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Opioids and Birth Defects.

Because opioid analgesics are widely used among women of reproductive age for pain, any potential detrimental effects of these drugs during pregnancy clearly are important to a large population of women.

To date, therapeutic doses of opioid analgesics have not been linked to an increased risk of major congenital malformations. But the data in pregnant women are limited, with few comparative studies on the risk of opioid exposure in the first trimester.

For these reasons, a recently published study using data from the National Birth Defects Prevention Study of infants born in 10 U S states between October 1997 and December 2005 raised considerable interest. The study reported a significant association between the therapeutic use of opioid analgesics early in pregnancy and several different birth defects. Among the 17,449 mothers who had a baby with a malformation, 2.6% reported use of opioids during pregnancy, compared with 2% of the 6,701 women in the control group, whose babies had no malformations. Treatment with an opioid analgesic between 1 month before and 3 months after conceiving was associated with a significantly increased risk of the following malformations in their infants: conoventricular septal defects (odds ratio, 2.7), atrioventricular septal defects (2.0), hypoplastic left heart syndrome (2.4), spina bifida (2.0), and gastroschisis (1.8).

Codeine and hydrocodone were the most common opioids women reported using (34.5% each), followed by oxycodone (14.4%) and meperidine (12.9%).

The authors considered a biologically plausible mechanism for their findings, and noted that their results were consistent with earlier studies, concluding that "it is critical that health care providers weigh the benefits of these medications along with their potential risks when discussing analgesic treatment options with patients who are or may become pregnant." The study, conducted by researchers at the Centers for Disease Control and Prevention (CDC), was published online in February (Am. J. Obstet. Gyn. 2011 [doi:10.1016/j.acog.2010.12.]). Despite the study's large sample size, in my view, the small effects detected were most likely due to recall bias as will be explained here. Importantly, the increased risk for the malformations suggested in the study has not been detected in numerous studies among large numbers of women who abuse and/or are addicted to opioids such as heroin, methadone, and oxycodone during pregnancy, and are exposed to far higher doses than women who are treated with therapeutic doses.

The recommendation made by the authors to consider the association when making treatment decisions implies that they proved causation. But this type of study can never prove causation. Women whose babies had a malformation were interviewed an average of 11 months after their estimated delivery date. There is a large body of research that has demonstrated marked differences in how women who have babies born with malformations recall what happened during their pregnancy compared with those with unaffected babies. Women who have babies with malformations are more likely to remember events and treatments they encountered during pregnancy, because they have a reason to go back and figure out what may have contributed to the outcome.

The only method to correct for this different memory pattern is to recruit a control group of mothers who have had a baby with other malformations that are not the focus of the study. As an example, a Motherisk study published in 1997 addressed whether Mobius syndrome (facial nerve and limb abnormalities) is caused by in utero exposure to the prostaglandin analogue misoprostol in Brazil, where the drug is misused by women in attempts to terminate pregnancy To control for the recall bias of participating mothers, the study included a control group of women who had a baby born with spina bifida, and found that these control mothers, despite having children with a malformation, did not recall taking misoprostol, whereas the majority of women with Mobius anomaly remembered taking misoprostol (N. Engl. J. Med. 1998; 338: 1881-5). Prospective controlled studies are needed to determine whether the association identified in the CDC study is genuine. A controlled study of a large group of women who abuse opioids as part of an addiction pattern, who are exposed to much higher opioid doses, would also be helpful in addressing this question.

Many of the calls we receive at Motherisk are from women who are in the first trimester and are concerned that they took an opioid before they knew they were pregnant. We counsel them that the analysis of the available data does not suggest they are at an increased risk of having a baby with a malformation. If a woman calls us and is planning a pregnancy or is in early pregnancy and, for example, is taking methadone to manage addiction, we recommend that she continue methadone because staying off illicit opioids is far more important.

For a woman who is in early pregnancy and needs a strong analgesic after surgery, we recommend using an opiate. We are now enrolling women who call us about having taken an opioid analgesic before they know the outcome of pregnancy in a prospective study.

Dr. Koren is a professor of pediatrics, pharmacology, pharmacy, medicine, and medical genetics at the University of Toronto. He heads the Research Leadership in Better Pharmacotherapy During Pregnancy and Lactation at the Hospital for Sick Children, Toronto, where he is director of the Motherisk Program. He also holds the Ivey Chair in Molecular Toxicology in the department of medicine, University of Western Ontario, London. Dr. Koren said he had no relevant financial disclosures. E-mail him at
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Author:Koren, Gideon
Publication:OB GYN News
Date:Jul 1, 2011
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