So-Called “Ozempic Babies” Raise Questions About Unintended Effects of GLP-1 Inhibitors

Oscillating between drug shortages and its misuse as the face of trendy, rapid weight loss, semaglutide (Ozempic; Novo Nordisk) has quickly become a household name among the American population. Its more recent limelight has been caused by emerging reports flooding social media and news outlets with claims that women have experienced unexpected pregnancies due to the medication. There are currently no available direct human studies focused on semaglutide and increasing female fertility, so it is nearly impossible to ascertain whether the medication is at the root of these unexpected pregnancies. There are, however, some proposed ways in which Ozempic might be causing unintended pregnancies.

Patient holding Ozempic injector | Image credit: Fernanda | stock.adobe.com

In recent years, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) such as semaglutide and dulaglutide (Trulicity; Eli Lilly) have been established as champions of modern pharmacological diabetes care. Notably, both medications received FDA approval for established cardiovascular benefits in 2023 and have emerging evidence for protective renal effects, as well.¹ A key aspect of the health benefits derived from GLP-1 RAs is found in the medications’ ability to slow gastric emptying, an alleged contributor to unplanned pregnancy. In a broad statement, Novo Nordisk said delayed gastric emptying “may influence the absorption of concomitantly administered oral medicinal products,”² which left many wondering whether contraceptive efficacy would be impacted by the medication.

Interestingly, within the same prescribing information, the company shared there was no clinically significant drug-drug interaction between semaglutide and ethinylestradiol or levonorgestrel.² In fact, all evaluated medications by the manufacturer, including ethinylestradiol and levonorgestrel, resulted in no dose adjustment recommendations.² This is supported by a consequent single-center, 1-sequence crossover study that illustrated injectable semaglutide at multiple strengths (0.25, 0.5, and 1.0 mg) did not reduce the bioavailability of ethinylestradiol or levonorgestrel in women 18 and older with a body mass index between 18.5 and 30 kg/m2.³ The only significant difference in pharmacokinetics the study noted was a 20% increase of area under the curve in levonorgestrel, meaning participants actually had greater exposure to the oral contraceptive when receiving injectable semaglutide treatment.³

Assuming a drug-drug interaction is not at the root of the new so-called “Ozempic baby boom,” experts are looking for alternative causes. Many point to the interplay between weight loss and its impact on fertility, as well as the off-label use of GLP-1 RAs to manage polycystic ovarian syndrome (PCOS).⁴ Insulin resistance, weight gain, and infertility are common features of PCOS, and due to this, PCOS is considered a risk factor for developing type 2 diabetes, which has prompted some providers to use GLP-1 RAs in this patient population.⁵ The Figure illustrates the multiple effects of GLP-1 RAs.⁶ In a recent review focused on the treatment of obesity and fertility, 5 randomized controlled trials illustrated that weight loss interventions with an average of 7% loss (9-20 pounds) resulted in higher rates of spontaneous conception.⁴ However, regarding improved fertility treatment outcomes and acute weight loss, a recent metanalysis highlighted that even significant weight loss did not improve clinical pregnancy or live birth rates.⁷ Therefore, increased unplanned pregnancies with concurrent semaglutide use in women who are not receiving fertility treatments could be indirectly tied to the drug’s ability to promote weight loss rather than a direct effect on fertility.

Figure.⁶ The multiple effects of glucagon-like peptide-1 receptor 1 agonists and a possible mechanism by which they may cause unplanned pregnancy in women with concurrent oral contraceptive use.

Although semaglutide may find a new role in pre-conceptive care for patients with type 2 diabetes through weight loss, GLP-1 RAs are generally avoided in pregnancy due to limited data on safe use in this population. Per Novo Nordisk’s prescribing information, use of semaglutide should be suspended 8 weeks before a patient plans to become pregnant and they should contact their health care provider for another way to manage their blood sugar.² With limited available human data, many providers reference results of injectable semaglutide in animal models. In pregnant rats, structural abnormalities and diminished growth in offspring were noted at clinically relevant exposures, while pregnant rabbits and cynomolgus monkeys experienced more frequent loss of pregnancy at the same dose.² However, a new observational, prospective cohort study with 168 pregnant women with GLP-1 RA exposure in their first trimester demonstrated no significant increased risk of pregnancy loss when compared with diabetes and overweight/obese reference groups.⁸ These same results were observed when comparing birth defects,⁸ and invite an opportunity for more research into the safety of semaglutide during pregnancy.

Unsurprisingly, there are many nuances to be considered when trying to establish an association between unplanned pregnancies and a popular medication. As of now, data suggest minimal risk of drug interactions between oral contraceptives and injectable semaglutide. It is also important to be aware that weight loss experienced from semaglutide can facilitate spontaneous conception, but this requires caution as GLP-1 RAs should generally be avoided in pregnancy. Despite this, new claims continue to emerge in mainstream media, further fueling a new wave of public interest in these medications.

References

1. American Diabetes Association Professional Practice Committee. 9: Pharmacologic Approaches to Glycemic Treatment. Standards of Care in Diabetes—2024. 2024;47(Supplement_1):S158-S178. doi:10.2337/dc24-S009

2. Ozempic (semaglutide injection). Package insert. Novo Nordisk USA; 2023.

3. Kapitza C, Nosek L, Jensen L, Hartvig H, Jensen CB, Flint A. Semaglutide, a once-weekly human GLP-1 analog, does not reduce the bioavailability of the combined oral contraceptive, ethinylestradiol/levonorgestrel. J Clin Pharm. 2015;55(5):497-504. doi:10.1002/jcph.443

4. Goldberg AS, Boots CE. Treating obesity and fertility in the era of glucagon-like peptide 1 receptor agonists. Fertility and Sterility. 2024;122(2):211-218. doi:10.1016/j.fertnstert.2024.05.154

5. Diamanti-Kandarakis E, Dunaif A. Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocrine Reviews. 2012;33(6):981-1030. doi:10.1210/er.2011-1034

6. Zhao X, Wang M, Wen Z, et al. GLP-1 receptor agonists: beyond their pancreatic effects. Front Endocrinol. 2021;12. doi:10.3389/fendo.2021.721135

7. Jeong HG, Cho S, Ryu KJ, Kim T, Park H. Effect of weight loss before in vitro fertilization in women with obesity or overweight and infertility: a systematic review and meta-analysis. Sci Reports. 2024;14:6153. doi:10.1038/s41598-024-56818-4

8. Dao K, Schechtman S, Weber-Schoendorfer C, et al. Use of GLP1 receptor agonists in early pregnancy and reproductive safety: a multicentre, observational, prospective cohort study based on the databases of six Teratology Information Services. BMJ Open. 2024;14(4):e083550. doi:10.1136/bmjopen-2023-083550