Preconception Leptin and Fecundability, Pregnancy, and Live Birth Among Women With a History of Pregnancy Loss

Torie C. Plowden; Shvetha M. Zarek; Elizabeth A. DeVilbiss; Jeannie G. Radoc; Keewan Kim; Lindsey A. Sjaarda; Enrique F. Schisterman; Robert M. Silver; Daniel L. Kuhr; Ukpebo R. Omosigho; Edwina H. Yeung; Sunni L. Mumford


J Endo Soc. 2019;3(11):1958-1968. 

In This Article

Abstract and Introduction


Context: With the increase of obesity, it is imperative to understand the neuroendocrine mechanisms, including the neuroendocrine hormone leptin, by which obese or overweight women are at increased risk for subfertility and infertility.

Objective: The objective was to examine associations between preconception serum leptin concentrations, fecundability, pregnancy, and live birth.

Design: Secondary analysis of a prospective cohort among women with prior pregnancy losses.

Setting: The study was conducted at four US medical centers (2006 to 2012).

Intervention: Not available.

Materials and Methods: Preconception serum leptin concentrations were measured at baseline, and women were followed for up to six menstrual cycles, and throughout pregnancy if they conceived. Discrete Cox proportional hazard regression models were used to assess fecundability odds ratios (FORs) and log-binomial regression to estimate risk ratios (RRs) for pregnancy and live birth. Models were adjusted for age, physical activity, treatment arm, and adiposity, either by measured waist-to-hip ratio or body mass index (BMI).

Results: High leptin concentrations were associated with decreased fecundability (FOR 0.72, 95% CI 0.58, 0.90), reduced risk of pregnancy (RR 0.87, 95% CI 0.78, 0.96) and live birth (RR 0.76, 95% CI 0.65, 0.89) comparing the upper to the lower tertile. However, adjustment for BMI in lieu of waist-to-hip ratio nullified observed associations.

Conclusions: In women with a history of pregnancy loss, relations between higher preconception leptin and fecundability were attenuated after adjustment for BMI, although not after adjustment for other markers of adiposity. Leptin may serve as a complementary marker of adiposity for assessment of obesity and reproductive outcomes.


The obesity epidemic has increased to unprecedented numbers in the past few decades.[1,2] Among women, the prevalence of overall obesity has increased substantially from 2005 to 2014,[2] with alarming estimates that two out of three women were overweight or obese in 2013.[1] With the increase of obesity, it is imperative to understand the mechanisms by which women are at increased risk for numerous health conditions, including subfertility and infertility.[3–5]

Obesity causes changes in body composition and the neuroendocrine axis, including the hormone leptin.[6] Leptin is a hormone produced by adipocytes that plays a crucial role in regulating appetite and metabolism.[6] In addition to communicating energy storage and food intake to the brain, leptin has been proposed as a marker of adipose abundance.[7,8] However, unlike other surrogates of adiposity such as waist-to-hip ratio (WHR) and body mass index (BMI), leptin has been associated with specific adipose deposits in the body.[9] In women there is a stronger association between leptin and subcutaneous fat as opposed to central or visceral fat.[9–11] In a recent meta-analysis, increased early pregnancy leptin concentrations were reported in women who subsequently developed gestational diabetes[12] despite similarities in body mass index.[11] In all, these studies suggest that leptin may serve as a unique and valuable marker for adiposity.

By facilitating energy-intensive processes such as oogenesis and ovulation, leptin also plays an important role in human reproduction.[13] Specifically, a threshold concentration of leptin is needed for the onset of puberty and maintenance of the menstrual cycle. Critically low concentrations or abnormal signaling are associated with delayed puberty and decreased fertility.[14] Correction of leptin concentrations using replacement doses has also been shown to reverse menstrual irregularity and central amenorrhea.[15] This reversal is likely through leptin's effect on the hypothalamic-pituitary-ovarian axis, as leptin stimulates luteinizing hormone secretion from the pituitary[16–18] and activates receptors for gonadotropin-releasing hormones in the hypothalamus.[15] Taken together, this suggests the importance of investigating the relation between adiposity, leptin, and human reproduction.

Few previous studies have examined the role of leptin concentrations as a marker of adiposity on human reproduction, particularly on fecundability and live birth. Past studies have typically been limited in comparing leptin concentrations between fertile women and women with unexplained infertility. These studies tended to find higher concentrations of leptin, whether measured in serum or ovarian follicular fluid, and lower endometrial leptin expression among women with infertility.[19–23] Higher follicular fluid concentration of leptin was associated with lower likelihood of live birth among women undergoing in vitro fertilization,[24] whereas another study found an association between higher nonfasting plasma leptin levels and improved likelihood of live birth in women with recurrent pregnancy loss.[25]

No prior studies have evaluated preconception leptin concentrations among women not undergoing fertility treatment and not all studies have accounted for other surrogates of adiposity. Thus, our objective was to evaluate the association between preconception serum leptin concentrations and fecundability, pregnancy, and live birth among women attempting natural pregnancy while accounting for other markers of adiposity.