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Opioid Resource Center
Disclosures: Andersson reports no relevant financial disclosures. Bateman reports receiving grants from the FDA and the National Institutes of Health during the conduct of the study; grants to his institution from Baxalta, Eli Lilly & Co., GlaxoSmithKline, Pacira and Takeda, outside the submitted work; and serving as a consultant to Aetion, Inc and the Alosa Foundation. Please see the studies for all other authors’ relevant financial disclosures. Cahill reports no relevant financial disclosures.
March 03, 2021
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Opioid, macrolide use in pregnancy not tied to overall birth defect risk

Disclosures: Andersson reports no relevant financial disclosures. Bateman reports receiving grants from the FDA and the National Institutes of Health during the conduct of the study; grants to his institution from Baxalta, Eli Lilly & Co., GlaxoSmithKline, Pacira and Takeda, outside the submitted work; and serving as a consultant to Aetion, Inc and the Alosa Foundation. Please see the studies for all other authors’ relevant financial disclosures. Cahill reports no relevant financial disclosures.
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Children born to mothers who used opioids and macrolide antibiotics do not have increased risks for major birth defects, according to two studies published in the BMJ.

Alison Cahill, MD, MSCI, a maternal-fetal medicine specialist in the Women’s Health Institute at the University of Texas at Austin who was not involved in the studies, told Healio Primary Care that while there had previously been some research that suggested exposure to these medications may be associated with an increased risk for fetal malformations, physicians remain “fairly confident” that is not the case.

Quote from Cahill on opioid use in pregnancy

“These are two, nicely done, large studies that kind of put to rest any remaining questions. There doesn’t seem to be an increased risk,” she said. “So, this kind of confirms the current state of practice.”

Opioid use in pregnancy

In one study, Brian T. Bateman, MD, associate professor of anesthesia at Brigham and Women’s Hospital, and colleagues found that prescription opioids in the first trimester “are not major teratogens.”

Bateman said the findings are “reassuring for both pregnant women and women of reproductive age who may become pregnant who need to take opioids.”

Photo of Brian Bateman
Brian T. Bateman

Bateman and colleagues conducted a population-based cohort study using a nationwide sample of pregnant women and their liveborn infants. The participants were included in the Medicaid Analytic eXtract (MAX) from 2000 through 2014 and the MarketScan Research Database from 2003 through 2015.

The researchers considered pregnancies to have opioid exposure if mothers filled at least two opioid prescriptions within the first trimester or during the first 90 days of their pregnancy. They evaluated congenital outcomes, cardiovascular malformations, ventricular septal defects, secundum atrial septal defects or a patent foramen not related to prematurity, neural tube defects, clubfoot and oral clefts among infants with and without opioid exposure during pregnancy.

A total of 1,602,580 publicly insured women — 4.4% of whom had opioid exposure during pregnancy — and 1,177,676 commercially insured women — 1.1% of whom had opioid exposure during pregnancy — were included in the study.

Bateman and colleagues determined that the absolute risk for malformations in the MAX cohort was 41 per 1,000 pregnancies (95% CI, 39.5-42.5) with opioid exposure and 32 per 1,000 pregnancies (95% CI, 31.7-32.2) without opioid exposure. In the MarketScan cohort, the absolute risk for malformations was 42.6 per 1,000 pregnancies (95% CI, 39 to 46.1) with opioid exposure and 37.3 per 1,000 pregnancies (95% CI, 37.0-37.7) without exposure.

The pooled unadjusted relative risks estimates were elevated for all outcomes, but moved substantially towards null after adjusting, with lowered risk estimates for overall malformation (RR = 1.06; 95% CI, 1.02-1.10), cardiovascular malformations (RR = 1.09; 95% CI, 1-1.18), atrial septal defect or patent foramen ovale (RR = 1.04; 95% CI, 0.88-1.24), neural tube defect (RR = 0.82; 95% CI, 0.53-1.27) and clubfoot (RR = 1.06; 95% CI, 0.88-1.28).

However, the risk for oral clefts remained high after adjustment (RR = 1.21; 95% CI, 0.98-1.5), and there was a higher risk for cleft palate with opioid exposure (RR = 1.62; 95% CI, 1.23-2.14).

While the findings suggest that prescription opioids are overall safe to use during the first trimester of pregnancy, Bateman stressed that the risks associated with opioid use should still be considered before prescribing.

“All of the same risks that apply outside of pregnancy — the risk of addiction, the risk of overdose — are all applicable to pregnant women as well, so our findings certainly shouldn’t be interpreted to mean that opioids are safe in this clinical context,” he said. “They still need to be used with great caution.”

Macrolides exposure during pregnancy

In another study, Niklas Worm Andersson, MD, of the department of epidemiology research at Statens Serum Institut, and colleagues conducted a nationwide register-based study of all pregnancies recorded in Denmark from 1997 through 2016.

The cohort included 1,192,539 live birth pregnancies, 13,019 of which had maternal macrolide use in the first trimester.

The researchers matched pregnancies with macrolide exposure to pregnancies with penicillin exposure in a 1:1 ratio. They also matched pregnancies with macrolide exposure to pregnancies without antibiotic exposure in a 1:4 ratio to compare outcomes.

Major birth defects occurred in 457 infants (35.1 per 1,000 pregnancies) with mothers who used macrolides during pregnancy, and in 481 infants (37.0 per 1,000 pregnancies) with mothers who used penicillin (RR = 0.95; 95% CI, 0.84-1.08), equating to an absolute risk difference of –1.8 per 1,000 pregnancies (95% CI; 6.4 to 2.7).

The risk for major birth defects was not significantly higher in women who used macrolides during their pregnancy compared with women who took macrolides shortly before their pregnancy (RR = 1; 95% CI, 0.88-1.14), with an absolute risk difference of –0.1 per 1,000 pregnancies (95% CI, 4.8 to 4.7).

The researchers also determined that the risk for birth defects was not significantly higher among women who used macrolides during pregnancy compared with those who did not use any antibiotics during pregnancy (RR = 1.05; 95% CI, 0.95-1.17), with an absolute risk difference of 1.8 per 1,000 pregnancies (95% CI, 1.7 to 5.3).

According to Andersson and colleagues, there were no significantly increased risks for specific subgroups of birth defects among children born to women who used macrolides during pregnancy.

Andersson told Healio Primary Care that the findings are in line with most of the previous work on macrolide use in pregnancy, but differ from a recent cohort study that showed macrolide use during the first trimester was associated with an increased risk for major birth defects, particularly cardiovascular defects.

However, he said that due to the larger sample size of his study, “we could provide estimates with a high precision and findings were not suggestive of an associated increased risk of major birth defects overall or of any specific subgroups of defects, including defects of the heart, with macrolide use compared with penicillin use in the first trimester.”

“Together with the majority of the previous published studies on this topic, we believe that our data provide reassurance about the risk of major birth defects when treatment with macrolide antibiotics is needed during pregnancy,” he said.

What this means for mothers

Cahill stressed that physicians should consider the risks and benefits of every medication that is prescribed to patients who are pregnant. However, she also noted that it is important to consider the mother’s condition.

“I think sometimes we get a little bit down in the rabbit hole about the risks,” she said. “Really, the choice not to prescribe a medication leaves whatever the medical complication we have untreated, and oftentimes that is riskier than the theoretical risks of the medication itself.”

For instance, she said physicians in the U.S. are aware of the ongoing opioid epidemic and the risks stemming from these medications, so they are already “incredibly judicious” when prescribing opioids.

Therefore, Cahill said that physicians should consider an opioid prescription for pregnant women who are experiencing pain that is worse than what could be treated with other medications.

“There certainly is a role for opioids, even in the first trimester, without fear for an association with malformations,” she added.

Similarly, she said macrolides have been proven to be very effective for a variety of infections, and physicians should not consider leaving infections in pregnant women untreated out of fear of birth defects.

“We shouldn’t leave maternal pain untreated, nor should we leave maternal infection untreated, as those are both medically unacceptable, and pregnant women can receive a variety of different classes of medications safely,” Cahill said.

References:

Andersson NW, et al. BMJ. 2021;doi:10.1136/bmj.n107.

Bateman, BT, et al. BMJ. 2021;doi:10.1136/bmj.n102.