Acetylsalicylic acid (ASA) and nonsteroidal anti-inflammatory drugs (NSAIDS) during pregnancy

Jochen G.W. Theis, MD

December, 1996

I have a patient with rheumatoid arthritis who needs ASA or another NSAID for pain control. She is now pregnant and is afraid to continue medication. How should I advise her?

The fetal and the neonatal risks associated with using cyclooxygenase inhibitors, such as ASA and other NSAIDs, during late pregnancy are the topic of ongoing debate.¹ In fetuses and neonates the cyclooxygenase products prostaglandin E₂ and I₂ are potent dilators of the ductus arteriosus and pulmonary resistance arteries. Treating animal fetuses with cyclooxygenase inhibitors leads to constriction of the ductus arteriosus and redistribution of blood flow in other fetal vascular beds.² This has led to concern that there might be a causal relationship between cyclooxygenase inhibitors, prenatal ductal closure, and postnatal development of persistant pulmonary hypertension of the newborn (PPHN).

However, the magnitude of the physiologic role of vasodilatory prostaglandins in maintaining human ductus arteriosus patency and in the perinatal transition of blood circulation has not been established.³ The existence of a causal association between fetal exposure to cyclooxygenase inhibitors and the occurrence of PPHN also remains unproven.

Recently, Van Marter et al⁴ attempted to investigate the association between several potential antenatal risk factors and PPHN. Using a case-control approach and interviewing mothers, they found an apparent association between antenatal consumption of ASA or NSAIDs and the occurrence of PPHN. Based on this apparent association and a discussion indicating biologic plausibility, the authors concluded that ASA and NSAIDs contribute to PPHN and that consuming these drugs during pregnancy should be avoided.

Case-control studies can be powerful epidemiologic tools for investigating suspected associations between fairly common antenatal exposures and rare pregnancy outcomes. This study design can be ineffective if the outcome of the pregnancy has an effect on the retrieval of risk factors that were present during the pregnancy. If risk factors are obtained through interviews, they are subject to recall bias, and this must be adequately addressed in the design of the study. Selection of an appropriate control group is of utmost importance because mothers of healthy babies are much more likely to forget and not report events perceived as minor than mothers of unhealthy babies.⁵ Failure to address recall bias actively is likely to result in false-positive associations similar to the results of early studies investigating the association between ASA and congenital malformations. One state-of-the-art case-control study, therefore, selected mothers of children with different malformations from the index malformation as the control group.⁶

Van Marter et al⁴ address the problem of recall bias by stating that they "do not have compelling evidence that control mothers selectively underreported any exposure." Most of the reported exposures took place during the first trimester, many even during the first month of pregnancy (ie, more than 6 months before the interview). At the time of exposure, many mothers were probably unaware of the pregnancy. The median number of tablets taken during the entire pregnancy was low (four for ASAs, eight for NSAIDs). Such brief and early exposures are easily forgotten by mothers of healthy babies and are likely to be reported more often by mothers of unhealthy newborns who try to remember "what went wrong?"

To causally link antenatal ASA and NSAID exposure to PPHN, the authors cite animal studies and case reports. However, unlike their own series, all these articles deal with exposures during late pregnancy. When evaluating biologic plausibility, it is important to understand that the effects of drugs on fetuses are highly dependent on the stage of fetal development and that they differ widely between first and third trimester.

Van Marter et al indirectly acknowledge the irrelevance of their citations by speculating on how exposure during early pregnancy might have caused neonatal PPHN. They speculate that SAS and NSAIDs might alter the pulmonary vasculature during early pregnancy with effects not visible until birth or that first-trimester use might be associated with third-trimester use of the drugs. However, persistent effects of ASA or NSAIDs after discontinuing the drug during early pregnancy have not been described, and an association between first-trimester and last-trimester use is negated by the authors' own data.

It is unfortunate that, based on a study with less than optimal design and with a lack of biologic plausibility, recommendations with possibly wide implications were made. With the data presented and the available evidence, the recommendation to avoid these drugs is more misleading than informative. It can lead to inadequate treatment of serious conditions during pregnancy, unnecessary fears after exposure, and perhaps even termination of otherwise wanted pregnancies.⁷

To date, no evidence indicates that first-trimester exposure to NSAIDs or ASA is associated with any adverse pregnancy out-come. As documented by studies evaluating low-dose ASA for treating preeclampsia, low-dose ASA appears to have no adverse effects on fetuses or neonates when given late in pregnancy.⁸

More controversial is the use of higher doses of NSAIDs in ASA during the second half of pregnancy. Fetal exposure to indomethacin during late pregnancy has been associated with constriction of the ductus arteriosus and oligohydramnios in utero and with a variety of neonatal diseases, such as patent ductus arteriosus, necrotizing enterocolitis, and respiratory distress syndrome.⁹ However, intrauterine effects were usually reversible upon discontinuation of the drug and the incidence of neonatal diseases was unlikely to be increased if indomethacin was given for only 2 to 3 days. In fact, the Society of Obstetricians and Gynecologists of Canada considers the short-term treatment of preterm labour with indomethacin worth further study.¹⁰

We need more information about the safety of NSAIDs or higher doses of ASA during the second half of pregnancy. The various fetal risks associated with use of these drugs during various stages of pregnancy illustrate well the complexity of issues in reproductive toxicology.

ANSWER

The patient should continue with ASA or another NSAID if clinically indicated. During the second half of pregnancy, her fetus should be monitored carefully. If high doses are needed, fetal ultra-sound and echocardiography should be used to monitor amniotic fluid and patency of the fetal ductus arteriosus. During the last 2 weeks of a term pregnancy, the dose should be reduced as much as the patient's condition allows to reduce the risks of peripartum bleeding, neonatal hemorrhage, and persistent fetal circulation.

References

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2. Coceani F, Olley PM. The control of cardiovascular shunts in the fetal and perinatal period. Can J Physiol Pharmacol 1988;66:1129-34.
3. Hammerman C. Patent ductus arteriosus. Clinical relevance of prostaglandins and prostaglandin inhibitors in PDA pathophysiology and treatment. Clin Perinatol 1995;22:457-79
4. Van Marter LJ, Leviton A, Allred EN, Pagano M, Sullivan KF, Cohen A, et al. Persistent pulmonary hypertension of the newborn and smoking and aspirin and nonsteroidal antiinflammatory drug consumption during pregnancy. Pediatrics 1996;97:658-63.
5. Werler MM, Pober BR, Nelson K, Holmes LB. Reporting accuracy among mothers of malformed and nonmalformed infants. Am J Epidemiol 1989;129:15-21.
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8. CLASP collaborative group. Low dose aspirin in pregnancy and early childhood development: follow up of the collaborative low dose aspirin study in pregnancy. Br J Obstet Gynaecol 1995;102:861-8.
9. Briggs GG, Freeman RK, Yaffee SJ. Drugs in pregnancy and lactation. 4th ed. Baltimore, Md: Williams and Wilkins, 1994:443-52.
10. Hannah M, Amankwah K, Barrett J, Bonin B, Burrows R, Cheng M. The Canadian consensus on the use of tocolytics for preterm labour. J Soc Obstet Gynaecol Can 1995;17:1089-138.