Prescription nonsteroidal anti-inflammatory drugs (NSAIDs) and miscarriage
FDA reviewed five observational studies that evaluated the risk of the spontaneous loss of a pregnancy before the 20th week with NSAID use.2-6 Miscarriage occurs in the general population at a frequency of about one in six pregnancies. Three retrospective case-control studies2-4 which included over 100,000 subjects reported a positive association between prescription non-aspirin NSAID exposure and miscarriage (adjusted odds ratio [aOR]=7.0, 95% confidence interval [CI]=2.8-17.7; aOR=3.4, 95% CI=0.9-12.8; and aOR=2.4, 95% CI=2.1-2.8). These findings are difficult to interpret due to methodologic limitations in the studies’ designs. For example, these studies did not identify the reason for NSAID use; women in these studies could have used NSAIDs for symptoms of miscarriage (i.e., cramping), so it could not be determined if NSAID use occurred before or after the onset of a miscarriage. In addition, these studies excluded potential NSAID users whose pregnancies ended in therapeutic (induced) abortion, possibly resulting in a finding of less NSAID use among controls compared to cases who experienced a miscarriage. Lastly, the studies did not consider the timing of study entry (i.e., the time during gestation when subjects were selected for the study). This is an important consideration given that the risk of miscarriage varies substantially by gestational age and, by definition, cannot occur after 20 weeks of gestation. In the absence of specific criteria, it cannot be determined whether the timing of study entry―and therefore risk of miscarriage at study entry―inherently differs with NSAID use.
Two other observational studies that included a total of 3,835 subjects were conducted in a prospective manner and were not subject to the same limitations in study design as the retrospective case-control studies above. However, these studies did not produce consistent results. One of the prospective cohort studies identified a positive association between prescription non-aspirin NSAID exposure and miscarriage, with an adjusted hazard ratio (aHR) of 1.8 (95% CI=1.0-3.2).5 The other prospective study evaluated the association between over-the-counter non-aspirin NSAIDs and miscarriage, and did not identify an increased risk (aHR=0.9, 95% CI=0.7-1.1).6
Based on our evaluation of these observational studies, we believe that the weight of evidence is inconclusive regarding a possible connection between NSAID use and miscarriage.
Opioids and neural tube defects
We reviewed two retrospective case-control studies that reported on opioid exposure in early pregnancy and risk of neural tube defects.7, 8 The studies used interviews to gather information from over 28,000 women on maternal opioid use during pregnancy. Both studies found that mothers of infants with neural tube defects were more likely than mothers of infants without neural tube defects to report opioid use in early pregnancy (aOR=2.2, 95% CI=1.2-4.2; aOR=2.0, 95% CI=1.3-3.2). Although both studies were generally well-designed to assess the association between opioids and neural tube defects, both were susceptible to similar study limitations. In particular, use of maternal interviews could have affected the validity of these studies’ findings. For example, mothers of neural tube defect-affected infants may have better recall of opioid exposure during their pregnancies than mothers of infants without birth defects. In addition, mothers of potentially exposed neural tube defect-affected infants may have higher rates of study participation.
Further investigation of this issue is needed before we can determine whether the weight of evidence supports the presence of an increased risk of neural tube defects related to opioid exposure in early pregnancy. The absolute risk of neural tube defects is low in the U.S. at about four to six per 10,000 live births.12, 13 Therefore, if true, a two-fold increased risk would represent a small increase in the absolute risk of neural tube defects.
Acetaminophen and attention deficit hyperactivity disorder (ADHD)
We evaluated a prospective cohort study that reported an increased association between acetaminophen use in pregnancy and ADHD in children.9 Assessed outcomes included diagnosis of hyperkinetic disorder (HKD) and ADHD medication use beginning at age 5 and ADHD-like behaviors based on maternal interview of the child’s behaviors at age 7. The study population included 64,322 pregnancies with information to assess HKD and ADHD medication use, and 40,916 pregnancies with information to assess child behavior.
In the study, mothers reporting any acetaminophen use during pregnancy reported more ADHD-like behavior in their children compared to unexposed mothers (adjusted risk ratio [aRR]=1.13, 95% CI=1.01-1.27). Women reporting any acetaminophen use in pregnancy were also significantly more likely to have a child with an HKD diagnosis (aRR=1.37, 95% CI=1.19-1.59) or a child who used ADHD medications (aHR=1.29, 95% CI=1.15-1.44), compared to unexposed women. Associations for all outcomes were strongest for acetaminophen use in multiple trimesters and for more than 20 weeks during pregnancy.
This study had a number of methodologic limitations that make the findings difficult to interpret. The authors did not assess overall markers of health, including health care utilization and/or medication utilization in the year prior to and during the index pregnancy, which might make the observed associations incorrect. No information was provided on the acetaminophen strength and number of dosage units taken; therefore, no conclusions can be made regarding a dose-response relationship. The authors also did not assess clinical ADHD diagnoses. Findings from two other observational studies of neurodevelopment in children exposed to acetaminophen during gestation are conflicting; however, neither of these studies specifically assessed ADHD as an outcome.14, 15
Based on our evaluation of these studies, we believe that the weight of evidence is inconclusive regarding a possible connection between acetaminophen use in pregnancy and ADHD in children.
