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Human Reproduction Vol.22, No.4 pp. 912–915, 2007 Advance Access publication December 15, 2006 The preconceptual contraception paradigm: obesityand infertility Reproductive and Maternal Medicine, Division of Developmental Medicine, University of Glasgow, Glasgow, UK 1To whom correspondence should be addressed at: Reproductive and Maternal Medicine, Division of Developmental Medicine,University of Glasgow, Glasgow Royal Infirmary, 3rd Floor, Queen Elizabeth Building, 10 Alexandra Parade, Glasgow G31 2ER, UK.
Tel: þ44 141 211 4706; Fax: þ44 141 552 0873; E-mail: [email protected] Obesity is a major health problem across the world. Recent editorials suggest that obese patients should be deniedtreatment of any kind aimed to improve ovulation rates and achieve pregnancy until they have reduced their BMI.
We propose that this approach is not a resolution of the problem, but indeed may amplify the maternal and perinatalcomplications attributed to fertility centres. Obesity independent of polycystic ovary syndrome (PCOS) is associatedwith anovulation, and minimal weight loss alone is an effective therapy for induction of ovulation in both obese womenand obese PCOS women. Consequently, lifestyle programmes encouraging weight loss should be considered to be anovulation induction therapy and due consideration for a potential pregnancy in an obese woman given. We proposethat women with a BMI in excess of 35 kg m2 should lose weight prior to conception—not prior to receiving infertilitytreatment. Therefore, clinicians undertaking the management of infertility in obese women should adopt measures toreduce their body mass prior to exposing them to the risks of pregnancy. We advocate that this approach should beaggressively managed including pharmacological strategies; intrinsic in this programme is the use of contraceptionand high-dose folic acid during that period of preconceptual weight reduction.
Key words: infertility/pregnancy outcomes/obesity/contraception recent single embryo transfer debates. There is an inherent Obesity has become a major health problem across the world.
conflict between their desire to achieve pregnancy while In the UK, obesity affects one-fifth of the female population, optimizing the maternal environment for fetal development.
with 18.3% of the female population in the reproductive age Failure to appreciate and convey these risks to patients may group (16 – 44 years) being classed as obese (Department of amplify the maternal and perinatal complications attributed Health, 2004). Similar rises have been observed in the pregnant population, with one in five women booking for antenatal carebeing clinically obese (Kanagalingam et al., 2005). Therelationship between female obesity and reproductive success Fetal risks attributable to maternal obesity is complex. Reduction in pregnancy potential has been reported Maternal obesity (BMI  30 kg m2) has significant detrimental for various infertility treatment procedures, but the effect is not impacts on fetal development with an increased risk of isolated universal, as one study demonstrated that implantation may fetal anomalies: anencephaly and spina bifida [OR 3.3 (95% even be promoted by obesity. In general, deleterious effects confidence interval (CI) 1.4 – 8.1)], spina bifida [OR 3.5 (95% have been revealed to be modest. Furthermore, the outcome CI 1.2 – 10.3)], exomphalos [OR 3.3 (95% CI 1.0 – 10.3)], of pregnancy in obese women is also highly complex, as nulli- atrial septal defect or ventricular septal defect cardiac defects parous mothers are more profoundly affected than multiparous.
[OR 3.5 (95% CI 1.0 – 10.3)], orofacial clefts [OR 1.3 As infertility treatments are generally effected in nulliparous (95% CI 1.11 – 1.53)] and also multiple anomalies [OR 2.0 women, observations of potential adverse outcomes related to (95% CI 1.0 – 3.8)] (Cedergren and Kallen, 2003; 2005; obesity should influence clinical practice in these patients. It Watkins et al., 2003). Furthermore, the association of obesity should be borne in mind that many women undertaking infer- with neural tube defects is not completely abolished by folic tility treatment are prepared to get pregnant at all costs with acid fortification of food and it has a reduced benefit in the little consideration of perinatal consequences, as seen in the prevention of neural tube defects in obese women [OR 0.52 The Author 2006. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.
All rights reserved. For Permissions, please email: [email protected] (95% CI 0.28 – 0.96)] compared to non-obese [OR 0.32 (95% Preterm birth can either be due to preterm labour or due to CI 0.14 – 0.73)] (Ray et al., 2005). Accurate estimates for elective preterm delivery. An interaction between parity and morbid obesity are limited; however, there does appear to be obesity has previously been noted in multiparous women not 7% increase in risk of fetal anomaly for each 1 unit incremen- at increased risk of preterm delivery (Cnattingius et al., tal increase in BMI above a 25 kg m2 (Watkins et al., 2003). A 1998). Among nulliparous women, the risk of elective potential over-estimate of risk due to termination of pregnancy preterm birth increases with BMI: overweight [OR 1.15 has been discounted by examination of postmortem and birth (95% CI 1.03 – 1.27)], obese [OR 1.52 (95% CI 1.31 – 1.77)] records (Callaway et al., 2006). Maternal choice with respect and morbidly obese [OR 2.13 (95% CI 1.75 – 2.58)], whereas to antenatal management may also be limited, as prenatal diag- the risk of spontaneous preterm birth decreased: overweight nosis of congenital anomalies is reduced in obese women [OR 0.89 (95% CI 0.82 – 0.98)], obese [OR 0.85 (95% CI despite repeated examinations (Hendler et al., 2005) and 0.73 – 0.99)] and morbidly obese [OR 0.81 (95% CI 0.64 – advanced ultrasound equipment (Hendler et al., 2004b), with 1.03)] (Smith et al., 2006). The net effect of obesity 10% of obese women having suboptimal four-chamber views depends, therefore, on the balance between the increased at 22 – 24 weeks gestation (Hendler et al., 2004a).
risk of elective preterm birth and the decreased risk of spon- Several studies have demonstrated an increased risk of mis- taneous preterm birth. This study demonstrated that morbidly carriage in obese women undergoing ART, with estimates of obese (BMI . 35) nulliparous women had a greater than risk of fetal loss before 20 weeks gestation of 27% [OR 2-fold risk of elective preterm birth but only a 20% lower 1.71 (95% CI 1.20 – 2.43)] for obese women, increasing to risk of spontaneous preterm birth, leading to an increased 31% if morbidly obese (BMI  35 kg m2) [OR 2.19 (95% risk of all-cause prematurity [OR 1.34 (95% CI 1.15 – 1.56)] CI 1.27 – 3.78)] (Wang et al., 2002). However, in spontaneous (Smith et al., 2006). Furthermore, 40% of morbidly obese nul- conceptions, obesity is also associated with an increased risk liparous women who had an elective preterm delivery had a of early miscarriage (6 – 12 weeks gestation) [OR 1.20 (95% diagnosis of pre-eclampsia compared with only 2.6% of the CI 1.01 – 1.46)] and recurrent miscarriage [OR 3.51 (95% CI rest of the population (Smith et al., 2006). Therefore, the 1.03 – 12.01)] (Lashen et al., 2004). The risk of fetal death is increase in iatrogenic preterm delivery is most likely due to not, however, restricted to early pregnancy, as the risk of the strong association between nulliparity, increasing BMI late fetal death increases consistently with increasing pre- pregnancy BMI. A series of 167 750 births from Sweden This study also highlighted the risk of nulliparous morbidly demonstrated that, among nulliparous women, the risk of obese women delivering an infant of ,1000 g, which was still fetal death after 28 weeks gestation is approximately alive at 1 year of age [OR 3.36 (95% CI 1.89 – 5.98)] (Smith doubled among women with a normal BMI, when compared et al., 2006). This group of children has a 40 – 45% risk of with lean women, tripled among those who were overweight severe neurodevelopmental delay in childhood and, therefore, and quadrupled among those who were obese [OR 4.3 (95% was used as a proxy measure of severe long-term morbidity CI 2.0 – 9.3)] (Cnattingius et al., 1998). Among parous (Ohls et al., 2004). Other delivery-related fetal outcomes women, the risk of fetal death is only increased in obese have also been related to BMI: the risk of fetal distress: women [OR 2.0 (95% CI 1.2 – 3.5)] (Cnattingius et al., obese [OR 1.61 (95% CI 1.53 – 1.69)], morbidly obese [OR 1998). A later study from Sweden with 805 275 women pro- 2.13 (95% CI 1.93 – 2.35)] and BMI . 40 [OR 2.52 (95% CI vided similar estimates of risk of late fetal death for obese 2.12 – 3.58)], meconium aspiration: obese [OR 1.64 (95% CI and morbidly obese women, but also demonstrated that 1 in 1.30 – 2.06)], morbidly obese [OR 2.87 (95% CI 2.13 – 3.85)] 121 women with a BMI . 40 had a stillbirth (Cedergren, and BMI . 40 [OR 2.85 (95% CI 1.60–5.07)]; shoulder dystocia: 2004). These risks are startlingly high; however, they may obese [OR 2.14 (95% CI 1.83 – 2.49)], morbidly obese [OR 2.82 be even potentially higher in obese women undergoing (95% CI 2.1 – 3.71)] and BMI . 40 [OR 3.14 (95% CI ART, as a meta-analysis of singleton IVF pregnancies suggested a significance of the risk of stillbirth due to ART These studies collectively demonstrate a strong association as compared to spontaneous conception [OR 4.3 (95% CI between maternal obesity in early pregnancy and a number 2.0 – 9.3)] (Jackson et al., 2004). The risk of death of the of severe fetal complications during early and late develop- child is not restricted to the antenatal period, with obesity ment, delivery and the neonatal period. Increased odds ratios having a significant impact on neonatal and infant mortality.
of rare complications describe events that remain rare.
The risk of early neonatal death (within the fist 7 days of However, the statistical increases in the major events described life) after adjustment for maternal age, parity smoking status above (stillbirth, neonatal death and prolonged morbidity) are and year of birth was [OR 1.59 (95% CI 1.25 – 2.01)] in tangible elements. Given that the subfertile population gener- obese women, with further increments in risk if the BMI ally experiences poorer perinatal outcomes than the population was .35 [OR 2.09 (95% CI 1.50 – 2.91)] or .40 [OR 3.41 as a whole, the role of obesity in infertility treatment clinics (95% CI 2.07 – 5.63)] (Cedergren, 2004). A study of 84 701 must be considered seriously. These complications are quite nulliparous women in Scotland showed that morbid obesity separate from the well-established maternal complications was associated with a significant increase in the risk of related to obesity, in particular, the hypertensive disorders of death within the first 28 days of life [OR 2.77 (95% pregnancy, gestational diabetes, thromboembolism, infection CI 1.54 – 4.99)]; however, the risk was not increased in multi- and the anaesthetic and obstetric problems associated with delivery and the post-partum period.
not restricted to obese women with PCOS. The issues are The effects of weight loss, by dint of calorie restriction and/or obesity and ovulation. The second is that metformin treatment exercise, have been studied in a relatively small number of of obese women with PCOS is less efficacious than that of cases, but with reasonable agreement among the studies.
normal weight women (Fleming et al., 2002) and that in the Weight loss, with or without exercise, results in improved obese group, it is no more likely than weight loss itself to insulin sensitivity and increased ovulation frequency with rela- improve ovulation rates (Tang et al., 2006). Therefore, the tively minor degrees of absolute weight reduction. Kiddy et al.
issue is not whether treatment with metformin should be dis- (1992) described 11 anovulatory obese women losing .5% of couraged, it is whether the patient should be protected from their pretreatment weight. About 9 of these 11 showed pregnancy during the time of weight reduction. In defence of improvement in reproductive function, as they either conceived metformin, it does reduce circulating androgens and hirsutism, (5) or experienced a more regular menstrual pattern. In and its use is associated with modest weight loss (Harborne contrast, the group losing ,5% of their initial weight recorded et al., 2003, 2005), with more consistent effects with the little improvement in reproductive function. Hollman et al.
higher doses (Harborne et al., 2005). However, the effect is (1996) reported that in 35 women undergoing a weight time-consuming with an average of 5 kg over 8 months, with reduction programme over 32 weeks who recorded a weight higher doses. In contrast, more profound effects may be loss of ,10%, there was menstrual period improvement in achieved using weight-reducing drugs such as orlistat, which 80% and pregnancy in 29%. One study in overweight achieved a 5% reduction in weight in 3 months compared women diagnosed with polycystic ovary syndrome (PCOS) with 1% with metformin (Jayagopal et al., 2005).
showed similar benefits of weight loss (Huber-Buchholzet al., 1999). About 18 infertile anovulatory women with PCOS and normal glucose tolerance (BMI 27 – 45 kg m2),underwent a 6-month diet and exercise programme. The Balen et al. (2006), somewhat arbitrarily, selected a BMI of patients, who responded with improved ovulation frequency, 35 kg m2 as the critical point above which fertility treatment showed an 11% reduction in central fat, whereas mean should be withheld. However, there is substantial clinical evi- weight loss was between 2 and 5% of starting weight over dence to support a BMI of ,30 kg m2 from the world litera- the programme. These data indicate that lifestyle modification, ture. With respect to the UK population and the specific risk of leading to improved insulin sensitivity with relatively neonatal death and extremely low birth weight infants, the cut- modest degrees of weight loss, commonly result in improved off value of 35 kg m2 has supportive evidence. However, we ovulation rates and conception. These programmes should assert that programmes encouraging weight loss, through either therefore be considered to be effective ovulation-induction diet or exercise or both, should be considered to be undertaking these measures should also be advised about contra-ception until that critical value of BMI 35 kg m2 is achieved.
Because of the associated risk of thromboembolism with com- There is an unfortunate conflict in these situations. Although the indicator for grade of obstetric/neonatal risk as outlined progesterone-only contraception, potential delays in return to is absolute BMI, the critical factor for restoring ovulation ovulation with depot preparations and risk of pelvic inflammatory appears to be percentage of weight lost and this may be disease with intrauterine devices, the obvious choice during this relatively modest. Correspondingly, a reduction in BMI from at risk preconceptual period would be barrier methods.
40 to 38 kg m2 is likely to restore ovulation in a womanclearly at tangible obstetric/neonatal risk. Indeed, in exerciseprogrammes, insulin sensitivity can be improved with even more modest absolute weight reduction, and ovarian function/ Women with a BMI in excess of 35 kg m2 should lose weight fertility can be normalized by this means (Clark et al., 1998).
prior to conception—not prior to receiving infertility treatment.
Although there is substantial evidence with respect to pregnancy Therefore, clinicians undertaking the management of infertility that exercise can modify metabolic and vascular risk factors, it in obese women should adopt measures to reduce their body has yet to be determined whether exercise reduces the risk of mass prior to exposing them to the risks of pregnancy. We adverse perinatal outcome. This collection of evidence means advocate that the approach should be aggressively managed that simply advising weight loss or even putting a patient into using strategies that may include the drugs such as metformin a weight reduction (lifestyle modification) programme is or orlistat. Intrinsic in this programme is the use of barrier con- actively putting a woman into a risk-prone situation, where the traception during that period of weight reduction. The combi- pregnancy-specific risks are now well quantified.
nation of weight loss, contraception and high-dose folic acid Balen et al. (2006) have proposed that obese patients with should become the standard preconceptual care for the obese PCOS should be denied treatment of any kind aimed to woman. Women need to be made aware that any potential improve ovulation rates and achieve pregnancy, including met- delay in therapy is in the best interests of mother and baby.
formin, until they have reduced their BMI to 35 kg m2. We In this context, we can potentially reduce the stigmatization suggest that this position is flawed, on two grounds. The first of asking obese women to lose weight before treatment is that obesity and the obstetrical/neonatal consequences are Huber-Buchholz MM, Carey DG and Norman RJ (1999) Restoration of reproductive potential by lifestyle modification in obese polycystic ovary Balen AH, Dresner M, Scott EM and Drife JO (2006) Should obese women syndrome: role of insulin sensitivity and luteinizing hormone. J Clin with polycystic ovary syndrome receive treatment for infertility? BMJ Jackson RA, Gibson KA, Wu YW and Croughan MS (2004) Perinatal Callaway LK, Prins JB, Chang AM and McIntyre HD (2006) The prevalence outcomes in singletons following in vitro fertilization: a meta-analysis.
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