 found a significant association between
acetaminophen use and motor milestone delay, but no associations
between either short- or long-term use of acetaminophen and any
other behavioral or temperamental problems as measured by the
Vlenterie et al., Neurodevelopmental Problems at 18 Months
Among Children Exposed to Paracetamol in Utero: A Propensity
Score Matched Cohort Study, 45(6) Int. J. Epidemiol. 1998
(2016).
41
76
ASQ.
Tovo-Rodrigues 2020 42 found no significant positive
associations between acetaminophen use and CBCL or Battelle’s
Development Index scores, but did find a few statistically
significant risk ratios below 1, which would suggest a
protective effect.
Liew 2016c 43 found just one statistically
significant association (sustained attention; 2.80; 95% CI 1.55.5) among 36 reported outcomes; some of the reported outcomes
in that study had risk ratios below 1, and all but one were
statistically insignificant.
Id. at 2012, 2014.
Some studies
found different results depending on who administered the
questionnaire (Avella-Garcia 2016, Parker 2020 44, Thompson
2014 45).
Some studies found significant results for boys but not
girls (Avella-Garcia 2016, Alemany 2021) and some found
Tovo-Rodrigues et al., Low Neurodevelopment Performance and
Behavioral/Emotional Problems at 24 and 48 Months in Brazilian
Children Exposed to Acetaminophen During Foetal Development, 34
Pediatr. Perinat. Epidemiol. 27 (2020).
42
Liew et al., Paracetamol Use During Pregnancy and Attention
and Executive Function in Offspring at Age 5 Years, 45 Int. J.
Epidemiol. 2009 (2016).
43
Parker et al., Maternal Acetaminophen Use During Pregnancy and
Childhood Behavioral Problems: Discrepancies Between Mother- and
Teacher-Reported Outcomes, 34(3) Paediatr. Perinat. Epidemiol.
2999 (2020).
44
Thompson et al., Association Between Acetaminophen Use During
Pregnancy and ADHD Symptoms Measured at Ages 7 and 11 Years,
9(9) PLoS One 1 (2014).
45
77
significant results for girls but not boys (Bornehag 2018, 46
Bertoldi 2020 47) or stronger results for girls (Ji 2018).
Dr. Baccarelli’s incomplete examination of the consistency
factor cannot be excused by his reliance on meta-analyses.
Dr.
Baccarelli states that he finds confirmation for his conclusion
on consistency from two meta-analyses (Gou 2019 and Alemany
2021) and from the Consensus Statement.
But again, any
examination of meta-analyses and the Consensus Statement
required more care.
Gou 2019 did not study ASD.
It searched for English-
language publications relating to ADHD.
Its authors stated that
although they found a “moderate” association between
acetaminophen use and ADHD development, “caution is advised when
considering whether this association is causal, because
potentially unidentified or inadequately controlled confounding
factors in the observed studies may have unpredictable effects
on the observed association”.
Id. at 205.
Bornehag et al., Prenatal Exposure to Acetaminophen and
Children’s Language Development at 30 Months, 51 Euro. Psych. 91
(2018).
46
Bertoldi et al., Associations of Acetaminophen Use During
Pregnancy and the First Year of Life with Neurodevelopment in
Early Childhood, 34(3) Paediatr. Perinat. Epidemiol. 267 (2020).
47
78
As explained above, Alemany 2021 is a meta-analysis of
(mostly) questionnaire responses regarding use of acetaminophen
during pregnancy and ASD and ADHD symptoms in six European
birth/child cohorts with 70,000 children. 48
It concluded that
children prenatally exposed to acetaminophen were 19% and 21%
more likely to subsequently have ASD and ADHD symptoms within
the borderline/clinical range than non-exposed children.
A
mother was classified as exposed to acetaminophen during her
pregnancy if she reported when questioned that she had taken
“any” dose.
Id. at 994.
This meta-analysis relied principally
on reports of “borderline/clinical symptoms” instead of
diagnoses of either ASD or ADHD.
Thus, the proportion of
children having symptoms associated with “Autism Spectrum
Conditions” (“ASC”) ranged between 0.9 and 12.9%, depending on
the cohort.
This compares, for example, to the incidence of
diagnosed ASD in the United States of from 1 to 2%.
In a finding that is supportive of Dr. Baccarelli’s
analysis, the authors of Alemany 2021 did state that
the consistent associations found across different
sensitivity analysis including examining ASC and ADHD
diagnosis in the largest cohort makes unlikely that
the observed relationship between prenatal
acetaminophen and ASC and ADHD symptoms is entirely
explained by unmeasured confounding.
48
Again, hospital diagnoses were available for one cohort.
79
Id. at 1001.
Nonetheless, it cautioned that its findings need
to be interpreted “with caution” given the various limitations
the authors identified with its analysis.
Id. at 1000.
What is remarkable, however, is that Dr. Baccarelli
contends that meta-analyses support his finding of consistency
but fails to mention Ricci 2013, of which he is well aware.
As
already discussed, Ricci 2023 concluded that there were too few
studies to conduct a meta-analysis for ASD or indeed for
anything other than ADHD.
Id. at 482.
This is true even though
it had searched for all published, peer-reviewed studies written
in English examining “the association between in utero
acetaminophen exposure and child neurodevelopmental outcomes:
ADHD, ASD, communication delays/disorder, motor delays/disorder,
and other developmental delays/disorders.”
Id. at 475.
located twenty-two studies of twenty-three cohorts.
It
While there
were enough studies to conduct a meta-analysis of ADHD, one
third of those were of low or very low quality.
Id. at 482.
Its meta-analysis suggested “a small increase in risk of child
ADHD associated with in utero acetaminophen exposure” but noted
that the certainty of the evidence was “low.”
high-quality studies to be done.
It called for
Id. at 483.
Dr. Baccarelli’s reference to the Consensus Statement when
discussing the issue of consistency is similarly troubling.
80
As
described earlier, the Consensus Statement has experienced
significant push-back from the scientific community and its
authors responded in Bauer 2022 by stating “we avoided any
inference of causality in our Consensus Statement.”
Id. at 192.
In rendering his finding regarding the consistency of the
evidence, Dr. Baccarelli does not address this debate or the
more recent clarification by the authors of the Consensus
Statement.
Of course, inconsistency of results in individual studies
is best explored on cross-examination.
Individual
inconsistencies in the literature do not, by themselves, render
Dr. Baccarelli’s opinion unreliable.
It is not the strength or
lack thereof of the data on which a Rule 702 court must focus.
And, as noted supra, not all Bradford Hill criteria need to be
satisfied to make an inference of causation.
But his wholesale
failure to address the highly heterogenous nature of the studies
or the inconsistencies between results that do address the same
outcomes means that his consistency opinion “is connected to
existing data only by the ipse dixit of the expert.”
522 U.S. at 146.
Joiner,
And because Dr. Baccarelli placed great weight
in his Bradford Hill analysis on his finding of consistency,
this is a significant barrier to the admission of his opinion.
81
3.
Strength of Association
The next Bradford Hill factor to be discussed is the
strength of association.
this factor as well.
Dr. Baccarelli placed great weight on
Underlying the factor is the understanding
that, where the association is stronger, the support for a
finding of causation is greater.
“Although lower relative risks
can reflect causality, the epidemiologist will scrutinize such
associations more closely because there is a greater chance that
they are the result of uncontrolled confounding or biases.”
RMSE at 602.
Dr. Baccarelli opines that there is a “moderate” degree of
association between in utero exposure to acetaminophen and an
increased risk of NDDs in children.
He finds that the strength
criterion is satisfied because so many of the findings in the
studies on which he relies were statistically significant,
because so many of the studies relied on maternal selfreporting, which he opines likely biased the exposure estimates
toward the null, and because even a small magnitude of risk has
public health importance given the prevalence in the use of
acetaminophen. 49
Dr. Baccarelli does not separately address the
strength of association for a diagnosis of either ASD or ADHD.
Dr. Baccarelli’s reference to the prevalence of acetaminophen
use to support his finding of strength of association is highly
questionable. Insofar as pregnant women are concerned, access
49
82
As Dr. Baccarelli acknowledges, most of the studies on
which he has relied show risk ratios between 1.0 and 2.0.
This
is a far smaller magnitude of risk than that identified by the
experts in Mirena II -- where the risk ratio was 7.69 for one
group and 3.90 for another, see Mirena II, 341 F. Supp. 3d at
243 -- and is also smaller than that reported in Daniels-Feasel
(2.2).
See Daniels-Feasel, 2021 WL 4037820, at *8.
The most
recent meta-analysis reviewed by Dr. Baccarelli characterized
the association between prenatal acetaminophen exposure and ADHD
as “small to moderate.”
Ricci 2023 at 481.
The FDA has
likewise characterized the associations found in Ystrom 2017,
Trønnes 2020, and Liew 2016c as “weak.”
FDA 2022 at 30-31.
Moreover, Dr. Baccarelli’s reliance on the statistical
significance of the study findings is questionable.
As already
to acetaminophen to treat fevers and pain is critical to their
health and the wellbeing of their children. No one involved in
this litigation disputes this. Therefore, it is particularly
important to conduct a reliable analysis of whether use of
acetaminophen causes ASD or ADHD without putting one’s thumb on
the scale. Dr. Baccarelli, as an author of Laue 2019,
recognized this very point. Laue 2019 stated: “[b]ecause of the
concerns regarding NSAIDs and high-dose aspirin, it is
critically important that the risks and benefits of treating
pain and fever during pregnancy with acetaminophen are
thoroughly studied and understood before any recommendations are
made to pregnant women.” Id. at 142. Likewise, Baker 2022,
which Dr. Baccarelli co-authored, concluded that “more work is
needed to rule out confounding by indication and to assess
generalizability before a change in clinical practice is
recommended.” Id. at 7.
83
discussed, it is misleading to characterize the highly
heterogenous body of literature as reporting consistent
statistically significant associations.
Many of the studies
found statistically insignificant or even negative associations.
For example, Alemany 2021 found an overall association of 1.19
for ASD (95% CI 1.07-1.33).
Id. at 998.
But of the six
underlying cohorts analyzed by this meta-analysis, only one (the
DNBC) reported a statistically significant association with ASD.
The DNBC was likewise the only study of the six with a
significant association in the ADHD analysis, which found an
overall association of 1.21 (95% CI 1.07-1.36).
Id.
Additionally, the weakness of the evidence of association
between in utero exposure to acetaminophen and ASD in particular
has been masked by Dr. Baccarelli’s decision to lump all NDD
studies together.
In the one study examining the association
between prenatal use and an ASD diagnosis that found an
association (Liew2016a), the association only existed for ASD
with HKD (1.51; 95% CI 1.19-1.92), not ASD without HKD (1.07;
95% CI 0.92-1.24).
Id. at 955.
Dr. Baccarelli opines that the magnitude of the risk in
many studies has been dampened due to the inability to directly
measure exposure to acetaminophen and the need to rely instead
on maternal memory and reporting.
84
He points to the measurement
of acetaminophen in umbilical cord plasma in Ji 2020 and in
meconium in Baker 2020 as more reliable measures of the in-utero
use of acetaminophen and as a consequence their association with
statistically significant risks of ADHD and ASD.
Ji 2020, as
already discussed, however, only measured peripartum exposure to
acetaminophen, so its relevance to prenatal exposure is highly
questionable.
Moreover, Ji 2020 has been sharply criticized on
other grounds. 50
Baker 2020 on the other hand, is a well-
regarded study, but it only measured the risk of ADHD, not ASD.
Baker 2020 detected acetaminophen in the meconium of almost 58%
of the cohort’s infants and reported a risk ratio of 2.43 for
ADHD.
But, that finding was accompanied by a wide confidence
interval (95% CI 1.41-4.21)), undercutting its reliability.
Id.
For example, the position statement by ENTIS, made in response
to the Consensus Statement, addressed Ji 2020 in depth, stating
that the study had
severe issues with external and internal validity. APAP or
metabolites were detected in every single of the 996
umbilical cord samples. This does not compare well to our
knowledge on the use of APAP during pregnancy. Among the
996 children, an unprecedented large proportion were
diagnosed with ADHD/ASD (37%) and only 33% had no
‘developmental disability’ diagnosis. Population
prevalence estimates of ADHD is around 3-5%. The validity
of the exposure construct ‘burden of APAP exposure’ is
undocumented and actual levels are not presented.
Analytical methods are insufficiently accounted for
including stability from up to 20 years of sample storage.
European Network of Teratology Information Services, Position
Statement on Acetaminophen (Paracetamol) in Pregnancy, at 2
(Oct. 3, 2021).
50
85
at 1077.
Among the study’s limitations, the authors noted that
they had not controlled for confounding by either indication or
genetics.
Id. at 1079.
Because Dr. Baccarelli’s discussion of this Bradford Hill
factor does not separately address the ASD, ADHD, and the other
NDD studies, he has not explained how the strength (or weakness)
of association evidence for each of them has impacted his
overarching assessment that the strength of the association
should be judged as moderate for all NDDs.
Moreover, given the
complexity of this issue, it was particularly incumbent upon Dr.
Baccarelli to consider with care the extent to which either
confounding by indication and/or genetic confounding ameliorated
any appearance of association.
As discussed below, Dr.
Baccarelli has failed to examine dispassionately and with care
the evidence of genetic confounding.
In sum, the plaintiffs have not shown that Dr. Baccarelli
has applied with sufficient rigor his profession’s methodology
for measuring the strength of association between in utero use
of acetaminophen and NDDs.
As a result, they have not shown
that there is a reliable basis for finding a moderate degree of
association between in utero use of acetaminophen and NDDs, much
less either ASD or ADHD.
For this reason as well, Dr.
Baccarelli’s opinion must be excluded.
86
4.
Specificity
An association exhibits specificity “if the exposure is
associated only with a single disease or type of disease.”
at 605.
RMSE
Where there is a good biological explanation for the
absence of specificity, for example when the toxin consists of
numerous harmful agents, a lack of specificity does not
necessarily undermine a finding of causation.
Id. at 606.
Dr. Baccarelli opines that the specificity criterion is not
satisfied.
He explains that not every child who develops NDDs
will have been exposed to acetaminophen in utero and that the
etiology of NDDs is multifactorial.
He argues, however, that
this factor is considered to be “all but irrelevant” by modern
epidemiologists.
While it is important not to overestimate the importance of
specificity, its absence highlights the complexity of the
causation analysis.
When the causal connection is complex, it
is particularly important for the epidemiologist to consider
whether the studies upon which she is relying adequately
considered confounding effects, among other things.
Baccarelli did not do.
87
This Dr.
5.
Temporality
A temporal or chronological relationship must exist for
causation to exist.
RMSE at 601.
If an exposure occurs after
the disease develops, it “cannot have caused the disease.”
Id.
Dr. Baccarelli’s analysis of temporality is contained in a
single paragraph.
He finds that temporality is satisfied
because prenatal use of acetaminophen has already occurred by
the time a child is diagnosed with ADHD or ASD.
This factor requires a more rigorous analysis than that
provided by Dr. Baccarelli.
The question is not whether the
exposure precedes the diagnosis but whether it precedes the
development of the disorder.
The studies Dr. Baccarelli
reviewed collected data about acetaminophen use at a variety of
points throughout pregnancy (and sometimes, as with Ji 2020, at
delivery).
A reliable assessment of the temporality factor
would engage with the fact that it is not currently known when
either ASD or ADHD develop in the fetal brain, and with the
possibility that some studies measured acetaminophen use either
before or after the development window.
6.
Dose-Response
The factor of the dose-response relationship, which Dr.
Baccarelli refers to as biologic gradient, means that the
greater the exposure, the greater the risk of disease.
88
If this
relationship exists, it is strong but not essential evidence of
causation since some causal agents require that the exposure
exceed a certain dose to have a causal effect.
RMSE at 603.
Dr. Baccarelli placed great weight on this factor, along
with consistency and strength of association.
He opines that
virtually every study that evaluated dose response found an
association between the number of days of prenatal acetaminophen
use and NDDs in children.
causation.
He finds this compelling evidence of
Dr. Baccarelli identifies six studies for ADHD, two
for ASD, and three for “general neurodevelopment.”
He
emphasizes that Ji 2020 and Baker 2020 51 found a “clear” dose
response.
He finds further support for his opinion in the
expert opinion of Dr. Louie.
opinion is inadmissible.
As discussed below, Dr. Louie’s
Dr. Louie opines that prenatal use of
acetaminophen for 28 days or more during a pregnancy can cause
ADHD and ASD -- a number that is neither reliably supported by
the sources upon which he relies, nor tethered to any particular
period during pregnancy.
Dr. Baccarelli is correct that Ji 2020 and Baker 2020 found
results consistent with a dose-response, but his statement that
It appears that Dr. Baccarelli’s reference in his report to
Baker 2022 is in fact a reference to Baker 2020. Thus, the
change has been made in this Opinion.
51
89
“virtually every study that was powered to evaluate, and did in
fact evaluate, dose response found an association” is
misleading, as is his reliance on Alemany 2021.
The authors of
Alemany 2021 stated that “dose and frequency of use were not
harmonized across cohorts and therefore, not analysed herein.”
Id. at 1001.
As will be discussed below, many of the animal
studies relied upon -- the only studies that could reliably
record dosage during pregnancy -- do not show a dose response.
The plaintiffs have not carried their burden of showing
that Dr. Baccarelli reliably applied epidemiological principles
to this component of the Bradford Hill analysis.
Dr.
Baccarelli’s dose-response opinion is more general than Dr.
Louie’s 28-days opinion.
While that generality helps him avoid
some of the pitfalls of Dr. Louie’s approach, it does not
grapple with a key issue in the underlying studies: none were
able to record the actual dosages taken by pregnant women.
The
closest approximation to dose in the underlying studies is days
of use.
Finally, Dr. Baccarelli’s reliance on Ji 2020 and Baker
2020 required a more careful reading of those studies.
Ji 2020
does not clearly map onto maternal dosing, because it only
measured acetaminophen in umbilical cord blood at delivery.
Baker 2020 did not adjust for indication or genetic confounding,
90
which is problematic because both factors can increase risk
ratios.
See Ricci 2023 at 482.
Like his consistency opinion,
Dr. Baccarelli’s dose-response opinion skates over the
complexities and limitations of the underlying literature, and
is therefore not admissible under Rule 702.
7.
Biological Plausibility
Biological plausibility depends upon existing knowledge
about the mechanisms by which the disease at issue develops.
Therefore, the weight assigned to this factor will depend upon
the state of science.
RMSE at 604-05.
Dr. Baccarelli opines that there are multiple plausible
biological mechanisms that could explain the association between
prenatal acetaminophen exposure and NDDs in offspring and
mentions oxidative stress as a known pathway.
He finds
confirmation for his opinion in the opinions offered by Drs.
Cabrera and Pearson.
Dr. Baccarelli finds that the plausibility
criterion is satisfied.
As will be explained in more detail during the discussion
of Dr. Cabrera’s report, the plaintiffs have not shown that any
expert opinion purporting to identify the physiological
processes that cause the development of either ASD or ADHD would
survive scrutiny under Rule 702.
At present, the precise
physiological process or processes by which these conditions, or
91
NDDs more generally, develop are unknown.
best developed hypotheses.
Scientists have at
Therefore, Dr. Baccarelli’s
conclusion that this factor is satisfied is stricken as failing
to reflect a reliable application of scientific principles.
The
absence of an admissible opinion by Dr. Baccarelli on biological
plausibility would not, however, preclude the admission of an
otherwise admissible opinion by him on causation.
8.
Coherence
Dr. Baccarelli next examines the coherence factor, which he
describes as looking at whether a causal relationship conflicts
with generally known facts about the history and biology of the
disease.
Dr. Baccarelli gives coherence only “minor” weight,
but believes it is satisfied.
Dr. Baccarelli opines that the association between prenatal
acetaminophen exposure and ADHD and ASD in children is coherent
with existing knowledge and understanding of the diseases and
their causes because environmental factors are known to affect
neurodevelopment during pregnancy and the rates of ADHD and ASD
have risen in tandem over the decades with use of acetaminophen.
The plaintiffs have shown that Dr. Baccarelli’s conclusion that
the coherence factor is satisfied reflects a reliable
application of scientific principles.
While the defendants take
issue with the accuracy of the data on which Dr. Baccarelli
92
relies to find an in tandem increase in the use of acetaminophen
and a rise in either ADHD or ASD, those disagreements do not
affect the admissibility of this opinion.
9.
Analogy
The analogy factor examines whether similar drugs have been
shown to cause the outcome of interest.
“Substantiation of
relationships similar to the putative causal relationship
increases the likelihood of causation.”
3d at 243.
Mirena II, 341 F. Supp.
Dr. Baccarelli placed “very little weight” on the
analogy factor, but found it satisfied.
Dr. Baccarelli finds this factor satisfied because “[t]he
FDA-approved label for Depakote, another drug previously used by
pregnant women . . . states that ‘the weight of the evidence
supports a causal association between valproate exposure in
utero and subsequent adverse effects on neurodevelopment,
including increases in [ASD and ADHD].”
Dr. Baccarelli states,
without citation or discussion, that “[v]alproic acid, like
acetaminophen, has been shown to increase oxidative stress and
deplete glutathione levels.”
This bare assertion, unaccompanied
by any discussion of the chemical structures of valproic acid
and acetaminophen, does not reflect a reliable application of
the analogy factor.
93
10.
Experiment
Finally, epidemiologists consider a relationship of
causation is more likely to exist if removing the exposure in a
population results in a decrease in the occurrence of the
disease or harm.
Here, ethical considerations prevent the
collection of direct experimental evidence.
Dr. Baccarelli assigns minimal weight to this factor, but
nevertheless finds this factor satisfied because, using a “more
modern approach”, he has considered animal studies.
As the
parties acknowledge, the animal studies cannot bear the full
weight of providing admissible evidence of causation in this
case.
They may, however, be supportive of other evidence of
causation.
The animal studies are addressed below, in
connection with the discussion of the reports of Drs. Cabrera
and Pearson.
11.
Genetic Confounding
In addition to the disqualifying deficiencies just
described, particularly with respect to the factors of
consistency and the strength of association, Dr. Baccarelli’s
Bradford Hill analysis is unreliable due to his failure to
assess with sufficient rigor the relevant evidence of
confounding by genetics.
By itself, this failure requires the
exclusion of his opinion.
94
As described earlier, according to the DSM, a recent fivecountry cohort estimated ASD heritability at 80%.
DSM at 64.
Similarly, the heritability of ADHD is estimated to be
approximately 74%.
Id. at 71.
The parties agree that the existence of genetic confounding
must be addressed when seeking to assess an association between
prenatal use of acetaminophen and either ASD or ADHD.
In its
2022 review of the literature, the FDA observed that studies are
“still limited by . . . the possibility of unmeasured
confounding by factors such as indication, other medications,
and genetic factors.”
FDA 2022 at 32.
The FDA observed in 2023
that high quality studies should adjust for confounders,
including “genetic factors or . . . relevant familial factors
such as parental neurobehavioral conditions (e.g., parental
ADHD) or psychiatric conditions.”
FDA 2023 at 27.
Many of the studies that Dr. Baccarelli collected in his
survey, including those upon which he relies most heavily,
acknowledge the need for more work to account for the
confounding effect of genetics.
See, e.g., Liew 2014 at 319,
Liew 2016a at 956, Ji 2020 at 188, Baker 2020 at 1079, Ricci
2023 at 482.
And, a few studies have been specifically designed
to try to measure that effect.
95
For example, Gustavson 2021 performed a sibling-control
analysis on data from the MoBa cohort. 52
siblings in the study.
There were over 29,000
The authors initially found a two-fold
increase in the risk of an ADHD diagnosis for children born to a
mother with a long-term use of acetaminophen (29 days or
greater) during the pregnancy (2.02; 95% CI 1.17-3.25).
5.
Id. at
After performing the sibling-control analysis, however, that
association was eliminated (1.06; 95% CI 0.51-2.05).
Id.
All
children, whether exposed or not to acetaminophen in utero, who
were born to a mother with long-term use of acetaminophen in one
pregnancy had an increased risk of receiving an ADHD diagnosis
compared to children of mothers who did not use acetaminophen in
any pregnancy (2.77; 95% CI 1.48-5.05).
Id. at 5, 7.
From this
nearly three-fold family effect, the authors concluded that
familial confounding factors may explain at least part of the
observed association between maternal long-term acetaminophen
use and ADHD.
In other words, a mother’s long-term use of
acetaminophen during pregnancy may indicate a preexisting risk
of ADHD in the child, rather than causing the increased risk.
The MoBa cohort is a population-based pregnancy cohort study
conducted by the Norwegian Institute of Public Health. Pregnant
women from all over Norway were recruited between 1999 and 2008.
Maternal questionnaires were answered at gestational weeks 17
and 30, as well as six months after birth. The study includes
more than 114,000 children.
52
96
Another study, Leppert 2019, was designed to test whether
maternal genetic risk scores were associated with early-life
exposures of their offspring to a variety of experiences, from
smoking to low birth weight.
One of the measured exposures was
in utero exposure to acetaminophen.
Of the pregnant women
recruited in Avon, United Kingdom in the years between 1990 and
1992, over 10,000 underwent genotyping for risk alleles
associated with ADHD, ASD, and schizophrenia.
The results from
the study suggest that mothers with higher ADHD polygenic risk
scores “may also be more likely to use acetaminophen in
pregnancy.”
Id. at 839.
It concluded that “to draw conclusions
about causality, future studies need to account for potential
genetic confounding.”
Id. at 840.
In particular, it observed
that “mothers with high genetic liability to ADHD may be at
increased risk for many adverse pregnancy factors.”
Id.
Further, the authors of Masarwa 2020 53 -- who had previously
conducted a meta-analysis, Masarwa 2018, 54 that found an
Masarwa et al., Acetaminophen Use During Pregnancy and the
Risk of Attention Deficit Hyperactivity Disorder: A Causal
Association or Bias?, 34 Paediatric Perinatal Epidemiology 309
(2020).
53
Masarwa et al., Prenatal Exposure to Acetaminophen and Risk
for Attention Deficit Hyperactivity Disorder and Autistic
Spectrum Disorder: A Systematic Review, Meta-Analysis, and MetaRegression Analysis of Cohort Studies, 187(8) Am. J.
Epidemiology 1817 (2018).
54
97
association between prenatal acetaminophen use and ADHD symptoms
-- updated their meta-analysis and conducted a bias analysis.
They concluded that the “observed association between
acetaminophen during pregnancy and the increased risk for ADHD
in the offspring is likely the result of bias.
This systematic
error appears to be predominantly driven by unmeasured
confounding and exposure misclassification.”
Id. at 316.
Despite the identified risk of genetic confounding, Dr.
Baccarelli gives short shrift to the issue.
The discussion in
his reports is incomplete, unbalanced and at times misleading. 55
In general, Dr. Baccarelli downplays those studies that
undercut his causation thesis and emphasizes those that align
with his thesis.
A stark example of Dr. Baccarelli’s result-
driven analysis appears in his discussion of two sibling-control
studies run from the same cohort -- the MoBa cohort -- eight
years apart.
Although the earlier study, Brandlistuen 2013, did
not include any diagnosis of ADHD in offspring, its conclusion
was a better fit for Dr. Baccarelli’s thesis, and he praises it,
stating that it offers “greater comfort that unmeasured,
residual confounding is not driving the association between
acetaminophen and ADHD.”
The more recent study, which due to
During his deposition, Dr. Baccarelli repeatedly evaded
defense counsel’s inquiries on the issue.
55
98
the passage of time was able to incorporate actual diagnoses of
ADHD, is Gustavson 2021.
It has already been described and its
results underscore the need to consider genetic confounding when
analyzing whether in utero exposure to acetaminophen has caused
ADHD.
Dr. Baccarelli is dismissive of the study’s results.
At
no point does he explain his disparate treatment of the two
studies.
Dr. Baccarelli’s dismissal of evidence that challenges his
thesis is also illustrated by his discussion of Ystrom 2017,
which also studied the MoBa cohort. 56
The authors of the study
concluded, “given that paternal use of acetaminophen is also
associated with ADHD, the causal role of acetaminophen in the
etiology of ADHD can be questioned” and cautioned that “[w]e do
not provide definitive evidence for or against a causal relation
between maternal use of acetaminophen and ADHD.” 57
Id. at 7.
In
his report, Dr. Baccarelli speculates that paternal use might
have been serving as an imperfect proxy for maternal use
Ystrom 2017 found an association between maternal prenatal use
of acetaminophen for 29 days or more and offspring diagnosed
with ADHD (2.20, 95% CI 1.50-3.24). Id. at 6. But the study
also found a two-fold association between paternal use of
acetaminophen for 29 days or more before conception and ADHD in
offspring (2.06; 95% CI 1.36-3.13). Id. at 7.
56
The FDA, in its 2022 literature review, noted that the “NCE
for paternal [use] suggests residual confounding.” FDA 2022 at
54.
57
99
because, among other things, “fathers and mothers often share
medications and medicine cabinets.”
This does not constitute a
scientifically sound treatment of Ystrom 2017.
Dr. Baccarelli is also willing to press conclusions that
study authors are not willing to make.
This willingness creates
an “analytical gap” between the conclusions reached by the
authors and the conclusions he draws from their work.
Daniels-Feasel, 2021 WL 4037820, at *10.
See
In doing so, Dr.
Baccarelli repeatedly ignores authors’ cautions that familial or
genetic confounding may explain, at least in part, the observed
association.
Overall, Dr. Baccarelli’s testimony does not reflect a
reliable application of scientific methods.
Of the three
Bradford Hill factors to which he accords the most weight, none
have been analyzed in a reliable manner.
Further, he “chooses
not to consider evidence that undercuts his opinion” -- namely,
evidence that genetic confounding may partially explain the
observed associations.
See Mirena II, 341 F. Supp. 3d at 252.
Because “each of [Dr. Baccarelli’s] departures from settled and
rigorous methodology favors the same outcome,” it “suggests
motivated, result-driven, reasoning.”
Id. at 251.
Dr.
Baccarelli’s proposed testimony regarding his Bradford Hill
100
analysis is inadmissible under the standards set forth by
Daubert and Rule 702.
B.
Navigation Guide
Dr. Baccarelli’s applications of the Navigation Guide are
similarly suspect.
As Dr. Baccarelli acknowledges, it is the
Bradford Hill methodology that epidemiologists have
traditionally used to address questions of causation.
In
contrast, the Navigation Guide is a tool used to summarize
evidence.
Or, as Dr. Baccarelli explains in his rebuttal
report, it is a “guide” that requires scientists to “objectively
analyze each study and then transparently rate each study
considered as part of the causal analysis.”
The Navigation Guide methodology involves conducting a
search of the relevant literature, extracting and evaluating
data from the studies identified, rating the quality and
strength of the evidence, and then coming to an overall
conclusion about an agent’s toxicity.
See Woodruff & Sutton,
The Navigation Guide Systematic Review Methodology: A Rigorous
and Transparent Method for Translating Environmental Health
Science into Better Health Outcomes, 122(1) Environ. Health
Perspect. 1007 (2014).
It is intended to be used by teams to
minimize bias in the evaluation of the evidence.
Dr. Baccarelli performed the analysis by himself.
101
Here, however,
As with the Bradford Hill criteria, there are many steps
within the Navigation Guide framework that call for expert
judgment.
Several steps require the expert to use her
subjective judgment to up- or down-grade an objective rating. 58
Thus, the Navigation Guide, like Bradford Hill, is a “flexible
methodology” that “can be implemented in multiple ways.”
Zoloft, 858 F.3d at 795.
Even assuming the Navigation Guide’s
utility in assessing causation for purposes of this litigation,
“each application is distinct and should be analyzed for
reliability.”
Id.
Dr. Baccarelli used the Navigation Guide methodology three
times: once each for studies concerning ASD, studies concerning
ADHD, and studies concerning other NDDs.
In his analysis for
ASD, Dr. Baccarelli reviewed six studies and included four of
them in his overall evaluation of the strength of the evidence
(the two he did not include, Leppert 2019 and Saunders 2019,
would, if credited, detract from the evidence of causality).
He
states that these four “consistently reported a positive
association between prenatal acetaminophen use and ASD, with an
Dr. Baccarelli readily admits that the downgrading of each
study is based on his judgment. Even in the case of summary
scores, he used those scores “only as a guide reflecting the
scores across the six factors. In other words, the summary
scores informed my decision of the final expert opinion scores,
but were not binding.”
58
102
exposure-response relationship observed in two of the three
studies.”
He rated two studies as “very strong” evidence: Ji
2020 and Liew 2016a.
As noted above, Ji 2020 only measures
peripartum exposure, the relevance of which Dr. Baccarelli does
not sufficiently explain.
Notably, he rated Alemany 2021 (a
meta-analysis) as “strong” evidence, but did not include Ricci
2023 (a more recent meta-analysis), presumably because of its
conclusion that there were too few ASD studies to reliably
conduct a meta-analysis.
Finally, his rating of Liew 2016a does
not contend with that study’s finding that acetaminophen was not
associated with ASD without HKD.
Dr. Baccarelli devotes only one paragraph to the section
titled “Final Determination Based on the Navigation Guide
Analysis About the Toxicity of Prenatal Acetaminophen Use and
Child’s ASD.”
Dr. Baccarelli asserts that the studies
consistently reported a positive association and that the
studies controlled for confounding.
Given the heterogeneity of
the evidence, these cursory assertions do not sufficiently
support his “final determination [] that there is strong
evidence of a causal link between prenatal acetaminophen use and
an increased risk of being diagnosed with ASD in children.”
As for ADHD, Dr. Baccarelli based his Navigation Guide
determination on “the evaluation of fifteen studies, including
103
four high-quality studies that provided very strong evidence of
an association and five studies that provide strong evidence of
an association.”
The rest of the paragraph describing the
determination is a near-verbatim copy of the paragraph on ASD.
His grading of the studies, examined closely, shows similar
evidence of “result-driven analysis.”
Lipitor, 892 F.3d at 634.
Perhaps most tellingly, Baccarelli separated Gustavson 2021
into two studies: the initial data (which reported an
association, and which Dr. Baccarelli rated as “strong
evidence”) and the sibling-control analysis (which attenuated
the association, and which Dr. Baccarelli downgraded from
“moderate” to “weak” evidence “due to concerns about small size
and the bias toward the null likely introduced by the
elimination of the effects of intermediate factors”).
Yet he
did not similarly downgrade Brandlistuen 2013, discussed supra,
instead rating it as “strong evidence” that acetaminophen causes
other NDDs.
But Brandlistuen 2013’s sibling-control analysis
would similarly “eliminat[e] the effects of intermediate
factors,” and it included 134 sibling pairs discordant on
exposure for greater than 28 days.
Id. at 1704.
Gustavson
2021, having the benefit of several more years of data on the
same cohort, included 380 families with siblings discordant on
exposure for 29 days or more.
Id. at 5.
104
This is a paradigmatic
example of interpreting results differently based on the outcome
of the study, Zoloft II, 858 F.3d at 797, and it is illustrative
of Dr. Baccarelli’s approach to the Navigation Guide, in which
he uses areas where an expert’s subjective opinion comes into
play to selectively downgrade studies not supporting his
analysis and vice versa.
Finally, Dr. Baccarelli also disregards relevant reviews of
epidemiological studies conducted by medical and governmental
associations.
He does not address the FDA’s repeated conclusion
that the epidemiological evidence does not support his opinions,
other than to note his disagreement with that conclusion.
Nor
does he grapple with the contrary conclusions of the American
College of Obstetricians and Gynecologists, the Society of
Obstetricians and Gynaecologists of Canada, or the European
Network of Teratology Information Services.
This “rejection of
a conclusion that could not be more relevant to his opinions is
alarming.”
Daniels-Feasel, 2021 4037820, at *12.
In sum, Dr. Baccarelli failed to sufficiently explain the
appropriateness of conducting a single Bradford Hill analysis
for NDDs which included ASD and ADHD, selectively analyzed the
consistency of the literature and the issue of genetic
confounding, repeatedly pressed conclusions that study authors
were not willing to make, and disregarded studies that do not
105
support his opinion due to limitations that he did not view as
disqualifying in studies that did support his opinion.
Together, these deficiencies demonstrate that his opinion does
not “reflect[] a reliable application of the principles and
methods to the facts of the case.”
Fed. R. Evid. 702.
Thus,
Dr. Baccarelli’s causation opinions are not admissible.
At oral argument, the plaintiffs asked the Court to focus
on the fact that Dr. Baccarelli is a preeminent epidemiologist,
which he is.
They ask that the Court ignore his published
statements acknowledging the weakness in the literature, arguing
that he has been correct to change his mind when rendering his
opinion here.
They stress the direction of the association
evidence, ignoring those studies finding no association or a
negative association.
They argue that it is unnecessary to
insist that a finding of association be statistically
significant, arguing that a more flexible standard should be
adopted.
They contend that the limitations expressed by authors
in their studies should be ignored as simply an overly
conservative requirement that scientists impose on each other to
get peer reviewed studies published.
They suggest that the
FDA’s surveillance of this issue since 2014 means little since
the FDA was not vigilant in reviewing the risks associated with
certain other drugs and that it has not performed a Bradford
106
Hill analysis.
These and more arguments like them do not
relieve the Court of the obligation to scrutinize the
methodology applied by Dr. Baccarelli to ensure that it is
sufficiently rigorous to pass muster by the standards
established by his discipline, Rule 702 and Daubert.
XI.
Dr. Cabrera
Dr. Robert Cabrera has provided an amended expert report of
June 22, 2023, a supplemental expert report dated July 17, and a
rebuttal expert report dated July 28.
He was deposed on August
2.
Dr. Cabrera’s expertise is in teratology, the study of
abnormalities, malformations, and developmental disorders that
occur during prenatal development.
He is an Associate Professor
of Molecular and Cellular Biology at Baylor College of Medicine
and an Adjunct Professor of Biology at San Jacinto College.
He
obtained his Ph.D. in Medical Sciences from Texas A&M University
Health Science Center.
His research focuses on the
interrelationships between maternal immunity and birth defect
risks, and he is currently leading research efforts to test
developmental toxicity of anti-retroviral therapies.
Dr.
Cabrera does not specialize in ASD or ADHD.
Dr. Cabrera was asked by plaintiffs’ counsel to examine the
developmental and reproductive toxicity of acetaminophen.
107
Dr.
Cabrera states that he reviewed the chemical profile of
acetaminophen; a published regulatory adverse outcome pathway
(“AOP”) linking mercury exposure to deficits in learning and
memory; and the preclinical, in vitro, ex vivo, and in vivo
studies of potential reproductive, developmental, and
neurodevelopmental effects of therapeutic doses of
acetaminophen.
Dr. Cabrera combined several methodologies in his report.
He relied in part on the AOP construct, which “consider[s] data
describing the adverse consequences of exposure to a toxin at
the molecular, cellular, tissue, organ, whole body, and
population levels in assessing questions of association and
causality.”
Dr. Cabrera applied parts of the published AOP 20,
and otherwise used the AOP construct to organize his weight of
the evidence analysis of whether acetaminophen exposure during
pregnancy can cause functional deficits in offspring,
specifically, ASD and ADHD.
He adds a brief Bradford Hill
analysis at the end of his report.
Dr. Cabrera offers both general causation and biological
mechanism opinions.
He opines that therapeutic dosages of
acetaminophen taken by pregnant women are sufficient to cause
neurotoxicity, neurodevelopmental disorders, ASD, and ADHD in
their children.
He primarily relies on two biological
108
mechanisms, the first involving oxidative stress and the second
involving endocannabinoid disruption. 59
Dr. Cabrera’s application of each of the above
methodologies is unreliable.
“unweighted and unmoored.”
His Bradford Hill analysis is
Mirena II, 341 F. Supp. 3d. at 247.
His weight of the evidence analysis repeatedly cherry picks
isolated findings in studies measuring multiple outcomes,
ignores inconsistent results, and dismisses the express
limitations of study authors.
He fails to adhere to principles
he claims are important guidelines for analyzing animal studies,
uncritically presents unreplicated and at times irrelevant
findings, and obfuscates critical gaps in his biological
mechanism analysis.
His testimony is inadmissible under Rule
702.
A.
Bradford Hill
Dr. Cabrera devotes only a few pages to his Bradford Hill
analysis.
There is an overarching methodological flaw in Dr.
Cabrera’s Bradford Hill analysis: he “does not explain the
weight that he attaches to any of the Bradford Hill criteria or
address the relationship among them.”
3d. at 248.
Mirena II, 341 F. Supp.
By “leaving obscure the weight that he attaches to
The plaintiffs originally identified a half dozen biological
mechanisms, but in their defense of these motions rely on two.
59
109
each of the nine Bradford Hill factors and the relationship
among them, Dr. [Cabrera’s] approach effectively disables a
finder of fact from critically evaluating his work.”
Id.
Because, as explained supra, “[f]lexible methodologies . . . can
be implemented in multiple ways,” it is critical that an expert
“explain 1) how conclusions are drawn for each Bradford Hill
criterion and 2) how the criteria are weighed relative to one
another.”
Zoloft, 858 F.3d at 796.
“Otherwise, such
methodologies are virtually standardless and their applications
to a particular problem can prove unacceptably manipulable.”
Mirena II, 341 F. Supp. 3d at 247.
Dr. Cabrera’s failure to
explain how he weighted the Bradford Hill factors renders his
analysis an unreliable application of a theoretically valid
methodology and is in itself a sufficient reason to exclude his
Bradford Hill opinion.
Further, like Dr. Baccarelli, he
conducts a transdiagnostic analysis, addressed to
“neurodevelopmental toxicity.”
He combines studies on ASD,
ADHD, and a variety of symptom outcomes without adequately
explaining his basis for doing so or confronting the
complexities created by this conflation.
In addition, Dr. Cabrera’s assessment of the individual
Bradford Hill factors is cursory and unreliable.
little more than his ipse dixit.
It amounts to
He acknowledges, for example,
110
that “[i]n general, an odds ratio between 1 and 2 is deemed low,
a ratio from 2 to 6 is deemed moderate, and a ratio above 6
deemed high.”
Despite the fact that the majority of studies
show at most (by his definition) a low odds ratio, he states
that the strength of association criterion is met.
To get to
that conclusion, he states that “the totality of the data is
consistent with ‘clear evidence of developmental toxicity’”
because there are “data that indicate a dose-related effect” on
functional deficits.
This conflation of the dose-response and
strength criteria is per se not reliable.
In any event, the
weakness in the evidence of any association cannot be overcome
by evidence of dose-response, which is similarly weak at best.
Dr. Cabrera also opines that the consistency factor is met.
His section on consistency spans all of five paragraphs and is
unreliable for the same reasons explained in detail supra with
regards to Dr. Baccarelli’s analysis.
Considering the
heterogenous nature of the epidemiological evidence -particularly the variety in exposure and outcome assessments -a much more thorough analysis would be necessary to reliably
opine on the literature’s consistency.
His temporality analysis is flawed for the same reason as
Dr. Baccarelli’s.
He finds the dose-response criterion
satisfied even though meta-analyses, which he places at the top
111
of the hierarchy of evidence, were unable to analyze a dose
response due to the heterogeny of exposure assessments in the
literature.
He states that the experiment criterion is met because
“[t]he available experimental evidence from animal models
consistently demonstrates dose-responsive reproductive,
developmental, and neurodevelopmental toxicity with pre-, periand post-natal [acetaminophen] exposures.”
As will be explained
in detail infra, this is a highly inaccurate representation of
the animal study literature.
Briefly, the animal studies, like
the epidemiology studies, measure many different behavioral and
biological outcomes; and, as with the epidemiology studies, the
devil is in the details.
Dr. Cabrera presents many studies as
“clear evidence” of acetaminophen’s purported impact on rodent
behavior and biology when in reality those studies reported
conflicting or unreplicated individual outcomes with varying
relevance to either ADHD or ASD.
As will be discussed infra, Dr. Cabrera’s analysis of the
biological mechanism contains key gaps in the causal chain;
given those gaps, his analysis of biological plausibility cannot
outweigh the weaknesses in the rest of his Bradford Hill
analysis.
To his credit, Dr. Cabrera does acknowledge that the
specificity factor “is not fully met”; however, without
112
specificity or a reliable analysis of strength, consistency,
temporality, dose-response, biological mechanism, or experiment,
Dr. Cabrera is left with coherence and analogy.
Without any
explanation of his weighting of the factors, the last two
factors alone cannot reliably be used to opine on general
causation.
Thus, Dr. Cabrera’s proposed testimony that a Bradford Hill
analysis supports his general causation opinion is inadmissible
under Rule 702.
B.
It must be excluded.
Adverse Outcome Pathway
Dr. Cabrera purports to offer several theories of
biological plausibility linking the use of acetaminophen to
NDDs, including ASD and ADHD.
But he does not identify a
mechanism by which either ASD or ADHD is created in utero.
For
this and the other reasons described below, his opinions of
biological plausibility are excluded.
In offering opinions of biological plausibility Dr. Cabrera
relies heavily on the OECD’s AOP 20. 60
According to the OECD,
“[a]n AOP is an analytical construct that describes a sequential
Tschudi-Monnet et al, Binding of electrophilic chemicals to
SH(thiol)-group of proteins and/or seleno-proteins involved in
protection against oxidative stress during brain development
leading to impairment of learning an memory, OECD Series on
Adverse Outcome Pathways, No. 20, OECD Publishing, Paris, at
https://doi.org/10.1787/4df0e9e4-en.
60
113
chain of causally linked events at different levels of
biological organization that lead to an adverse health or
ecotoxicological effect.” 61
Thus, an AOP is a useful construct
to consider plausible biological mechanisms by which chemicals
may impact health.
AOPs progress from data on molecular
interactions with the chemical, to cellular responses, to organ
responses, to responses at the organism (and sometimes
population) level.
Dr. Cabrera uses this analytical construct
to structure his weight of the evidence analysis.
To the extent that Dr. Cabrera opines that his application
of acetaminophen studies to AOP 20 provides independent support
for his causation opinion regarding ADHD and ASD, his testimony
is inadmissible for the following reasons.
The authors of AOP
20 state that
[t]he weight-of-evidence supporting the relationship
between the described key events is based mainly on
developmental effects observed after an exposure to the
heavy metal, mercury, known for its strong affinity to many
SH-/seleno-containing proteins, but in particular to those
having anti-oxidant properties, such as glutathione (GSH).
Id. at 4.
The AOP posits that chemicals binding to, e.g., GSH
depletes those protective proteins, resulting in decreased
protection against oxidative stress, which in turn results in
Organisation for Economic Co-operation and Development,
Adverse Outcome Pathways, at
https://www.oecd.org/chemicalsafety/testing/adverse-outcomepathways-molecular-screening-and-toxicogenomics.htm.
61
114
increased oxidative stress.
Oxidative stress then causes a
cascade of events leading to cell injury and/or death, which
then leads to decreased network formulation and function, and
then to impairment in learning and memory.
Id.
Because this litigation involves acetaminophen, not
mercury, and ADHD and ASD, which may or may not involve deficits
in learning and memory, Dr. Cabrera must independently fill the
gaps at the beginning and end of the pathway.
That is, a
reliable application of the AOP/weight of the evidence
methodology he purports to perform must show that maternal
prenatal acetaminophen use can cause depletion of GSH in the
fetal brain, and that “decreased network formulation and
function” can lead to ASD and ADHD.
Otherwise, his causation
and oxidative stress biological mechanism opinions would be
connected to existing data “by the ipse dixit of the expert.”
Mirena II, 341 F. Supp. 3d at 271 (citation omitted).
His
attempt to fill these gaps does not reflect a reliable
application of scientific principles.
Briefly, Dr. Cabrera posits that a minor but toxic
metabolite of acetaminophen, N-acetyl-p-benzoquinone imine
(“NAPQI”), which accounts for about 5-15% of metabolized
acetaminophen, binds to GSH, initiating the pathway described
above.
Although GSH depletion is generally accepted as a
115
biologically plausible mechanism for liver toxicity resulting
from acetaminophen overdose, there is no replicated data showing
that prenatal exposure to clinically relevant doses of
acetaminophen causes GSH depletion in the fetal brain.
Most
studies that Dr. Cabrera cites in support of this link in the
chain examined either adult rodents (thus having limited
relevance to prenatal exposure), doses too high to be clinically
relevant, and/or reduction of GSH in the liver, not the brain.
The studies that did measure GSH in the brain after
prenatal exposure do not support his oxidative stress theory.
For example, he relies on Klein 2020 62 and Rigobello 2021 63 as
providing evidence that acetaminophen reduces GSH.
But Klein
2020 found that exposure to acetaminophen during gestation did
not affect “GSH levels in the prefrontal cortex or hippocampus .
. . indicating that the exposure regimen did not cause long-term
alterations in oxidative balance in these two brain regions.”
Id. at 6.
Rigobello 2021 found decreased GSH in the hippocampus
in males only at the lower tested dose, and no difference from
Klein et al., Gestational Exposure to Paracetamol in Rats
Induces Neurofunctional Alterations in the Progeny, 77
Neurotoxicology and Teratology (2020) (“Klein 2020”).
62
Rigobello et al., Perinatal Exposure to Paracetamol: Dose and
Sex-Dependent Effects in Behavior and Brain’s Oxidative Stress
Markers in Progeny, 408 Behavioral Brain Research e113294 (2021)
(“Rigobello 2021”).
63
116
controls in females, at the higher tested dose, or in the other
brain regions studied (prefrontal cortex, striatum, and
cerebellum).
Id. at 6.
Thus, out of sixteen measurements of
GSH in the brain, only one supports Dr. Cabrera’s theory; the
other fifteen do not.
Yet he includes Rigobello 2021 in a chart
as evidence of decreased GSH with no mention of the fifteen
findings of no effect.
Further, in his weight of the evidence analysis, he states
that “[t]he effects described above by exposing acetaminophen
were dose and duration dependent.
Exposure to greater doses and
for longer durations increased the effects on brain tissues and
behavior.”
But he does not mention that Rigobello 2021’s one
significant GSH finding only occurred at the lower dose -- the
opposite of a dose-response.
That study’s authors note that the
“non-monotonic relationship observed . . . may be a consequence
of an adaptive response[, however,] this is a speculative
hypothesis that warrants future studies.”
Id. at 5.
Similar issues arise in Dr. Cabrera’s analysis of the final
gap in the AOP’s causal chain -- that is, whether this causal
pathway can lead to ADHD and ASD.
Dr. Cabrera cites many
studies of animal behavior in support of this causal link.
behavioral outcomes measured by these studies are highly
variable and of contested translational validity, i.e.,
117
The
scientists disagree over whether the outcomes measured are
indicative of clinically relevant traits in humans. 64
For
example, scientists place rodents in compartments containing
marbles atop bedding and measure how many marbles the rodent
buries; theoretically, an increase in the number of marbles
buried is indicative of repetitive and restrictive behaviors
associated with ASD in humans.
Another test places a rodent in
a central chamber connected to two other chambers: one with an
object and one with another rodent.
Scientists then measure the
amount of time spent exploring the cage with the ‘social peer’
compared to the time in the cage with the object.
Another
outcome measured is pup ultrasonic vocalizations, where a young
rodent is separated from its mother, and the quantity and
quality of its calls are recorded.
As with the oxidative stress marker studies, Dr. Cabrera
presents isolated findings from behavioral studies in his weight
of the evidence analysis without reconciling inconsistent
findings.
For example, he states that Baker 2023 provides
“clear evidence” of impaired social behavior.
In fact, the
findings of Baker 2023, which measured dozens of outcomes, are
much more mixed.
For example, pup ultrasonic vocalizations were
See, e.g., Silverman et al., Reconsidering Animal Models Used
to Study Autism Spectrum Disorder: Current State and Optimizing
Future, 21(5) Genes Brain Behav. e12803 (2022).
64
118
measured on four days.
The authors found one significant change
(an increase in vocalizations rather than the expected decrease)
in males on postnatal day 8.
Id. at 4.
But there were no
significant changes in vocalizations among males on the other
three days or among females on any day.
Id.
Another study, Harshaw 2022, 65 is presented as “clear
evidence of impaired social-emotional and repetitive behaviors.”
But the authors of that study, which also found a variety of
potentially inconsistent results, stated that “[a] key
implication of our findings is that no simple conclusion
regarding the relative safety vs. danger of [acetaminophen]
early in life is yet possible.”
Id. at 13.
Further, some animal behavior studies relied upon by Dr.
Cabrera measure the acute effects of acetaminophen administered
to adult rodents and are thus only peripherally relevant.
e.g., Ishida 2007, 66 Gould 2012. 67
See,
Notably, Dr. Cabrera takes
Harshaw & Warner, Interleukin-1B-induced Inflammation and
Acetaminophen During Infancy: Distinct and Interactive Effects
on Social-Emtional and Reptetitive Behavior in C57BL/6J Mice,
220 Pharmacology, Biochemistry and Behavior e173463 (2022).
65
Ishida et al., Effect of Acetaminophen, a Cyclooxygenase
Inhibitor, on Morris Water Maze Task Performance in Mice, 21(7)
J. Psychopharmacology 757 (2007).
66
Gould et al., Acetaminophen Differentially Enhances Social
Behavior and Cortical Cannabinoid Levels in Inbred Mice, 38
Prog. Neuropsychopharmacology Biol. Psych. 260 (2012).
67
119
issue with Zhao 2017’s 68 use of adult rats but not with Ishida
2007’s or Gould 2012’s, perhaps because unlike those two
studies, Zhao 2017 found that acetaminophen may in fact
“alleviate cognitive impairment” due to its “antioxidant and
anti-inflammatory properties.”
Id. at 13.
Dr. Cabrera’s
dismissal of Zhao 2017 as an “[i]inadequate study of
developmental toxicity” and simultaneous branding of Ishida 2007
and Gould 2012 as “clear evidence” of learning deficits and
repetitive behavior, respectively, is an example of “cherrypick[ing] those findings that support his conclusions while
failing to note that they also suffer from the same weaknesses
as the studies he disregards.”
Daniels-Feasel, 2021 WL 4037820,
at *9.
Thus, Dr. Cabrera does not reliably fill two critical gaps
in his application of the adverse outcome pathway construct.
These gaps are therefore fatal to his general causation opinion
to the extent it relies on the adverse outcome pathway analysis,
because there is “too great an analytical gap between the data
and the opinion proffered.”
Joiner, 522 U.S. at 146.
But the
above issues are also emblematic of several overarching
methodological flaws in Dr. Cabrera’s weight of the evidence
Zhao et al., Acetaminophen Attenuates LipopolysaccharideInduced Cognitive Impairment Through Antioxidant Activity, 14 J.
Neuroinflammation 17 (2017).
68
120
analysis: cherry-picking isolated findings, ignoring
inconsistent findings, and disregarding limitations expressed by
a study’s authors as well as generally accepted statistical
principles.
Cherry-picking of isolated findings is of particular
concern here given that most of the studies measured many
markers of oxidative stress and behavioral outcomes at once and
many did not correct for multiple comparisons.
“Repeated
testing complicates the interpretation of significance levels”
because “[i]f enough comparisons are made, random error almost
guarantees that some will yield [significant] findings, even
when there is no real effect.”
RMSE at 256.
When studies did
correct for multiple comparisons and as a result found no
significant effects, for example in Saad 2016, 69 Dr. Cabrera
argues that the authors should not have corrected for multiple
comparisons.
Dr. Cabrera cites an article from the American
Statistical Association on the strengths and weaknesses of
overreliance on statistical significance, 70 but that article does
Saad et al., Is There a Causal Relation Between Materanl
Acetaminophen Administration and ADHD?, 11(6) PLoS One e0157380
(2016). Saad 2016 concluded that “[o]ur results do not support
a causal relationship” and thus “[r]esults of epidemiological
studies may be due to confounding factors that were not
accounted for.” Id. at 9.
69
Wasserstein & Lazar, The ASA Statement on p-Values: Context,
Process, and Purpose, 70 The American Statistician 129 (2016).
70
121
not take issue with multiple comparison corrections at all.
More importantly, it is the role of the district court to
“function as a gatekeeper; it is not for the courts to be the
pioneers, forging new trails in scientific thinking, especially
when that means departing from well-established research
principles, such as the principle of statistical significance.”
In re Zoloft (Sertraline Hydrochloride) Products Liability
Litigation, 26 F. Supp. 3d 449, 456 (E.D. Pa. 2014).
Thus, Dr. Cabrera’s general causation opinion is
inadmissible under Rule 702, as his biological mechanism opinion
based on oxidative stress.
His proposed testimony regarding
endocannabinoid disruption is far less developed than his
oxidative stress opinion.
XII. Dr. Hollander
Dr. Eric Hollander has provided an amended expert report of
June 22, 2023, and a rebuttal report dated July 28.
He was
deposed on August 9.
Dr. Hollander is a psychiatrist who specializes in
neuropharmacology and neuropsychiatry.
He received his M.D.
from SUNY Downstate Medical College, Brooklyn, New York in 1982.
He is a Professor of Psychiatry and Behavioral Sciences and the
Director of the Autism and Obsessive Compulsive Spectrum Program
at the Psychiatry Research Institute of Montefiore-Einstein at
122
Albert Einstein College of Medicine and Montefiore Medicine in
the Bronx.
He is Chair of the Board of Directors of the
International College of Obsessive Compulsive Spectrum
Disorders.
He currently serves as the Director of the Spectrum
Neuroscience and Treatment Institute.
He has published more
than 500 peer-reviewed papers and served as an editor for 20
books, including the textbook Autism Spectrum Disorders.
Dr. Hollander was asked by plaintiffs’ counsel to opine
about “the interconnectedness of various neurodevelopmental
disorders, including [ASD and ADHD]”; whether the scientific
evidence regarding the association between prenatal exposure to
acetaminophen and NDDs “informs the question of whether prenatal
exposure” to acetaminophen can “cause” ASD and ADHD; and whether
there are “plausible biological mechanisms” to explain how
acetaminophen “can cause” ASD and ADHD.
As reflected in his initial report, Dr. Hollander was not
asked to and does not (initially) opine that acetaminophen
causes ASD or ADHD, that it is appropriate to conduct a
transdiagnostic Bradford Hill analysis to answer that question,
or that Drs. Baccarelli and Cabrera properly structured their
transdiagnostic analyses.
Instead, in response to the questions
posed to him, he opines that ASD and ADHD are “highly
heterogenous” both in terms of etiology and presentation and do
123
not have a single cause or risk factor.
He explains that they
do, however, overlap with each other and other NDDs.
He adds
that, because of this overlap, transdiagnostic processes can
provide valuable insight.
Speaking from his extensive
experience as a treating psychiatrist, he opines that clinicians
must take a transdiagnostic approach in their assessments of
patients, because without such an approach “similarities in
behavioral profiles between [ASD and ADHD] disorders could lead
to challenges in both the diagnosis and intervention efforts.”
Dr. Hollander defines a transdiagnostic process as a
“mechanism that underlies and connects a group of disorders that
transcends traditional diagnostic boundaries.”
He opines that
based on the interconnectedness of NDDs, including ADHD and ASD,
“it is appropriate to review the body of evidence that measures
symptoms of neurodevelopmental disorders and to not limit the
analysis to studies that focus on ASD and ADHD as specified
outcomes when evaluating the potential causal association
between prenatal [acetaminophen] exposure and ASD and ADHD in
offspring.”
Dr. Hollander opines as well that there are
“multiple, plausible mechanisms of action to explain how
[acetaminophen] can impact fetal brain development and lead to
neurodevelopmental disorders in offspring.”
124
Dr. Hollander’s rebuttal report, unlike his initial report,
includes a Bradford Hill analysis and a general causation
opinion.
During his deposition, Dr. Hollander confirmed that
the first time he conducted a Bradford Hill analysis was in his
rebuttal report.
Holl. Dep. at 29:12; 71:15-21.
A rebuttal
report generally provides an expert the opportunity to respond
to criticisms of the original report by the other experts or
provide an update should new science have emerged in the
interim.
A rebuttal report is not the proper avenue to
introduce entirely new analyses or opinions. 71
Nevertheless, the
Court will assess the reliability of the opinion offered in the
rebuttal report after assessing the reliability of the initial
report.
The defendants argue that Dr. Hollander’s proposed
testimony is inadmissible insofar as he seeks to transform a
simple observation that ASD and ADHD can have overlapping
features “into a blank check to treat studies of these
conditions (indeed, virtually all neurodevelopmental disorders)
interchangeably” and because it fails to address critical
evidence or account for the limitations of studies on which he
relies heavily.
They add that his untimely Bradford Hill
The plaintiffs relied at oral argument on the Bradford Hill
analyses conducted by Drs. Baccarelli and Cabrera.
71
125
analysis should be stricken because, inter alia, he misstates
basic epidemiological principles and was insufficiently familiar
with “the building blocks of his own opinions.”
The defendants
are correct.
As for Dr. Hollander’s opinion regarding evidence of a
biologically plausible mechanism, it is relatively cursory and
suffers from the same critical gaps as Dr. Cabrera’s analysis.
For instance, Dr. Hollander misleadingly references Ghanem
2016’s 72 “finding that NAPQI is generated in the brain.”
That
publication is not a study but rather a comprehensive literature
review that concluded that, while toxic doses of acetaminophen
“promote oxidative stress and produces damage to different cell
types in the brain . . . this should be the subject of further
investigations to clearly discriminate between liver-driven
versus true in situ adverse effects of APAP in brain.”
130.
Id. at
The authors stated it was “very important to point out
that additional investigations on this subject are needed to
define the pathways mediating APAP toxicity in the brain.”
Id.
Most strikingly, they also “want[ed] to re-emphasize that there
is sufficient and convincing evidence that APAP at low doses has
a protective effect in the brain.”
Id.
Ghanem et al., Acetaminophen; From Liver to Brain: New
Insights Into Drug Pharmacological Action and Toxicity, 109
Pharmacol. Res. 119 (2016).
72
126
A.
Transdiagnostic Approach
It bears emphasizing that the transdiagnostic Bradford Hill
analysis undertaken by Drs. Baccarelli and Cabrera is not a
methodology that has been subjected to peer review and
publication either generally or as applied to ASD and ADHD. 73
It
is not a methodology that has been tested; it has no established
error rate or published standards.
Accordingly, Dr. Hollander
plays a critical role for the plaintiffs.
They rely on Dr.
Hollander to give his imprimatur to the transdiagnostic Bradford
Hill analysis of causation applied by their other experts.
His
reports do not do so.
As already described in connection with the discussion of
Drs. Baccarelli and Cabrera, their analyses do not separately
address the complexity of the universe of ASD studies and that
of ADHD studies and then examine whether a combined analysis can
and should be done.
Nor do their Bradford Hill analyses confine
themselves to studies that relate to diagnoses of ASD and ADHD.
Instead, their single transdiagnostic analysis relied as well on
studies of symptoms that reflect many endpoints relevant to NDDs
One meta-analysis, Alemany 2021, did reference several
Bradford Hill factors in passing. That publication’s cursory
reference to Bradford Hill factors is not a sufficient basis for
the plaintiffs’ contention that a transdiagnostic Bradford Hill
can reliably support a general causation opinion for ASD and
ADHD.
73
127
generally, including to ASD and ADHD.
But, again, there was no
separate analysis of, for instance, the consistency among the
findings in those symptom studies, the strengths of any
association, or any other relevant Bradford Hill factor, before
the results of those studies were combined with the conclusions
they drew from studies of ASD and ADHD.
Instead, the
unstructured approach adopted by the plaintiffs’ experts
permitted cherry-picking, allowed a results-driven analysis, and
obscured the complexities, inconsistencies, and weaknesses in
the underlying data.
No expert presented by the plaintiffs -- not Dr.
Baccarelli, Dr. Cabrera, or Dr. Hollander –- describes how to
structure a reliable transdiagnostic Bradford Hill analysis,
either generally or specifically to assess whether in utero
exposure to acetaminophen causes ASD and/or ADHD.
Dr. Hollander
in particular has not suggested whether a structure akin to that
just outlined or some other structure altogether should be used
to create a reliable transdiagnostic analysis of causation.
Dr.
Hollander’s opinions are rendered on a far more abstract plane.
Dr. Hollander opines in his initial report that “there is
significant overlap and co-morbidity between the symptoms of ASD
and ADHD, and there may be overlap in the underlying biology
that accounts for common features that supersede traditional
128
diagnostic categories.”
That opinion -- that there may be
overlap in the underlying biology of some of the symptoms of the
disorders, which may be relevant to a causal analysis -- appears
to be a reliable assessment of the literature cited by Dr.
Hollander.
What it is not, however, is the linchpin that allows
the plaintiffs’ Bradford Hill analyses to be admitted.
Dr. Hollander observes, unremarkably, that traditional
diagnostic categories do not always reflect the constellation of
symptoms that he sees in his patients.
Dr. Hollander then cites
Barch 2020 74 for the proposition that biological factors behind
symptoms “cut across traditional diagnostic boundaries, as
demonstrated by recent transdiagnostic research that shows
shared neural, genetic physiological, structural, and
psychological traits.”
Barch 2020 is a short editorial by a
Washington University faculty member that discusses the promise
and potential pitfalls of transdiagnostic research.
As
described by Barch, the focus on transdiagnostic research is
whether neural alterations in the human brain may be associated
with broad risk factors for psychopathology, cutting across
individual diagnostic categories.
Although the editorial
focuses on schizophrenia, bipolar disorder, major depression,
Barch, What Does it Mean to be Transdiagnostic and How Would
We Know?, 177(5) Am. J. Psychiatry 370 (2020).
74
129
anxiety disorders, and substance disorders -- not NDDs -- it
does note that “some dimensions of disordered behavior cut
across traditional diagnostic boundaries, and thus the
biological factors that align with these dimensions also likely
cut across traditional diagnostic boundaries.”
Id. at 370.
Of particular relevance to the Rule 702 motions at issue
here, Barch is careful to “raise[] the question of what we mean
by transdiagnostic and how we should define and determine what
neural or psychological impairments are transdiagnostic.”
Id.
As regards “examining whether a particular symptom or behavior
dimension relates to a particular neurobiological factor
‘transdiagnostically,’” Barch states that “strong claims about
transdiagnostic relationships would seem to require
demonstrating that such dimensional relationships hold within
diagnostic categories as well as across diagnostic categories,
or at least that the dimensional relationships do not differ
across diagnostic groups.”
Id. at 371.
Barch, therefore,
provides no support for finding that the transdiagnostic
Bradford Hill analysis undertaken by the plaintiffs’ experts is
accepted by the scientific community.
As further support for his contention that a
transdiagnostic approach will become more common and is helpful
to understanding the biology behind overlapping disorders, such
130
as ASD and ADHD, Dr. Hollander cites Vandewouw 2023. 75
Vandewouw
2023 is a case-control study that used neuroimaging data to
explore whether certain functional brain characteristics could
be linked to behaviors implicated in neurodevelopmental
conditions.
Vandewouw 2023 found that “homogeneity in the
neurobiology of neurodevelopmental conditions corresponded to
behavior, not diagnostic category.”
Id. at 1.
The participants
included children who had been diagnosed with ASD, ADHD, and
obsessive-compulsive disorder between the ages of 5 and 19, and
others who were developing “typically.”
The authors found
subgroups with similar biology that differed significantly in
intelligence and hyperactivity and impulsivity problems but did
not show consistent alignment with the diagnostic categories.
Id. at 10.
Further, the children without neurodevelopmental
disorders “were also spread across all identified brain-based
subgroups, emphasizing that an overlap in neurobiology exists
not only across conditions, but also across typical
development.”
Id. at 11.
The authors suggest that their
findings should “promot[e] a shift in the research community
away from classic case-control designs that rely on diagnostic
Vandewouw et al., Identifying Replicable Subgroups in
Neurodevelopmental Conditions Using Resting-State Functional
Magnetic Resonance Imaging Data, 6(3) JAMA Network Open: e232066
(2023).
75
131
categories, which have increasingly been shown not to reflect
distinct biological and phenotypic constructs.”
Id. at 12.
Vandewouw 2023 also indicates, as Dr. Hollander opines, that “a
holistic and transdiagnostic approach that uses continuous
measures of behavior is necessary to fully understand the highly
heterogenous conditions of ASD and ADHD.” 76
And finally, as
Vandewouw 2023 observes, transdiagnostic research may be
“promoting a shift in the research community” towards new types
of study design that help “target treatments and interventions.”
Id.
The findings of Vandewouw 2023 are surely relevant to the
research community’s prioritization of topics and choice of
study designs, today and in the future.
It may be that as more
transdiagnostic research is done, scientists will be able to
connect specific neurobiology with specific symptoms, with
resulting implications for both treatment and causal analyses.
What Vandewouw 2023 does not do, though, is transform the
observation that ASD and ADHD share some symptoms and are
sometimes co-morbidities into carte blanche for conducting a
single causal analysis for these two disorders.
Nowhere in his
Dr. Hollander misstates the findings of Vandewouw 2023,
stating that the study found differences not only in
hyperactivity and impulsivity but also “externalizing behaviors,
conduct problems, [and] emotion regulation difficulties.”
76
132
initial report does Dr. Hollander state that proof of a causal
relationship between exposure to acetaminophen and development
of ADHD suffices as proof of a causal relationship between
exposure to acetaminophen and development of ASD, or vice
versa. 77
And, as Dr. Hollander noted in his deposition, he does
not opine that “if acetaminophen is associated with
hyperactivity, then it must also cause ASD and ADHD.”
Holl.
Dep. at 339:24-340:3.
Thus, Dr. Hollander’s opinion regarding a transdiagnostic
analysis is largely irrelevant.
It is insufficiently tethered
to the transdiagnostic Bradford Hill analyses presented by the
plaintiffs’ experts to support their admissibility, and it is
too undeveloped to be otherwise admissible.
B.
Bradford Hill Analysis
In his rebuttal report, Dr. Hollander presents a Bradford
Hill analysis.
That analysis is inadmissible.
The plaintiffs
have not shown that it reflects Dr. Hollander’s own work.
Moreover, it suffers from the same deficiencies that appear in
Dr. Baccarelli’s Bradford Hill analysis, which it largely
In his rebuttal report, Dr. Hollander states that “[i]f
acetaminophen exposure during pregnancy causes hyperactivity in
ASD and ADHD individuals, and if hyperactivity is a common
feature of ADHD and ASD, then acetaminophen causes ADHD and
ASD.” At his deposition, however, he walked back this
statement. Holl. Dep. at 336:3-340:3.
77
133
mimics.
Finally, because Dr. Hollander rushed to assemble a
Bradford Hill analysis, it contains so many errors in its
description of the relevant research that it is inherently
unreliable.
Dr. Hollander’s Bradford Hill analysis was created in the
small window of time permitted him to file a rebuttal report.
He did not therefore have months to prepare his own, independent
analysis.
It does not appear that he independently reviewed the
body of relevant literature or that he created a written
analysis of the studies he mentions.
He readily acknowledged in
his deposition that he relied upon the assessment of the
epidemiology presented in Dr. Baccarelli’s’ expert report.
At
the deposition, Dr. Hollander looked at a summary chart created
by Dr. Baccarelli nearly every time defense counsel asked him
about a study referenced in his report.
Dr. Hollander’s unfamiliarity with the underlying
epidemiological studies upon which he claims to have relied was
stark.
For example, his rebuttal report states that several
high-quality “meta-analyses” show a positive association between
prenatal exposure to acetaminophen and ASD and ADHD, and then
lists studies that are not meta-analyses. 78
Later, when he does
Dr. Hollander lists Liew 2014, Avella-Garcia 2016, and Ystrom
2017.
78
134
cite five actual meta-analyses, in his section on the strength
of association factor, he states that the association between
acetaminophen exposure and “ASD and ADHD has been found
consistently in meta-analyses and systematic reviews.”
He cites
Masarwa 2018, Ricci 2023, Gou 2019, Kim 2020, 79 and Alemany 2021.
But Gou 2019 and Kim 2020 only addressed ADHD.
Ricci 2023 found
the literature on ASD too sparse and heterogenous to perform a
meta-analysis -- implicitly critiquing Alemany 2021’s approach.
And the authors of Masarwa 2018 published another study in 2020,
Masarwa 2020, determining their 2018 results were due to
unmeasured confounding and exposure misclassification, a
development Dr. Hollander failed to mention in his report.
The deficiencies in Dr. Hollander’s Bradford Hill analysis
no doubt reflect the limited time he had to prepare his opinion.
That excuse, however, does not render his Bradford Hill analysis
admissible.
His analysis fails to pass muster under Rule 702
and Daubert.
XIII.
Dr. Pearson
Dr. Brandon Pearson submitted an expert report of June 21,
2023.
He supplemented the report on July 14.
report is dated July 28.
His rebuttal
He was deposed on August 11.
Kim et al., Environmental Risk Factors, Protective Factors,
and Peripheral Biomarkers for ADHD: An Umbrella Review, 7(11)
Lancet Psych. 955 (2020).
79
135
Dr. Pearson is an Assistant Professor of Environmental
Health Sciences at Columbia University.
He received his Ph.D.
in Behavioral Neuroscience at the University of Hawaii and in
2015 completed a postdoctoral fellowship at the University of
North Carolina at Chapel Hill.
During the fellowship he
shadowed clinicians assessing ASD.
In 2017, he established an independent research laboratory
at Columbia focused on neurotoxicology.
Neurotoxicology focuses
on understanding how chemicals, drugs, and environmental factors
can impact the structure and function of the nervous system.
Dr. Pearson’s laboratory conducts studies using cell cultures,
fish and mice, human observational cohorts, and human
biospecimens.
He has experience extrapolating data from animal
studies to human populations.
He is a co-investigator and
laboratory director of the Columbia Center for Children’s
Environment Health.
He has published 40 peer-reviewed articles.
Dr. Pearson has studied acetaminophen toxicity for
approximately ten years, largely through research with mice.
He
has performed inter-disciplinary work with Dr. Baccarelli and
Canadian researchers on a birth cohort analysis of meconium
acetaminophen levels and ADHD outcomes.
Dr. Pearson was asked to address the following issues: is
the hypothesis that there is a causal association between in
136
utero exposure to acetaminophen and NDDs, including ASD and
ADHD, “consistent with existing biological knowledge and
preclinical literature;” and “[i]s there sufficient preclinical
evidence to conclude that in utero exposure to acetaminophen can
cause NDDs, including ASD and/or ADHD?”
Dr. Pearson’s report
“does not give an opinion on epidemiological methods,
confounding, clinical dose, or human cases” except as relates
directly to the preclinical findings he discusses.
Scientists have designed studies of animals in order to
test hypotheses and to test drug interventions.
Examples of the
endpoints studied in animal models are discussed supra in
relation to Dr. Cabrera’s report.
Dr. Pearson explains that the
animal models of ADHD are less developed than animal models of
ASD because the relevant ADHD animal studies have been used
principally to test ADHD treatments.
Through genetic
manipulation and selective breeding, rodent species have been
created as “genetic models of ADHD-like phenotypes.”
They
display behaviors characterized as hyperactive (such as
increased locomotion), impulsive (e.g., choosing a smaller but
immediate reward instead of a larger, delayed award) and
inattentive (e.g., after learning a display-reward task, failing
at the task when the duration of the display decreases).
137
The core of Dr. Pearson’s initial report describes studies
of mice and rats.
From that review, Dr. Pearson opines that
preclinical studies show that acetaminophen (1) causes
neurodevelopmental disruption; (2) is capable of causing
cascading changes in central nervous system structures,
molecular pathways, and neurotransmission in offspring exposed
in utero; and (3) disrupts neurodevelopment via multiple
mechanisms, including oxidative stress, DNA damage, and
endocannabinoid system disruption.
He also opines that the
weight of the preclinical studies supports the biological
plausibility of an association between in utero exposure to
acetaminophen and NDDs including ASD and ADHD because these
preclinical studies account for confounding factors that may be
present in epidemiological studies.
The defendants argue that Dr. Pearson’s reports must be
stricken as fundamentally unreliable.
Because animal studies
require us to assume that the chemical of interest behaves
similarly in a different species, expert opinions relying on
animal studies “may only be admitted where the gap between what
[they] reasonably imply and more definitive scientific proof of
causality is not too great.”
at *14 (citation omitted).
Daniels-Feasel, 2021 WL 4037820,
Beyond that impediment, the
defendants argue that Dr. Pearson’s methodology is flawed.
138
They
point to the difference between the essential features of ASD
and ADHD described in the DSM and the modeled animal behaviors
and his admission that the studies point in contradictory
directions, arguing that his opinions rely on cherry-picking
those that support his thesis.
Dr. Pearson states early in his report that data is
reliable when “there is a sufficient amount of quality data that
are internally consistent.”
He notes that it is an objective of
integrating lines of evidence, “[i]n case of inconsistencies, to
try to understand and explain the reasons for them, possibly
deciding if more than one answer to the formulated problem is
plausible.”
As described above, the preclinical data on acetaminophen’s
effects on animal biology and behavior contain many
inconsistencies.
Dr. Pearson does acknowledge that the studies
he has surveyed point in a variety of directions and are often
at odds with each other.
Indeed, throughout his report, Dr.
Pearson describes many of the limitations and inconsistencies in
the data.
Critically, however, in drawing his conclusion, Dr. Pearson
takes the position that the “heterogeneity of the results,” with
even individual studies showing “mixed or bidirectional
results,” is “not a reason to dismiss the effects” of
139
acetaminophen shown in the studies.
He opines, without
citation, that “neurodevelopmental perturbation of prenatal APAP
can manifest in various ways in terms of directionality” -- that
is, that any change in behavior provides evidence of causation
regardless of the direction of the change.
Dr. Pearson insists
that the “heterogeneity of ultimate endpoints seen in the
preclinical studies . . . makes sense given the context of the
extremely delicate cascading cellular processes disturbed by
APAP use.”
“[N]othing in either Daubert or the Federal Rules of
Evidence requires a district court to admit opinion evidence
that is connected to existing data by only the ipse dixit of the
expert.”
Joiner, 522 U.S. at 146.
Dr. Pearson’s decision to
confine his late-in-the-game, ipse dixit assertion that
heterogeneity and outright inconsistency of results don’t
ultimately matter to a single paragraph in the conclusion
section is concerning.
It also presents a deviation from the
principles of scientific reliability Dr. Pearson promotes
earlier in his report -- a telltale indication that his ultimate
opinion does not “reflect[] a reliable application of the
principles and methods to the facts of the case.”
Rule 702.
The result is that “there is simply too great an analytical
gap between the data and the opinion proffered.”
140
Joiner, 522
U.S. at 146.
Dr. Pearson’s expert testimony is thus
inadmissible under Rule 702.
XIV. Dr. Louie
Dr. Stan Louie filed an amended expert report on June 21,
2023, and a reply report on July 28.
He was deposed on August
7.
Dr. Louie is a Professor of Clinical Pharmacy at the
University of Southern California, Alfred Mann School of
Pharmacy and Pharmaceutical Sciences.
He received his Doctor of
Pharmacy degree from the University of California, San
Francisco, School of Pharmacy.
His research currently includes
drug development for inflammatory and immune-mediated diseases.
Dr. Louie has also focused on developing new drugs or new
chemical entities.
He is the founder and President of
StimuFact, Inc., a consulting company that advises clients on
drug development.
He is a co-founder of start-up companies in
the pharmaceutical industry.
Dr. Louie was asked to determine the “dose/duration” at
which prenatal exposure to acetaminophen increases the risk of
developing ASD and ADHD.
Dr. Louie opines that acetaminophen
taken for at least 28 days over the course of a pregnancy, for a
total of between 18.2 grams and 112 grams, increases the risk of
developing ASD and ADHD in offspring two-fold.
141
He explains that
the reason for this increased risk is that acetaminophen can
deplete glutathione (“GSH”), thereby causing oxidative stress
systemically and in the brain and that one its metabolites,
NAPQI, and its adducts can induce oxidative stress, immune
reactivity, and inflammation.
To reach these opinions, Dr. Louie did not conduct any
research of his own; he relied on his review of others’ studies.
He did not perform either a Bradford Hill or a weight of the
evidence analysis.
Instead, he reviewed first the literature
provided him by plaintiffs’ counsel, and then the literature
resulting from his own “comprehensive” literature search.
He
located seven studies with findings about the duration of
exposure and elevations in risk.
Of these, he assigned the
greatest weight to Brandlistuen 2013.
He concluded that a wider
body of literature also supported his conclusion.
The defendants contend that Dr. Louie’s opinions are
unreliable.
For one thing, as he admitted at his deposition,
his epidemiological analysis of causation depends entirely on
Dr. Baccarelli’s analysis, and therefore must be excluded if Dr.
Baccarelli’s analysis fails to survive.
Moreover, they contend,
his opinions are not supported by the studies on which he
reports he relied.
142
The plaintiffs have not shown that Dr. Louie’s expert
reports are admissible pursuant to Rule 702.
His opinion of
causation must be stricken since it relies on Dr. Baccarelli’s
expert reports.
The plaintiffs acknowledge that Dr. Louie was
not asked and did not seek to perform a Bradford Hill or other
general causation analysis.
But, even if another expert had admissible evidence on the
issue of general causation, the plaintiffs have failed to show
that Dr. Louie has presented any admissible opinion about
dose/duration.
His opinions are inadmissible due to their
omissions and their misstatement of the evidence on which he
purports to rely.
Dr. Louie’s reports fail to address several obvious issues.
He does not explain when in the course of a pregnancy the 28-day
use of acetaminophen creates a risk for the offspring, for
instance, whether it arises in a particular trimester or each
trimester.
Nor does he distinguish between use for consecutive
days or sporadic use over the duration of the entire pregnancy.
He simply opines that the cumulative use of acetaminophen for 28
days over the course of nine months creates a two-fold risk of
both ASD and ADHD.
He does not provide any basis for finding
that such an unbounded use of acetaminophen poses any risk.
143
The plaintiffs argue that there is nothing unscientific
about lumping together all pregnant women who use acetaminophen
for more than 28 days at any point during the nine months of
their pregnancies.
But, Dr. Louie provides no scientific basis
for doing so, and it was his burden to explain why such
aggregations of behavior are scientifically sound.
Instead, it
appears that he selected this metric because the few studies
that have included data on duration of use chose to divide their
study participants into two categories reflecting use of fewer
or more than 28 days.
This does not suffice to provide a
scientifically sound basis for a causation opinion or a
dose/response opinion.
As significantly, Dr. Louie’s opinion is not supported by
the seven studies on which he purports to have relied.
seven studies he identifies are:
The
Brandlistuen 2013, Liew 2014,
Liew 2016, Vlenterie 2016, 80, Ystrom 2017, Gervin 2017, 81 and
Gustavson 2021.
During the briefing on these motions, the
plaintiffs appear to have abandoned any reliance on two of these
studies:
Vlenterie 2016 and Gervin 2017.
Vlenterie et al., Neurodevelopmental Problems at 18 Months
Among Children Exposed to Paracetamol in Utero: A Propensity
Score Matched Cohort Study, 5(6) Int. J. Epidemiol. 1998 (2016).
80
Gervin et al., Long Term Prenatal Exposure to Paracetamol is
Associated with DNA Methylation Differences in Children
Diagnosed with ADHD, 9 Clin. Epigenetics 77 (2017).
81
144
Dr. Louie represents that Brandlistuen 2013, Ystrom 2017
and Gustavson 2021 found that acetaminophen exposure beyond 28
days showed a two-fold increased risk for childhood “ADHD and
ASD diagnosis.”
diagnosis.
Not so.
None of these studies involved an ASD
Moreover, while he placed the “greatest weight” on
Brandlistuen 2013, a sibling control study, it did not involve
even an ADHD diagnosis.
Brandlistuen 2013 evaluated psychomotor, behavior, and
temperament problems using the ASQ, CBCL, and EAS questionnaires
for evaluating children who were, at the time of the study,
three years of age.
Id. at 1708.
The authors of Brandlistuen
2013 noted that future studies should seek to include clinical
diagnoses.
Id. at 1711.
Nor is Brandlistuen 2013 a reliable
source for measuring risk as of 28 days of exposure.
As
described earlier in this Opinion, the article reports on a
study of the MoBa cohort, which collected data from mothers at
weeks 17 and 30 of their pregnancies, and 6 months after the
child’s birth.
Id. at 1703.
The mothers indicated whether they
had used acetaminophen and other medications to treat various
ailments, such as fever and back pain.
The women reported the
number of days they had used the drug during each four-week
period within the pregnancy.
Id. at 1704.
The study then
divided all mothers with two or more children into two groups:
145
those who used acetaminophen for 27 days or less and those who
used it for 28 days or more.
Thus, mothers with widely varying
exposures were grouped together in the latter category.
The
authors note that they could not take dose into consideration
“because it was not reported, and we could not distinguish
between continuous use for 28 days or more and long-term
sporadic use across pregnancy because the number of mothers
reporting continuous use was too small.”
Id. at 1712.
Also, as already described in this Opinion, the other two
studies come with significant caveats.
In Ystrom 2017, because
the paternal use of acetaminophen was found to be associated
with ADHD, the authors warned that “the causal role of
acetaminophen in the etiology of ADHD can be questioned.”
at 7.
Id.
While Gustavson 2021 found that there was a two-fold
increased risk of receiving an ADHD diagnosis if the child was
born to a mother who used acetaminophen 28 days or more during
the pregnancy, that increased risk “was no longer present” after
adjusting for the sibling mean.
Id. at 10.
The authors
suggested that maternal long-term use of acetaminophen may be a
marker for increased familial risk of ADHD.
Id.
Dr. Louie attempted to salvage his reliance on Gustavson
2021’s pre-sibling-control result at his deposition, by
explaining that he gave virtually no weight to the sibling146
control results because, as he stated, “I don’t know where I
read it, but it was the number of patients that were evaluated
were relatively low.”
Louie Dep. at 119.
He admitted he did
not read the supplemental materials of Gustavson 2021.
116-118.
Id. at
The authors of Gustavson 2021 do note that because
only discordant siblings contribute to detecting associations in
sibling control models, even with the large MoBa cohort,
“reduced power is reflected in wide confidence intervals.”
at 5.
Id.
But the authors stated they were “not aware of any other
data that could be used to perform a more powered sibling
control study of prenatal acetaminophen exposure and ADHD,” id.,
and concluded that their sibling control results suggest that
the association “may at least partly be due to familial
confounding.”
Id.
at 8.
As the plaintiffs acknowledge, an
expert’s opinion may not exceed the limitations that authors
place on their own studies.
Thus, neither Ystrom 2017 nor
Gustavson 2021 supports Dr. Louie’s opinion that taking a
certain dose of acetaminophen or taking it more than 28 days
creates a two-fold risk for either ASD or ADHD.
A discussion of the remaining two studies would not
resurrect a reliable or admissible basis for Dr. Louie’s
opinion.
His biological mechanism opinion is inadmissible for
the same reasons discussed supra with respect to Dr. Cabrera’s
147
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