Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2023 Jul 7.
Published in final edited form as: Curr Obstet Gynecol Rep. 2023 Feb 27;12(2):138–146. doi: 10.1007/s13669-023-00350-1

Pharmacologic Treatment of Obesity in Reproductive Aged Women

Akua Nuako 1, Lucy Tu 2,3, Karen J Campoverde Reyes 4,5, Shradha M Chhabria 6,7, Fatima Cody Stanford 8,9,10
PMCID: PMC10328448  NIHMSID: NIHMS1884086  PMID: 37427372

Abstract

Purpose of Review

This report will review existing literature on weight loss outcomes for various anti-obesity medications (AOMs) as well as their effects on human fertility, pregnancy, or breastfeeding.

Recent Findings

There is a paucity of research on the effects of AOMs on human pregnancy and fertility. The majority of AOMs are not recommended during pregnancy and breastfeeding due to known or unclear risks of harm to offspring.

Summary

As the prevalence of obesity rises, AOMs have proven to be effective tools for weight loss in the general adult population. When prescribing AOMs to reproductive-aged women, providers should consider both the cardiometabolic benefits of these medications and potential effects that AOMs might have on hormonal contraception, pregnancy, or breastfeeding. Animal studies in rats, rabbits, and monkeys have suggested teratogenic effects of several medications discussed in this report. However, a lack of data on the use of many AOMs during human pregnancy or lactation makes it difficult to comment on the safety of their use in these time periods. Some AOMs show promise in promoting fertility while others might decrease the efficacy of oral contraceptives, highlighting some of the special considerations that must be taken when prescribing AOMs to reproductive-aged women. More research into the risks and benefits of AOMs in the context of reproductive-aged women’s unique healthcare needs is an important step in improving this population’s access to effective treatments for obesity.

Keywords: Obesity, Pharmacotherapy, Women’s health, Anti-obesity agents, Semaglutide, Liraglutide, Orlistat, Phentermine, Topiramate, Naltrexone, Bupropion, Tirzepatide, Plenity, Metformin, Zonisamide

Introduction

The prevalence of obesity among adults in the USA grew from 30.5% in 1999–2000 to 42.4% in 2017‒2018. Increasing rates of obesity present significant public health concerns as people with this disease face an increased risk of numerous comorbidities, including type II diabetes mellitus (T2DM), cardiovascular disease, and various cancers [1]. Weight loss of ~2–10% can mitigate the risks of several adverse health outcomes for individuals with obesity and should thus be strongly encouraged in this population [2].

People who lose weight from diet and exercise alone may regain up to half of the weight they lose in 1 year [3]. Anti-obesity medications (AOMs) are powerful additions to lifestyle interventions for weight management in adults with obesity (BMI ≥ 30 kg/m2) or BMI ≥ 27 kg/m2 and at least one weight-related comorbidity.1 Anti-obesity medications (AOMs) are considered effective if a patient loses ≥ 5% of their starting weight after 12 weeks on a therapeutic dose of the medication [4].

Women face a heavy burden of disease from obesity. Notably, in 2017–2018, the rate of class III obesity (BMI ≥ 40 kg/m2) was significantly higher among women than men (11.5% vs. 6.9%, respectively) [1]. Women with obesity have higher rates of endometrial and ovarian cancers as well as subfecundity and infertility than women with healthy weight [5, 6]. More than 1.1 million pregnant women in the USA with obesity carry an elevated risk of several obesity-related adverse pregnancy outcomes (APOs), including hypertensive disorders of pregnancy, gestational diabetes, acute liver injury, emergency cesarean delivery, and stillbirth, among others [7, 8]. Importantly, weight loss is not recommended during pregnancy due to a higher risk of small-for-gestational-age babies; prepartum and postpartum weight loss are considered safer methods of reducing the risk of APOs [8, 9]. As there are numerous negative outcomes in women’s health associated with obesity, it is important to provide reproductive-aged women with optimal options for weight management.

Despite the large population of women affected by obesity, there is little research focused on how various AOMs affect pregnancy, lactation, and other aspects of women’s health. Concern over fetal harm from AOMs in the event of pregnancy is legitimate given limited data on their use in human subjects; however, AOMs might also have the potential to improve reproductive outcomes in patients who use them to achieve healthy weight before pregnancy. It is crucial to provide reproductive-aged women with reliable, reversible options for contraconception that allow them to make informed decisions about timing pregnancies while taking AOMs. Weight management requires a long-term, integrated approach, making it crucial for providers to understand the risks and benefits of AOMs for reproductive-aged women across various stages of life and fertility.

The majority of reviews on anti-obesity pharmacotherapy focus on its use in the general adult population. To highlight unique considerations regarding the use of these medications in reproductive-aged women, this report will present existing clinical data surrounding weight loss for several AOMs as well as reproductive outcomes associated with their use.

Methodology

At the time of writing, this review covers all AOMs approved for long-term and short-term use in the USA by the US Food and Drug Administration (FDA). The list of off-label medications included in this paper is not exhaustive. Weight loss data for each AOM was taken from phase 2 or phase 3 clinical trials found using a PubMed search for key terms (including obesity, weight loss, and the brand or generic names of the respective AOMs) performed in August 2022. Data regarding the effects of AOMs on fertility, pregnancy, and lactation is taken from phase 4 clinical trials found using a PubMed search with similar key terms and pre-clinical trials featured in FDA Highlights of Prescribing Information or the Drugs and Lactation Database.

Anti-Obesity Medications: Weight Loss Data and Outcomes in Reproductive Health

Anti-Obesity Medications FDA-Approved for Long-Term Use

Semaglutide

Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist. In 2021, the FDA approved Wegovy (2.4 mg subcutaneous (SQ) semaglutide weekly) for chronic weight management in adults [10]. Ozempic (SQ) and Rybelsus (oral) are other forms of semaglutide that are approved for T2DM management but not for weight loss.

GLP-1 agonists work by increasing insulin secretion from the pancreas while decreasing glucagon secretion to improve glucose homeostasis [11]. Semaglutide also works on dysregulated central and peripheral neuronal pathways to stimulate satiety and energy expenditure while reducing energy intake [12]. This medication has a black box warning regarding the risk of thyroid C-cell tumors and is not recommended for patients with a personal or family history of medullary thyroid cancer (MTC) or type 2 multiple endocrine neoplasia (MEN2). It is unclear if the risk of thyroid cancer is clinically significant in humans, as these warnings were the result of studies on rats. There is a relative contraindication for patients with a history of acute pancreatitis. The most common side effects include gastrointestinal symptoms like nausea and vomiting [13].

The eight seminal Semaglutide Treatment Effect in People with Obesity (STEP) trials demonstrated the potent weight loss effects of Wegovy.2 In January 2022, the randomized control trial (RCT) STEP 8 showed an average weight loss of 15.8% in 338 adults after 68 weeks [14]. Although the study did not report how many reproductive-aged women were included in the trials, 78.4% of participants were female and participants’ mean age was 49 years. Additionally, semaglutide shows promising cardiometabolic benefits beyond weight loss. SUSTAIN 6 is an RCT including 3297 individuals with T2DM that found lower rates of major adverse cardiovascular events (MACE) in patients taking SQ semaglutide vs. placebo (HR 0.74; 95% CI, 0.58 to 0.95). Around 40% of participants were female in SUSTAIN 6 with an average age ~65 [15].

Studies on how semaglutide affects human reproductive health are limited. Pregnant rats with clinically relevant exposures to this medication produced offspring with reduced growth and increased skeletal and visceral malformations. Pregnant cynomolgus monkeys showed more frequent early pregnancy losses and smaller offspring at exposures ≥ one-time human exposure. Given that animal data suggests the possibility of harm to offspring, semaglutide is not recommended for women who are pregnant or breastfeeding. Due to its long half-life, semaglutide should be discontinued at least 2 months before a planned pregnancy. An increase in estrus cycle length (time spent “in heat”) and a decreased number of corpora lutea were observed in female rats receiving semaglutide, suggesting that this medication might impact fertility [13].

Liraglutide

Liraglutide is another GLP-1 agonist with a mechanism of action and side effects similar to that of semaglutide. Saxenda is the brand name of liraglutide with a maintenance dose of 3 mg SQ daily, which the FDA approved in 2014 for chronic weight management. Like Wegovy, Saxenda is not recommended for those with a personal or family history of MTC or MEN2. Victoza is the brand name of a formulation of liraglutide up to 1.8 mg SQ daily that is FDA-approved for T2DM management but not for obesity.

The SCALE trial followed 3731 patients with obesity receiving Saxenda; over 56 weeks, 63.2%, and 33.1% of all participants significantly lost at least 5% and 10% of their body weight, respectively. This trial was made up of 78% women with an average age of 45 [16].

There is little direct data on liraglutide use during human pregnancies. Vascular, renal, osseous, and oropharyngeal malformations have been observed in offspring of pregnant rats receiving liraglutide at a dose ≥ 0.8 × the equivalent systemic human exposures from 3 mg SQ liraglutide daily. Another trial found a treatment-related reduction of neonatal growth in suckling rat pups exposed to liraglutide through breast milk. Per the FDA Medication Guide, liraglutide “should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.” While there is not an official recommendation for when to stop liraglutide before pregnancy, liraglutide has a shorter half-life than semaglutide which is recommended to be stopped 2 months before a pregnancy [17].

Liraglutide may improve human fertility, particularly for women with polycystic ovarian syndrome (PCOS). An RCT including 30 women with co-morbid obesity and PCOS found that those who added liraglutide 1.2 mg to metformin for 12 weeks had significantly higher pregnancy rates after in vitro fertilization compared to those who took metformin alone (pregnancy rate per embryo transfer 85.7% vs. 28.6%, respectively; P = 0.03) [18]. Another RCT following 72 women with PCOS found improved ovarian function, higher menstrual regularity, and reduced androgen levels in the group receiving 1.8 mg daily SQ liraglutide vs. placebo [19].

Orlistat

Orlistat (brand names: Alli and Xenical) obtained its FDA approval as an AOM in 1999. It inhibits gastric and pancreatic lipases, thus reducing intestinal fat absorption by up to one-third. It is administered three times daily around meals with a recommendation that patients limit their fat intake to < 30% of meals [20]. In a 4-year, double-blind prospective study including 3305 participants with obesity, those taking orlistat 120 mg three times daily lost a mean of 5.8 kg vs. 3.0 kg in the placebo group (P < 0.001). Fifty-five percent of the participants were women and the average age was ~43 years [21].

Animal studies in rats and rabbits have shown no embryotoxicity or teratogenicity even at supratherapeutic doses [22]. Generally, orlistat is not widely used for obesity management because it produces uncomfortable side effects, like fecal urgency, oily stools, and fecal incontinence, without inhibiting hunger [23]. Additionally, patients on orlistat may require fat-soluble vitamin supplementation [24]. Conversely, orlistat may be beneficial for patients with dyslipidemia [25].

Phentermine-topiramate

Phentermine-topiramate (Qsymia) received FDA approval as an AOM in 2012. Phentermine is a sympathomimetic amine anorectic, and topiramate is an antiepileptic drug. Phentermine suppresses hunger and stimulates energy expenditure by inducing catecholamine release in the hypothalamus. The mechanism of action (MOA) of topiramate includes modulation of central voltage-gated ion channels, stimulation of GABA activity, and inhibition of excitatory glutamate receptors and carbonic anhydrase activity. Qsymia is contraindicated in patients with uncontrolled hypertension, glaucoma, hyperthyroidism, seizure disorders, and eating disorders. It is also contraindicated for people who take monoamine oxidase inhibitors or those who abruptly discontinue alcohol, benzodiazepines, barbiturates, antiepileptic drugs, or chronic use of opioids. Of note, sudden discontinuation of Qsymia can precipitate a seizure [26].

Khera and colleagues evaluated 28 randomized clinical trials with 29,018 patients comparing active intervention to placebo (orlistat, 16 trials; lorcaserin, three trials; naltrexone-bupropion, four trials; phentermine-topiramate, two trials; liraglutide, two trials) and one multiple-group trial comparing liraglutide and orlistat against placebo; they found that excess weight loss compared with placebo was the highest with phentermine-topiramate (8.8 kg (95% CI, 8.0–9.6 kg)). At least 10% weight loss was seen in ~54% of participants taking Qsymia vs. ~34% for liraglutide, ~30% for naltrexone-bupropion, ~25% for lorcaserin, and ~20% for orlistat. The percentage of women in these studies ranged from 45 to 92% with the median of average age among studies ~46 years [27]. Topiramate alone has been used “off label” as monotherapy for weight loss. A meta-regression of 10 RCTs showed a mean weight loss of 4.11 kg (95% CI: −4.92 to −3.30) in trials ≤ 28 weeks in duration and a mean weight loss of 6.58 kg in studies > 28 weeks for patients taking topiramate as monotherapy for obesity [28].

Qsymia is contraindicated in pregnancy largely secondary to effects from topiramate. Besides increasing the risk of fetal mortality in animal studies, topiramate also increases the risk of cleft lip and/or cleft palate among fetuses. The FDA dissuades the use of topiramate monotherapy in reproductive-aged women as a treatment for any diseases “not associated with permanent injury or death” due to known risks of fetal harm. Diarrhea and somnolence have been reported in nursing infants whose mothers are receiving topiramate; thus, this medication is also not recommended for use in breastfeeding women. Notably, topiramate may interact with oral combined contraceptive medications, possibly decreasing contraceptive efficacy and increasing breakthrough bleeding [29].

Naltrexone-bupropion

Naltrexone-bupropion (Contrave) was FDA-approved for obesity treatment in 2014. It is composed of naltrexone, an opioid-receptor antagonist, and bupropion, a dopamine and noradrenaline reuptake inhibitor, which jointly modulate the mesolimbic dopamine circuit’s reward system and the hypothalamus’ appetite regulation center to reduce energy intake [30].

Le Roux and colleagues [31] described a post hoc analysis of six studies where the weight loss effects of naltrexone-bupropion (NB) were studied vs. placebo. The proportion of NB-treated patients who maintained at least a 5% weight loss was 89% at week 52, 55% at week 104, and 44% at week 208. Female participants made up 61% of the studies with average age range ~45–61.

While bupropion monotherapy is typically prescribed for the treatment of depression, its use is also associated with weight loss that gives it potential as an AOM. An RCT comprised of 50 women with obesity taking bupropion showed a mean weight loss of 12.9% (95% CI: 7.3–18.5) by the end of the 24-week trial [32]. Obesity increases the incidence of depression, and the prevalence of depression is approximately double for women with obesity compared to their male counterparts [33]. Therefore, the potential anti-depressant effects of this medication might offer dual benefits for this population.

Early fetal loss was observed in pregnant rats and rabbits receiving supratherapeutic doses of oral naltrexone [30]. Per the FDA, most human and animal studies do not suggest a high risk of APOs in subjects taking bupropion. However, some animal studies have shown decreased fetal weight and increased fetal malformations at supratherapeutic doses. Additionally, there have been some limited reports of seizures among breastfeeding infants of mothers taking buproprion [34].

Special Mention–Tirzepatide

While it is currently only FDA-approved for treating T2DM in adults, tirzepatide (Mounjaro) shows excellent weight loss potential. This weekly SQ injection is a dual-agonist for the two main incretins: GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). A recent double-blind RCT with 2539 participants with obesity but not diabetes found a mean percentage change in weight at week 72 of −15.0% with 5-mg weekly SQ doses of tirzepatide, −19.5% with 10-mg doses, and −20.9% with 15-mg doses vs. −3.1% with placebo (P < 0.001 for all comparisons with placebo) [35]. Mild to moderate GI side effects (nausea, vomiting, diarrhea) were observed, similar to GLP-1 agonists. Tirzepatide is also not recommended for patients with a history of MTC or MEN2 based on studies in rats [36].

Tirzepatide may reduce the efficacy of oral hormonal contraceptives; therefore, patients using oral hormonal contraceptives should switch to non-oral contraceptive methods for 4 weeks after initiation and 4 weeks after each dose escalation [36].

Special Mention–Plenity

Plenity is a non-systemic superabsorbent hydrogel made of modified cellulose cross-linked with citric acid that was FDA-approved as a device to treat overweight or obesity in 2019. When taken orally before a meal, Plenity mixes with water and ingested food and expands into a matrix that occupies ~1/4 of the average adult stomach, increasing satiety [37].

GLOW was a double-blind RCT that showed that patients taking Plenity vs. placebo were twice as likely to achieve ≥ 5% and ≥ 10% weight loss (OR: 2.0, P = 0.0008; OR: 2.1, P = 0.0107, respectively) [38].

There is minimal data on the use of Plenity in pregnancy; therefore, the safety of device for pregnant women cannot be established [37].

Anti-Obesity Medications FDA-Approved for Short-Term Use

Sympathomimetic Agents

Sympathomimetic agents have been used as pharmacotherapy for obesity since the 1930s. The anorexic effects of these medications are enacted through catecholamine release in the hypothalamus, as previously described. Four medications in this class are FDA-approved for short-term use as AOMs for up to 12 weeks: phentermine, benzphetamine, diethylpropion, and phendimetrazine [39]. When used with other treatment modalities, these medications can help reduce dietary consumption and produce modest weight loss between 5 and 10% on average in 3 months [39, 40]. Given their sympathomimetic mechanism of action, phendimetrazine and benzphetamine are considered class III controlled substances, and diethylpropion and phentermine are considered class IV controlled substances in the USA, reflecting the moderate risk of dependence and potential for abuse associated with these medications [41]. Phentermine is more commonly utilized and studied than benzphetamine, diethylpropion, and phendimetrazine.

A recent study of ~30,000 South Korean pregnant women exposed to AOMs, including phentermine and phendimetrazine, found higher average birth weight and rates of large size for gestational age (≥ 4000 g) among babies of the exposure group [42•]. Additionally, these medications are excreted in human milk, and with unknown effects on infants, their use is not recommended in breastfeeding mothers [43–46].

Off-Label Obesity Pharmacotherapy

Metformin

Metformin is a biguanide antihyperglycemic medication used to improve glucose tolerance in patients with T2DM by decreasing hepatic glucose production, decreasing intestinal absorption of glucose, and improving insulin sensitivity in peripheral tissues [47]. Weight loss data for metformin is mixed and studies have not consistently found ≥ 5% body weight loss among adults taking the medication. However, metformin seems to have other important cardiometabolic benefits as demonstrated by an RCT including ~3200 nondiabetic people that found a 31% reduction in the incidence of T2DM in the group taking metformin vs. placebo (95% CI: 17 to 43%) [48].

Compared to other medications included in this report, there is a relative abundance of studies on the use of metformin during human pregnancy and lactation; among these studies, there is varied data on the risk profile of this medication. A study examining first-trimester metformin use by diabetic women vs. nondiabetic women using metformin for subfertility found that metformin use for diabetes was associated with an increased risk of many birth defects while metformin use for subfertility was only associated with an increased risk of atrial septal defect secundum, anorectal defects, and limb reduction defects [49]. Other studies have found no significant adverse effects in infants with mothers taking metformin. Additionally, the use of metformin during pregnancy is associated with lower gestational weight gain and higher postpartum weight loss [47, 48]. However, metformin does not appear to reduce the incidence of gestational diabetes or improve other direct markers of maternal or child outcomes [48–50]. Ultimately, the FDA still advises women with diabetes to use insulin during pregnancy for optimal blood glucose control [45]. Regarding its effects on fertility, a Cochrane review found that metformin therapy did not significantly improve fertility as measured by the live birth rate among women with comorbid obesity and PCOS [51].

Metformin levels in breastmilk remain relatively constant during its maternal use [50]. While metformin may be detectable in the serum of breastfeed infants, prospective studies have shown no adverse effects on breastfeeding infants. Metformin has been suggested as a galactogoue in women with reduced milk supply, though further studies confirming its effectiveness may be required [51]. An RCT following 186 women with PCOS who received metformin during pregnancy vs. placebo found no significant difference in the duration of exclusive or partial breastfeeding between these groups [52]. Caution is recommended when using metformin for mothers with newborn and premature infants and those with renal impairment [52].

SGLT-2 Inhibitors

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a class of antihyperglycemic medications approved for managing T2DM that work in the proximal renal tubule to reduce glucose reabsorption and increase urinary glucose excretion [53, 54]. In a meta-analysis of 116 RCTs and combined cohort studies including nearly 100,000 patients taking canagliflozin, empagliflozin, sotagliflozin, or licogliflozin, the mean weight reduction was −1.79 kg (95% CI: −1.93 to −1.66) among the group taking SGLT-2 inhibitors compared with placebo in a dose–response relationship [54].

Results from animal studies suggest that the use of SGLT-2 inhibitors during pregnancy may lead to non-reversible renal damage in fetuses. These studies have also detected canagliflozin in the milk of lactating rats. Because of this animal data and the dearth of parallel studies in humans, the FDA does not recommend using SGLT-2 inhibitors during the second and third trimesters of pregnancy or while breastfeeting [53].

Zonisamide

Zonisamide is an antiepileptic medication whose MOA in weight loss involves modulation of central serotonergic and dopaminergic activity [55]. A 2011 RCT showed that ~55% of 225 participants receiving 400 mg of zonisamide alongside lifestyle counseling lost ≥ 5% of their body weight over 1 year (P = 0.007) and ~32% lost ≥ 10% of their body weight over 1 year (P = 0.001) [56].

Studies containing very few (< 5) human mothers taking therapeutic levels of zonisamide and their infants found relatively high levels of this drug in subjects’ breast milk and the blood of the breastfeeding infants. While levels of the drug in breast milk remained stable in the first weeks postpartum, levels of zonisamide in breastfeeding infants’ serum decreased over the infant’s first month of life. No adverse outcomes were reported among breastfeeding infants with mothers taking zonisamide in these small studies. In animal studies, zonisamide exposure during pregnancy has been associated with embroyonic malformations and reproductive toxicity. Given there is only a small amount of data on the use of zonisamide in human pregnancy or lactation, other anti-epileptic agents are preferred if possible. If alternate agents are not an option, some providers recommend that mothers who take zonisamide only partially breastfeed to minimize infants’ exposure to the drug [57, 58].

Amylin

Amylin is a neuroendocrine peptide hormone co-secreted with insulin by the pancreas’ β-cells. It is vital in central glucoregulation, suppressing inappropriate glucagon secretion and regulating gastric emptying [59]. Amylin agonists, including pramlintide, are approved by the FDA as antihyperglycemic agents and adjunctive therapy to mealtime insulin for patients with T2DM [59, 60]. One study of patients with obesity and no comorbid diabetes taking pramlintide showed that nearly half of participants achieved ≥ 5% weight loss at four months and that 41–65% of participants did so by 12 months of treatment [61]. Emerging drugs in this class, such as cagrilintide, have demonstrated over 50% of patients achieving ≥ 10% weight loss over 26 weeks [62].

To date, the FDA reports insufficient trial data on pramlintide in pregnancy to determine any potential adverse maternal or fetal risks. However, some increases in congenital anomalies were observed in animal studies at supratherapeutic doses. Still, pramlintide appears to have a low potential to cross the placental barrier. No data is currently available on the presence or potential effects of amylin agonists in breastmilk [60].

Summary

Obesity is a large public health concern growing in prevalence among reproductive-aged women, putting those affected at increased risk of several adverse outcomes in cardiometabolic and reproductive health. Reproductive-aged women face overlapping systems of stigma surrounding obesity, as women of all ages report higher levels of weight-stigma experiences than men, and fertility loss often induces shame, distress, and reduced self-esteem in those it affects [63, 64]. Healthy weight loss can mitigate the numerous risks that obesity presents to both mental and physical health.

The pharmacotherapy discussed in this report includes FDA-approved medications for longterm use (semaglutide, liraglutide, orlistat, phentermine-topiramate, naltrexone-bupropion), medications FDA-approved for use < 12 weeks duration (sympathomimetic agents), and several off-label pharmacotherapies (bupropion, topiramate, zonisamide, SGLT-2 inhibitors, and amylin agonists). The vast majority of these medications do not have adequate data on reproductive outcomes to make definitive statements about their effects on human fertility or pregnancy. This fact highlights the importance of the Drugs and Lactation Database (LactMed), which provides one of the only sources of information about AOMs that is primarily focused on outcomes relevant to women’s reproductive health. The database contains evidence from human and animal studies about how much of an AOM is typically found in mothers’ and infants’ blood, whether a medication is transmitted through breastmilk, and whether there are known adverse effects of a medication for breastfeeding infants (recommending alternatives where indicated). In the future, more studies should follow the example of the LactMed Database by focusing on the reproductive ramifications as well as the cardiometabolic outcomes of AOMs in women of reproductive age (using ethical methods of investigation). Many of the existing studies on antiobesity pharmacotherapy center on populations older than this group for whom questions about reproductive health are not as relevant. Providers should inform reproductive-aged women about the lack of knowledge of the effects that various AOMs might have on pregnancy, fertility, or lactation. It is crucial to counsel these women on contraception, especially long-acting reversible options such as intra-uterine devices or hormonal implants, in order to allow them to control the timing of pregnancies while taking AOMs or considering their use. While taking caution to prevent adverse reproductive outcomes is understandable, this concern should not preclude reproductive-aged women from receiving effective AOMs alongside appropriate contraceptive counseling. Helping more reproductive-aged women find safe and efficacious treatments for obesity will have myriad health benefits affecting multiple generations.

Funding

Fatima Cody Stanford declares funding from the National Institutes of Health grants NIDDK U24 DK132733 and P30 DK040561. The rest of the authors have no declarations.

Footnotes

1

Overweight is commonly defined as BMI ≥ 25 kg/m2.

2

STEP 7 is ongoing.

Conflict of Interest The authors don’t have any conflict of interest.

Compliance with Ethical Standards

Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

Data Availability

Data sharing not applicable to this article as no data-sets were generated or analysed during the current study.

References

Papers of particular interest, published recently, have been highlighted as:

• Of importance

  • 1.Hales CM, Carroll MD, Fryar CD, Ogden CL. Prevalence of obesity and severe obesity among adults: United States, 2017–2018. Centers for Disease Control and Prevention; 2020. p. 8. [PubMed] [Google Scholar]
  • 2.Jensen MD, Ryan DH, Apovian CM, Ard JD, Comuzzie AG, Donato KA, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. J Am Coll Cardiol. 2014;63(25 Pt B):2985–3023. 10.1016/j.jacc.2013.11.004. [DOI] [PubMed] [Google Scholar]
  • 3.Curioni CC, Lourenço PM. Long-term weight loss after diet and exercise: a systematic review. Int J Obes (Lond). 2005;29(10):1168–74. 10.1038/sj.ijo.0803015. [DOI] [PubMed] [Google Scholar]
  • 4.Prescription medications to treat overweight & obesity. https://www.niddk.nih.gov/health-information/weight-management/prescription-medications-treat-overweight-obesity. Revised June 2021. Accessed 7 Aug 2022.
  • 5.Webb PM. Obesity and gynecologic cancer etiology and survival. Am Soc Clin Oncol Educ Book. 2013. 10.1200/EdBook_AM.2013.33.e222. [DOI] [PubMed] [Google Scholar]
  • 6.Dag ZO, Dilbaz B. Impact of obesity on infertility in women. J Turk Ger Gynecol Assoc. 2015;16(2):111–7. 10.5152/jtgga.2015.15232. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Chen C, Xu X, Yan Y. Estimated global overweight and obesity burden in pregnant women based on panel data model. PLoS One. 2018;13(8):e0202183. 10.1371/journal.pone.0202183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.American College of Obstetricians and Gynecologists’ Committee on Practice, Bulletins-Obstetrics. Obesity in Pregnancy: ACOG Practice Bulletin, Number 230. Obstet Gynecol. 2021;137(6):128–44. 10.1097/AOG.0000000000004395. [DOI] [PubMed] [Google Scholar]
  • 9.Ogunwole SM, Zera CA, Stanford FC. Obesity management in women of reproductive age. JAMA. 2021;325(5):433–4. 10.1001/jama.2020.21096. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.FDA approves new drug treatment for chronic weight management, first since 2014. FDA. Washington, DC: Center for Drug Evaluation and Research. June 2021. [Google Scholar]
  • 11.Chao AM, Tronieri JS, Amaro A, Wadden TA. Semaglutide for the treatment of obesity. Trends Cardiovasc Med. 2021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Alabduljabbar K, Vincent RP, le Roux CW. Semaglutide is precipitating a revolution in obesity care. In: Translational Metabolic Syndrome Research. Elsevier; 2022. [Google Scholar]
  • 13.WEGOVY (semaglutide injection) for subcutaneous use. Highlights of prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215256s000lbl.pdf. Revised June 2021. Accessed 8 Aug 2022. [Google Scholar]
  • 14.Rubino DM, Greenway FL, Khalid U, O’Neil PM, Rosenstock J, Sørrig R, et al. Effect of weekly subcutaneous semaglutide vs daily liraglutide on body weight in adults with overweight or obesity without diabetes: the STEP 8 randomized clinical trial. JAMA. 2022;327(2):138–50. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Marso SP, Holst AG, Vilsboll T. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2017;376(9):891–2. 10.1056/NEJMc1615712. [DOI] [PubMed] [Google Scholar]
  • 16.Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med. 2015;373(1):11–22. 10.1056/NEJMoa1411892. [DOI] [PubMed] [Google Scholar]
  • 17.SAXENDA (liraglutide injection) for subcutaneous use. Highlights of prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206321s007lbl.pdf. Revised October 2018. Accessed 8 Aug 2022. [Google Scholar]
  • 18.Salamun V, Jensterle M, Janez A, Bokal EV. Liraglutide increases IVF pregnancy rates in obese PCOS women with poor response to first-line reproductive treatments: a pilot randomized study. Eur J Endocrinol. 2018;179(1):1–11. [DOI] [PubMed] [Google Scholar]
  • 19.Nylander M, Frøssing S, Clausen HV, Kistorp C, Faber J, Skouby SO. Effects of liraglutide on ovarian dysfunction in polycystic ovary syndrome: a randomized clinical trial. Reprod Biomed Online. 2017;35(1):121–7. [DOI] [PubMed] [Google Scholar]
  • 20.Heck AM, Yanovski JA, Calis KA. Orlistat, a new lipase inhibitor for the management of obesity. Pharmacother J Hum Pharmacol Drug Ther. 2000;20(3):270–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Torgerson JS, Hauptman J, Boldrin MN, Sjöström L. XENical in the Prevention of Diabetes in Obese Subjects (XENDOS) study. A randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Clin Diabetol. 2004;5(2):95–104. [DOI] [PubMed] [Google Scholar]
  • 22.XENICAL (orlistat) capsule. Highlights of prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020766s029lbl.pdf. Revised January 2012. Accessed 7 Aug 2022. [Google Scholar]
  • 23.Saunders KH, Umashanker D, Igel LI, Kumar RB, Aronne LJ. Obesity pharmacotherapy. Med Clin. 2018;102(1):135–48. [DOI] [PubMed] [Google Scholar]
  • 24.Pilitsi E, Farr OM, Polyzos SA, Perakakis N, Nolen-Doerr E, Papathanasiou A-E, et al. Pharmacotherapy of obesity: available medications and drugs under investigation. Metabolism. 2019;92:170–92. [DOI] [PubMed] [Google Scholar]
  • 25.Wierzbicki AS, Reynolds TM, Crook MA. Usefulness of Orlistat in the treatment of severe hypertriglyceridemia. Am J Cardiol. 2002;89(2):229–31. 10.1016/s0002-9149(01)02208-1. [DOI] [PubMed] [Google Scholar]
  • 26.Qsymia (phentermine and topiramate extended-release) capsules. Highlights of prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/022580s021lbl.pdf. Revised June 2022. Accessed 9 Aug 2022. [Google Scholar]
  • 27.Khera R, Murad MH, Chandar AK, Dulai PS, Wang Z, Prokop LJ, et al. Association of pharmacological treatments for obesity with weight loss and adverse events: a systematic review and meta-analysis. JAMA. 2016;315(22):2424–34. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Kramer CK, Leitão CB, Pinto LC, Canani LH, Azevedo MJ, Gross JL. Efficacy and safety of topiramate on weight loss: a meta-analysis of randomized controlled trials. Obes Rev. 2011;12(5):e338–47. 10.1111/j.1467-789x.2010.00846.x. [DOI] [PubMed] [Google Scholar]
  • 29.Topamax (topiramate) tablets for oral use. Highlights of prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/020505s062,020844s053lbl.pdf. Revised January 2022. Accessed 9 June 2022. [Google Scholar]
  • 30.CONTRAVE (naltrexone HCl and bupropion HCl) extended release tablet. Highlights of prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/022580s021lbl.pdf. Revised September 2014. Accessed 9 Aug 2022. [Google Scholar]
  • 31.Le Roux CW, Astrup A, Fujioka K, Greenway F, Lau DCW, Van Gaal L, et al. 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial. Lancet. 2017;389(10077):1399–409. [DOI] [PubMed] [Google Scholar]
  • 32.Gadde KM, Parker CB, Maner LG, Wagner HR, Logue EJ, Drezner MK, et al. Bupropion for weight loss: an investigation of efficacy and tolerability in overweight and obese women. Obes Res. 2001;9(9):544–51. [DOI] [PubMed] [Google Scholar]
  • 33.Fulton S, Décarie-Spain L, Fioramonti X, Guiard B, Nakajima S. The menace of obesity to depression and anxiety prevalence. Trends Endocrinol Metab. 2022;33(1):18–35. [DOI] [PubMed] [Google Scholar]
  • 34.Wellbutrin (bupropion hydrochloride) tablets. Highlights of prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/018644s054lbl.pdf. Accessed 9 June 2022. [Google Scholar]
  • 35.Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387:205–16. [DOI] [PubMed] [Google Scholar]
  • 36.MOUNJARO (tirzepatide) injection for subcutaneous use. Highlights of prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215866s000lbl.pdf. Revised May 2022. Accessed 9 Aug 2022. [Google Scholar]
  • 37.Plenity Giruzzi N. (Oral Superabsorbent Hydrogel). Clin Diabetes. 2020;38(3):313–4. 10.2337/cd20-0032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Greenway FL, Aronne LJ, Raben A, Astrup A, Apovian CM, Hill JO, et al. A randomized, double-blind, placebo-controlled study of Gelesis100: a novel nonsystemic oral hydrogel for weight loss. Obesity (Silver Spring). 2019;27(2):205–16. 10.1002/oby.22347. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Stăcescu Ș, Hancu G, Podar D, Todea Ș, Tero-Vescan A. A historical overview upon the use of amphetamine derivatives in the treatment of obesity. J Pharm Care. 2019;7:72–9. [Google Scholar]
  • 40.Kang JG, Park CY. Anti-obesity drugs: a review about their effects and safety. Diabetes Metab J. 2012;36(1):13–25. 10.4093/dmj.2012.36.1.13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Lists of scheduling actions, controlled substances, regulated chemicals. In: U.S. Department of Justice DEA, Diversion Control Division, Drug & Chemical Evaluation Section, U.S. Department of Justice; Revised January 2023. Accessed January 18, 2023. [Google Scholar]
  • 42. Choi EJ, Han JY. Pregnancy outcomes after inadvertent exposure of anti-obesity drugs during pregnancy. Clin Exp Obstet Gynecol. 2021;48(3):514–22. • This study is unique in that it followed pregnancy outcomes for a large group of human women (~30,000) who were inadvertently exposed to AOMs such as phentermine during pregnancy. The vast majority of studies related to human pregnancy and anti-obesity pharmacotherapy contain a very small number of subjects due to ethics concerns. This study provided a unique opportunity to observe natural data on this topic in a manner that mitigated some related ethics concerns.
  • 43.Fendique ER (phendimetrazine tartrate) extended release capsules. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/018074Orig1s037lbl.pdf. Revised November 2020. Accessed 9 June 2022.
  • 44.Adipex-P (phentermine) capsules. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/085128s065lbl.pdf. Revised April 2012. Accessed 9 June 2022.
  • 45.Tenuate (diethylpropion hydrochloride USP) tablets. https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/11722s029,12546s032lbl.pdf. Revised November 2003. Accessed 9 June 2022.
  • 46.Didrex (benzphetamine hydrochloride) tablets. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/012427s031lbl.pdf. Revised April 2020. Accessed 9 June 2022.
  • 47.Glucophage (metformin hydrochloride) tablets. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020357s037s039,021202s021s023lbl.pdf. Revised April 2017. Accessed 9 June 2022.
  • 48.Lentferink YE, Knibbe CAJ, Van Der Vorst MMJ. Efficacy of metformin treatment with respect to weight reduction in children and adults with obesity: a systematic review. Drugs. 2018;78(18):1887–901. 10.1007/s40265-018-1025-0. [DOI] [PubMed] [Google Scholar]
  • 49.Dukhovny S, Van Bennekom CM, Gagnon DR, Hernandez Diaz S, Parker SE, Anderka M, et al. Metformin in the first trimester and risks for specific birth defects in the National Birth Defects Prevention Study. Birth Defects Research. 2018;110(7):579–86. 10.1002/bdr2.1199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Metformin. Drugs and Lactation Database (LactMed(R)). https://www.ncbi.nlm.nih.gov/books/NBK501020/. Revised March 2022. Accessed 18 Jan 2023. [Google Scholar]
  • 51.Nommsen-Rivers L, Thompson A, Riddle S, Ward L, Wagner E, King E. Feasibility and acceptability of metformin to augment low milk supply: a pilot randomized controlled trial. J Hum Lact. 2019;35(2):261–71. 10.1177/0890334418819465. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Vanky E, Nordskar JJ, Leithe H, Hjorth-Hansen AK, Martinussen M, Carlsen SM. Breast size increment during pregnancy and breastfeeding in mothers with polycystic ovary syndrome: a follow-up study of a randomised controlled trial on metformin versus placebo. BJOG. 2012;119(11):1403–9. 10.1111/j.1471-0528.2012.03449.x. [DOI] [PubMed] [Google Scholar]
  • 53.Invokana (canagliflozin) tablets. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/204042s034lbl.pdf. Revised August 2020. Accessed 9 June 2022.
  • 54.Cheong AJY, Teo YN, Teo YH, Syn NL, Ong HT, Ting AZ, et al. SGLT inhibitors on weight and body mass: a meta-analysis of 116 randomized-controlled trials. Obesity. 2022;30(1):117–28. [DOI] [PubMed] [Google Scholar]
  • 55.Gadde KM, Franciscy DM, Wagner Ii HR, Krishnan KRR. Zonisamide for weight loss in obese adults. JAMA. 2003;289(14):1820. 10.1001/jama.289.14.1820. [DOI] [PubMed] [Google Scholar]
  • 56.Gadde KM, Kopping MF, Wagner HR, Yonish GM, Allison DB, Bray GA. Zonisamide for weight reduction in obese adults: a 1-year randomized controlled trial. Arch Intern Med. 2012;172(20):1557–64. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Zonisamide. Drugs and Lactation Database (LactMed(R)). Revised September 2020. Accessed January 18, 2023. [Google Scholar]
  • 58.Zonegran (zonisamide) tablets. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020789s036lbl.pdf. Revised April 2020. Accessed 9 June 2022.
  • 59.Aronne L, Fujioka K, Aroda V, Chen K, Halseth A, Kesty NC, et al. Progressive reduction in body weight after treatment with the amylin analog pramlintide in obese subjects: a phase 2, randomized, placebo-controlled, dose-escalation study. J Clin Endocrinol Metab. 2007;92(8):2977–83. [DOI] [PubMed] [Google Scholar]
  • 60.Symlin (pramlintide acetate) tablets. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021332s028lbl.pdf. Revised December 2019. Accessed 9 June 2022.
  • 61.Smith SR, Aronne LJ, Burns CM, Kesty NC, Halseth AE, Weyer C. Sustained weight loss following 12-month pramlintide treatment as an adjunct to lifestyle intervention in obesity. Diabetes Care. 2008;31(9):1816–23. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Dehestani B, Stratford NR, le Roux CW. Amylin as a future obesity treatment. J Obes Metab Syndr. 2021;30(4):320. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Sattler KM, Deane FP, Tapsell L, Kelly PJ. Gender differences in the relationship of weight-based stigmatisation with motivation to exercise and physical activity in overweight individuals. Health Psychol Open. 2018;5(1):2055102918759691. 10.1177/2055102918759691. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Worthington AK, Burke EE, Leahy C. A comprehensive examination of infertility stigma among fertile and infertile women in the United States. Fertil Steril. 2019;112(3):e378. 10.1016/j.fertnstert.2019.07.1082. [DOI] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

Data sharing not applicable to this article as no data-sets were generated or analysed during the current study.

RESOURCES