Elsevier

Annals of Epidemiology

Volume 27, Issue 10, October 2017, Pages 645-653.e2
Annals of Epidemiology

Original article
Risk comparison for prenatal use of analgesics and selected birth defects, National Birth Defects Prevention Study 1997–2011

https://doi.org/10.1016/j.annepidem.2017.09.003Get rights and content

Abstract

Purpose

To compare the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and/or opioids to the use of acetaminophen without NSAIDs or opioids with respect to associations with birth defects.

Methods

We used data from the National Birth Defects Prevention Study (1997–2011). Exposure was self-reported maternal analgesic use from the month before through the third month of pregnancy (periconceptional). Adjusted odds ratios (aORs) were calculated to examine associations with 16 birth defects.

Results

Compared to acetaminophen, mothers reporting NSAIDs were significantly more likely to have offspring with gastroschisis, hypospadias, cleft palate, cleft lip with cleft palate, cleft lip without cleft palate, anencephaly, spina bifida, hypoplastic left heart syndrome, pulmonary valve stenosis, and tetralogy of Fallot (aOR range, 1.2–1.6). Opioids were associated with tetralogy of Fallot, perimembranous ventricular septal defect, and ventricular septal defect with atrial septal defect (aOR range, 1.8–2.3), whereas use of both opioids and NSAIDs was associated with gastroschisis, cleft palate, spina bifida, hypoplastic left heart syndrome, and pulmonary valve stenosis (aOR range, 2.0–2.9).

Conclusions

Compared to periconceptional use of acetaminophen, selected birth defects occurred more frequently among infants of women using NSAIDs and/or opioids. However, we could not definitely determine whether these risks relate to the drugs or to indications for treatment.

Introduction

Chronic and acute nonobstetric pain during pregnancy is common and can arise from prepregnancy maternal conditions such as sickle cell disease, arthritis, headache, injury, and surgery (collectively affecting up to 25% of pregnant women [1], [2], [3], [4], [5]), as well as pregnancy-related conditions such as lower back pain and pelvic pain (together affecting 22%–72% of pregnant women [6], [7]). The selection of safe and effective pain management strategies during pregnancy is challenging [8], [9]. Early embryonic exposure to certain pain medications can result in potentially harmful effects on the fetus [9], [10]. Alternatively, fear about the use of drugs during pregnancy, both substantiated and unfounded, can lead to undertreatment of pregnant women for painful conditions; comorbidities due to inadequate pain management can also be harmful to the fetus [8], [9], [11], [12].

Analgesic use during pregnancy is estimated to range from approximately 50% to 80% [13], [14], with the majority of use occurring during the first trimester, which is of particular concern due to potential teratogenic risk during the period of organogenesis [15]. Some of the most commonly used analgesics for pain management in the first trimester include acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids (reported first trimester use in 41%–59% [14], [16], 8%–24% [14], [17], [18], 2%–11% [19], [20], respectively). Previous studies have examined teratogenic effects of analgesic use during the first trimester, and while acetaminophen is generally considered safe in regard to teratogenicity, findings for NSAIDs and opioids have been inconsistent [9], [11], [12], [21].

Research is needed to comparatively assess the safety of these analgesics to help guide the treatment of pain in pregnancy [9], [22]. The objectives of our study were (1) to document the prevalence and patterns of self-reported use of acetaminophen, NSAIDs, and opioids during pregnancy and (2) to compare the use of early pregnancy NSAIDs and/or opioids to acetaminophen with respect to associations with selected birth defects.

Section snippets

Materials and methods

The National Birth Defects Prevention Study (NBDPS) was a population-based, multisite, case-control study of more than 30 major structural birth defects across 10 centers in the United States (Arkansas, California, Georgia, Iowa, Massachusetts, North Carolina, New Jersey, New York, Texas, and Utah). Birth defect cases, including live born, stillborn, and induced abortions, were identified by each Center's birth defects registry, excluding cases with a known cause (e.g., chromosomal or genetic

Descriptive analysis

Among 29,078 case and 10,962 control mothers meeting our initial inclusion criteria for the descriptive analysis, 81% of cases and 80% of controls reported analgesic use in B3–P9, with 57% of cases and 54% of controls reporting periconceptional analgesic use (Fig. 1, Fig. 2). Acetaminophen use increased slightly from B1–P1 and decreased before delivery (ranging in B3–P9 between 42% and 47% among cases and 39% and 46% among controls). NSAID use was highest during the 3 months before pregnancy

Conclusions

In this analysis, we found that approximately 80% of women reported analgesic use in pregnancy, with approximately 50%–60% reporting use periconceptionally. In addition, we found that compared to periconceptional use of acetaminophen, selected birth defects, both non-heart and heart, occurred more frequently among women reporting use of NSAIDs. The occurrence of selected birth defects was even higher among women reporting use of opioids. However, those associations were generally confined to

Acknowledgments

Drug information in the National Birth Defect Prevention Study is coded using the Slone Epidemiology Center Drug Dictionary, under license from the Slone Epidemiology Center at Boston University. The authors thank the participating families, scientists, and staff from all of the NBDPS sites. The authors wish to acknowledge Dr. Margaret Honein, National Center on Birth Defects and Developmental Disabilities at the Centers for Disease Control and Prevention, for her contributions to this project.

References (36)

  • S.C. Tinker et al.

    Maternal injuries during the periconceptional period and the risk of birth defects, National Birth Defects Prevention Study, 1997-2005

    Paediatr Perinat Epidemiol

    (2011)
  • K.M. Kuczkowski

    Nonobstetric surgery during pregnancy: what are the risks of anesthesia?

    Obstet Gynecol Surv

    (2004)
  • I.M. Mogren et al.

    Low back pain and pelvic pain during pregnancy: prevalence and risk factors

    Spine

    (2005)
  • H.C. Ostgaard et al.

    Prevalence of back pain in pregnancy

    Spine

    (1991)
  • F. Coluzzi et al.

    Chronic pain management in pregnancy and lactation

    Minerva Anestesiol

    (2014)
  • M.J. Wunsch et al.

    Treatment of pain in pregnancy

    Clin J Pain

    (2003)
  • D. Kennedy

    Analgesics and pain relief in pregnancy and breastfeeding

    Aust Presc

    (2011)
  • M. Babb et al.

    Treating pain during pregnancy

    Can Fam Physician

    (2010)
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    The findings and conclusions in this report are those of the authors and do not necessarily represent the official positions of the U.S. Centers for Disease Control and Prevention or the Food and Drug Administration.

    Martha Werler previously served on the advisory boards of studies aimed at identifying adverse outcomes related to pregnancy use of medications for rheumatoid arthritis. The studies were funded by pharmaceutical companies who may manufacture pain medications. Other authors report no conflict of interest.

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