Case Report: Exenatide Use During Pregnancy : The Endocrinologist

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00019616-200905000-00008ReportThe EndocrinologistThe Endocrinologist© 2009 Lippincott Williams & Wilkins, Inc.19May 2009 p 119-121Case ReportExenatide Use During PregnancyCase ReportWilliams, Jennifer MD*; Pomeroy, Nathan E. MD, MPH†; Pop-Busui, Rodica MD, PhD†; Lash, Robert MD†; Douyon, Liselle MD†; Chames, Mark MD*; Wyckoff, Jennifer MD†From the *Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI; and †Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI.Reprints: Jennifer Wyckoff, MD, Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan, 1500 E, Medical Center Dr, 3920 Taubman Center, SPC 5354, Ann Arbor, MI 48109. E-mail: [email protected]:To describe the effects on pregnancy outcomes of exposure to exenatide through the first trimester of pregnancy.Methods:A 35-year-old woman with type 2 diabetes mellitus, hypertension, infertility, oligomenorrhea, and morbid obesity, conceived spontaneously while taking multiple medications, including exenatide. The pregnancy was diagnosed incidentally at 14 weeks gestational age, and exenatide was discontinued at that time.Results:Fetal ultrasonography and echocardiography revealed no anomalies, and fetal growth was normal. Preeclampsia became superimposed on chronic hypertension at 38 weeks, and a complicated labor and delivery followed. No congenital anomalies were observed in the infant.Conclusions:In this one case, there were no congenital malformations or other adverse outcomes of pregnancy after exposure to exenatide through the first trimester. This case underscores the importance of counseling all women of reproductive age with preexisting diabetes regarding pregnancy.Exenatide is a subcutaneously injected incretin-mimetic used in the treatment of type 2 diabetes. It is the first drug in a new class that acts as analogs of glucagon-like peptide-1 (GLP-1). It was approved for use in April 2005 for patients who had not achieved treatment targets with oral antidiabetic agents.1 In addition to its glucose lowering effects, exenatide has also been shown to cause weight loss in a substantial number of subjects.2–4 It is now commonly used in the treatment of type 2 diabetes, but is not currently approved for use in pregnancy.5 We report on a patient who inadvertently conceived and completed the first trimester of pregnancy while being treated with exenatide.CASE PRESENTATIONA 35-year-old primigravida with history of poorly controlled type 2 diabetes, hypertension, and obesity presented to the emergency department with urinary complaints. She was diagnosed with a urinary tract infection as well as a 14-week intrauterine pregnancy. She was then referred to our clinic.The patient had a 15-year history of diabetes that was noteworthy for poor glycemic control and sporadic care. Her disease was complicated by proliferative retinopathy and microalbuminuria. She had been treated with multiple oral antidiabetic agents and insulin without attaining treatment targets. Exenatide was added to her regimen approximately 11 months before her presentation to our clinic. She tolerated it without side effects and lost 18 pounds. At a visit with her primary physician around the time of conception, a hemoglobin A1c (A1c) was 10.3% and her weight was 362 pounds. The remainder of her medical history was noteworthy for hypertension, obesity, and hyperlipidemia. Her gynecologic history was significant for longstanding oligomenorrhea although her periods had become more frequent in the 6 months before conception. Her surgical history was negative. Her medications included exenatide, rosiglitazone, metformin, glargine insulin, monopril, metoprolol, atorvastatin, and aspirin. Nitrofurantoin had been added the day prior in the emergency department for treatment of her urinary tract infection. She was a nonsmoker and had a family history of type 2 diabetes and obesity.On initial physical examination, her weight was 354 pounds. Blood pressure was 104/59 mm Hg. Her abdominal examination was notable for central obesity. The uterine fundus was not palpable. Abdominal ultrasound confirmed an active fetus with normal cardiac activity and a gestational age of 14 weeks and 2 days. The remainder of her physical examination was unremarkable. Hemoglobin A1c was 10.7%.Monopril was discontinued secondary to known fetotoxicity and recently described teratogenicity.6 Although the period of organogenesis was completed at the time of her presentation, we also discontinued exenatide, rosiglitazone, metformin, and atorvastatin secondary to limited experience with these agents during pregnancy. She was continued on insulin (glargine with the addition of lispro) and metoprolol.At 18 weeks’ gestation, she underwent a fetal anatomic survey. Biometry was consistent with her established dating. Amniotic fluid and visualized anatomy were normal; however, the ultrasound was limited secondary to body habitus and fetal position. Follow-up ultrasound was normal. Fetal echocardiography performed at 23 and 32 weeks gestation was again limited due to maternal body habitus and fetal position but did not reveal any abnormalities. The pregnancy progressed with minimal maternal weight gain, improved glucose control, and normal fetal growth (Table 1).JOURNAL/endst/04.03/00019616-200905000-00008/table1-8/v/2021-02-17T201907Z/r/image-tiff Summary of Clinical DataAt 38 weeks, she developed superimposed preeclampsia, and was admitted for induction of labor. She was managed with intravenous insulin and magnesium sulfate. After a prolonged induction, she developed an intraamniotic infection and was started on antibiotics. Ultimately, she underwent a primary low transverse cesarean section for fetal intolerance of labor. She delivered a 2835 g female infant with Apgars of 1, 1, and 2 at 1, 5, and 10 minutes. Cord gases revealed an arterial pH 7.196 (base deficit: 0.2) and venous pH 7.233 (base deficit: 0.4).The infant was intubated, resuscitated, and treated empirically for sepsis. Within hours of birth, the infant became mildly encephalopathic, and therefore underwent body cooling for 72 hours per institutional protocol. Blood cultures confirmed Escherichia coli sepsis and she was treated with a prolonged antibiotic course. Her clinical condition improved. Magnetic resonance imaging on day of life 8 was normal and she was discharged home on day of life 13. Follow-up at 2 months revealed a weight of 4620 g (38th percentile) and normal neurodevelopment.The patient was discharged home on postpartum day 2. She returned on postpartum day 10 with a wound infection, which required debridement in the operating room on 2 occasions, application of a negative pressure wound therapy device, and antibiotics. At 3.5 months postpartum, her wound has healed.COMMENTCurrently, there is limited information regarding the impact of GLP-1 or its analog, exenatide, on the developing fetus. Theoretical concerns relate to the possible role of endogenous GLP-1 in normal pancreatic development. This may be mediated by its effect on transcription factor PDX-1, which is a Hox-type homeodomain-transcription factor felt to be essential for fetal β-cell proliferation and differentiation.7 GLP-1 and exenatide have both been shown to influence PDX-1 expression in animal models and human cell lines.7–9 Therefore, if exenatide were to cross the placenta, it could influence pancreatic development.The ability of exenatide to cross the placenta has been evaluated in both animals and human models. In vivo studies of placental transfer in mice, rats, and rabbits have shown negligible passage of drug across the placental barrier.10 A human ex vivo placental transfer model confirmed similar findings at concentrations up to 10 times higher than typical doses used in clinical practice.10 Despite the apparent negligible transfer of exenatide across the placenta, in vivo studies in mice and rabbits have demonstrated reduced fetal growth and skeletal (ossification) abnormalities at doses 3 to 12 times the typical human dose.11 No abnormalities in pancreatic development have been reported. The significance of these findings for human pregnancy is unclear.Reports of any exenatide use in pregnancy are limited. In the initial clinical trials of exenatide and extended follow-up, 5 conceptions were reported. Exenatide was discontinued immediately at pregnancy diagnosis. These pregnancies resulted in 3 uncomplicated term deliveries, 1 elective termination, and 1 spontaneous miscarriage at 6 weeks gestation. Our case is the first report of exenatide used throughout the period of organogenesis. We are unaware of any other experience with this medication during human pregnancy.It is also of interest that our patient experienced significant weight loss while on exenatide therapy before conception, which may have contributed to her improved fertility. Significant weight loss has previously been seen with this therapy and has been noted to be ongoing in patients at 2 years after initiation of treatment.12 Weight reduction in other settings has been shown to play a significant role in the restoration of menstruation and ovulation in obese women.13–16 Likewise, our patient experienced a change in her menstrual cycles with her weight loss that may have been associated with an improvement in her fertility. Such an association has implications with respect to initiating treatment in the obese woman of reproductive age. It is conceivable that other obese, diabetic women will experience an improvement in fertility, and therefore risk becoming pregnant while taking this medication. As such, counseling of these patients before initiation of treatment is critical.In this case, the fetus had no apparent problems related to organ development despite exposure to exenatide during organogenesis. However, this case demonstrates the complexities of caring for the obese, diabetic patient during pregnancy and the puerperium. Obesity and diabetes during pregnancy are associated with a variety of adverse obstetrical and fetal outcomes,17,18 and of these, our patient experienced preeclampsia, prolonged induction of labor, intraamniotic infection, cesarean delivery, postpartum uterine infection, and a prolonged wound closure. Furthermore, her infant had a prolonged neonatal intensive care unit course. Given the frequency of these complications in obese, diabetic women, measures that optimize preconception weight loss and glucose control are of critical importance in improving pregnancy outcomes.In summary, although information to be gleaned from this one exposure during organogenesis is limited, this is the first case that we are aware of reporting on an anatomically normal fetus after exposure to exenatide throughout organogenesis. Given the demonstrated benefits on weight loss, and the known benefits of weight loss on ovulation, we anticipate additional occurrences.REFERENCES1.Todd JF, Bloom SR. Incretins and other peptides in the treatment of diabetes. Diabet Med. 2007;3:223–232.[Context Link][Full Text][CrossRef][Medline Link]2.DeFronzo RA, Ratner RE, Han J, et al. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. 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