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Hynes highlights concerning findings from animal studies: “There was an increased risk of miscarriage and fetal abnormalities,” she said while also noting that animal studies do not always correlate with human studies.
Manufacturers like Novo Nordisk stress there is insufficient data to determine risks in human pregnancies.
Growing number of pregnancies among semaglutide users
A recent observational study published in JAMA provides some initial reassurance. The study, which used data from four Nordic countries, the US MarketScan Database and the Israeli Maccabi Health Services database, did not find a greater risk of major congenital malformations in infants after periconceptional use of GLP-1 receptor agonists and other second-line antidiabetic medications compared with insulin. The report authors stressed: “Although reassuring, confirmation from other studies is needed, and continuous monitoring will provide more precise estimates as data accumulate.” Semaglutide remains a popular subject of clinical trials, but a recent review of clinical trials revealed a dearth of studies focused on GLP-1 RAs in pregnant women.
The Washington Post recently highlighted a growing number of pregnancies in users of GLP-1 receptor agonists like semaglutide. The paper notes that some doctors speculate that the weight loss effects of GLP-1 drugs may increase the chances of unexpected pregnancy in some patients by improving hormonal balance and ovulation. The drugs could also interfere with the absorption of oral contraceptives in some cases, it noted.
The need for more data
The lack of human data remains a significant issue. Hynes clarifies: “Human studies have not been done to see if semaglutide increases the chance for pregnancy-related problems such as preterm delivery or low birth weight.”
Furthermore, the lack of data extends beyond pregnancy. “There is no data on breastfeeding as well,” Hynes added.
“This is my opinion, but drug companies need to study pregnancy and not have it shelved off as a contraindication as it is very important,” Hynes said. “Women, particularly minority women, have high numbers of obesity-related morbidity in pregnancy,” she noted.
The journal Drug Design, Development and Therapy echoes these concerns. Based on animal studies, it warns that GLP-1 receptor agonists like semaglutide “should not be used in pregnancy due to potential risks of embryofetal mortality, structural abnormalities, and alterations to growth.” The journal underscores the lack of human data and advises women planning to get pregnant to discontinue semaglutide at least two months beforehand.
Such message is pragmatic, but is unlikely to cover all cases. Hynes noted that “half of U.S. pregnancies are unplanned.”
Pregnancy an exclusion criteria in trials, but pregnancies still occurred
The SUSTAIN (Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes) clinical trial program, which led to the FDA approval of semaglutide for type 2 diabetes treatment, excluded women who were pregnant, breastfeeding or intending to become pregnant. Yet a total of 44 pregnancies were reported in the phase 3 clinical development program (STEP 1-6, 8 and TEENS) and phase 2 dose-ranging study. Of these, 35 women were treated with Wegovy (semaglutide), one with another GLP-1 drug, Saxenda (liraglutide), and eight with a placebo. In all cases, the patients were exposed to the trial product for a short period until the pregnancy was discovered, and the treatment was discontinued.
While one baby in the SUSTAIN 5 trial was born with “no known congenital abnormalities” after the mother received semaglutide for about 9 weeks, there were two notable cases in the STEP trials. In the adult STEP 1 trial, one child exposed to semaglutide was born with a congenital anomaly of the external ear. In the adolescent STEP TEENS trial, another child exposed to semaglutide was diagnosed with intrauterine growth restriction, an asymmetric variant, between birth and one month of age, although this was not considered an abnormal outcome. See the “Mother to Baby” fact sheet on semaglutide.
The thalidomide shadow
According to Hynes, the absence of standardized guidelines is especially worrisome. She emphasized the crucial importance of administering pregnancy tests to women of reproductive age prior to commencing treatment with GLP-1 receptor agonists. Hynes pointed out that the manufacturer’s instructions advise discontinuing the medication two months before attempting to conceive. “In addition, we must be transparent and tell them we do not know effects on the human fetus, and it could be harmful,” Hynes said. “We just do not know.”
Hynes acknowledges the significant lack of data on the impact of GLP-1 RAs during pregnancy. Patient education is crucial, as Hynes explained, “I tell all my patients that this has not been studied at all in human pregnancy, but animal studies do show potential risk. I also tell them animal studies are not human studies and do not correlate.” The medical saga of thalidomide, which was tied to severe birth defects when taken during pregnancy in the late 1950s and early 1960s, initially appeared to be safe in animal studies. Thalidomide was “metabolized very differently in rat models than humans,” Hynes said.
Knowledge gaps for OB/GYNs
The knowledge gap extends beyond patients, as Hynes pointed out, “OB/GYNs need more education and guidance. I gave a lecture to OB/GYNs this past January which was well attended. Many do not know about these medications, and many of their patients are currently on them.”
The lack of regulation and the increasing popularity of GLP-1 RAs for weight loss among young women further complicate the issue. “Some are buying it from compound pharmacies, which are often not regulated,” Hynes noted. “Terzepatide, another GLP-1 but also with GIP activation, is also being used by many young women desiring weight loss.”
Given the uncertainties, Hynes suggested, “There is also the option of telling them not to take it, as there could be potential risks in childbearing ages.” Yet she also acknowledges that as more women experience weight loss with these medications, unintended pregnancies may occur. “We will likely have more data soon, as patients will likely get pregnant on Ozempic, intentionally and otherwise. It is already being done by patient report. This is not the way it should be done, but as women lose weight, they will likely get pregnant.”
Filed Under: clinical trials, Drug Discovery, Metabolic disease/endicrinology, Obstetrics & gynecology
