Summary of Teratology Studies:
MAJOR CONGENITAL ANOMALIES
Several cohort studies have found marginal evidence supporting an association of maternal use of acetaminophen during the first and second trimesters of pregnancy with congenital cryptorchidism. This includes 22,449 exposed male children in the Danish National Birth Cohort (hazard ratio=1.33, 95% confidence interval 1.00-1.77) (Jensen et al., 2010, 2011) and 3184 boys enrolled in a Dutch study (odds ratio=1.85, 95% confidence interval 1.02-3.37) (Snijder et al., 2012). A dose-dependent relationship was found between the occurrence of cryptorchidism and the frequency of maternal acetaminophen use during the first or second trimester of pregnancy in an independent study of 491 boys in Denmark and Finland (Kristensen et al., 2011).
The overall prevalence of congenital anomalies was no greater than expected among 26,424 children whose mothers used acetaminophen during the first trimester of pregnancy in the Danish National Birth Cohort (Rebordosa et al., 2008). However, an association was seen with congenital anomalies of the ear, face, or neck in this study (hazard ratio=1.82, 95% confidence interval 1.11-2.99). Congenital anomalies were observed 2.3 times more often than expected (95% confidence interval 1.0-5.4 times) in a Danish study of 55 infants whose mothers were given prescriptions for daily acetaminophen treatment during the first trimester of pregnancy or in the month before conception (Thulstrup et al., 1999). The distribution of congenital anomalies in this study did not indicate a causal link with acetaminophen.
No association with maternal acetaminophen use and congenital anomalies was found among the infants of 9989 mothers who used acetaminophen during the first trimester of pregnancy in multiple cohort studies (Jick et al., 1981; Aselton et al., 1985; Rosa et al., 1993).
The frequency of maternal use of acetaminophen during the first trimester or anytime during pregnancy was no greater than expected among children with congenital anomalies (11,610 cases), microcephaly (166 cases), cardiac (466 cases) and renal (192 cases) anomalies, neural tube defects (538 cases), and gastroschisis (286 cases) in multiple case-control studies (Zierler & Rothman, 1985; Shaw et al., 1998; Abe et al., 2003; Cleves et al., 2004; Feldkamp et al., 2010; Kerr et al., 2019; Weber et al., 2019).
However, marginal positive findings have been reported in some case-control studies. Maternal first-trimester acetaminophen use was more frequent than expected among infants with amniotic bands involving only the limbs (53 cases, odds ratio=2.1, 95% confidence interval 1.1-3.9) or involving the face or neural tube, with or without limb involvement (20 cases, odds ratio=3.4, 95% confidence interval 1.1-10.3) (Werler et al., 2003). An association with maternal use of acetaminophen during embryogenesis was observed among 601 infants with primary cleft palate (odds ratio=3.7, 95% confidence interval 1.1-12.0) but not among 1374 infants with isolated cleft lip with or without cleft palate in the Hungarian Case-Control Surveillance of Congenital Anomalies (Puho et al., 2007). Overall acetaminophen use during pregnancy has also been associated with a slightly increased risk of gastroschisis (216 cases, odds ratio=1.5, 95% confidence interval 1.1-2.2) (Werler et al., 2002).
The frequency of maternal use of acetaminophen during embryogenesis was greater than expected among infants with tetralogy of Fallot (59 cases, adjusted odds ratio=1.6, 95% confidence interval 1.1-2.3) (Marsh et al., 2014). This result may be due to chance because of the large number of phenotypic comparisons made.
ADVERSE PREGNANCY AND NEONATAL OUTCOMES
The use of acetaminophen during pregnancy was not associated with adverse perinatal outcomes, including preterm birth, low birth weight or low weight for gestational age in a meta-analysis of several large cohort and case-control studies (Castro et al., 2022). Furthermore, no increased risk of preterm birth or low birth weight among women with autoimmune disorders who used acetaminophen in pregnancy was reported in the MotherToBaby prospective cohort study (Killion et al., 2021). In other cohort and case-control studies, the prevalences of stillbirth, miscarriage, or amniotic bands were not increased among 80,652 women who used acetaminophen anytime during pregnancy (Pastore et al., 1999; Li et al., 2003; Rebordosa et al., 2009; Feldkamp et al., 2010; Smarr et al., 2019).
A 2019 observational study from the prospective German Embryotox cohort found that third trimester acetaminophen use was not associated with ductus arteriosus closure or fetal renal impairment in infants born to 604 women who used acetaminophen during the third trimester (Dathe et al., 2019). Although a case series analysis of 25 cases of fetal ductus arteriosus constriction or closure suggested that an association with maternal acetaminophen use during pregnancy was likely (Allegaert et al., 2019), the data were limited by inadequate descriptions of used analgesic medications and lacked detail in some cases on dose and timing of prenatal acetaminophen use.
Hepatoxicity and nephrotoxicity occur as complications of acetaminophen overdosage in adults. Similar effects have been observed among infants born to women who took large therapeutic or toxic doses of acetaminophen late in pregnancy (Aw et al., 1999; Wilkes et al., 2005). Fetal distress and fetal death have occurred in pregnant women who took hepatotoxic overdoses of acetaminophen in the second or third trimester (Rosevear & Hope, 1989; Thornton & Minns, 2012; Franko et al., 2013).
LONG-TERM HEALTH OUTCOMES
There is controversy over whether the limited positive associations that have been observed between maternal use of acetaminophen during pregnancy and asthma in the child reflect a causal relationship or result from incompletely controlled confounding due to maternal asthma or infections (Migliore et al., 2015).
Acetaminophen use during pregnancy has been associated with an increased risk of asthma/wheeze in children whose mothers used acetaminophen during pregnancy in multiple prospective and retrospective cohort studies (Sordillo et al., 2015; Liu et al., 2016; Magnus et al., 2016; Shaheen et al., 2019; Liew et al., 2021) but this association is not found in all investigations (Piler et al., 2018).
An elevated risk of childhood asthma was associated with gestational acetaminophen exposure in a meta-analysis that included 1,043,109 individuals (odds ratio=1.19, 95% confidence interval 1.12-1.27; p<0.00001) (Fan et al., 2017). This relationship remained significant when the sample was restricted to children with first trimester acetaminophen exposure only (odds ratio=1.21, 95% confidence interval 1.14-1.28). A 2021 analysis of six systematic reviews and three additional studies reported a maximum of a 1.5-fold increase in odds of asthma developing in acetaminophen exposed children (Singh et al., 2021).
In a record-linkage study from Taiwan, an increased prevalence of maternal acetaminophen use in pregnancy was reported among 2529 mothers of children affected with atopic dermatitis compared to mothers of unaffected children (Li et al., 2021). The associations were dose-dependent and strongest when acetaminophen exposure occurred in the first or second trimester or in all trimesters of pregnancy.
NEURODEVELOPMENTAL OUTCOMES
A growing number of studies and reviews have raised considerable public attention reporting associations of prenatal acetaminophen use and adverse childhood neurodevelopmental outcomes (Bauer et al., 2021). However, some investigators cautioned against an inference of causality based on inadequate evidence from the reported data (Liew & Ernst, 2021; Alwan et al., 2022; Damkier et al., 2022). It is important to note that the studies reported below suffer from serious biases, including variability in selection and adjustment of various potential confounders as well as issues with quality and validity of neurodevelopmental outcome definitions.
An increased risk of attention-deficit/hyperactivity disorder in children whose mothers used acetaminophen during pregnancy has been reported in numerous epidemiology studies (Liew et al., 2014; Thompson et al., 2014; Ystrom et al., 2017; Chen et al., 2019; Baker et al., 2020) and a 2019 meta-analysis of 244,940 mother-child dyads (pooled adjusted risk ratio=1.25, 95% confidence interval 1.17-1.34) (Gou et al., 2019). Third trimester exposure appeared to be related to a higher prevalence of attention-deficit/hyperactivity disorder childhood diagnoses. Several cohort studies have also reported associations of maternal acetaminophen use during pregnancy and increased odds of having a child on the autism spectrum (Avella-Garcia et al., 2016; Liew et al., 2016b; Ji et al., 2020). A meta-analysis of data from 132,738 mother-child pairs identified a modest increase for autism spectrum diagnoses in children born to mothers who used acetaminophen during pregnancy (risk ratio=1.19, 95% confidence interval 1.14-1.25) (Masarwa et al., 2018). The authors noted that this finding was likely influenced by uncontrolled confounding variables. Furthermore, a broad range of other cognitive and behavioral outcomes including conduct problems, reduced IQ scores, deficits in executive function, and oppositional defiant disorder symptoms have been associated with maternal use of acetaminophen during pregnancy (Liew et al., 2016a, c; Stergiakouli et al., 2016; Ruisch et al., 2018; Golding et al., 2020; Rifas-Shiman et al., 2020; Tronnes et al., 2020; Inoue et al., 2021). Delays in early communication and language development have also been documented in children prenatally exposed to acetaminophen (Vlenterie et al., 2016; Bornehag et al., 2018).
In contrast, results from several large population-based cohort studies demonstrated either no effect of acetaminophen on cognitive/behavioral performance or inconclusive results (Brandlistuen et al., 2013; Laue et al., 2019; Bertoldi et al., 2020; Tovo-Rodrigues et al., 2020).
OTHER NEURODEVELOPMENTAL OUTCOMES
An increased risk of cerebral palsy was found among children born to 90,952 mothers who used acetaminophen during pregnancy in the Danish National Birth Cohort and the Norwegian Mother and Child Cohort Study, but the association was of borderline statistical significance (adjusted odds ratio=1.3, 95% confidence interval 1.0-1.7) (Petersen et al., 2018).
ANIMAL TERATOLOGY STUDIES
Studies in pregnant mice and rats have shown no evidence of a teratogenic effect of acetaminophen treatment in doses similar to those used clinically in humans (Scialli et al., 2010). Similarly, mouse studies using human therapeutic levels of treatment found no adverse effect of maternal acetaminophen treatment on litter size (Iacob et al., 2019), offspring hyperkinetic behavior (Saad et al., 2016), and risk of allergic airway disease (Lee et al., 2015). In two independent studies however, reduced fetal weights and increased airway inflammation were observed in animals with a history of prenatal exposure (Karimi et al., 2015; Thiele et al., 2015). Alterations of several behavioral endpoints were observed among the offspring of pregnant rats treated with acetaminophen at a dose falling within the human therapeutic range, in an experimental study that suggests acetaminophen may be a developmental neurotoxicant (Klein et al., 2020).
Selected References:
(Each paper is classified as a review [R], human case report [C], human epidemiological study [E], human clinical series [S], animal study [A], or other [O].)
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