Glucagon-like peptide-1 receptor agonists and safety in the preconception period

Abstract

Purpose of review

Glucagon-like peptide 1 (GLP-1) receptor agonists (RAs) are becoming increasingly popular for the treatment of type II diabetes and obesity. Body mass index (BMI) thresholds at in vitro fertilization (IVF) clinics may further drive the use of these medications before infertility treatment. However, most clinical guidance regarding optimal time to discontinue these medications prior to conception is based on animal data. The purpose of this review was to evaluate the literature for evidence-based guidance regarding the preconception use of GLP-1 RA.

Recent findings

16 articles were found in our PubMed search, 10 were excluded as they were reviews or reported on animal data. Included were 3 case reports detailing pregnancy outcomes in individual patients that conceived while on a GLP-1 RA and 2 randomized controlled trials (RCTs) and a follow-up study to one of the RCTs that reported on patients randomized to GLP-1 RA or metformin prior to conception. No adverse pregnancy or neonatal outcomes were reported.

Summary

There are limited data from human studies to guide decision-making regarding timing of discontinuation of GLP-1 RA before conception. Studies focused on pregnancy and neonatal outcomes would provide additional information regarding a safe washout period. Based on the available literature a 4-week washout period prior to attempting conception may be considered for the agents reviewed in this publication.

INTRODUCTION

Obesity is a worldwide epidemic that continues to affect a large portion of the United States population. According to the National Health and Nutrition Examination Survey (NHANES), the prevalence of obesity in adults between 2017 and 2018 was 42.4% [1], while the prevalence of diabetes was 14.0% between 2013 and 2016 [2]. This sobering statistic takes a particular toll on women of reproductive age, with 34% affected by obesity [3] including 25% of all women who become pregnant [4]. In addition, women with polycystic ovary syndrome (PCOS), the most common endocrinopathy in this age group, are uniquely affected by obesity, metabolic syndrome, and insulin resistance. Obesity affects symptom severity of PCOS by augmenting insulin resistance, thus increasing circulating insulin levels and subsequent androgen levels [5]. Literature also supports that women with PCOS and obesity have difficulty sustaining weight loss with lifestyle modifications alone [6]. Furthermore, the negative impact of obesity on fertility and spontaneous pregnancy potential only adds to the impact of obesity on reproductive age women [7–9].

In a survey of Society for Assisted Reproductive Technology (SART) clinics with a 19.5% response rate, 64.9% reported having a formal policy for obesity [10]. In addition, 84% of clinics with a policy responded that they had a BMI limit for offering in vitro fertilization (IVF).

BMI restrictions are enforced by these clinics due to lower IVF success rates and anesthesia risks with patients above a certain threshold, as well as morbidity associated with obesity and pregnancy. This further reduces access to infertility treatment among the increasing proportion of patients with infertility with concomitant obesity. Furthermore, attempts to meet those BMI requirements via lifestyle modifications or weight-loss surgery may delay treatment in patients, whose outcomes are poor with increasing age. In view of this, patients and providers have in recent years turned to glucagon-like peptide 1 receptor agonists to support BMI optimization prior to fertility treatments.

Glucagon-like peptide 1 receptor agonist in reproductive age patients

GLP-1 RAs are Federal Drug Administration (FDA) approved antidiabetic and antiobesity medications with incretin-mimetic activity [11,12]. These glucose-lowering agents have been shown to induce significant hemoglobin A1C reduction and offer important cardiovascular benefits [11,13]. Of particular interest is the additional advantage of weight loss, even in patients who do not have type II diabetes. GLP-1 RA treatment, with or without metformin, has been shown to help with weight loss and metabolic changes in patients with PCOS [14,15]. More specifically, a meta-analysis of seven randomized controlled trials of liraglutide, a long acting GLP-1 RA, treatment in patients with PCOS indicated decreased body mass index (BMI) and serum testosterone over 12 weeks. Insulin levels and sensitivity (measured by Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), however, were not significantly decreased [16].

In addition to favorable changes in androgen parameters, increased menstrual regularity has also been demonstrated with GLP-1 RA treatment [14,15,17]. Additionally, a meta-analysis of eight randomized controlled trials evaluating metformin treatment versus GLP-1 RA in patients with PCOS showed that the latter is more effective in reducing insulin resistance, BMI, and abdominal circumference [18].

The effectiveness of GLP-1RA in improving reproductive parameters such as menstrual cyclicity and androgen levels may be explained by the weight loss itself, as a reduction in body weight has been shown to improve hyperandrogenism and reproductive function in women with PCOS [19].

Physiology of glucagon-like peptide 1

GLP-1 is a member of the incretin hormone family, secreted by L-cells in the gut after food intake, with insulinotropic action. In addition, this hormone has been shown to induce satiety by delaying gastric emptying and acting on the brain directly and via the vagus nerve [20–25], thus causing weight loss.

Some studies suggest that there may be a complex interaction between incretins and the reproductive system. A recent review article by Jestenrle et al. [26] underlined that preclinical models and clinical studies have shown that the GLP-1 receptor is present throughout the reproductive system. Furthermore, GLP-1 may have anti-inflammatory and antifibrotic action in the endometrium and gonads, particularly in obesity, diabetes, and PCOS. Given the above evidence, GLP-1 may be highly implicated in reproductive physiology, thus suggesting an important role for GLP-1 RA in treating women with PCOS, obesity, and infertility.

Fertility and obesity

Obesity, independently of anovulation, has been associated with decreased fecundity. An inverse relationship between increasing BMI and time to spontaneous conception has been demonstrated, while there are mixed data regarding the impact of obesity on ART outcomes [5,7–9]. More specifically, there are data to support that obesity may negatively affect antiretroviral therapy (ART) outcomes by prolonging the duration of stimulation and increasing gonadotropin needs [27]. Obesity has also been shown to potentially be associated with poor oocyte and embryo quality and impaired endometrial receptivity [5,28]. However, there are mixed results regarding improved ART outcomes with preconception weight loss. An analysis of two multicenter trials in patients with PCOS, obesity/overweight, and infertility showed improved ovulation and live birth rates in women who underwent ovulation induction after weight loss compared to patients who did not lose weight [29]. Conversely, a recent meta-analysis of fifteen randomized controlled trials on prepregnancy lifestyle changes and reproductive outcomes reports that the benefit of preconception weight loss is limited to spontaneous pregnancy and not ART [30]. However, the obstetrical and fetal risks associated with obesity are well documented, and preconception weight loss is recommended. While pharmacotherapy may be an effective way to achieve the above goals, weight loss agents are contraindicated in pregnancy and should be discontinued preconception [31,32].

Glucagon-like peptide 1 receptor agonist and pregnancy

GLP-1 RAs are classified as pregnancy class C medications as they have been shown to cross the placenta and cause fetal growth restriction and congenital anomalies in animals. Thus, these medications are contraindicated in pregnancy, and contraception is recommended during their use [13]. The above recommendations are based on animal studies [33]. The overall guidance in the literature regarding the length of discontinuation of GLP-1 RA before conception is inconsistent, ranging from one to three months, and is generally based on animal data and recommendations for oral antidiabetic agents [13,34–36]. The fact that many of the GLP-1 RA available are long-acting with a half-life of 2.4 h to 2 weeks further complicates the management of these medications in women of reproductive age.

The FDA inserts on exenatide, albiglutide, lixisenatide, and semaglutide present data on congenital malformations, embryo-fetal mortality, and growth restrictions in mice, rats, rabbits, and monkeys after exposure to GLP-1 RA during the organogenesis period. Most of these adverse effects were reported following a higher dosage than the maximum human recommended dose with toxic vs. maximum doses: exenatide (3–12× clinical dose 5–10 mcg), albiglutide (39x clinical dose 30–50 mg), lixisenatide (1, 6, 9, 200, 400× clinical dose 20 mcg), dulaglutide (5, 7, 18× clinical dose 0.75–4.5 mg) and semaglutide (1, 3, 5× clinical dose 0.5 mg) [33,37–40].

There are mixed data regarding the administration in the preconception period in animal studies. A recent study monitoring the effects of preconception administration of exendin-4, a long-acting GLP-1RA, in mice’s preconception and prenatal period showed minimal adverse effects on the mice and their pups [41]. Notably, the manufacturers of these agents acknowledge the lack of well controlled human studies on the safety of these medications. Furthermore, their manufacturer inserts include the disclaimer that GLP-1 RA should be discontinued in pregnancy unless the risk of uncontrolled diabetes by discontinuing the drug justifies the potential fetal risks. The manufacturers maintain pregnancy registries to monitor pregnancy outcomes in pregnant women exposed to GLP-1 RA agonists. In one study, fetal exposure was found to be negligible when assessing ex vivo human placental transmission of exenatide [42].

The lack of long-term human data presents a significant gap in the care of reproductive-age patients. With the increasing prevalence of obesity and metabolic syndrome in patients with PCOS [43,44] it is reasonable to anticipate that we will continue to have more patients that may become pregnant while on a GLP-1 agonist and inadvertently have periconceptional/fetal exposure to a category C medication class.

Given the paucity of human safety data on GLP-1 RAs in pregnancy and the need to balance treatment of obesity and type II diabetes with pregnancy planning, we reviewed the available literature on the use of GLP-1 RA agonists in the preconception and early pregnancy period. We specifically focused our attention on the optimal time to discontinue these agents prior to conception, in view of the risk of rebound weight gain after cessation of treatment.

METHODS

This is a narrative review of the literature on the use of GLP-1 RA in pregnancy and preconception. Studies on treatment with a GLP-1 RA and pregnancy or fertility were evaluated. PubMed database and Google Scholar searches were performed using the following keywords: GLP-1 agonist, GLP-1 RA, glucagon-like peptide-1 receptor agonist, in combination with the following reproductive-related terms, pregnancy, liraglutide, exenatide, albiglutide, polycystic ovarian syndrome, dulaglutide, semaglutide, lixisenatide, fetal malformation, embryogenesis, preconception.

Articles were selected for inclusion if they reported on the use of GLP-1 RA in the preconception period or early pregnancy, on pregnancy rates, and if they reported pregnancy complications or fetal outcomes. Importantly, due to the limited number of studies published, case reports were also included. The flow of the selection of articles is represented in Fig. 1.

FIGURE 1.

Flow diagram of articles reviewed, excluded and included.

RESULTS

Our initial search yielded sixteen articles referencing GLP-1 RA use before and during early pregnancy and guidance on the recommended washout period. Of those sixteen articles, only six reported on data from human subjects treated with GLP-1 RA. Of those six articles, two studies were randomized controlled trials (RCTs) [34,45].

Randomized controlled trials

The first RCT by Liu et al. evaluated the effect of exenatide on weight loss, metabolic benefits, and pregnancy rates in patients with PCOS who had overweight and obesity [45]. In this prospective study, 176 patients were randomized to either treatment with metformin 1000 mg twice daily or exenatide 10 mcg twice daily for 12 weeks, followed by 2 weeks of metformin 1000 mg treatment for all patients. The size of the study population was according to a power analysis to a power of 80%. Both groups were advised on lifestyle changes with diet and exercise. Contraception was advised in the first 12 weeks of the study, while couples were advised to have unprotected intercourse during the second 12-week period. The study’s exenatide arm showed increased loss of weight and fat as well as decreased insulin resistance measured by HOMA IR. Furthermore, the patients treated with exenatide had an increased menstrual frequency ratio at 12weeks of treatment and a higher spontaneous pregnancy rate at 12weeks after discontinuation of treatment (43.6% vs. 18.7, P < 0.05) [45].

The group then reported on extended follow-up data on the study population for 64 weeks [46^▪]. Following the initial 24-week study period, patients who did not achieve pregnancy were offered up to three ovulation induction cycles. Patients who did not achieve pregnancy after three ovulation cycles were then offered one IVF and embryo transfer (ET) cycle. Patients were followed up every 4 weeks until pregnancy or until week 64 of the study. Patients who achieved pregnancy through any means were followed up until delivery. Importantly, the authors underlined that the population reported on for this pregnancy outcome analysis (ITT, n = 160) differed slightly from the one presented in the initial article as several patients declined ART or had ART at a different facility. In addition, the spontaneous pregnancy rate reported in this analysis (PP) differed as patients that were lost to follow-up were not included. However, the rate of natural conception in the exenatide group was still significantly higher when compared to the control group (29.2 vs. 14.7%, P = 0.03).

Final pregnancy rates did not differ between the two groups (exenatide vs. metformin, 79.2% vs. 76%, P = 0.65). In addition, rates of miscarriage, live birth, preterm delivery, and incidence of gestational diabetes and hypertension were similar in both groups. Furthermore, no significant difference was noted concerning maternal gestational weight gain and neonatal birth weight (9.62 ± 1.90 kg vs. 9.81 ± 1.78 kg, P = 0.72; 3.05 ± 0.33 kg vs. 3.02 ± 0.30 kg; P = 0.90, respectively). Interestingly, there was no specific washout period for the exenatide group, which can be explained by the fact that the study group was treated with the immediate release agent with a half-life of 2.4 h. No adverse pregnancy events were reported.

The second randomized controlled trial to report on GLP-1 RA agonist treatment in the preconception period followed 28 patients with PCOS, obesity, and infertility, randomized to 1000 mg of metformin daily or metformin plus 1.2 mg of subcutaneous liraglutide daily for 12 weeks [34]. Both patient groups also underwent lifestyle modifications with exercise and diet. Controlled ovarian hyperstimulation for IVF was started following a 4-week washout period.

There was no significant difference in weight loss between the two groups (7 kg loss in metformin group vs. 7.5 kg loss in liraglutide and metformin group). At the same time, the pregnancy per ET rate was significantly higher in the combination group when compared to the metformin group [85.7% (6/7) vs. 28.57% (2/7), P = 0.03]. In addition, there was a trend toward a higher cumulative pregnancy rate in the combination group. The overall pregnancy rate was higher in the combination group of 9/13 (69.2%) patients versus 5/14 (35.7%), thought the sample size was limited. This included two spontaneous pregnancies in each group over the 12 months that patients were followed posttreatment. The study did not report on long-term pregnancy outcomes. They did, however, report no difference between the two groups with regards to the number of oocytes and mature oocytes retrieved as well as embryologic data (fertilization rate, day 5 embryos per patient, blastocysts per patient, blastulation rate, transferred embryos, pregnancyrate per cycle, implantation rate, cryopreservation rate, number of cryopreserved embryos per patient).

The authors concluded that short-term preconception treatment with liraglutide in combination with metformin was superior to metformin alone regarding fertility. They also reported that treatment with a washout period appeared acceptable based on the Liu study and case studies of preconception and early pregnancy exposure to GLP-1 RA.

Case reports

The remaining three articles comprised case reports. Greco reported on a 37-year-old patient with type II diabetes who had been on liraglutide 1.8 mg daily for 2 years and was found to be at 13 weeks of gestation. Liraglutide was discontinued and replaced with insulin treatment. No pregnancy or neonatal complications were reported [47].

Burlina et al. presented a case of a patient with type II diabetes, treated with dulaglutide (1.5 mg/week) and metformin (1000 mg twice daily) starting 6 weeks before conception and continuing to 15 weeks of gestation. Once pregnancy was diagnosed, insulin treatment was initiated, and dulaglutide was discontinued. No complications were reported during pregnancy, neonatal weight was appropriate for gestational age, and no congenital malformations or neonatal comorbidities were reported [48^▪].

Finally, Yang reported on a 26-year-old patient with PCOS, oligomenorrhea, obesity, and insulin resistance who was treated with exenatide 20 mcg daily for 2 months. A month after discontinuing treatment, the patient underwent ovulation induction and conceived. The pregnancy was reported to be uncomplicated with a term delivery of a normal-weight neonate [49].

The above studies are summarized in Table 1.

Table 1.

Agents reviewed, time of discontinuation and complications

Article	GLP-1 RA dosing	Half-life	Study washout period	Pregnancy/neonatal complications
Randomized controlled trials
Liu et al./Li et al.	Exenatide 10 mcg b.i.d. s.c.	2.4 h	None	No difference in: • Spontaneous abortion • Live birth • Preterm delivery • Gestational diabetes • Pregnancy associated hypertension • Maternal gestational weight gain • Neonatal birth weight
				ART outcomes
Salamun et al.	Liraglutide 1.2mg q.d. s.c.	13 h	4 weeks	No difference in: • Retrieved oocytes per patient • Mature oocytes per patient • Fertilization rate • Oocyte degeneration rate • Oocyte immaturity rate • Day 5 embryos per patient • Blastocysts per patient • Blastulation rate • Transferred embryos • Pregnancy rate per cycle • Implantation rate • Cryopreservation rate • Number of cryopreserved embryos per patient
Case reports
Yang	Exenatide 20 mcg QD sc	2.4 h	1 month	None
Burlina et al.	Dulaglutide 1.5 mg Q/W s.c.	5 days	None/ up to 15 weeks gestation	None
Greco	Liraglutide 1.8 mg daily s.c.	13 h	None/ up to 13 weeks gestation	None

DISCUSSION

Summary

Despite the growing popularity of GLP-1 RA treatment in women with obesity and PCOS, there are limited data from human studies on their use in the preconception period.

In our literature review, only two randomized controlled trials assessed pregnancy outcomes in women after treatment with GLP-1 RA [34,45], and one of those reported on obstetrical and neonatal outcomes [46^▪]. These studies showed that GLP-1 RA treatment may increase spontaneous and ART pregnancy rate per ET by 25% and 57.1%, respectively [34,45].

The remainder of the literature reporting on pregnancy outcomes in women exposed to GLP-1 RA consists of case reports [47,48^▪,49]. Even though none of the above trials and case studies showed adverse pregnancy outcomes, the number of patients reported was small and safe conclusions cannot be drawn, especially with no long-term follow-up on neonatal and childhood outcomes.

CONCLUSION

GLP-1 RAs are an FDA approved and well established class of antidiabetic and antiobesity medications with significant benefits for patients with obesity and PCOS. Most of these patients are women of reproductive potential who may have limited access to infertility treatment given BMI restrictions in place for patient and pregnancy safety. In addition, weight loss interventions such as lifestyle modifications and weight loss surgery may further delay infertility treatment, to the detriment of the reproductive outcome, that is correlated with age. Therefore, the need for GLP-1 agonists may be even greater in this population. Available recommendations regarding the safety of these drugs in pregnancy are based on animal studies. These recommended washout periods range from 1 to 3 months. There are limited data from human studies to guide decision-making on the optimal time to discontinue these medications before conception. Given the well established risks associated with obesity in pregnancy, the significant advantages that treatment with GLP-1 RA agonists offer, and the potential for rebound weight gain after cessation of GLP1-RAs, further studies reporting on pregnancy, maternal and neonatal outcomes in the setting of GLP-1 RA treatment are needed.

KEY POINTS.

• Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are increasingly popular medications approved for the treatment of obesity and type II diabetes.

• BMI limits at in vitro fertilization clinics may increase the use of these medications in patients prior to infertility treatment.

• Only two randomized controlled trials (RCTs), one follow-up study from one of the RCTs and three case reports reported pregnancy and neonatal data from patients treated with GLP-1 RA prior to conception or in early pregnancy.

• No adverse effects were reported from use of GLP-1 RA in the preconception period or early pregnancy.

• Further studies reporting on pregnancy, maternal and neonatal outcomes in the setting of GLP-1 RA treatment are needed.