C.E. Boots

Does obesity increase the risk of miscarriage in spontaneous conception: a systematic review.

Obesity has become an epidemic in developed societies. Retrospective studies suggest that obesity is associated with miscarriage in assisted reproduction. The objective of this study was to evaluate whether obesity is associated with miscarriage in spontaneous conception. We conducted a systematic review of published studies with pooled analysis. A literature review was performed. Studies in which fertility drugs or in vitro fertilization were used were excluded, unless data could be extracted for spontaneous conception. Data were compared for obese (body mass index [BMI]: ≥28 or 30 kg/m (2)), overweight (BMI: 25 to 29 kg/m (2)), and normal-weight (BMI: <25 kg/m (2)) women, with pooled odds ratios (ORs). Recurrent miscarriage data were analyzed separately. Six studies met the criteria for a cohort of 28,538 women. Pooled analysis revealed a higher miscarriage rate of 13.6% in 3800 obese versus 10.7% in 17,146 normal-BMI women (OR: 1.31; 95% confidence interval [CI], 1.18 to 1.46). Although the cohort was small, there was a higher prevalence of recurrent early miscarriage in obese versus normal-BMI women (0.4% versus 0.1%; OR: 3.51; 95% CI, 1.03 to 12.01). In women with recurrent miscarriage, there was a higher miscarriage rate in the obese versus nonobese women (46% versus 43%; OR: 1.71; 95% CI, 1.05). Based on retrospective studies, we concluded that obesity is associated with a higher miscarriage rate in women who conceive spontaneously. Larger prospective studies are urgently needed to verify these preliminary results.

Frequency of euploid miscarriage is increased in obese women with recurrent early pregnancy loss

OBJECTIVE To determine whether the frequency of euploid miscarriage is increased in obese women with recurrent early pregnancy loss (REPL). DESIGN Observational cohort study using prospectively collected data. SETTING Academic RPL program. PATIENT(S) A total of 372 women with REPL, defined as ≥2 pregnancy losses<10 weeks, and at least one ultrasound-documented miscarriage with chromosome results. INTERVENTION(S) Body mass index (BMI) was measured at the initial consultation and at each subsequent pregnancy. Conventional cytogenetic analysis and, when indicated, microsatellite analysis and/or comparative genomic hybridization was performed. MAIN OUTCOME MEASURE(S) Frequency of euploid miscarriage in obese (BMI≥30 kg/m2) and nonobese (BMI<30 kg/m2) subjects, before and subsequent to REPL evaluation. RESULT(S) There were 578 miscarriages with chromosome results. Of the subjects, 18% were obese at the time of miscarriage. The mean maternal age at miscarriage was similar between the obese and nonobese groups. Due to the high rate of maternal cell contamination in the prior miscarriages, only subsequent miscarriages with chromosome results were included in the primary analysis. Of the 117 subsequent miscarriages, the frequency of an euploid miscarriage among obese women was 58% compared with 37% of nonobese women (relative risk=1.63; 95% confidence interval 1.08-2.47). CONCLUSION(S) Obese women with REPL have an increased frequency of euploid miscarriage, which is a known risk factor for subsequent miscarriage.

Metabolic control of oocyte development: linking maternal nutrition and reproductive outcomes

Obesity, diabetes, and related metabolic disorders are major health issues worldwide. As the epidemic of metabolic disorders continues, the associated medical co-morbidities, including the detrimental impact on reproduction, increase as well. Emerging evidence suggests that the effects of maternal nutrition on reproductive outcomes are likely to be mediated, at least in part, by oocyte metabolism. Well-balanced and timed energy metabolism is critical for optimal development of oocytes. To date, much of our understanding of oocyte metabolism comes from the effects of extrinsic nutrients on oocyte maturation. In contrast, intrinsic regulation of oocyte development by metabolic enzymes, intracellular mediators, and transport systems is less characterized. Specifically, decreased acid transport proteins levels, increased glucose/lipid content and elevated reactive oxygen species in oocytes have been implicated in meiotic defects, organelle dysfunction and epigenetic alteration. Therefore, metabolic disturbances in oocytes may contribute to the diminished reproductive potential experienced by women with metabolic disorders. In-depth research is needed to further explore the underlying mechanisms. This review also discusses several approaches for metabolic analysis. Metabolomic profiling of oocytes, the surrounding granulosa cells, and follicular fluid will uncover the metabolic networks regulating oocyte development, potentially leading to the identification of oocyte quality markers and prevention of reproductive disease and poor outcomes in offspring.

Inflammation and Human Ovarian Follicular Dynamics.

Inflammation is a biologic process that mediates tissue effects including vasodilation, hyperemia, edema, collagenolysis, and cell proliferation through complex immunologic pathways. In regard to the ovary, inflammation has key physiologic roles in ovarian folliculogenesis and ovulation. On the other hand, inflammatory processes are subject to underlying pathology and, if pushed, proinflammatory conditions may have a negative impact on ovarian follicular dynamics. Obesity and polycystic ovary syndrome (PCOS) serve as examples of conditions associated with chronic endogenous production of low-grade proinflammatory cytokines. Both conditions negatively impact ovarian folliculogenesis and ovulation. The pages that follow summarize the role of inflammation in normal ovarian follicular dynamics and evidence for its role in mediating the negative effects of obesity and PCOS on ovarian follicular dynamics. The review concludes with a summary supporting a role for lifestyle factors that favorably impact inflammatory process involved in obesity and PCOS to improve ovarian function.

Does methotrexate administration for ectopic pregnancy after in vitro fertilization impact ovarian reserve or ovarian responsiveness

OBJECTIVE To evaluate the effects of methotrexate (MTX) on the future fertility of women undergoing IVF by comparing ovarian reserve and ovarian responsiveness in the IVF cycle before and after an ectopic pregnancy (EP) treated with MTX. DESIGN Retrospective cohort study. SETTING Private reproductive endocrinology and infertility practice. PATIENT(S) Sixty-six women undergoing IVF before and after receiving MTX for an EP. INTERVENTION(S) Methotrexate administration and ovarian stimulation. MAIN OUTCOME MEASURE(S) Markers of ovarian reserve (day 3 FSH, antral follicle count), measures of ovarian responsiveness (duration of stimulation, peak E2 level, total dose of gonadotropins, number of oocytes retrieved, fertilization rate), and time from MTX administration to subsequent IVF cycle. RESULT(S) There were no differences after MTX administration in body mass index (BMI), FSH, or antral follicle count. A greater dose of gonadotropins was used in the cycle after MTX, but there were no differences in numbers of oocytes retrieved or high quality embryos transferred. As expected, there was a slight increase in age in the subsequent IVF cycle. The pregnancy rates (PR) were comparable to the average PRs within the practice when combining all age groups. CONCLUSION(S) Methotrexate remains the first line of therapy for medical management of asymptomatic EP and does not compromise ovarian reserve, ovarian responsiveness, or IVF success in subsequent cycles.

Obesity-induced oocyte mitochondrial defects are partially prevented and rescued by supplementation with co-enzyme Q10 in a mouse model

STUDY QUESTION Does supplementation with co-enzyme Q10 (CoQ10) improve the oocyte mitochondrial abnormalities associated with obesity in mice? SUMMARY ANSWER In an obese mouse model, CoQ10 improves the mitochondrial function of oocytes. WHAT IS KNOWN ALREADY Obesity impairs oocyte quality. Oocytes from mice fed a high-fat/high-sugar (HF/HS) diet have abnormalities in mitochondrial distribution and function and in meiotic progression. STUDY DESIGN, SIZE, DURATION Mice were randomly assigned to a normal, chow diet or an isocaloric HF/HS diet for 12 weeks. After 6 weeks on the diet, half of the mice receiving a normal diet and half of the mice receiving a HF/HS diet were randomly assigned to receive CoQ10 supplementation injections for the remaining 6 weeks. PARTICIPANTS/MATERIALS, SETTING, METHODS Dietary intervention was initiated on C57Bl6 female mice at 4 weeks of age, CoQ10 versus vehicle injections were assigned at 10 weeks, and assays were conducted at 16 weeks of age. Mice were super-ovulated, and oocytes were collected and stained to assess mitochondrial distribution, quantify reactive oxygen species (ROS), assess meiotic spindle formation, and measure metabolites. In vitro fertilization was performed, and blastocyst embryos were transferred into control mice. Oocyte number, fertilization rate, blastulation rate and implantation rate were compared between the four cohorts. Bivariate statistics were performed appropriately. MAIN RESULTS AND THE ROLE OF CHANCE HF/HS mice weighed significantly more than normal diet mice (29 versus 22 g, P< 0.001). CoQ10 supplementation did not influence weight. Levels of ATP, citrate, and phosphocreatine were lower and ROS levels were higher in HF/HS mice than in controls (P< 0.001). CoQ10 supplementation significantly increased the levels of metabolites and decreased ROS levels in oocytes from normal diet mice but not in oocytes from HF/HS mice. However, CoQ10 completely prevented the mitochondrial distribution abnormalities observed in the HF/HS mice. Overall, CoQ10 supplementation significantly increased the percentage of normal spindle and chromosome alignment (92.3 versus 80.2%, P= 0.039). In the sub-analysis by diet, the difference did not reach statistical significance. When undergoing IVF, there were no statistically significant differences in the number of mature oocytes, the fertilization rate, blastocyst formation rates, implantation rates, resorption rates or litter size between HF/HS mice receiving CoQ10 or vehicle injections. LIMITATIONS, REASONS FOR CAUTION Experiments were limited to one species and strain of mice. The majority of experiments were performed after ovulation induction, which may not represent natural cycle fertility. WIDER IMPLICATIONS OF THE FINDINGS Improvement in oocyte mitochondrial distribution and function of normal, chow-fed mice and HF/HS-fed mice demonstrates the importance of CoQ10 and the efficiency of the mitochondrial respiratory chain in oocyte competence. Clinical studies are now needed to evaluate the therapeutic potential of CoQ10 in womens reproductive health. STUDY FUNDING/COMPETING INTERESTS C.E.B. received support from the National Research Training Program in Reproductive Medicine sponsored by the National Institute of Health (T32 HD040135-13) and the Scientific Advisory Board of Vivere Health. K.H.M received support from the American Diabetes Association and the National Institute of Health (R01 HD083895). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER This study is not a clinical trial.

Early Pregnancy in Obese Women

Obesity affects many aspects of female reproduction. Studies have demonstrated a clear association between obesity and menstrual irregularities, anovulation, infertility, pregnancy loss, in addition to many pregnancy complications. In this chapter, we will focus on the impact of an elevated body mass index on early pregnancy. Evidence suggests that obesity increases the risk of early pregnancy loss following spontaneous conception, in women with a history of recurrent pregnancy loss, and in women undergoing assisted reproductive technologies. We will also review the pathophysiology underlying these associations and propose that the effects of obesity are multifactorial, influencing the oocytes, embryonic development, and the endometrium.