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Obesity and Reproduction

      Abstract

      Objective

      To provide a comprehensive review and evidence-based recommendations for the delivery of fertility care to women with obesity.

      Outcomes

      The impact of obesity on fertility, fertility treatments, and both short and long-term maternal fetal outcomes was carefully considered.

      Evidence

      Published literature was reviewed through searches of MEDLINE and CINAHL using appropriate vocabulary and key words. Results included systematic reviews, clinical trials, observational studies, clinical practice guidelines, and expert opinions.

      Values

      The Canadian Fertility & Andrology Society (CFAS) is a multidisciplinary, national non-profit society that serves as the voice of reproductive specialists, scientists, and allied health professionals working in the field of assisted reproduction in Canada. The evidence obtained for this guideline was reviewed and evaluated by the Clinical Practice Guideline (CPG) Committee of the CFAS under the leadership of the principal authors.

      Benefits, Harms, and Costs

      The implementation of these recommendations should assist clinicians and other health care providers in counselling and providing reproductive care to women with obesity.

      Validation

      This guideline and its recommendations have been reviewed and approved by the membership, the CPG Committee and the Board of Directors of the CFAS.

      Sponsors

      Canadian Fertility & Andrology Society.

      Recommendations

      Twenty-one evidence based recommendations are provided. These recommendations specifically evaluate the impact of obesity on natural fertility, fertility treatments, and maternal-fetal outcomes. Strategies to lose weight and BMI cut-offs are also addressed.

      Résumé

      Objectif

      Présenter une revue exhaustive ainsi que des recommandations fondées sur des données probantes en matière de soins de fertilité offerts aux femmes présentant une obésité.

      Résultats

      L'incidence de l'obésité sur la fertilité, les traitements de fertilité et les issues maternelles et fœtales à court et à long terme a été analysée avec soin.

      Données

      Des études publiées récupérées au moyen de recherches dans MEDLINE et CINAHL à l'aide d'une terminologie appropriée et de mots-clés ont été évaluées. Les documents retenus comprenaient des revues systématiques, des essais cliniques, des études observationnelles, des directives cliniques et des opinions d'experts.

      Valeurs

      La Société canadienne de fertilité et d'andrologie est une organisation multidisciplinaire nationale à but non lucratif qui se veut la voix des spécialistes de la procréation, des scientifiques et des professionnels de la santé alliés qui travaillent dans le domaine de la procréation assistée au Canada. Les résultats obtenus ont été évalués par le Comité des lignes directrices de pratique clinique de la Société canadienne de fertilité et d'andrologie, sous la direction des auteurs principaux.

      Avantages, inconvénients, coûts

      La mise en œuvre de ces recommandations devrait aider les cliniciens et les autres fournisseurs de soins de santé à offrir du counseling et des soins de fertilité aux femmes qui présentent une obésité.

      Validation

      Cette directive clinique et les recommandations qu'elle contient ont été révisées et approuvées par les membres de la Société canadienne de fertilité et d'andrologie, ainsi que par son Comité des lignes directrices de pratique clinique et son conseil d'administration.

      Commanditaire

      Canadian Fertility & Andrology Society.

      Recommandations

      Vingt et une recommandations fondées sur des données probantes sont proposées. Plus précisément, ces recommandations décrivent les conséquences de l'obésité sur la fertilité naturelle, les traitements de fertilité et les issues maternelles et fœtales. Des stratégies pour la perte de poids et les seuils d'IMC sont aussi abordés.
      Reviewed and approved by the Canadian Fertility & Andrology Society Clinical Practice Guideline Committee: William Buckett, MD; Jon Havelock, MD; Kim Liu, MD; Neal Mahutte, MD (Chair); Jason Min, MD; Jeff Roberts, MD; Sony Sierra, MD; Heather Shapiro, MD; Camille Sylvestre, MD.

      Introduction

      The purpose of this guideline is to provide a framework for the delivery of fertility care to women with obesity. In Canada, as in many other countries, the prevalence of obesity in adults is increasing. More than half of Canadian men and women are overweight, and from 1978 to 2011 the rate of obesity increased from 14 to 26%.
      • Brauer P.
      • Connor Gorber S.
      • Shaw E.
      • et al.
      Recommendations for prevention of weight gain and use of behavioural and pharmacologic interventions to manage overweight and obesity in adults in primary care.
      Furthermore, the proportion of Canadians who are obese now exceeds the proportion of Canadians who regularly smoke (11%) or drink alcohol to excess (16%).
      • Vandevijvere S.
      • Chow C.C.
      • Hall K.D.
      • et al.
      Increased food energy supply as a major driver of the obesity epidemic: a global analysis.
      The World Health Organization (WHO) defines obesity as abnormal or excessive fat accumulation that impairs health.
      Obesity: preventing and managing the global epidemic. Report of a WHO consultation.
      Obesity is most commonly defined using body mass index (BMI). BMI is the weight in kilograms divided by the square of height in metres (kg/M2). The international cut-off values for defining underweight, normal weight, overweight and obese using BMI are listed in Table 1. It should be noted that other measures of obesity such as waist circumference, waist-to-hip ratio and the Edmonton obesity scoring system have merit,
      • Lee C.M.
      • Huxley R.R.
      • Wildman R.P.
      • et al.
      Indices of abdominal obesity are better discriminators of cardiovascular risk factors than BMI: a meta-analysis.
      • Paterson N.
      • Sharma A.M.
      • Maxwell C.
      • et al.
      Obesity-related health status is a better predictor of pregnancy with fertility treatment than body mass index: a prospective study.
      but that this guideline focuses primarily on BMI as this is the measure most commonly used in the obesity and reproductive medicine literature.
      Table 1Internationally recognized BMI cut-off values for underweight, normal weight, overweight and obese
      Obesity: preventing and managing the global epidemic. Report of a WHO consultation.
      BMICategory
      <18.5Underweight
      18.5–24.9Normal Weight
      25–29.9Overweight
      30–34.9Obesity Class I
      35–39.9Obesity Class II
      ≥40Obesity Class III
      BMI: body mass index.
      Excessive caloric intake is the fundamental cause of obesity. Globally we are seeing an increase in the consumption of energy-dense foods, and a reduction in physical activity.
      • Vandevijvere S.
      • Chow C.C.
      • Hall K.D.
      • et al.
      Increased food energy supply as a major driver of the obesity epidemic: a global analysis.
      The health consequences of this imbalance include cardiovascular disease, diabetes, musculoskeletal disorders, sleep apnea and an increased risk of certain malignancies, such as breast, endometrial and colon cancer.
      • Aune D.
      • Sen A.
      • Prasad M.
      • et al.
      BMI and all cause mortality: systematic review and non-linear dose-response meta-analysis of 230 cohort studies with 3.74 million deaths among 30.3 million participants.
      • Calle E.E.
      • Rodriguez C.
      • Walker-Thurmond K.
      • et al.
      Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults.
      It has been estimated that in young adults a BMI >45 reduces life expectancy by as much as 5 to 20 years.
      • Fontaine K.R.
      • Redden D.T.
      • Wang C.
      • et al.
      Years of life lost due to obesity.
      Obesity also has a profound impact on reproductive health. Women who have obesity are at increased risk for menstrual dysfunction, anovulatory infertility and pregnancy-related complications.
      • Ramsay J.E.
      • Greer I.
      • Sattar N.
      ABC of obesity. Obesity and reproduction.
      In this guideline we will highlight the current literature related to obesity and reproduction, and present evidence-based recommendations using GRADE (Table 2).
      Table 2GRADE
      Recommendations are graded according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. GRADE offers two strengths of recommendation: strong and week. The strength of the recommendation is based on the quality of supporting evidence, degree of uncertainty about the balance between desirable and undesirable effects, degree of uncertainty or variability in patient values and preferences and degree of uncertainty about whether the intervention represents a wise use of resources.

      Strong recommendations are those for which the Canadian Task Force on Preventive Health Care is confident that the desirable effects of an intervention outweigh its undesirable effects (strong recommendation for an intervention) or that the undesirable effects of an intervention outweigh its desirable effects (strong recommendation against an intervention). A strong recommendation implies that most individuals will be best served by the recommended course of action.

      Weak recommendations are those for which the desirable effects probably outweigh the undesirable effects (weak recommendation for an intervention) or undesirable effects probably outweigh the desirable effects (weak recommendation against an intervention), but appreciable uncertainty exists. Weak recommendations result when the balance between desirable and undesirable effects is small, the quality of evidence is lower, or there is more variability in the values and preferences of patients. A weak recommendation implies that most people would want the recommended course of action but that many would not. Clinicians must recognize that different choices will be appropriate for each individual, and they must help each person arrive at a management decision that is consistent with his or her values and preferences. Policy-making will require substantial debate and involvement of various stakeholders.

      Quality of evidence is graded as high, moderate, low or very low, based on how likely further research is to change the task force's confidence in the estimate of effect.

      What is the Impact of Obesity on Female Fertility?

      The impact of obesity on fecundity is complex.
      • Brewer C.J.
      • Balen A.H.
      The adverse effects of obesity on conception and implantation.
      • Pantasri T.
      • Norman R.J.
      The effects of being overweight and obese on female reproduction: a review.
      Perhaps the best understood association is that between obesity and anovulation. Obesity induces a hormonal milieu consisting of insulin resistance, hyperinsulinemia, low sex hormone-binding globulin, elevated androgens, increased peripheral conversion of androgens to estrogens, increased free insulin-like growth factor 1 and high leptin.
      • Norman J.E.
      The adverse effects of obesity on reproduction.
      • Pasquali R.
      • Gambineri A.
      • Pagotto U.
      The impact of obesity on reproduction in women with polycystic ovary syndrome.
      The combined effect of these changes causes hypothalamic dysfunction, aberrant gonadotropin secretion, reduced folliculogenesis and lower luteal progesterone levels.
      • Pasquali R.
      • Gambineri A.
      Metabolic effects of obesity on reproduction.
      • Pasquali R.
      • Pelusi C.
      • Genghini S.
      • et al.
      Obesity and reproductive disorders in women.
      • Jain A.
      • Polotsky A.J.
      • Rochester D.
      • et al.
      Pulsatile luteinizing hormone amplitude and progesterone metabolite excretion are reduced in obese women.
      As a result, menstrual irregularity is more common in women with obesity, and increases in frequency with the level of obesity.
      • Castillo-Martinez L.
      • Lopez-Alvarenga J.C.
      • Villa A.R.
      • et al.
      Menstrual cycle length disorders in 18- to 40-y-old obese women.
      • Polotsky A.J.
      • Hailpern S.M.
      • Skurnick J.H.
      • et al.
      Association of adolescent obesity and lifetime nulliparity–the Study of Women's Health Across the Nation (SWAN).
      Several cohort studies have shown that the incidence of anovulatory infertility is more than twice as likely in women with obesity compared to normal BMI controls.
      • Rich-Edwards J.W.
      • Goldman M.B.
      • Willett W.C.
      • et al.
      Adolescent body mass index and infertility caused by ovulatory disorder.
      • Grodstein F.
      • Goldman M.B.
      • Cramer D.W.
      Body mass index and ovulatory infertility.
      • Jacobsen B.K.
      • Knutsen S.F.
      • Oda K.
      • et al.
      Obesity at age 20 and the risk of miscarriages, irregular periods and reported problems of becoming pregnant: the Adventist Health Study-2.
      Interestingly, the distribution of body fat is also important. It has been shown that women with higher waist circumference (excess abdominal fat) are more likely to suffer from anovulation than obese women with the same BMI who have less abdominal fat.
      • Kuchenbecker W.K.
      • Groen H.
      • Zijlstra T.M.
      • et al.
      The subcutaneous abdominal fat and not the intraabdominal fat compartment is associated with anovulation in women with obesity and infertility.
      • Moran C.
      • Hernandez E.
      • Ruiz J.E.
      • et al.
      Upper body obesity and hyperinsulinemia are associated with anovulation.
      However, even in ovulatory women, obesity appears to inhibit natural fecundity and prolong the time to conception.
      • Polotsky A.J.
      • Hailpern S.M.
      • Skurnick J.H.
      • et al.
      Association of adolescent obesity and lifetime nulliparity–the Study of Women's Health Across the Nation (SWAN).
      • Gesink Law D.C.
      • Maclehose R.F.
      • Longnecker M.P.
      Obesity and time to pregnancy.
      • Jensen T.K.
      • Scheike T.
      • Keiding N.
      • et al.
      Fecundability in relation to body mass and menstrual cycle patterns.
      • Zaadstra B.M.
      • Seidell J.C.
      • Van Noord P.A.
      • et al.
      Fat and female fecundity: prospective study of effect of body fat distribution on conception rates.
      • Rich-Edwards J.W.
      • Spiegelman D.
      • Garland M.
      • et al.
      Physical activity, body mass index, and ovulatory disorder infertility.
      A study of 3029 Dutch women with ovulatory cycles, at least one patent fallopian tube and whose partner had normal semen parametres revealed that the likelihood of pregnancy within a 12 month period was reduced by 4% for each kg/M2 increase in BMI over 29.
      • van der Steeg J.W.
      • Steures P.
      • Eijkemans M.J.
      • et al.
      Obesity affects spontaneous pregnancy chances in subfertile, ovulatory women.
      In that study, women with a BMI of 35 had a 26% lower likelihood of spontaneous pregnancy, and women with a BMI of 40 had a 43% lower likelihood of spontaneous pregnancy than women with a BMI between 21 and 29. The authors commented that frequency of intercourse may be one potential cofounder. Obesity has been associated with decreased sexual desire, erectile dysfunction and decreased frequency of sexual intercourse.
      • Kolotkin R.L.
      • Zunker C.
      • Ostbye T.
      Sexual functioning and obesity: a review.
      However, a Danish study of 1651 women that controlled for frequency of sexual intercourse, cycle regularity and waist circumference confirmed a progressive increase in the time to pregnancy among both nulliparous and parous women as the BMI increased from 25 to 30 to over 35.
      • Wise L.A.
      • Rothman K.J.
      • Mikkelsen E.M.
      • et al.
      An internet-based prospective study of body size and time-to-pregnancy.
      Obesity may also alter the endometrium.
      • Wise M.R.
      • Jordan V.
      • Lagas A.
      • et al.
      Obesity and endometrial hyperplasia and cancer in premenopausal women: a systematic review.
      There is evidence of altered endometrial gene expression during the implantation window of natural cycles in obese women.
      • Bellver J.
      • Martinez-Conejero J.A.
      • Labarta E.
      • et al.
      Endometrial gene expression in the window of implantation is altered in obese women especially in association with polycystic ovary syndrome.
      Similarly, there is evidence of lower implantation and clinical pregnancy rates in obese donor egg recipients.
      • Dessolle L.
      • Darai E.
      • Cornet D.
      • et al.
      Determinants of pregnancy rate in the donor oocyte model: a multivariate analysis of 450 frozen-thawed embryo transfers.
      • Provost M.P.
      • Acharya K.S.
      • Acharya C.R.
      • et al.
      Pregnancy outcomes decline with increasing recipient body mass index: an analysis of 22,317 fresh donor/recipient cycles from the 2008–2010 Society for Assisted Reproductive Technology Clinic Outcome Reporting System registry.
      Recommendations
      • 1.
        Women with obesity should be advised that their risk of anovulatory infertility is more than twice that of non-obese women (strong recommendation, moderate quality evidence).
      • 2.
        Women with obesity should be advised that even when ovulatory, their natural fecundity rates are reduced (strong recommendation, moderate quality evidence).

      What is the Impact of Obesity on Male Fertility?

      Obesity often affects both partners in a relationship.
      • Cobb L.K.
      • McAdams-DeMarco M.A.
      • Gudzune K.A.
      • et al.
      Changes in body mass index and obesity risk in married couples over 25 years: the ARIC cohort study.
      • Chen H.J.
      • Liu Y.
      • Wang Y.
      Socioeconomic and demographic factors for spousal resemblance in obesity status and habitual physical activity in the United States.
      For men with obesity the average temperature of the scrotum may be higher due to closer contact with surrounding tissues.
      • Palmer N.O.
      • Bakos H.W.
      • Fullston T.
      • et al.
      Impact of obesity on male fertility, sperm function and molecular composition.
      • Jo J.
      • Kim H.
      The relationship between body mass index and scrotal temperature among male partners of subfertile couples.
      Moreover, the combination of insulin resistance, reduced sex hormone binding globulin and increased peripheral conversion of androgens to estrogens may also disrupt gonadotropin release.
      • Pasquali R.
      Obesity and androgens: facts and perspectives.
      • Practice Committee of the American Society for Reproductive Medicine
      Obesity and reproduction: a committee opinion.
      • Jensen T.K.
      • Andersson A.M.
      • Jorgensen N.
      • et al.
      Body mass index in relation to semen quality and reproductive hormones among 1,558 Danish men.
      Consequently, men with obesity have decreased testosterone levels, that correlate negatively with both their fasting insulin and leptin levels.
      • Pitteloud N.
      • Hardin M.
      • Dwyer A.A.
      • et al.
      Increasing insulin resistance is associated with a decrease in Leydig cell testosterone secretion in men.
      • Isidori A.M.
      • Caprio M.
      • Strollo F.
      • et al.
      Leptin and androgens in male obesity: evidence for leptin contribution to reduced androgen levels.
      Despite these changes research regarding the relationship between male obesity and semen parametres has yielded conflicting results.
      • Du Plessis S.S.
      • Cabler S.
      • McAlister D.A.
      • et al.
      The effect of obesity on sperm disorders and male infertility.
      Some cohort studies have reported an association between male obesity and oligospermia,
      • Jensen T.K.
      • Andersson A.M.
      • Jorgensen N.
      • et al.
      Body mass index in relation to semen quality and reproductive hormones among 1,558 Danish men.
      • Hammoud A.O.
      • Wilde N.
      • Gibson M.
      • et al.
      Male obesity and alteration in sperm parameters.
      • Wang E.Y.
      • Huang Y.
      • Du Q.Y.
      • et al.
      Body mass index effects sperm quality: a retrospective study in Northern China.
      • Hakonsen L.B.
      • Thulstrup A.M.
      • Aggerholm A.S.
      • et al.
      Does weight loss improve semen quality and reproductive hormones? Results from a cohort of severely obese men.
      while others have found no such association.
      • Aggerholm A.S.
      • Thulstrup A.M.
      • Toft G.
      • et al.
      Is overweight a risk factor for reduced semen quality and altered serum sex hormone profile?.
      • Li Y.
      • Lin H.
      • Ma M.
      • et al.
      Semen quality of 1346 healthy men, results from the Chongqing area of southwest China.
      • Chavarro J.E.
      • Toth T.L.
      • Wright D.L.
      • et al.
      Body mass index in relation to semen quality, sperm DNA integrity, and serum reproductive hormone levels among men attending an infertility clinic.
      • Duits F.H.
      • van Wely M.
      • van der Veen F.
      • et al.
      Healthy overweight male partners of subfertile couples should not worry about their semen quality.
      • Martini A.C.
      • Tissera A.
      • Estofan D.
      • et al.
      Overweight and seminal quality: a study of 794 patients.
      • Eskandar M.
      • Al-Asmari M.
      • Babu Chaduvula S.
      • et al.
      Impact of male obesity on semen quality and serum sex hormones.
      • Macdonald A.A.
      • Stewart A.W.
      • Farquhar C.M.
      Body mass index in relation to semen quality and reproductive hormones in New Zealand men: a cross-sectional study in fertility clinics.
      Likewise, meta-analyses have reported conflicting results with one reporting an increased risk of oligospermia and azoospermia,
      • Sermondade N.
      • Faure C.
      • Fezeu L.
      • et al.
      BMI in relation to sperm count: an updated systematic review and collaborative meta-analysis.
      while two others reported no impact of male obesity on semen parametres.
      • MacDonald A.A.
      • Herbison G.P.
      • Showell M.
      • et al.
      The impact of body mass index on semen parameters and reproductive hormones in human males: a systematic review with meta-analysis.
      • Campbell J.M.
      • Lane M.
      • Owens J.A.
      • et al.
      Paternal obesity negatively affects male fertility and assisted reproduction outcomes: a systematic review and meta-analysis.
      Similarly, data regarding the impact of obesity on sperm DNA fragmentation has been mixed, with some studies suggesting a negative effect,
      • Campbell J.M.
      • Lane M.
      • Owens J.A.
      • et al.
      Paternal obesity negatively affects male fertility and assisted reproduction outcomes: a systematic review and meta-analysis.
      • Dupont C.
      • Faure C.
      • Sermondade N.
      • et al.
      Obesity leads to higher risk of sperm DNA damage in infertile patients.
      • Fariello R.M.
      • Pariz J.R.
      • Spaine D.M.
      • et al.
      Association between obesity and alteration of sperm DNA integrity and mitochondrial activity.
      while others report no differences.
      • Bandel I.
      • Bungum M.
      • Richtoff J.
      • et al.
      No association between body mass index and sperm DNA integrity.
      • Eisenberg M.L.
      • Kim S.
      • Chen Z.
      • et al.
      The relationship between male BMI and waist circumference on semen quality: data from the LIFE study.
      • Rybar R.
      • Kopecka V.
      • Prinosilova P.
      • et al.
      Male obesity and age in relationship to semen parameters and sperm chromatin integrity.
      Thus, although it is clear that obese couples have a higher incidence of infertility,
      • Ramlau-Hansen C.H.
      • Thulstrup A.M.
      • Nohr E.A.
      • et al.
      Subfecundity in overweight and obese couples.
      it remains unclear to what extent changes in sperm quality contribute to this association.
      In contrast the literature clearly shows that obese men have a higher incidence of erectile dysfunction.
      • Kolotkin R.L.
      • Zunker C.
      • Ostbye T.
      Sexual functioning and obesity: a review.
      • Pasquali R.
      Obesity, fat distribution and infertility.
      • Han T.S.
      • Tajar A.
      • O'Neill T.W.
      • et al.
      Impaired quality of life and sexual function in overweight and obese men: the European Male Ageing Study.
      Several randomized controlled trials have demonstrated that lifestyle changes associated with weight loss may improve erectile dysfunction in obese men.
      • Esposito K.
      • Giugliano F.
      • Di Palo C.
      • et al.
      Effect of lifestyle changes on erectile dysfunction in obese men: a randomized controlled trial.
      • Collins C.E.
      • Jensen M.E.
      • Young M.D.
      • et al.
      Improvement in erectile function following weight loss in obese men: the SHED-IT randomized controlled trial.
      Similarly, improvement in erectile function have been documented after bariatric surgery.
      • Kun L.
      • Pin Z.
      • Jianzhong D.
      • et al.
      Significant improvement of erectile function after Roux-en-Y gastric bypass surgery in obese Chinese men with erectile dysfunction.
      • Groutz A.
      • Gordon D.
      • Schachter P.
      • et al.
      Effects of bariatric surgery on male lower urinary tract symptoms and sexual function.
      • Efthymiou V.
      • Hyphantis T.
      • Karaivazoglou K.
      • et al.
      The effect of bariatric surgery on patient HRQOL and sexual health during a 1-year postoperative period.
      • Mora M.
      • Aranda G.B.
      • de Hollanda A.
      • et al.
      Weight loss is a major contributor to improved sexual function after bariatric surgery.
      • Reis L.O.
      • Favaro W.J.
      • Barreiro G.C.
      • et al.
      Erectile dysfunction and hormonal imbalance in morbidly obese male is reversed after gastric bypass surgery: a prospective randomized controlled trial.
      Recommendation
      • 3.
        Men with obesity should be advised that they have increased risk of erectile dysfunction, and that this may be improved with weight loss (strong recommendation, high quality evidence).

      What is the Impact of Female Obesity on Fertility Treatments?

      Obesity has been associated with a reduced response to gonadotropins.
      • Dodson W.C.
      • Kunselman A.R.
      • Legro R.S.
      Association of obesity with treatment outcomes in ovulatory infertile women undergoing superovulation and intrauterine insemination.
      • Balen A.H.
      • Platteau P.
      • Andersen A.N.
      • et al.
      The influence of body weight on response to ovulation induction with gonadotrophins in 335 women with World Health Organization group II anovulatory infertility.
      In a large retrospective cohort study of 1189 gonadotropin/intrauterine insemination (IUI) cycles, BMI over 30 was associated with significantly higher gonadotropin requirements, prolonged gonadotropin stimulation, lower peak estradiol levels, and fewer large and medium size follicles.
      • Souter I.
      • Baltagi L.M.
      • Kuleta D.
      • et al.
      Women, weight, and fertility: the effect of body mass index on the outcome of superovulation/intrauterine insemination cycles.
      The reduced responsiveness of obese women to gonadotropins is likely due to the increased volume of distribution. A randomized, cross-over study showed that there was no difference in gonadotropin absorption between subcutaneous and intramuscular routes, but that a decline in area under the curve occurred in women with elevated BMI.
      • Steinkampf M.P.
      • Hammond K.R.
      • Nichols J.E.
      • et al.
      Effect of obesity on recombinant follicle-stimulating hormone absorption: subcutaneous versus intramuscular administration.
      The same decline in area under the curve is true for injections of HCG, but in this case two separate cross-over studies have reported better serum levels if HCG is given intramuscularly compared to subcutaneously.
      • Shah D.K.
      • Missmer S.A.
      • Correia K.F.
      • et al.
      Pharmacokinetics of human chorionic gonadotropin injection in obese and normal-weight women.
      • Chan C.C.
      • Ng E.H.
      • Chan M.M.
      • et al.
      Bioavailability of hCG after intramuscular or subcutaneous injection in obese and non-obese women.
      With regard to clinical pregnancy rates in women with obesity undergoing gonadotropin IUI study findings are mixed. Some studies report no difference
      • Dodson W.C.
      • Kunselman A.R.
      • Legro R.S.
      Association of obesity with treatment outcomes in ovulatory infertile women undergoing superovulation and intrauterine insemination.
      • Balen A.H.
      • Platteau P.
      • Andersen A.N.
      • et al.
      The influence of body weight on response to ovulation induction with gonadotrophins in 335 women with World Health Organization group II anovulatory infertility.
      • Mulders A.G.
      • Laven J.S.
      • Eijkemans M.J.
      • et al.
      Patient predictors for outcome of gonadotrophin ovulation induction in women with normogonadotrophic anovulatory infertility: a meta-analysis.
      in the clinical pregnancy rates in obese patients compared to non-obese controls, while several other report a paradoxical increase.
      • Souter I.
      • Baltagi L.M.
      • Kuleta D.
      • et al.
      Women, weight, and fertility: the effect of body mass index on the outcome of superovulation/intrauterine insemination cycles.
      • Wang J.X.
      • Warnes G.W.
      • Davies M.J.
      • et al.
      Overweight infertile patients have a higher fecundity than normal-weight women undergoing controlled ovarian hyperstimulation with intrauterine insemination.
      • McKnight K.K.
      • Nodler J.L.
      • Cooper Jr, J.J.
      • et al.
      Body mass index-associated differences in response to ovulation induction with letrozole.
      • Isa A.M.
      • Abu-Rafea B.
      • Alasiri S.A.
      • et al.
      Age, body mass index, and number of previous trials: are they prognosticators of intra-uterine-insemination for infertility treatment?.
      Possible reasons for an increased effectiveness of gonadotropin/IUI in women with obesity include correction of anovulation, and compensation for erectile dysfunction and decreased frequency of intercourse.
      In IVF patients, female obesity is associated with increased gonadotropin requirements (both increases starting dose and duration of gonadotropins), higher cycle cancellation rates, decreased peak estradiol levels and decreased oocyte yield.
      • Fedorcsak P.
      • Dale P.O.
      • Storeng R.
      • et al.
      Impact of overweight and underweight on assisted reproduction treatment.
      • Shah D.K.
      • Missmer S.A.
      • Berry K.F.
      • et al.
      Effect of obesity on oocyte and embryo quality in women undergoing in vitro fertilization.
      • Pinborg A.
      • Gaarslev C.
      • Hougaard C.O.
      • et al.
      Influence of female bodyweight on IVF outcome: a longitudinal multicentre cohort study of 487 infertile couples.
      • Luke B.
      • Brown M.B.
      • Stern J.E.
      • et al.
      Female obesity adversely affects assisted reproductive technology (ART) pregnancy and live birth rates.
      • Zhang D.
      • Zhu Y.
      • Gao H.
      • et al.
      Overweight and obesity negatively affect the outcomes of ovarian stimulation and in vitro fertilisation: a cohort study of 2628 Chinese women.
      • Dechaud H.
      • Anahory T.
      • Reyftmann L.
      • et al.
      Obesity does not adversely affect results in patients who are undergoing in vitro fertilization and embryo transfer.
      • Maheshwari A.
      • Stofberg L.
      • Bhattacharya S.
      Effect of overweight and obesity on assisted reproductive technology–a systematic review.
      • Zander-Fox D.L.
      • Henshaw R.
      • Hamilton H.
      • et al.
      Does obesity really matter? The impact of BMI on embryo quality and pregnancy outcomes after IVF in women aged </=38 years.
      • Dokras A.
      • Baredziak L.
      • Blaine J.
      • et al.
      Obstetric outcomes after in vitro fertilization in obese and morbidly obese women.
      However, there has been little consensus regarding the impact of female obesity on IVF success rates. Some studies have reported reductions of clinical pregnancy and live birth rates on the order of 15% to 30% in obese women undergoing IVF compared to non-obese controls.
      • Fedorcsak P.
      • Dale P.O.
      • Storeng R.
      • et al.
      Impact of overweight and underweight on assisted reproduction treatment.
      • Pinborg A.
      • Gaarslev C.
      • Hougaard C.O.
      • et al.
      Influence of female bodyweight on IVF outcome: a longitudinal multicentre cohort study of 487 infertile couples.
      • Luke B.
      • Brown M.B.
      • Stern J.E.
      • et al.
      Female obesity adversely affects assisted reproductive technology (ART) pregnancy and live birth rates.
      • Zander-Fox D.L.
      • Henshaw R.
      • Hamilton H.
      • et al.
      Does obesity really matter? The impact of BMI on embryo quality and pregnancy outcomes after IVF in women aged </=38 years.
      • Petersen G.L.
      • Schmidt L.
      • Pinborg A.
      • et al.
      The influence of female and male body mass index on live births after assisted reproductive technology treatment: a nationwide register-based cohort study.
      • Bellver J.
      • Ayllon Y.
      • Ferrando M.
      • et al.
      Female obesity impairs in vitro fertilization outcome without affecting embryo quality.
      Other studies have reported reductions in clinical pregnancy and live birth rates of more than 50%.
      • Moragianni V.A.
      • Jones S.M.
      • Ryley D.A.
      The effect of body mass index on the outcomes of first assisted reproductive technology cycles.
      • Jungheim E.S.
      • Lanzendorf S.E.
      • Odem R.R.
      • et al.
      Morbid obesity is associated with lower clinical pregnancy rates after in vitro fertilization in women with polycystic ovary syndrome.
      In contrast, at least nine studies have reported no discernable impact of female obesity on IVF pregnancy rates.
      • Zhang D.
      • Zhu Y.
      • Gao H.
      • et al.
      Overweight and obesity negatively affect the outcomes of ovarian stimulation and in vitro fertilisation: a cohort study of 2628 Chinese women.
      • Dechaud H.
      • Anahory T.
      • Reyftmann L.
      • et al.
      Obesity does not adversely affect results in patients who are undergoing in vitro fertilization and embryo transfer.
      • Maheshwari A.
      • Stofberg L.
      • Bhattacharya S.
      Effect of overweight and obesity on assisted reproductive technology–a systematic review.
      • Dokras A.
      • Baredziak L.
      • Blaine J.
      • et al.
      Obstetric outcomes after in vitro fertilization in obese and morbidly obese women.
      • Sathya A.
      • Balasubramanyam S.
      • Gupta S.
      • et al.
      Effect of body mass index on in vitro fertilization outcomes in women.
      • Legge A.
      • Bouzayen R.
      • Hamilton L.
      • et al.
      The impact of maternal body mass index on in vitro fertilization outcomes.
      • Schliep K.C.
      • Mumford S.L.
      • Ahrens K.A.
      • et al.
      Effect of male and female body mass index on pregnancy and live birth success after in vitro fertilization.
      • Haghighi Z.
      • Rezaei Z.
      • Es-Haghi Ashtiani S.
      Effects of women's body mass index on in vitro fertilization success: a retrospective cohort study.
      • Vilarino F.L.
      • Christofolini D.M.
      • Rodrigues D.
      • et al.
      Body mass index and fertility: is there a correlation with human reproduction outcomes?.
      The most comprehensive study to date regarding the impact of female obesity on IVF outcomes is from the Society for Assisted Reproductive Technology (SART) registry.
      • Provost M.P.
      • Acharya K.S.
      • Acharya C.R.
      • et al.
      Pregnancy outcomes decline with increasing body mass index: analysis of 239,127 fresh autologous in vitro fertilization cycles from the 2008–2010 Society for Assisted Reproductive Technology registry.
      This analysis involved 239 127 fresh IVF cycles from 2008 to 2010 and included over 6000 cycles in women with a BMI 30 to 40 and almost 1000 cycles in women with a BMI over 40. The results of this study are summarized in Table 3. In brief, there is a slight decline in the number of oocytes retrieved and the number of high quality embryos as the BMI rises over 40. Implantation, clinical pregnancy and live birth rates all decline gradually with increasing severity of obesity. However, the absolute decline in pregnancy rates is small. Based on the data reported, implantation rates declined by approximately 0.2% to 0.25% and live birth rates declined by approximately 0.3% to 0.4% for each 1 kg/M2 increase in BMI over 25. Thus the overall likelihood of a live birth per cycle start declined from 31.4% in women with a normal BMI, to 28% in women with BMI 30 to 34.9, to 24.3% in women with a BMI 40 to 44.5, and down to 21.2% in women with a BMI >50.
      Table 3The impact of female obesity on IVF Outcomes
      BMI

      18.5–24.9
      BMI

      25–29.9
      BMI

      30–34.9
      BMI

      35–39.9
      BMI

      40–44.9
      BMI

      45–49.9
      BMI

      >50
      Number of IVF cycles134 58854 82224 92211 74740841292463
      Oocytes retrieved12.412.312.312.111.611.210.5
      Cancellation rate10.3%11.3%11.3%12.2%13.3%14.2%11.7%
      Embryos transferred2.42.42.42.42.42.52.3
      Implantation rate29.5%28.3%26.9%25.8%23.6%22.9%20.3%
      Clinical pregnancy rate37.9%36.8%35.7%33.7%32%30.6%30%
      Pregnancy loss rate11.3%12.7%14.6%15.3%14.8%17.6%20.3%
      Live birth rate31.4%29.8%28%26.3%24.3%22.8%21.2%
      Adapted from Provost et al.
      • Provost M.P.
      • Acharya K.S.
      • Acharya C.R.
      • et al.
      Pregnancy outcomes decline with increasing body mass index: analysis of 239,127 fresh autologous in vitro fertilization cycles from the 2008–2010 Society for Assisted Reproductive Technology registry.
      BMI: body mass index.
      The exact mechanism by which obesity lowers IVF success rates is unclear. Some studies have demonstrated alterations in embryo development
      • Leary C.
      • Leese H.J.
      • Sturmey R.G.
      Human embryos from overweight and obese women display phenotypic and metabolic abnormalities.
      • Metwally M.
      • Cutting R.
      • Tipton A.
      • et al.
      Effect of increased body mass index on oocyte and embryo quality in IVF patients.
      and day-3 spent culture media metabolomics
      • Bellver J.
      • De Los Santos M.J.
      • Alama P.
      • et al.
      Day-3 embryo metabolomics in the spent culture media is altered in obese women undergoing in vitro fertilization.
      while others have not detected any changes of indicators of embryo quality between obese women and non-obese controls.
      • Zander-Fox D.L.
      • Henshaw R.
      • Hamilton H.
      • et al.
      Does obesity really matter? The impact of BMI on embryo quality and pregnancy outcomes after IVF in women aged </=38 years.
      • Bellver J.
      • Mifsud A.
      • Grau N.
      • et al.
      Similar morphokinetic patterns in embryos derived from obese and normoweight infertile women: a time-lapse study.
      • Bellver J.
      • Pellicer A.
      • Garcia-Velasco J.A.
      • et al.
      Obesity reduces uterine receptivity: clinical experience from 9,587 first cycles of ovum donation with normal weight donors.
      • Goldman K.N.
      • Hodes-Wertz B.
      • McCulloh D.H.
      • et al.
      Association of body mass index with embryonic aneuploidy.
      Alternatively, obesity may alter endometrial receptivity.
      • Bellver J.
      • Martinez-Conejero J.A.
      • Labarta E.
      • et al.
      Endometrial gene expression in the window of implantation is altered in obese women especially in association with polycystic ovary syndrome.
      • Metwally M.
      • Tuckerman E.M.
      • Laird S.M.
      • et al.
      Impact of high body mass index on endometrial morphology and function in the peri-implantation period in women with recurrent miscarriage.
      Perhaps the best model to help elucidate the impact of obesity on reproduction is oocyte donation. Several studies have suggested that obesity does not impact donor egg recipient implantation or live birth rates
      • Styne-Gross A.
      • Elkind-Hirsch K.
      • Scott Jr, R.T.
      Obesity does not impact implantation rates or pregnancy outcome in women attempting conception through oocyte donation.
      • Jungheim E.S.
      • Schon S.B.
      • Schulte M.B.
      • et al.
      IVF outcomes in obese donor oocyte recipients: a systematic review and meta-analysis.
      • Coyne K.
      • Whigham L.D.
      • O'Leary K.
      • et al.
      Gestational carrier BMI and reproductive, fetal and neonatal outcomes: are the risks the same with increasing obesity?.
      ; while other studies have found a negative association.
      • Bellver J.
      • Melo M.A.
      • Bosch E.
      • et al.
      Obesity and poor reproductive outcome: the potential role of the endometrium.
      • DeUgarte D.A.
      • DeUgarte C.M.
      • Sahakian V.
      Surrogate obesity negatively impacts pregnancy rates in third-party reproduction.
      • Cardozo E.R.
      • Karmon A.E.
      • Gold J.
      • et al.
      Reproductive outcomes in oocyte donation cycles are associated with donor BMI.
      Again, the most comprehensive data comes from the SART registry.
      • Provost M.P.
      • Acharya K.S.
      • Acharya C.R.
      • et al.
      Pregnancy outcomes decline with increasing recipient body mass index: an analysis of 22,317 fresh donor/recipient cycles from the 2008–2010 Society for Assisted Reproductive Technology Clinic Outcome Reporting System registry.
      In an analysis of 22 317 fresh donor/recipient cycles performed between 2008 and 2010 the implantation rate (49%) and live birth rate (51%) in normal BMI recipients declined to 41% in women with a BMI over 40. Moreover, the pregnancy loss rate before 24 weeks gestation increased from 8.6% in normal BMI recipients to 13.5% in recipients with a BMI over 40.This finding is consistent with that of a meta-analysis of miscarriage risk after oocyte donation in obese recipients.
      • Metwally M.
      • Ong K.J.
      • Ledger W.L.
      • et al.
      Does high body mass index increase the risk of miscarriage after spontaneous and assisted conception? A meta-analysis of the evidence.
      Since the embryos came primarily from young, healthy donors there is no reason to suspect that the differences were related to an embryo factor. Indeed, an observational cohort study of 372 women with recurrent pregnancy loss showed that euploid miscarriages were significantly more common in women with obesity (58%) compared to non-obese controls (37%).
      • Boots C.E.
      • Bernardi L.A.
      • Stephenson M.D.
      Frequency of euploid miscarriage is increased in obese women with recurrent early pregnancy loss.
      This increase in pregnancy loss rate (8.6% with normal BMI to 13.5% with BMI over 40) in oocyte recipients is comparable to the change in pregnancy loss reported by SART in women using their own eggs: 11.3% with normal BMI to 14.8% with BMI 40 to 45, 17.6% with BMI 45–50 and 20.3% with BMI over 50
      • Provost M.P.
      • Acharya K.S.
      • Acharya C.R.
      • et al.
      Pregnancy outcomes decline with increasing body mass index: analysis of 239,127 fresh autologous in vitro fertilization cycles from the 2008–2010 Society for Assisted Reproductive Technology registry.
      suggesting that changes in embryo quality are probably not the primary driver for the BMI related increase in pregnancy loss rates after IVF. Obesity clearly increases miscarriage risk. However, the absolute risk of pregnancy loss in women with obesity undergoing IVF is still lower than the reported risk of spontaneous pregnancy loss in women with 2 or more prior pregnancy losses (25%) or women age over 40 (≥35%).
      • Nybo Andersen A.M.
      • Wohlfahrt J.
      • Christens P.
      • et al.
      Maternal age and fetal loss: population based register linkage study.
      Aside from IVF outcomes, it is important to also recognize that obesity complicates the delivery of assisted reproductive technologies. In obese women undergoing controlled ovarian hyperstimulation, the ovaries may shift to a higher position in the pelvis, making them more difficult to visualize with transvaginal scanning and increasing the risk of complications with oocyte retrieval such as bleeding, infection, and injury to surrounding tissue. In addition, the risks of providing anesthesia to obese patients is well described, and makes management of these patients through non-hospital centres a challenge. In a recent survey of obesity policies at IVF facilities in the United States, 62% of respondents cited anesthesia concerns as the primary reason for their BMI cut-off.
      • Kaye L.
      • Sueldo C.
      • Engmann L.
      • et al.
      Survey assessing obesity policies for assisted reproductive technology in the United States.
      Recommendations
      • 4.
        Women with severe obesity should be advised of a lower oocyte yield with IVF (strong recommendation, moderate quality evidence).
      • 5.
        Women with an elevated BMI should be advised that implantation rates, clinical pregnancy rates and live birth rates decline with increasing severity of obesity. The best available evidence regarding live birth rates suggests a decline of approximately 0.3% to 0.4% for each 1 kg/M2 increase in BMI over 25 (strong recommendation, moderate quality evidence).
      • 6.
        Women with obesity should be advised that pregnancy loss rates prior to 24 weeks gestation increase as BMI increases (strong recommendation, moderate quality evidence).
      • 7.
        Women with obesity using an egg donor should be advised that the live birth rate per cycle start is lower compared to non-obese recipients (strong recommendation, moderate quality evidence).
      • 8.
        Women should be advised that obesity can compromise pelvic ultrasound imaging and the safety of oocyte retrieval (strong recommendation, low quality evidence).

      What is the Impact of Obesity on Maternal Risks of Pregnancy?

      The risk of miscarriage is increased in women with obesity who conceive with IVF, irrespective of whether they use their own eggs or donor eggs. Miscarriage risks are also increased for women with obesity who conceive spontaneously. A recent Danish cohort study involving over 5000 women reported a hazard ratio for miscarriage of 1.23 in obese women compared to non-obese controls.
      • Hahn K.A.
      • Hatch E.E.
      • Rothman K.J.
      • et al.
      Body size and risk of spontaneous abortion among danish pregnancy planners.
      Similar results were reported in a British population study involving 1644 women with obesity and 3288 controls (odds ratio 1.2 for miscarriage if obese).
      • Lashen H.
      • Fear K.
      • Sturdee D.W.
      Obesity is associated with increased risk of first trimester and recurrent miscarriage: matched case-control study.
      Among women with recurrent miscarriages the association with obesity may be even greater. Two studies have suggested that among women with recurrent miscarriages the odds of the next pregnancy resulting in miscarriage is elevated 3- to 4-fold in obese patients.
      • Lashen H.
      • Fear K.
      • Sturdee D.W.
      Obesity is associated with increased risk of first trimester and recurrent miscarriage: matched case-control study.
      • Metwally M.
      • Saravelos S.H.
      • Ledger W.L.
      • et al.
      Body mass index and risk of miscarriage in women with recurrent miscarriage.
      Women with obesity who conceive are also at greater risk for gestational diabetes. The baseline risk of gestational diabetes in over one million pregnancies in Ontario from 1996 to 2010 was documented as 4.1%.
      • Feig D.S.
      • Hwee J.
      • Shah B.R.
      • et al.
      Trends in incidence of diabetes in pregnancy and serious perinatal outcomes: a large, population-based study in Ontario, Canada, 1996–2010.
      Similarly, a study of over 400 000 pregnancies in Alberta found that the incidence of gestational diabetes increased from 3.1% in 2000 to 4.6% in 2009.
      • Nerenberg K.A.
      • Johnson J.A.
      • Leung B.
      • et al.
      Risks of gestational diabetes and preeclampsia over the last decade in a cohort of Alberta women.
      In British Columbia, a study of 226 000 singleton pregnancies from 2004 to 2012 reported the incidence of gestational diabetes as 7.9%.
      • Schummers L.
      • Hutcheon J.A.
      • Bodnar L.M.
      • et al.
      Risk of adverse pregnancy outcomes by prepregnancy body mass index: a population-based study to inform prepregnancy weight loss counseling.
      In that study the risk of gestational diabetes increased steadily with increasing BMI (Table 4). The risk of gestational diabetes was doubled with a BMI over 30 and more than tripled with a BMI over 40.
      Table 4Risk of adverse maternal and perinatal outcomes with increasing BMI in a population cohort study of over 226 000 pregnancies in British Columbia
      BMI

      18.5–24.9

      n = 144 502
      BMI

      25–29.9

      n = 46 317
      BMI

      30–34.9

      n = 17 210
      BMI

      35–39.9

      n = 6695
      BMI

      ≥40

      n = 3380
      P value
      Gestational diabetes6.1%9.7%13.7%16.6%20.8%<0.001
      Preeclampsia3.4%6.4%10%12.8%16.3%<0.001
      Macrosomia1.4%2.8%3.8%4.5%6.1%<0.001
      Shoulder dystocia3.5%4.1%4.1%4.4%4.1%<0.001
      Birth injury from shoulder dystocia0.1%0.1%0.1%0.2%0.3%<0.001
      Cesarean delivery26.5%33.1%38.2%43.1%49.7%<0.001
      Indicated birth <37 weeks1.6%2%2.5%3.4%4.1%<0.001
      Stillbirth0.3%0.3%0.4%0.4%0.6%<0.001
      Birth <32 weeks0.6%0.6%0.6%0.6%0.5%NS
      Maternal mortality0.6%0.6%0.6%0.5%0.6%NS
      Adapted from Schummers et al.
      • Schummers L.
      • Hutcheon J.A.
      • Bodnar L.M.
      • et al.
      Risk of adverse pregnancy outcomes by prepregnancy body mass index: a population-based study to inform prepregnancy weight loss counseling.
      BMI: body mass index.
      The risk of preeclampsia is doubled in women that are overweight, and tripled in those that are obese.
      • Schummers L.
      • Hutcheon J.A.
      • Bodnar L.M.
      • et al.
      Risk of adverse pregnancy outcomes by prepregnancy body mass index: a population-based study to inform prepregnancy weight loss counseling.
      • Marchi J.
      • Berg M.
      • Dencker A.
      • et al.
      Risks associated with obesity in pregnancy, for the mother and baby: a systematic review of reviews.
      The risk further increases with the severity of obesity (Table 4). It has been suggested that increasing physical activity in pregnancy may reduce the incidence of both gestational diabetes and pre-eclampsia.
      • Sanabria-Martínez G.
      • García-Hermoso A.
      • Poyatos-León R.
      • et al.
      Effectiveness of physical activity interventions on preventing gestational diabetes mellitus and excessive maternal weight gain: a meta-analysis.
      However, a recent multicentre randomized control trial in over 1500 women with obesity found no difference in the incidence of gestational diabetes or macrosomia in women randomized to behavioural intervention in pregnancy, versus routine care.
      • Poston L.
      • Bell R.
      • Croker H.
      • et al.
      Effect of a behavioural intervention in obese pregnant women (the UPBEAT study): a multicentre, randomised controlled trial.
      A recent Canadian meta-analysis revealed that there is a 31% increased risk of delivery prior to 37 weeks in obese women.
      • Marchi J.
      • Berg M.
      • Dencker A.
      • et al.
      Risks associated with obesity in pregnancy, for the mother and baby: a systematic review of reviews.
      • Lutsiv O.
      • Mah J.
      • Beyene J.
      • et al.
      The effects of morbid obesity on maternal and neonatal health outcomes: a systematic review and meta-analyses.
      This may be related to the higher incidence of preterm premature rupture of membranes (PPROM) and need for medical induction of labour. PPROM might be more common in obese patients with increased circulating adipokines and inflammatory proteins. Increased rates of sleep apnea and antenatal depression have also been reported.
      • Marchi J.
      • Berg M.
      • Dencker A.
      • et al.
      Risks associated with obesity in pregnancy, for the mother and baby: a systematic review of reviews.
      • Lutsiv O.
      • Mah J.
      • Beyene J.
      • et al.
      The effects of morbid obesity on maternal and neonatal health outcomes: a systematic review and meta-analyses.
      A systematic review of the risks associated with obesity in pregnancy demonstrated that pregnant women with obesity have a longer duration of labour, particularly the first stage (4.7 hours compared with 4.1 hours in non-obese women).
      • Norman S.M.
      • Tuuli M.G.
      • Odibo A.O.
      • et al.
      The effects of obesity on the first stage of labor.
      • Kobayashi N.
      • Lim B.H.
      Induction of labour and intrapartum care in obese women.
      • Bogaerts A.
      • Witters I.
      • Van den Bergh B.R.H.
      • et al.
      Obesity in pregnancy: altered onset and progression of labour.
      Women who with obesity have less successful trials of labour and vaginal birth after Caesarean section (VBAC): 54% to 68% success if BMI >29, 13% if weight >136 kg/300 lbs. There is increased fetal distress, instrumental delivery, and shoulder dystocia in women with obesity going through labour (Table 4).
      • Marchi J.
      • Berg M.
      • Dencker A.
      • et al.
      Risks associated with obesity in pregnancy, for the mother and baby: a systematic review of reviews.
      • Lutsiv O.
      • Mah J.
      • Beyene J.
      • et al.
      The effects of morbid obesity on maternal and neonatal health outcomes: a systematic review and meta-analyses.
      The Caesarean section rate increases significantly with increasing BMI (Table 4).
      • Marchi J.
      • Berg M.
      • Dencker A.
      • et al.
      Risks associated with obesity in pregnancy, for the mother and baby: a systematic review of reviews.
      • Weiss J.L.
      • Malone F.D.
      • Emig D.
      • et al.
      Obesity, obstetric complications and cesarean delivery rate–a population-based screening study.
      • Calderon A.C.
      • Quintana S.M.
      • Marcolin A.C.
      • et al.
      Obesity and pregnancy: a transversal study from a low-risk maternity.
      There are also increases in wound infection and dehiscence, post-partum hemorrhage and DVT.
      • Marchi J.
      • Berg M.
      • Dencker A.
      • et al.
      Risks associated with obesity in pregnancy, for the mother and baby: a systematic review of reviews.
      • Weiss J.L.
      • Malone F.D.
      • Emig D.
      • et al.
      Obesity, obstetric complications and cesarean delivery rate–a population-based screening study.
      • Anderson V.
      • Chaboyer W.
      • Gillespie B.
      The relationship between obesity and surgical site infections in women undergoing caesarean sections: an integrative review.
      Recommendations
      • 9.
        Women with obesity should be advised that they have increased prenatal risk of having gestational diabetes and preeclampsia (strong recommendation, moderate quality evidence).
      • 10.
        Women with obesity should be advised of increased peri-partum risks such as a prolonged first stage of labour, less success with VBAC, increased instrumental deliveries, shoulder dystocia and cesarean section rates (strong recommendation, moderate quality evidence).
      • 11.
        Women with obesity should be aware that these obstetrical risks are increased with higher BMI (strong recommendation, moderate quality evidence).

      What is the Impact of Obesity on Fetal/Neonatal Risks of Pregnancy?

      Women with obesity are also at an increased risk of fetal macrosomia (Table 4), an association compounded by the presence of gestational diabetes. A recent Swedish population-based cohort study involving 1 249 908 singleton births between 1998 and 2012 documented an incidence of macrosomia of 7.7% for non-obese women without gestational diabetes, compared to 14% in gestational diabetics.
      • Hilden K.
      • Hanson U.
      • Persson M.
      • et al.
      Overweight and obesity: a remaining problem in women treated for severe gestational diabetes.
      The odds ratio for macrosomia in women with obesity was 2.55 (95% CI 2.51–2.59) without gestational diabetes compared to 6.50 (95% CI 6.10–6.92) with. Macrosomia increases the need for obstetrical interventions like induction of labour and Caesarean section, and increases the incidence of a number of complications such as shoulder dystocia, nerve palsy, and NICU admission. Maternal obesity also increases the risk of obesity in the child, with a higher risk of diabetes and cardiovascular disease later in life.
      • Hilden K.
      • Hanson U.
      • Persson M.
      • et al.
      Overweight and obesity: a remaining problem in women treated for severe gestational diabetes.
      • Harper A.
      Reducing morbidity and mortality among pregnant obese.
      • Johnsson I.W.
      • Haglund B.
      • Ahlsson F.
      • et al.
      A high birth weight is associated with increased risk of type 2 diabetes and obesity.
      • Fadl H.
      • Magnuson A.
      • Ostlund I.
      • et al.
      Gestational diabetes mellitus and later cardiovascular disease: a Swedish population based case-control study.
      • Lawlor D.A.
      • Lichtenstein P.
      • Langstrom N.
      Association of maternal diabetes mellitus in pregnancy with offspring adiposity into early adulthood: sibling study in a prospective cohort of 280,866 men from 248,293 families.
      The National Birth Defect Prevention Study found that the mothers of offspring with anomalies were more likely to have obesity, with an odds ratio of 1.3 to 2.1, suggesting that maternal adiposity alters development in the embryonic period.
      • Waller D.K.
      • Shaw G.M.
      • Rasmussen S.A.
      • et al.
      Prepregnancy obesity as a risk factor for structural birth defects.
      In the 10 249 cases compared to the 4065 controls, there was a 39% increase in neural tube defects,
      • Correa A.
      • Marcinkevage J.
      Prepregnancy obesity and the risk of birth defects: an update.
      with 50% increase in spina bifida, and 20% increase in oral clefts. Hydrocephaly (OR 1.68), anorectal atresia (OR 1.48), limb reduction anomalies (OR 1.34) and cardiovascular anomalies were also increased. The metabolic basis for those anomalies is not known, but poor glycemic control may play a role. Some have advocated for increased folic acid supplementation but evidence to support this practice is unclear.
      • Chitayat D.
      • Matsui D.
      • Amitai Y.
      • et al.
      Folic acid supplementation for pregnant women and those planning pregnancy: 2015 update.
      Obesity can also prevent visualization of congenital defects on ultrasound possibly leading to their discovery later in pregnancy or lack of prenatal detection. A large retrospective study demonstrated 20% less detection of anomalous fetuses in women with high BMI compared to normal BMI.
      ACOG practice bulletin no 156: obesity in pregnancy.
      Recommendation
      • 12.
        Women with obesity should be advised that their risk of having a baby with macrosomia or a congenital anomaly is increased (strong recommendation, moderate quality evidence).

      What Screening Tests are Appropriate for Women with Obesity Seeking Fertility Care?

      The 2006 Canadian clinical practice guidelines on the management and prevention of obesity in adults and children contain recommendations for assessment of obesity and its complications.
      • Lau D.C.
      • Douketis J.D.
      • Morrison K.M.
      • et al.
      2006 Canadian clinical practice guidelines on the management and prevention of obesity in adults and children [summary].
      Obesity induces insulin resistance and a baseline inflammatory state and increases the risk of diabetes, hypertension, dyslipidemia and cardiovascular disease.
      • Tchernof A.
      • Despres J.P.
      Pathophysiology of human visceral obesity: an update.
      • Lewis G.F.
      • Carpentier A.
      • Adeli K.
      • et al.
      Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes.
      • Mokdad A.H.
      • Ford E.S.
      • Bowman B.A.
      • et al.
      Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001.
      • Guh D.P.
      • Zhang W.
      • Bansback N.
      • et al.
      The incidence of co-morbidities related to obesity and overweight: a systematic review and meta-analysis.
      • Schmiegelow M.D.
      • Andersson C.
      • Kober L.
      • et al.
      Associations between body mass index and development of metabolic disorders in fertile women–a nationwide cohort study.
      The prevalence of diabetes in the United States general population increases with BMI (8% risk if normal BMI, 43% risk if BMI ≥40 kg/m2) and obesity is the most important modifiable risk factor for the prevention of type 2 diabetes.
      • Gregg E.W.
      • Cheng Y.J.
      • Narayan K.M.
      • et al.
      The relative contributions of different levels of overweight and obesity to the increased prevalence of diabetes in the United States: 1976–2004.
      • Nguyen N.T.
      • Nguyen X.M.
      • Lane J.
      • et al.
      Relationship between obesity and diabetes in a US adult population: findings from the National Health and Nutrition Examination Survey, 1999–2006.
      An analysis of the United States National Health and Nutrition Examination Survey (NHANES) found the prevalence of diabetes in 2011–2012 among adults aged 22 to 44 years was 5.0% (95% CI 3.8–6.7), and when stratified by BMI, the increase in prevalence of diabetes from 1988 to 2012 was seen only among those with BMI ≥30, regardless of age.
      • Menke A.
      • Casagrande S.
      • Geiss L.
      • et al.
      Prevalence of and trends in diabetes among adults in the United States, 1988–2012.
      NHANES also found that regardless of age, ethnicity, education or smoking habits, lipid profile worsened and the risk of hypertension increased with increasing BMI.
      • Brown C.D.
      • Higgins M.
      • Donato K.A.
      • et al.
      Body mass index and the prevalence of hypertension and dyslipidemia.
      In this study, woman age 20–39 with a BMI ≥30 were 7 times more likely to have high blood pressure, 3.4 times more likely to have high cholesterol, and 13.2 times more likely to have low HDL cholesterol than women with a BMI <25. Not surprisingly obesity, and particularly central obesity, is associated with increased risk of cardiovascular disease.
      • Brown C.D.
      • Higgins M.
      • Donato K.A.
      • et al.
      Body mass index and the prevalence of hypertension and dyslipidemia.
      • Yusuf S.
      • Hawken S.
      • Ounpuu S.
      • et al.
      Obesity and the risk of myocardial infarction in 27,000 participants from 52 countries: a case-control study.
      • Yusuf S.
      • Hawken S.
      • Ounpuu S.
      • et al.
      Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study.
      Abundant literature demonstrates that elevated BMI is associated with an increased risk for complex endometrial hyperplasia and endometrial cancer in premenopausal women.
      • Torres M.L.
      • Weaver A.L.
      • Kumar S.
      • et al.
      Risk factors for developing endometrial cancer after benign endometrial sampling.
      • Lacey Jr, J.V.
      • Chia V.M.
      • Rush B.B.
      • et al.
      Incidence rates of endometrial hyperplasia, endometrial cancer and hysterectomy from 1980 to 2003 within a large prepaid health plan.
      • Heller D.S.
      • Mosquera C.
      • Goldsmith L.T.
      • et al.
      Body mass index of patients with endometrial hyperplasia: comparison to patients with proliferative endometrium and abnormal bleeding.
      • Epplein M.
      • Reed S.D.
      • Voigt L.F.
      • et al.
      Risk of complex and atypical endometrial hyperplasia in relation to anthropometric measures and reproductive history.
      • Weiss J.M.
      • Saltzman B.S.
      • Doherty J.A.
      • et al.
      Risk factors for the incidence of endometrial cancer according to the aggressiveness of disease.
      In a recent review the pooled odds ratio for endometrial cancer was 5.3 in women with a BMI >30 and 19.8 in women with a BMI >40.
      • Wise M.R.
      • Jordan V.
      • Lagas A.
      • et al.
      Obesity and endometrial hyperplasia and cancer in premenopausal women: a systematic review.
      Similarly, a prospective cohort study followed 495 477 women in the United States for 16 years showed a significant increase in risk of mortality from cancers according to BMI.
      • Calle E.E.
      • Rodriguez C.
      • Walker-Thurmond K.
      • et al.
      Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults.
      Compared to non-obese controls, women with a BMI of 40 or more had a relative risk of 2.1 for dying from breast cancer and a relative risk of 6.3 of dying from endometrial cancer.
      Women with obesity are also at risk for obstructive sleep apnea: periodic, partial or complete obstruction of the upper airway during sleep which leads to repetitive arousal from sleep.
      • Peppard P.E.
      • Young T.
      • Palta M.
      • et al.
      Longitudinal study of moderate weight change and sleep-disordered breathing.
      The airway obstruction may also cause episodic sleep-associated oxygen desaturation, episodic hypercapnia, significant negative intrathoracic pressure and cardiovascular dysfunction.
      • American Society of Anesthesiologists Task Force on Perioperative Management of patients with obstructive sleep apnea
      Practice guidelines for the perioperative management of patients with obstructive sleep apnea: an updated report by the American Society of Anesthesiologists Task Force on Perioperative Management of patients with obstructive sleep apnea.
      Approximately 35% of women with a BMI ≥35 report symptoms compatible with obstructive sleep apnea.
      • Grunstein R.R.
      • Stenlof K.
      • Hedner J.
      • et al.
      Impact of obstructive sleep apnea and sleepiness on metabolic and cardiovascular risk factors in the Swedish Obese Subjects (SOS) Study.
      • Sjostrom L.
      • Narbro K.
      • Sjostrom C.D.
      • et al.
      Effects of bariatric surgery on mortality in Swedish obese subjects.
      Sleep apnea exacerbates the cardio-metabolic risk attributed to obesity and metabolic syndrome.
      • Drager L.F.
      • Togeiro S.M.
      • Polotsky V.Y.
      • et al.
      Obstructive sleep apnea: a cardiometabolic risk in obesity and the metabolic syndrome.
      Self-reported sleep apnea appears to be an independent prognostic marker of all-cause mortality.
      • Marshall N.S.
      • Delling L.
      • Grunstein R.R.
      • et al.
      Self-reported sleep apnoea and mortality in patients from the Swedish Obese Subjects study.
      Recommendations
      • 13.
        Women with obesity should be informed that they are at increased risk of metabolic abnormalities (diabetes, dyslipidemia, hypertension), cardiovascular disease, breast and endometrial cancer (strong recommendation, moderate quality evidence).
      • 14.
        Prior to starting fertility treatment, women with obesity should be advised to have screening for and appropriate management of comorbidities such as diabetes, hypertension and dyslipidemia (strong recommendation, moderate quality evidence).

      What are the Most Effective Treatments to Help Infertile Women with Obesity Lose Weight?

      Canadian guidelines on managing obesity have focused primarily on eating habits and exercise.
      • Lau D.C.
      • Douketis J.D.
      • Morrison K.M.
      • et al.
      2006 Canadian clinical practice guidelines on the management and prevention of obesity in adults and children [summary].
      The 2015 Canadian Task Force on Preventive Health Care recommended structural behavioural interventions focused on diet and exercise as first-line treatment for patients with a BMI 30 to 39.9.
      • Brauer P.
      • Connor Gorber S.
      • Shaw E.
      • et al.
      Recommendations for prevention of weight gain and use of behavioural and pharmacologic interventions to manage overweight and obesity in adults in primary care.
      Pharmacotherapy and surgery are options for more severe cases of obesity (BMI ≥40). It should be noted that body weight is tightly regulated by a complex homeostatic system and that powerful neuroendocrine mechanisms defend the body against weight loss, thus accounting for the over 95% recidivism (weight regain) generally associated with behavioural obesity management.
      • Rueda-Clausen C.F.
      • Ogunleye A.A.
      • Sharma A.M.
      Health benefits of long-term weight-loss maintenance.
      • Karmali S.
      • Brar B.
      • Shi X.
      • et al.
      Weight recidivism post-bariatric surgery: a systematic review.
      The same is seen when pharmacologic treatments are discontinued or bariatric surgery is reversed.

      Lifestyle Modification

      Obesity has been associated with poor body image, low self-esteem, depression and anxiety, all of which may influence binge eating.
      • Peterson R.E.
      • Latendresse S.J.
      • Bartholome L.T.
      • et al.
      Binge eating disorder mediates links between symptoms of depression, anxiety, and caloric intake in overweight and obese women.
      • Friedman K.E.
      • Ashmore J.A.
      • Applegate K.L.
      Recent experiences of weight-based stigmatization in a weight loss surgery population: psychological and behavioral correlates.
      One of the challenges of lifestyle modification is breaking this pattern and introducing behavioural strategies that facilitate weight loss and prevent weight regain.
      • Byrne S.M.
      • Cooper Z.
      • Fairburn C.G.
      Psychological predictors of weight regain in obesity.
      Lifestyle modification with diet and exercise yields modest weight loss. Dietary interventions typically focus on reduced energy uptake from fat and carbohydrates, and increased uptake of fruits, vegetables, whole grains and nuts. The Diabetes Prevention Program (DPP, 3234 participants)
      Diabetes Prevention Program (DPP) Research Group
      The Diabetes Prevention Program (DPP): description of lifestyle intervention.
      • Knowler W.C.
      • Barrett-Connor E.
      • Fowler S.E.
      • et al.
      Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.
      and Diabetes Prevention Study (DPS, 522 participants)
      • Tuomilehto J.
      • Lindstrom J.
      • Eriksson J.G.
      • et al.
      Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance.
      showed that weight loss of approximately 4 to6 kg could be achieved following an intensive program of lifestyle changes (counselling, education, support, changes in exercise and diet) and that this was sufficient to reduce the incidence of type 2 diabetes, metabolic syndrome and dyslipidemia in individuals at risk. Unfortunately, weight lost in the first year of lifestyle intervention is gradually gained back, and in the DPP study, total weight loss in the intervention group was 2 kg after 10 years, which was only 1 kg more than in the control group.
      • Knowler W.C.
      • Fowler S.E.
      • Hamman R.F.
      • et al.
      10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study.
      Indeed, the meta-analysis on which the current Canadian weight loss guidelines are based noted an average weight loss of only 3.1 kg (95% CI 2.4–3.9) with behavioural interventions.
      • Peirson L.
      • Douketis J.
      • Ciliska D.
      • et al.
      Treatment for overweight and obesity in adult populations: a systematic review and meta-analysis.

      Pharmacotherapy

      Current Canadian guidelines recommend adding pharmacological treatment only when lifestyle modification is not sufficient to achieve or maintain clinically significant weight loss.
      • Brauer P.
      • Connor Gorber S.
      • Shaw E.
      • et al.
      Recommendations for prevention of weight gain and use of behavioural and pharmacologic interventions to manage overweight and obesity in adults in primary care.
      The rationale for this approach is that behavioural modification has better benefit-to-harm ratio than pharmacotherapy. In Canada, two drugs are currently approved by Heath Canada for the treatment of obesity- Orlistat and Liragutide. Orlistat (Xenical®) is a selective absorption fat inhibitor.
      • Henness S.
      • Perry C.M.
      Orlistat: a review of its use in the management of obesity.
      • Torgerson J.S.
      • Hauptman J.
      • Boldrin M.N.
      • et al.
      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.
      • Hollander P.A.
      • Elbein S.C.
      • Hirsch I.B.
      • et al.
      Role of orlistat in the treatment of obese patients with type 2 diabetes. A 1-year randomized double-blind study.
      It exerts an effect in the digestive tract by binding to gastric and pancreatic lipases and prevents absorption of at least 30% of dietary fat. However, side effects include flatulence, greasy stool, fecal urgency and abdominal cramps. Liragutide (Saxenda®) is an analogue of human glucagon-like-peptide-1.
      • Astrup A.
      • Rossner S.
      • Van Gaal L.
      • et al.
      Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study.
      • Pi-Sunyer X.
      • Astrup A.
      • Fujioka K.
      • et al.
      A randomized, controlled trial of 3.0 mg of liraglutide in weight management.
      Liragutide leads to weight loss by decreasing appetite. The most common side effects are nausea, diarrhea and hypoglycaemia by stimulating insulin secretion and inhibiting glucagon. Liragutide 1.2 to 3 mg subcutaneously per day may lead to greater weight loss (4.8–7.2 kg after 20 weeks) than Orlistat 120 mg by mouth 3 times per day (4.1 kg after 20 weeks).
      • Astrup A.
      • Rossner S.
      • Van Gaal L.
      • et al.
      Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study.
      The safety of both of these drugs in pregnancy is unknown. Although metformin is not specifically approved by Health Canada for weight loss, its properties in this regard have been well studied.
      • Brauer P.
      • Connor Gorber S.
      • Shaw E.
      • et al.
      Recommendations for prevention of weight gain and use of behavioural and pharmacologic interventions to manage overweight and obesity in adults in primary care.
      • Malin S.K.
      • Kashyap S.R.
      Effects of metformin on weight loss: potential mechanisms.
      • Chilton M.
      • Dunkley A.
      • Carter P.
      • et al.
      The effect of antiobesity drugs on waist circumference: a mixed treatment comparison.
      • Leblanc E.S.
      • O'Connor E.
      • Whitlock E.P.
      • et al.
      Effectiveness of primary care-relevant treatments for obesity in adults: a systematic evidence review for the U.S. Preventive Services Task Force.
      • Worsley R.
      • Jane F.
      • Robinson P.J.
      • et al.
      Metformin for overweight women at midlife: a double-blind, randomized, controlled trial.
      • McDonagh M.S.
      • Selph S.
      • Ozpinar A.
      • et al.
      Systematic review of the benefits and risks of metformin in treating obesity in children aged 18 years and younger.
      • Ghandi S.
      • Aflatoonian A.
      • Tabibnejad N.
      • et al.
      The effects of metformin or orlistat on obese women with polycystic ovary syndrome: a prospective randomized open-label study.
      • Lim S.S.
      • Norman R.J.
      • Clifton P.M.
      • et al.
      The effect of comprehensive lifestyle intervention or metformin on obesity in young women.
      • Metwally M.
      • Amer S.
      • Li T.C.
      • et al.
      An RCT of metformin versus orlistat for the management of obese anovulatory women.
      Current data suggests that metformin induces weight loss of an average of 1.9 kg, while Orlistat on average 3.1 kg.
      • Peirson L.
      • Douketis J.
      • Ciliska D.
      • et al.
      Treatment for overweight and obesity in adult populations: a systematic review and meta-analysis.
      Unfortunately, even in controlled trials with fixed timelines, drop-out rates with weight loss medications typically exceed 30%.
      • Fabricatore A.N.
      • Wadden T.A.
      • Moore R.H.
      • et al.
      Attrition from randomized controlled trials of pharmacological weight loss agents: a systematic review and analysis.

      Bariatric Surgery

      Bariatric surgery is considered when the BMI is over 40, or if BMI exceeds 35 with comorbidities, and if other weight loss attempts have failed.
      • Lau D.C.
      • Douketis J.D.
      • Morrison K.M.
      • et al.
      2006 Canadian clinical practice guidelines on the management and prevention of obesity in adults and children [summary].
      Bariatric surgery modifies the architecture of the digestive tract in order to limit caloric intake. There are restrictive procedures such as vertical banded gastroplasty, laparoscopic adjustable gastric banding or sleeve gastrectomy designed to accelerate the feeling of “being full,” and there are malabsorptive procedures such as biliopancreatic diversion with or without duodenal switch that are designed to reduced nutrient absorption. Bariatric surgery may also be a mixed restrictive/malabsorptive procedure as Roux en Y gastric bypass. In malabsorptive or mixed procedures, the greater the excluded intestinal portion, the greater the decrease in caloric intake.
      • DeMaria E.J.
      Bariatric surgery for morbid obesity.
      • Griffith P.S.
      • Birch D.W.
      • Sharma A.M.
      • et al.
      Managing complications associated with laparoscopic Roux-en-Y gastric bypass for morbid obesity.
      Bariatric surgery typically induces significant weight loss. The Swedish Obese Subjects (SOS) study included over 2000 bariatric surgery patients and showed that maximal weight loss was achieved after 1 year (gastric bypass 45 kg, vertical banded gastroplasty 30.8 kg and gastric banding 24.9 kg) but that significant weight reduction was maintained even after 10 years of follow-up (gastric bypass 29.6 kg, vertical banded gastroplasty 19.5 kg and gastric banding 15.6 kg).
      • Sjostrom L.
      • Lindroos A.K.
      • Peltonen M.
      • et al.
      Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery.
      Other studies have confirmed profound weight loss 1 to 2 years after gastric bypass surgery (29–45 kg), biliopancreatic diversion (48 kg) and sleeve-gastrectomy (25.1 kg).
      • Schauer P.R.
      • Bhatt D.L.
      • Kirwan J.P.
      • et al.
      Bariatric surgery versus intensive medical therapy for diabetes–3-year outcomes.
      • Mingrone G.
      • Panunzi S.
      • De Gaetano A.
      • et al.
      Bariatric surgery versus conventional medical therapy for type 2 diabetes.
      Furthermore, bariatric surgery improves metabolic profile and significantly reduces all-cause mortality.
      • Sjostrom L.
      • Narbro K.
      • Sjostrom C.D.
      • et al.
      Effects of bariatric surgery on mortality in Swedish obese subjects.
      • Adams T.D.
      • Gress R.E.
      • Smith S.C.
      • et al.
      Long-term mortality after gastric bypass surgery.
      In fact, bariatric surgery has been shown to be more effective than usual care in the prevention of type 2 diabetes,
      • Carlsson L.M.
      • Peltonen M.
      • Ahlin S.
      • et al.
      Bariatric surgery and prevention of type 2 diabetes in Swedish obese subjects.
      and more effective than medical therapy in the treatment of type 2 diabetes in obese patients.
      • Mingrone G.
      • Panunzi S.
      • De Gaetano A.
      • et al.
      Bariatric surgery versus conventional medical therapy for type 2 diabetes.
      Finally, among obese patients with uncontrolled type 2 diabetes, three years of intensive medical therapy plus bariatric surgery results in significantly better glycemic control and weight reduction than medical therapy alone.
      • Schauer P.R.
      • Bhatt D.L.
      • Kirwan J.P.
      • et al.
      Bariatric surgery versus intensive medical therapy for diabetes–3-year outcomes.
      Mortality associated with bariatric surgery is less than 1%.
      • Buchwald H.
      • Estok R.
      • Fahrbach K.
      • et al.
      Trends in mortality in bariatric surgery: a systematic review and meta-analysis.
      The most common postoperative complications in the SOS study were pulmonary complications (6.1%). Other complications (<5%) are bleeding, venous thrombosis, wound infections, anastomotic leaks.
      • Sjostrom L.
      • Narbro K.
      • Sjostrom C.D.
      • et al.
      Effects of bariatric surgery on mortality in Swedish obese subjects.
      Long term complications include vitamin deficiencies in 20% to 50% of cases. Surgical complications (internal bowel herniation) related to the previous bariatric procedure may also impact 1% of pregnancies.
      • Andreasen L.A.
      • Nilas L.
      • Kjaer M.M.
      Operative complications during pregnancy after gastric bypass–a register-based cohort study.
      Depending on the procedure, complications may lead to health problems: anemia (iron, B12 and folate deficiencies), osteopenia (loss in calcium and vitamin D), alopecia (zinc deficiency), muscle weakness (magnesium deficiency), visual disorders, neuropathy, and hemorrhagic disease (Vitamins A, C, E and K deficiencies).
      • Bloomberg R.D.
      • Fleishman A.
      • Nalle J.E.
      • et al.
      Nutritional deficiencies following bariatric surgery: what have we learned?.
      • Poitou Bernert C.
      • Ciangura C.
      • Coupaye M.
      • et al.
      Nutritional deficiency after gastric bypass: diagnosis, prevention and treatment.
      For these reasons bariatric surgery requires long-term monitoring.

      Delay of Conception after Bariatric Surgery

      There are no prospective randomized trials addressing time to conception after bariatric surgery. Nevertheless, concerns over the impact of rapid weight loss and vitamins deficiencies on the mother and fetus, delaying pregnancy for one to two years after bariatric surgery has been recommended.
      • Beard J.H.
      • Bell R.L.
      • Duffy A.J.
      Reproductive considerations and pregnancy after bariatric surgery: current evidence and recommendations.
      • Monson M.
      • Jackson M.
      Pregnancy after bariatric surgery.
      • Siega-Riz A.M.
      • King J.C.
      Position of the American Dietetic Association and American Society for Nutrition: obesity, reproduction, and pregnancy outcomes.
      A retrospective study comparing 104 pregnancies conceived less than one year after bariatric surgery to 385 pregnancies conceived more than year after bariatric surgery found no differences between the two groups regarding bariatric complications, pregnancy related complications or perinatal outcomes.
      • Sheiner E.
      • Edri A.
      • Balaban E.
      • et al.
      Pregnancy outcome of patients who conceive during or after the first year following bariatric surgery.
      Similarly, a Danish cohort study involving 158 women who conceived within the first year of Roux en Y gastric bypass surgery to 128 women who conceived after one year found no difference obstetric or neonatal outcomes between the two groups.
      • Kjaer M.M.
      • Nilas L.
      Timing of pregnancy after gastric bypass-a national register-based cohort study.
      Thus, particularly in the late reproductive years, the possible benefits of postponing pregnancy must be balanced against the risk of declining reproductive potential with advancing age.

      Adverse Obstetric and Neonatal Outcomes after Bariatric Surgery

      Bariatric surgery significantly reduces the risk of gestational diabetes, fetal macrosomia and hypertensive disorders of pregnancy.
      • Willis K.
      • Lieberman N.
      • Sheiner E.
      Pregnancy and neonatal outcome after bariatric surgery.
      • Aricha-Tamir B.
      • Weintraub A.Y.
      • Levi I.
      • et al.
      Downsizing pregnancy complications: a study of paired pregnancy outcomes before and after bariatric surgery.
      • Johansson K.
      • Cnattingius S.
      • Naslund I.
      • et al.
      Outcomes of pregnancy after bariatric surgery.
      • Amsalem D.
      • Aricha-Tamir B.
      • Levi I.
      • et al.
      Obstetric outcomes after restrictive bariatric surgery: what happens after 2 consecutive pregnancies?.
      Unfortunately, bariatric surgery also increases the risk of maternal anemia
      • Shai D.
      • Shoham-Vardi I.
      • Amsalem D.
      • et al.
      Pregnancy outcome of patients following bariatric surgery as compared with obese women: a population-based study.
      and the risk of small-for-gestational age (SGA) infants.
      • Johansson K.
      • Cnattingius S.
      • Naslund I.
      • et al.
      Outcomes of pregnancy after bariatric surgery.
      • Berlac J.F.
      • Skovlund C.W.
      • Lidegaard O.
      Obstetrical and neonatal outcomes in women following gastric bypass: a Danish national cohort study.
      • Kjaer M.M.
      • Lauenborg J.
      • Breum B.M.
      • et al.
      The risk of adverse pregnancy outcome after bariatric surgery: a nationwide register-based matched cohort study.
      In nationwide Danish registry-based cohort study obese women who conceived following bariatric surgery were 3.3 times less likely to have a large-for-gestational age (LGA) infant but 2.3 times more likely to have a SGA infant compared to BMI matched controls.
      • Kjaer M.M.
      • Lauenborg J.
      • Breum B.M.
      • et al.
      The risk of adverse pregnancy outcome after bariatric surgery: a nationwide register-based matched cohort study.
      Similarly, a nationwide Swedish registry-based cohort study that matched 670 pregnancies in women who had previously undergone bariatric surgery to five controls matched for pre-surgery BMI reported reduced risks for gestational diabetes (1.9% vs. 6.8%) and LGA infants (8.6% vs. 22.4%) but a higher risk for SGA infants (15.6% vs. 7.6%).
      • Johansson K.
      • Cnattingius S.
      • Naslund I.
      • et al.
      Outcomes of pregnancy after bariatric surgery.
      In that study, the median time from surgery to conception was 1.1 years and, of concern, the risk of still birth or neonatal death (1.7% vs. 0.7%; OR 2.39; 95% CI 0.98–5.85; P = 0.06) was slightly higher in the bariatric surgery group.
      To date there does not appear to be a difference in obstetrical or neonatal outcomes based on the type of bariatric surgery performed. A study that compared laparoscopic gastric banding, ring vertical gastroplasty and vertical banded gastroplasty reported no significant differences in subsequent obstetric or perinatal outcomes between the three procedures.
      • Sheiner E.
      • Balaban E.
      • Dreiher J.
      • et al.
      Pregnancy outcome in patients following different types of bariatric surgeries.
      Similarly, another study reported comparable neonatal outcomes between women conceiving after laparoscopic adjustable gastric banding and Roux en Y gastric bypass.
      • Ducarme G.
      • Parisio L.
      • Santulli P.
      • et al.
      Neonatal outcomes in pregnancies after bariatric surgery: a retrospective multi-centric cohort study in three French referral centers.
      Recommendations
      • 15.
        Women with obesity should be advised that modest reductions in weight combined with lifestyle modification will improve their metabolic profile (strong recommendation, moderate quality evidence).
      • 16.
        Women with obesity should be offered or referred for lifestyle modifications (diet + exercise) as a first-line effort to help them lose weight (strong recommendation, low quality evidence).
      • 17.
        Women with obesity who fail to lose weight with lifestyle modification may be offered a referral to other practitioners/specialists who can appropriately counsel them regarding alternative therapies such as pharmacotherapy and bariatric surgery (strong recommendation, moderate quality evidence).
      • 18.
        Women who have undergone bariatric surgery should be advised that the possible benefits of waiting for 1–2 years after surgery before attempting conception should be balanced against the decline in fertility related to advancing age (strong recommendation, low quality evidence).
      • 19.
        Women who have undergone bariatric surgery should be advised that they are at lower risk for fetal macrosomia, gestational diabetes and hypertension, but at higher risk for small-for-gestational age infants (strong recommendation, good quality evidence).

      Is There Data Demonstrating a Difference in Outcomes for Women with Obesity Who Lose Weight Compared to Women with Obesity Who Proceed Directly to Treatment?

      In anovulatory women with obesity, weight loss of 5% to 10% can induce ovulation and increase the chance of pregnancy.
      • Clark A.M.
      • Thornley B.
      • Tomlinson L.
      • et al.
      Weight loss in obese infertile women results in improvement in reproductive outcome for all forms of fertility treatment.
      • Huber-Buchholz M.M.
      • Carey D.G.
      • Norman R.J.
      Restoration of reproductive potential by lifestyle modification in obese polycystic ovary syndrome: role of insulin sensitivity and luteinizing hormone.
      • Sim K.A.
      • Partridge S.R.
      • Sainsbury A.
      Does weight loss in overweight or obese women improve fertility treatment outcomes? A systematic review.
      • Crosignani P.G.
      • Colombo M.
      • Vegetti W.
      • et al.
      Overweight and obese anovulatory patients with polycystic ovaries: parallel improvements in anthropometric indices, ovarian physiology and fertility rate induced by diet.
      • Crosignani P.G.
      • Vegetti W.
      • Colombo M.
      • et al.
      Resumption of fertility with diet in overweight women.
      One weight loss intervention study randomized 49 women to either an intensive 12-week dietary intervention (n = 27) or simply written instructions on how to lose weight (n = 22).
      • Sim K.A.
      • Dezarnaulds G.M.
      • Denyer G.S.
      • et al.
      Weight loss improves reproductive outcomes in obese women undergoing fertility treatment: a randomized controlled trial.
      The 22 women who completed the intensive intervention lost an average of 6.6 kg while the controls lost an average of 1.6 kg. Despite just a 5 kg difference in weight loss the authors reported significantly more pregnancies (48% vs. 14%; P = 0.007) and live births (44% vs. 14%) in the intervention group. Similarly, striking results (live birth rates of 71% vs. 37%; n = 52) have been reported for women with a BMI >25 who succeed in achieving meaningful weight loss (≥10% of their weight).
      • Kort J.D.
      • Winget C.
      • Kim S.H.
      • et al.
      A retrospective cohort study to evaluate the impact of meaningful weight loss on fertility outcomes in an overweight population with infertility.
      Following bariatric surgery, it has been estimated that 58% of previously infertile women with obesity may conceive spontaneously.
      • Milone M.
      • De Placido G.
      • Musella M.
      • et al.
      Incidence of successful pregnancy after weight loss interventions in infertile women: a systematic review and meta-analysis of the literature.
      Bariatric surgery may also increase the number and quality of oocytes obtained at the time of IVF treatment
      • Christofolini J.
      • Bianco B.
      • Santos G.
      • et al.
      Bariatric surgery influences the number and quality of oocytes in patients submitted to assisted reproduction techniques.
      ; however, it is unclear if this increase actually improves clinical outcomes.
      • Chavarro J.E.
      • Ehrlich S.
      • Colaci D.S.
      • et al.
      Body mass index and short-term weight change in relation to treatment outcomes in women undergoing assisted reproduction.
      Recommendation
      • 20.
        Women with obesity should be advised that weight loss improves spontaneous fecundity rates (strong recommendation, low quality evidence).

      Should There be a National BMI Cut-Off for Access to Fertility Care?

      Concerns regarding poor clinical outcomes and maternal/fetal risks have led to calls to restrict access to fertility treatments in women with elevated BMI.
      • Farquhar C.M.
      • Gillett W.R.
      Prioritising for fertility treatments–should a high BMI exclude treatment?.
      • Gillett W.R.
      • Putt T.
      • Farquhar C.M.
      Prioritising for fertility treatments–the effect of excluding women with a high body mass index.
      A 2014 survey of Canadian IVF medical directors found that 50% of respondents imposed a BMI cut-off.
      • Dayan N.
      • Spitzer K.
      • Laskin C.A.
      A focus on maternal health before assisted reproduction: results from a pilot survey of Canadian IVF medical directors.
      The median upper permitted BMI was 38 and the interquartile range was between 35 and 40. The National Institute of Clinical Excellence (NICE) guideline states that it is desirable to achieve a BMI below 30 prior to commencing fertility treatment.
      • Arden M.A.
      • Duxbury A.M.
      • Soltani H.
      Responses to gestational weight management guidance: a thematic analysis of comments made by women in online parenting forums.
      In 2000, clinical priority criteria in New Zealand restricted women with a BMI >32 from accessing fertility treatment.
      • Pandey S.
      • Maheshwari A.
      • Bhattacharya S.
      Should access to fertility treatment be determined by female body mass index?.
      In 2007, the British Fertility Society recommended deferring fertility treatment until a woman's BMI was below 35,
      • Balen A.H.
      • Anderson R.A.
      Impact of obesity on female reproductive health: British Fertility Society, Policy and Practice Guidelines.
      and most IVF units in the United Kingdom impose BMI cut-offs between 30 and 35.
      • Zachariah M.
      • Fleming R.
      • Acharya U.
      Management of obese women in assisted conception units: a UK survey.
      Thus far the American Society for Reproductive Medicine has resisted calling for a national BMI cut-off.
      • Practice Committee of the American Society for Reproductive Medicine
      Obesity and reproduction: a committee opinion.
      However, many providers believe that BMI cut-offs should exist.
      • Harris I.D.
      • Python J.
      • Roth L.
      • et al.
      Physicians' perspectives and practices regarding the fertility management of obese patients.
      In a 2014 survey of 349 clinics, 35% (n = 120) reported using a BMI or body weight cut-off to determine IVF eligibility.
      • Turner-McGrievy G.M.
      • Grant B.L.
      Prevalence of body mass index and body weight cut-off points for in vitro fertilization treatment at U.S. clinics and current clinic weight loss strategy recommendations.
      In that study the mean BMI cut-off was 38.4 and the mean weight cut-off was 130 kg. Among the clinics with a BMI cut-off, only 54% provided weight loss instructions for their patients. Another survey that involved 77 responding clinics reported that 65% had a BMI cut-off (50% between 35–40, 24% between 40–45).
      • Nybo Andersen A.M.
      • Wohlfahrt J.
      • Christens P.
      • et al.
      Maternal age and fetal loss: population based register linkage study.
      Most cited anesthesia requirements as the primary reason for having a cut-off, and only 38% of respondents had a BMI cut-off for intrauterine insemination.
      Clearly, there is no consensus in clinical practice. Furthermore, we must recognize that any specific cut-off value is arbitrary, and that for many patients, weight loss is difficult to achieve. Most weight loss interventions result in less than 7 kg of weight reduction. For a woman of average height (163.5 cm) this results in 3 kg/M2 or less change in BMI. Although it might improve their metabolic profile, it is unclear that this amount of weight reduction substantially changes the maternal/fetal risks of pregnancy.
      The situation is further complicated by the increasing number of women who are obese. From an ethics perspective, clinician's duty to respect their patients' decision-making autonomy is counterbalanced by their duty to do no harm. This duty extends not only to the patient with obesity, who may suffer irreversible health complications as a consequence of pregnancy, but also to the child-not-yet-born whose health may be significantly compromised as a consequence of the mother's obesity. Clearly, weight loss should be encouraged. However, the risk, benefits and limitations of weight loss interventions prior to fertility treatment should be balanced against the risks, benefits and limitations of proceeding directly to fertility treatments.
      It is important to recognize that denying fertility care leads to stigmatization, may be perceived as discriminatory; and can exacerbate feelings of low self-esteem, social isolation, anxiety and depression.
      • Heitmann B.L.
      • Tang-Peronard J.
      Psychosocial issues in female obesity.
      • Muennig P.
      The body politic: the relationship between stigma and obesity-associated disease.
      • Laredo S.E.
      Obesity, polycystic ovary syndrome, infertility treatment: asking obese women to lose weight before treatment increases stigmatisation.
      Moreover, denying fertility treatment to older obese women or women with diminished ovarian reserve until they have lost a specific amount of weight may cost them valuable time and any chance of pregnancy.
      • Sneed M.L.
      • Uhler M.L.
      • Grotjan H.E.
      • et al.
      Body mass index: impact on IVF success appears age-related.
      In other areas of healthcare, the risk of complications does not necessarily prevent obese patients from receiving elective medical care. Although obese women face a higher chance of obstetric complications their absolute risks remain low. Moreover, their risk of complications does not clearly exceed the risk of complications encountered with other pre-existing medical conditions such as diabetes, hypertension and epilepsy. Thus, in the absence of simple, safe effective strategies that reliably help patients with obesity lose weight in a timely fashion, it is difficult to advocate for a universal BMI cut-off in place of careful counselling, screening for metabolic abnormalities and informed consent.
      Recommendation
      • 21.
        Programs that impose BMI cut-offs should offer resources for patients to help them lose weight and should inform patients about both the risks and benefits of delaying fertility treatment (strong recommendation, low quality evidence).

      Conclusion

      The prevalence of obesity is steadily increasing and affects a substantial number of reproductive age women in Canada. Obesity reduces natural fertility rates and those from fertility treatments. Women with obesity have a reduced response to fertility medications, reduced likelihood of success with assisted reproductive technologies, increased risk of miscarriage and increased risk of maternal/fetal complications in pregnancy. Weight loss is the mainstay of treatment and is important for optimizing the safety and success of natural and treatment-related conception. Unfortunately, it is not easy for patients with obesity to lose weight and, aside from bariatric surgery, most interventions result in only modest weight reductions that are difficult to maintain. Therefore, patients with obesity should be assessed carefully in the preconception period and comorbid conditions addressed. A careful balance should then be sought between the principle to do no harm and the responsibility to respect patient autonomy.

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