REVIEW CPD

Optimizing reproductive health in women with obesity and

Matea Belan MSc, Soren Harnois-Leblanc MSc, Blandine Laferrère MD, Jean-Patrice Baillargeon MD MSc

n Cite as: CMAJ 2018 June 18;190:E742-5. doi: 10.1503/cmaj.171233

nfertility, defined as a failure to achieve a pregnancy after at least 12 months of regular and unprotected sexual inter- KEY POINTS course, affects 15% of all couples in Canada.1 Costs associ- • Obesity is a known risk factor for female infertility and can affect Iated with assisted reproductive technologies are growing, such maternal and newborn health. that equitable access to high-quality reproductive care is a chal- • Expert guidance recommends that women with obesity and lenge for health care systems. Obesity is a known modifiable risk infertility adopt a healthy lifestyle aimed at losing weight before factor for female infertility and can affect maternal health; it also natural or medically assisted conception. puts the offspring’s health at risk both as a newborn and later in • Lifestyle interventions promoting weight loss have, in most life (cardiometabolic health).2 As such, addressing obesity in studies, shown improvement of in women with obesity, women seeking to become pregnant would be prudent, espe- mainly increasing the chance of spontaneous pregnancy. cially given that 25% of Canadian women of reproductive age are • Lifestyle modification is the preferred approach to preconception overweight ( [BMI] 25–30) and 19% are obese weight loss, over bariatric surgery or pharmacologic agents. (BMI > 30).3 We review evidence on the effects of obesity on women’s fertility, recommendations regarding obesity manage- ment in women with infertility, and evidence of the benefits of women, there was a linear decline of 4% in the chances of a weight loss and lifestyle changes for fertility and pregnancy out- spontaneous pregnancy for each increase of one point in the BMI comes (Box 1 outlines our search strategy). score in obese women.9 Yet there are few existing cohort studies including obese women without PCOS, since the condition is What is the relation between obesity and fairly common, clinically exacerbated by obesity and the most women’s fertility? common cause of infertility in women.10,11 In women seeking fertility treatments, obesity was associated The risk of infertility is increased by 78% and 27% in women of with a decrease in pregnancy12,13 and live-birth rates.13 Further- childbearing age with obesity and overweight, respectively, as more, to achieve a pregnancy, women with obesity undergoing compared with women of normal weight (BMI 18.5–25).4 Obesity fertility treatments (intrauterine insemination or in vitro fertiliza- can negatively affect women’s fertility via menstrual and ovula- tion) are more likely to need higher doses of and tory disorders. Such disorders include polycystic ovary syndrome have more cancelled cycles12,14 and lower quality.15 A (PCOS), the most common cause of female infertility, affecting meta-analysis found no associations between being overweight 6% to 10% of women of child-bearing age. resistance is and risks of ovarian hyperstimulation syndrome and multiple considered to play an important role in the association between pregnancies compared with normal-weight women, but reported PCOS and obesity, because elevated circulating levels of insulin a slight decline in the live-birth rate following assisted reproduc- stimulate production by the ovaries.5 Moreover, higher tive technologies in obese women (odds ratio [OR] 0.90, 95% levels of circulating triglycerides and fatty acids, which are asso- confidence interval [CI] 0.82–1.00).11 ciated with obesity and , may directly induce androgen production in predisposed women.6 Obesity, especially What is the effect of maternal obesity at central obesity, exacerbates clinical features of PCOS:7,8 obesity conception on offspring? has a negative impact on the effectiveness of fertility treatments and confers a higher risk of pregnancy complications7 and Although fertility treatments are becoming more efficient in cardiometabolic­ diseases.5 However, the negative effects of obe- overcoming the effects of obesity on women’s fertility, prepreg- sity on women’s reproductive health are observed even in nancy and gestational obesity are serious risk factors for preg- women with no apparent ovulatory or menstrual dysfunctions. In nancy and neonatal complications. According to an extensive a large prospective cohort, with more than 3000 eumenorrheic systematic review of published reviews, pregnant women with

E742 CMAJ | JUNE 18, 2018 | VOLUME 190 | ISSUE 24 © 2018 Joule Inc. or its licensors REVIEW 20 E743 After After 30 to clomiphene to clomiphene 29 26 or not 28 However, obesity and insulin 5 Women with PCOS could benefit could benefit Women with PCOS 24 which are linked to adverse meta- 25 In comparison to women having access to In comparison to women having access to 10 In 2010, the ESHRE pointed out that the goal of ESHRE pointed out In 2010, the 20–22 ISSUE 24 ISSUE | Two three-arm RCTs involving women with obesity and obesity and Two three-arm RCTs involving women with

27 A systematic review of 11 observational studies and random- A systematic review of 11 observational studies A recent multicentre RCT that enrolled more than 600 women There are few studies that have assessed the benefits of life- There are few studies that have assessed ized controlled trials (RCTs), most of which included women included women ized controlled trials (RCTs), most of which found that the inci- undergoing in vitro fertilization treatments, in was increased birth and live pregnancy of spontaneous dence compared with con- women allocated to a lifestyle intervention trols. more from weight loss than women without PCOS because, for for than women without PCOS because, more from weight loss obe- higher central have tend to they obesity, of same degree the sity and insulin resistance, PCOS who were previously resistant 5% weight loss should not be mandatory to access fertility treat- to access loss should not be mandatory 5% weight treat- before fertility lifestyle modifications ments. However, preg- the treatments, prevent improve success of ments can costs. and limit associated neonatal complications, nancy and Do lifestyle modifications and weight loss Do lifestyle modifications outcomes in women with improve fertility obesity and infertility? during the preconception period Weight loss recommendations on and infertility are primarily based in women with obesity women with PCOS, among whom studies studies conducted in modification can improve metabolic have shown that lifestyle and reproductive outcomes. fertility treatments from the outset, and using intention-to-treat analyses, women in the experimental group displayed higher rates of spontaneous pregnancy (26.1% v. 16.2%; rate ratio 1.61, 95% CI 1.16–2.24) and needed fewer cycles of fertility treatment (679 v. 1067), albeit with a significantly lower rate of vaginal delivery of a live singleton after 24 months (27.1% v. 35.2%; rate ratio 0.77, 95% CI 0.60–0.99). Of note, the high drop-out rate of 22%, mainly observed in the intervention group, and the long the of benefits true the diluted have may duration follow-up intervention over time. bolic and reproductive outcomes. resistance are important factors in the disturbance of the repro- resistance are important factors in the disturbance ductive axis in women without PCOS as well. 12 months of follow-up, 90% of women who completed the inter- 78% conceived, of whichvention resumed spontaneous , 33% conceived spontaneously, and 67% delivered a live newborn, as compared with none of the women in the control group. evaluated a six-month lifestyle intervention designed to induce a 5% to 10% weight loss, before the initiation of assisted reproduc- tive technologies. citrate reported that the combination of clomiphene citrate with citrate reported that the combination of clomiphene ovulation rates as lifestyle intervention increased the women’s compared with clomiphene citrate alone. general population ofstyle interventions as first-line therapy in the research groupwomen with obesity and infertility. An Australian that consisted ofreported in 1998 the fertility effects of a program activity practicesweekly group sessions with supervised physical topics. nutritional different covering workshops and scribing any fertility treatments, according to guidance from from to guidance according treatments, any fertility scribing expert bodies. VOLUME 190 VOLUME | The The 19–23 This risk 17 Newborns 2 JUNE 18, 2018 | CMAJ Because the safety of hypocaloric diets, Because the safety of hypocaloric diets, 19 18 In addition, maternal prepregnancy BMI and excessive BMI prepregnancy addition, maternal In 2,16 Box 1: Evidence used in this review Box 1: Evidence reviews on the subject PubMed to find relevant We searched of used a small number the past 10 years. We published within ofmainly to reach all types broaden our research, keywords to OR and fertility: [“weight loss” interventions in obesity studies and OR “multidisciplinary AND [“lifestyle” “weight management”] AND [“fertil*” OR “infertil*” ORintervention/program”] for these keywords was limited to titles“pregnan*”]. The search to our criteria, a total of 78 reviewsand abstracts. Corresponding we included the 6 most recent andwere proposed, of which We added 14 original research articlesrelevant to the subject. milestone studies in their field. Tenbecause they were considered from health organizations relevantarticles representing guidelines included in this review. to the subject were also may be carried through epigenetic mechanisms and perpetuates may be carried through epigenetic mechanisms and cardiometa- the transgenerational vicious cycle of obesity bolic diseases.

As outlined above, extensive data support strong associations strong associations As outlined above, extensive data support as well as notable between obesity and infertility in women, women. obese for complications neonatal and pregnancy Accordingly, targeting women with obesity before conception may be essential to reduce the burden of infertility and costs of fertility treatment, as well as obesity and cardiometabolic dis- eases. As such, physicians should warn women with obesity seeking fertility treatments about the potential consequences on their own health and the health of their future child should they conceive. Many health organizations worldwide recommend that women with obesity be assisted to adopt a healthy lifestyle before conception and maintain it during pregnancy. How should physicians advise overweight and How should physicians advise treatment? obese women who seek infertility obesity have significantly higher odds of gestational diabetes (OR higher odds of gestational diabetes (OR obesity have significantly (OR 2.93 to 4.14), antenatal (OR 1.43) 3.01 to 5.55), preeclampsia (OR delivery cesarean and 1.30), (OR depression postpartum and women. 2.01 to 2.26), compared with normal-weight gestational weight gain are consistently associated with early associated with early gestational weight gain are consistently offspring. development of obesity and diabetes in the 2007 consensus workshop group of the European Society of 2007 consensus workshop group of the European Society of Human Reproduction and Embryology (ESHRE) and the Ameri- can Society for Reproductive Medicine recommended a 5% as obese are who PCOS with women for weight body in decrease a first-line treatment. born to mothers with obesity are at a higher risk of preterm birth born to mothers with obesity are at a higher (< 32 gestation; adjusted OR 1.33, 95% CI 1.12–1.57), mac- weeks’ (> 4500 rosomia death perinatal 2.39–4.37), CI 95% 3.23, OR g; anomalies — (relative risk 1.34, 95% CI 1.22–1.47) and congenital 95% CI 1.86–2.29) and including neural tube defects (OR 2.24, - com — 1.12–1.51) CI 95% 1.30, (OR anomalies cardiovascular prepregnancy normal with mothers to born newborns with pared weight. pharmacologic agents and bariatric surgery on pregnancy out- should providers care health understood, well not are comes advise women with obesity to improve their lifestyle before pre- REVIEW Questions forfutureresearcharesummarizedinBox2. sufficiently poweredRCTsmayofferaclearerevidencebase. interventions arenotyetknown,andfurtherwell-designed but theoptimalpreconceptionweightlossandtypesoflifestyle quality. eous pregnancyratesafterbariatricsurgeryareoflowtomoderate text ofinfertility.Studiessuggestinganimprovementinspontan ­ interventions have notbeen thoroughly investigated in thecon- women matchedforBMIwhodidnotundergosurgery. women afterRoux-en-Ygastricbypasssurgerycomparedwith E744 2 diabetes. weight lossandrisksofobesity-relatedcomorbidities,suchastype interventions arelesseffectivethanbariatricsurgeryintermsof of weight-lossinterventionsinthegeneralpopulation,lifestyle According toadetailedsystematicreviewonthelong-termeffect Bariatric surgery macologic agentsandbariatricsurgery. to patientswhoareobese:modificationoflifestylehabits,phar- Three maintypesofweight-lossinterventionscanbeproposed trying toconceive? considered forwomenwithobesitywhoare Which interventionsforweightlossshouldbe of conceptionto atleast12to24monthsafterthe procedure. sidered asafertilitytreatmentand recommendsdelayingthetime states thatsurgicalweight-loss interventionsshouldnotbecon- between obesityandadversereproductiveeffectsinwomen, 5.85). toward increasedneonatalmortality (OR2.39,95%CI0.98– small for gestational age (OR 2.20, 95% CI 1.64–2.95) and a trend that bariatricsurgerywasassociatedwithhigherriskofnewborns age. These results were confirmed in two recent reviews showing surgical group, but an increase in newborns smallforgestational found adecreaseingestationalhypertensionanddiabetes the Evidence suggeststhatthereisadose–responserelation • • • • • • Box 2:Unansweredquestions 34,35 development ofcardiometabolicdiseasesintheoffspring? adverse maternalandneonataloutcomes,aswellthefuture lifestyle modificationsorweightlosspreventtherisksof In womenwithobesity,towhatextentdopreconception fertility treatmentsinwomenwithobesityandinfertility? Are lifestyleinterventionscost-effectiveincomparisonto in additiontopromotingweightloss? Do specificlifestylemodificationshaveadirecteffectonfertility that shouldberecommended? obesity andinfertility,whatistheoptimalweight-lossthreshold improve fertilityandpregnancyoutcomesinwomenwith If weightlossisrequiredinadditiontolifestylemodification main focusinwomenwhoareobeseandinfertile? Should weightloss,ratherthanlifestylemodifications,bethe improve reproductivefunctioninwomenwhoareobese? By whatmechanismsdolifestylemodificationorweightloss 32 The American College of Obstetricians and Gynecologists TheAmericanCollegeofObstetricians andGynecologists A recent retrospective cohort study assessed pregnant Arecentretrospectivecohortstudyassessedpregnant 31 However, the effects of weight loss through surgical However,theeffectsofweightlossthroughsurgical CMAJ | JUNE18, 2018 33 This study Thisstudy 8,36 9,13 7

| VOLUME 190 group lifestyle and weight loss before conception in infertile women, our ogists, toencourageandsustainweightloss.Topromotehealthy ting, including support from kinesiologists, dietitians and psychol- of lifestyleinterventionsandprogramsinamultidisciplinaryset- ical activity. support inadoptinghealthylifestylehabitssuchasdietandphys­ organizations recommendforwomenwithobesityandinfertilityis weight-loss drugs,theonlyinterventionthathealth Owing to the potential risks associated with bariatric surgery or Lifestyle interventions ity. studied torecommendtheiruseinobesewomenwithinfertil- treatment ofobesityinpregnancyhasnotbeensufficientlywell The safetyofpharmacologicweight-lossagentsapprovedforthe Pharmacologic agents transgenerational transmissionofcardiometabolic diseases. fertility-treatment costs, pre- andperinatal complications, and in lifestylechangesbeforeconception couldreducetheburdenof obesity whoconsultfertilityclinics andsupportingthemtoengage encouraged toadoptahealthy lifestyle.Targetingwomenwith fertility treatmentsshouldbe well informedoftheserisksand safety of lifestyle modification, women with obesity who seek among womenwithobesity.Becauseofthisevidenceandthe supports lifestylemodificationandweightlosstoimprovefertility and newbornhealth,aswellwomen’sfertility.Evidence There isconvincingevidencethatobesityaffectsmaternal,fetal Conclusion placebo. gain buthadanincreasedriskofpreeclampsiacomparedwitha women takingmetformindisplayedlowergestationalweight pregnancy, adouble-blindRCThasreportedthatnondiabetic is notconsideredaweight-losstherapy.Regardingitsuseduring because thiseffectisinconsistentandrelativelymild,metformin and riskoflarge-for-gestational-agenewborns. line therapy. improve theirfertility,althoughitisnotrecommendedasfirst- mothers andtheiroffspring. to understandtheirpotentialconsequencesonthehealthof vidualized dietandphysicalactivityplans. ologists shouldbeencouraged,whenpossible,toestablishindi - tic, timely)objectives.Referralsofpatientstodietitiansandkinesi - help patientssetSMART(specific,measurable,attainable,realis- vational interviewingtechniquesshouldbeusedbyphysiciansto vigorous physicalactivities,aimingfor30to60minutesdaily.Moti- and balanced diet, as well as the regular practice of moderate to encouraged toadvisetheirpatientsontheimportanceofahealthy activity and counselling on nutritional habits. Physicians are including individualmotivationalinterviews,adviceonphysical sity inadults, ical practiceguidelineonthepreventionandmanagementofobe- cant and sustained weight loss in obese women with PCOS, 37 Metformin hasbeenextensively used inwomenwithPCOSto Studies in this specific patient population may be warranted 43 andothers 40 Noeffectswereobservedonneonatalbirthweight 20,22,23,41 | ISSUE 24 38 42 Itsusehasbeenassociatedwithclinicallysignifi- there is strong evidence supporting the importance thereisstrongevidencesupportingtheimportance Accordingtothe2015updatedCanadianclin­ 10 haveusedamultidisciplinaryapproach 40 39 but REVIEW

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drafted the manuscript, which all of the authors revised for important for revised authors the of all which manuscript, the drafted intellectual content. All of the authors gave final approval of the version to be published and agreed to be accountable for all aspects of the work. Funding: Jean-Patrice Baillargeon is supported by the Department of Medicine of the Université de Sherbrooke. Matea Belan is supported by a grant from Fonds de recherche du Québec – Santé. Soren Harnois- Leblanc was supported by a grant from the Faculty of Medicine and Health Sciences of the Université de Sherbrooke. Correspondence to: Jean-Patrice Baillargeon, JP.Baillargeon@ USherbrooke.ca 38. 39. 40. 41. 42. 43. 37. 35. 36. 24. 25. 26. 27. 33. 34. 23. 28. 29. 30. 31. 32. VOLUME 190 VOLUME |

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