Following up on its December publication of a final rule that sets standards for how information about using medicines during pregnancy and breastfeeding is presented in the labeling of prescription drugs and biological products, the FDA reviewed a number of published studies that raised concerns about the risks of using prescription or over the counter pain medicines during pregnancy. The FDA considered the use of nonsteroidal anti-inflammatory drugs and the risk of miscarriage, the association between acetaminophen use in pregnancy and ADHD in children, and opioid exposure in early pregnancy with the risk of neural tube defects. Regarding opioid exposure in early pregnancy and the risk of birth defects, the CDC published a report raising concerns about the rate at which women of child-bearing age are prescribed opioids.
- Nakhai-Pour HR, Broy P, Sheehy O, Bérard A. Use of nonaspirin nonsteroidal anti-inflammatory drugs during pregnancy and the risk of spontaneous abortion. CMAJ 2011;183:1713-20. PMID 21896698.
- Nielsen GL, Sørensen HT, Larsen H, Pedersen L. Risk of adverse birth outcome and miscarriage in pregnant users of non-steroidal anti-inflammatory drugs: population based observational study and case-control study. BMJ 2001;322:266-70. PMID: 11157526.
- Nielsen GL, Skriver MV, Pedersen L, Sørensen HT. Danish group reanalyses miscarriage in NSAID users. BMJ 2004;328:109. PMID: 14715618.
- Li DK, Liu L, Odouli R. Exposure to non-steroidal anti-inflammatory drugs during pregnancy and risk of miscarriage: population based cohort study. BMJ 2003;327:368. PMID: 12919986.
- Edwards DR, Aldridge T, Baird DD, Funk MJ, Savitz DA, Hartmann KE. Periconceptional over-the-counter nonsteroidal anti-inflammatory drug exposure and risk for spontaneous abortion. Obstet Gynecol 2012;120:113-22. PMID: 22914399.
The FDA, along with multiple published commentators, did not draw conclusions based on the first three studies because of methodological limitations of the retrospective case-control studies. The FDA found the methodologies of the second two observational studies were sound. However, the results differed. Li, et al, identified a positive association between prescription non-aspirin NSAID exposure and miscarriage. However, Li, et al conceded that their findings needed confirmation in studies designed specifically to examine the apparent association. Edwards, et al, did not identify an increased risk. Based on its evaluation of the two conflicting observational studies, the FDA found that the weight of evidence was inconclusive regarding a possible connection between NSAID use and miscarriage.
Second, the FDA reviewed one prospective cohort study that reported an increased association between acetaminophen use in pregnancy and ADHD in children.
- Liew Z, Ritz B, Rebordosa C, Lee PC, Olsen J. Acetaminophen use during pregnancy, behavioral problems, and hyperkinetic disorders. JAMA Pediatr 2014;168:313-20. PMID: 24566677.
In the study, mothers reporting any acetaminophen use during pregnancy reported more ADHD-like behavior in their children compared to unexposed mothers. Women reporting any acetaminophen use in pregnancy were also significantly more likely to have a child with a hyperkinetic disorder (HKD) diagnosis or a child who used ADHD medications, compared to unexposed women. Associations for all outcomes were strongest for acetaminophen use in multiple trimesters and for more than 20 weeks during the pregnancy. However, the FDA, along with multiple published commentators, found that the study was susceptible to methodological limitations. Additionally, the FDA noted that two other observational studies of neurodevelopment in children exposed to acetaminophen during gestation conflicted with this study, although neither of those studies specifically assessed ADHD as an outcome.
- Streissguth AP, Treder RP, Barr HM, Shepard TH, Bleyer WA, Sampson PD, et al. Aspirin and acetaminophen use by pregnant women and subsequent child IQ and attention decrements. Teratology 1987;35:211-9. PMID: 3603404.
- Brandlistuen RE, Ystrom E, Nulman I, Koren G, Nordeng H. Prenatal paracetamol exposure and child neurodevelopment: a sibling-controlled cohort study. Int J Epidemiol 2013;42:1702-13. PMID: 24163279.
The FDA concluded that the weight of the evidence was inconclusive regarding a possible connection between acetaminophen use in pregnancy and ADHD in children.
Third, the FDA reviewed two retrospective case-control studies that reported on opioid exposure in early pregnancy and risk of neural tube defects.
- Yazdy MM1, Mitchell AA, Tinker SC, Parker SE, Werler MM. Periconceptional use of opioids and the risk of neural tube defects. Obstet Gynecol 2013;122:838-44. PMID: 24084542.
- Broussard CS, Rasmussen SA, Reefhuis J, Friedman JM, Jann MW, Riehle-Colarusso T, et al. Maternal treatment with opioid analgesics and risk for birth defects. Am J Obstet Gynecol. 2011;204:314.e1-11. PMID: 21345403.
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. However, the FDA found that both studies were susceptible to study limitations. In particular, use of maternal interviews could have affected the validity of these studies’ findings. The FDA concluded that further investigation of this issue was needed before it could determine whether the weight of the evidence supports the presence of an increased risk of neural tube defects related to opioid exposure in early pregnancy.
The CDC took a much more definitive position with regard to opioid use in pregnancy. The CDC’s announcement of its study on how opioids are widely prescribed to reproductive-age women despite risks in pregnancy stated that previous studies of opioid use in pregnancy suggested these medications might increase the risk of neural tube defects (major defects of the baby’s brain and spine), congenital heart defects, and gastroschisis (a defect of the baby’s abdominal wall). There is also a risk of neonatal abstinence syndrome (NAS) from exposure to medications such as opioids in pregnancy. NAS occurs when a newborn experiences symptoms of withdrawal from medications or drugs taken by a mother during pregnancy. The CDC report goes on to explain that the development of birth defects often results from exposures during the first few weeks of pregnancy, which is a critical period for organ formation. Given that many pregnancies are not recognized until well after the first few weeks and half of all U.S. pregnancies are unplanned, all women who might become pregnant are at risk. Therefore, it is important to assess opioid medication use among all women of reproductive age.
If the FDA’s inconclusive results leave you looking for more information about pain medication use during pregnancy, consider MothertoBaby.org, a service of the non-profit Organization of Teratology Information Specialists, among other organizations. Mother to Baby provides evidence-based information to mothers, health care professionals, and the general public about medications and other exposures during pregnancy and while breastfeeding. See also various state agencies such as the Utah Department of Health and other organization publications such as American Family Physician “Over-the-Counter Medications During Pregnancy.”
By Sarah Kelman, JD, and the experts and editors at Medical Law Perspectives.
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See the CDC Report on Opioids and Women of Reproductive Age
See the CDC Report on Medications and Pregnancy
For more details on the FDA’s Standards for Drug Labeling: Pregnant and Breastfeeding Women, see the Scalpel Weekly News, December 22, 2014.
See also Medical Law Perspectives, January 2015 Report: Mothers, Infants, and Obstetrical Injuries: Labor and Delivery Liability.
See also Medical Law Perspectives, January 2014 Report: Prescription Painkillers: Risks for Patients, Pharmacists, and Physicians.