Extremes of body mass do not adversely affect the outcome of superovulation and in-vitro fertilization

Hany Lashen1,3, William Ledger2, Andrés López Bernal2 and David Barlow2

1 Department of Obstetrics and Gynaecology, Solihull Hospital, Solihull, West Midlands, B91 2JL and 2 Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford Radcliffe Hospital, Oxford, UK


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The effect of extremes of body mass on ovulation is well recognized by clinicians. However, the effect of obesity and extreme underweight on the outcome of in-vitro fertilization (IVF) cycles has received relatively little attention. In a retrospective nested case-control study we examined the effect of the extremes of body mass index (BMI) on IVF–embryo transfer outcome at a university-based IVF unit. A total of 333 patients were included in the study; 76 obese patients (BMI > 27.9) with 152 controls, and 35 underweight patients (BMI < 19) with 70 controls. The patients were matched with their controls in age ± 1 year, day 3 follicle stimulating hormone (FSH) concentration, daily dose of gonadotrophin (±37.25 IU), gonadotrophin preparation and the year of treatment. The following parameters were compared between the study and control groups: duration of administration and dose of gonadotrophin, number of follicles aspirated, number of eggs, fertilization rate, number of embryos, serum oestradiol concentration on human chorionic gonadotrophin (HCG) day (peak oestradiol), clinical pregnancy rate, implantation rate, miscarriage rate, and incidence of ovarian hyperstimulation syndrome. Apart from a significantly lower peak oestradiol concentration (P = 0.009) in the obese patients, they and the underweight patients were not significantly different from their normal controls. The extremes of body mass index do not adversely affect the outcome of IVF–embryo transfer treatment. However, the obese patients had lower peak oestradiol concentrations than their normal controls despite receiving similar gonadotrophin doses.

Key words: body mass index/IVF–embryo transfer/obesity/underweight


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Advancing female age, elevated basal follicle stimulating hormone (FSH) concentrations and extremes of body mass are all believed to have an adverse effect on the outcome of assisted conception cycles. Obesity produces a variety of alterations in the reproductive system in humans and in animal models (Bray, 1997Go). In a prospective cohort study, Mitchell and Rogers (1953) reported that 13 out of 15 obese women with amenorrhoea resumed their menses with weight reduction alone. Furthermore, Rich-Edwards et al. (1994) in a large-scale retrospective study, found that women with a body mass index (BMI) > 24 kg/m2 at age 18 years were at a significantly increased risk of primary anovulatory infertility. Excess weight, in association with the polycystic ovary syndrome (PCOS), is a known risk factor for ovarian hyperstimulation syndrome after gonadotrophin stimulation and weight loss is a recognized treatment for anovulatory infertility in obese women (Green et al., 1988Go; Clark et al., 1993; Grodstein et al., 1994Go; Pasquali et al., 1997Go). Extremely low body mass as seen in anorexia nervosa, excessive exercise or systemic illness is equally well known to be associated with anovulation and infertility (Frisch, 1978Go, 1987Go, 1988Go; Scott and Johnston, 1982Go; Schweiger et al., 1987Go). However, although extremes of weight occupy a disproportionate amount of physician time in infertility practice, the effects of obesity and extreme underweight on the outcome of in-vitro fertilization (IVF) cycles have received relatively little attention.

The response to ovarian stimulation with clomiphene citrate appears to alter at either extreme of the weight spectrum (Shepard et al., 1979Go), and underweight women were reported to perform better than their normal weight counterparts when gonadotrophins were used for ovulation induction (Halme et al., 1986Go). The apparent absence of an adverse effect of excess body mass on IVF outcome was first described by Lewis et al. (1991) in a retrospective study of the ovarian response to standardized treatment with clomiphene citrate and human menopausal gonadotrophin for the purpose of IVF–embryo transfer and gamete intra-Fallopian transfer (GIFT). However, obesity and extreme underweight are often seen as potentially treatable threats to the success of assisted conception and patients are commonly advised to try and normalize their weight before undertaking IVF. Obese (BMI > 27.9) and extremely underweight (BMI < 19) patients form about 15% of our IVF practice, and many find weight loss or gain difficult. We have therefore conducted a study based on our prospectively collected clinical database to ascertain the extent to which extremes of body mass affect IVF outcome.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
This was a retrospective nested case-control study of the prospectively-collected database of the Oxford Fertility Unit. We reviewed data on all IVF cycles started from 1 January 1995 to 31 December 1996 inclusive. The protocol for pituitary down-regulation, controlled ovarian hyperstimulation and human chorionic gonadotrophin (HCG) administration remained consistent throughout the study period.

Selection of patients
Two groups of patients were included in the study: obese patients (BMI > 27.9) and underweight patients (BMI < 19). Only white Caucasian women of all diagnostic categories, with normal day 3 FSH (3–12 IU/l), in their first IVF–embryo transfer treatment cycle were included in the study. The BMI value for the individual woman was calculated by dividing the body weight (kg) by the height2 (m2) and the chosen cut-off points represented the 10th and 90th centiles of our population. For each patient in the two study groups we randomly selected two controls from the next successive patient in the database. The controls were white Caucasian patients with a normal early follicular phase FSH (3–12 IU/l), and a BMI between 20 and 24, who were age matched to the patients in the study groups to within 1 year, the starting FSH dose (±37.5 IU), the gonadotrophin preparation, and the year of treatment. Controls and patients were not matched for the indication for IVF treatment. The authors were not aware of the patients' response to stimulation or their IVF outcome when selecting the control group.

IVF protocol
The IVF–embryo transfer protocol has been described in detail elsewhere (Lockwood et al., 1995Go). We employed intranasal gonadotrophin releasing hormone agonist (GnRHa) given daily from day 21 of the cycle (or 21 days after the start of a gestagen-induced bleed if the patient was severely oligo- or amenorrhoeic). Confirmation of pituitary down-regulation after the analogue-induced withdrawal bleed required a serum oestradiol concentration of <20 pg/ml (74 nmol/l). Highly purified urinary derived FSH preparations were used for ovarian stimulation (Metrodin HP®; Serono UK Ltd) in >77% of cycles, during the study period.

The outcome measures the duration of GnRHa treatment required to achieve the pituitary down-regulation, the FSH/luteinizing hormone (LH) ratio, the total required FSH dose, the duration of ovarian stimulation, the number of follicles aspirated, the number of eggs obtained, normal fertilization rate (number of normally fertilized eggs/total number of eggs), the number of embryos produced, the peak oestradiol concentration (on day of HCG), the number of embryos transferred, the clinical pregnancy rate per cycle, the implantation rate and the incidence of ovarian hyperstimulation syndrome.

Statistical analysis
The statistical analysis was carried out using the Minitab for Windows statistical package. The results are expressed as median [95% confidence interval (CI)]. Due to the abnormal distribution of the data, the non-parametric Mann–Whitney test was used to compare the outcome in the studied and control groups. The {chi}2 and Fisher's exact tests were used to compare proportions when appropriate.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The obese patients group comprised 76 patients while the underweight group comprised 35 patients who fulfilled the inclusion criteria. The matching controls included 152 patients for the obese group and 70 patients for the underweight group.

The obese group
Seventy six patients were included in this group. The range of their BMI was 27.7–41.7. In 36/76 (47%) the BMI was >30, and in 40/76 (53%) the BMI was between 27.7 and 29.9. The incidence of polycycstic ovarian syndrome (PCOS) was similar in the obese patients and their controls. The median (95% confidence interval) of the matching criteria (age, BMI, starting gonadotrophin dose and early follicular phase FSH), and the compared outcome measures for this group and their matching controls are summarized in Table IGo. Apart from significantly lower peak oestradiol concentrations in the obese patients, there were no significant differences between the obese patients and their control group despite a significantly higher BMI.


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Table I. Obese patients versus normal controls. Data are medians (95% confidence interval)
 
The underweight group
Thirty five patients had BMI ranging from 15–18.9. The median (95% CI) of the matching criteria (age, BMI, starting gonadotrophin dose and early follicular phase FSH), and the compared parameters for this group and their matching controls are summarized in Table IIGo. There were no significant differences between the underweight patients and their selected normal controls despite a significantly lower BMI.


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Table II. Underweight patients versus normal controls. Data are medians (95% confidence interval)
 

    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The present study has demonstrated that underweight or overweight patients entering IVF treatment do not appear to be at excess risk of cycle cancellation, reduction in number of follicles, oocytes or embryos, or have lower chances of ongoing pregnancy than their normal weight counterparts. Our results contradict the belief held by many practitioners in assisted conception that obesity (with or without PCOS) can adversely affect ovarian response to gonadotrophin stimulation. The similarity in the incidence of PCOS between the obese patients and their controls is not surprising since it has been reported that only one third of the PCOS patients are obese (Clayton et al., 1993Go).

Various studies have identified adverse effects of excessive body mass on ovulation induction and IVF outcome. Chong et al. (1986) reported that patients >25% ideal body weight required a significantly higher gonadotrophin dose to induce ovulation.

Central adiposity (android fat distribution) has more impact on the reproductive sequelae associated with obesity (Norman and Clark, 1998Go).

Zullo et al. (1996) suggested that a doubling of gonadotrophin dose was necessary for adequate ovarian stimulation in non-PCOS obese patients with a waist:hip ratio of 0.8 or more. Furthermore, Wass et al. (1997) reported that women with an android fat distribution, defined as a waist:hip ratio >0.8, had less than half the pregnancy rate of those with gynaecoid body shape in IVF–embryo transfer treatment.

Crosignani et al. (1994) reported that patients with a BMI >22 had a less favourable outcome at IVF compared to those <20. However, in their uncontrolled study they did not comment on the early follicular phase FSH, particularly that the mean number of oocytes retrieved ranged from 2.9–3.4 which many would consider a low response. Furthermore, their first definition of ovarian response is not one which is widely recognized in current practice and the second definition does not include a description of the number of IVF cycles that failed to reach oocyte recovery due to over-response.

Lewis et al. (1991) could not find a clear relationship between body mass and response to ovarian stimulation or the outcome of IVF treatment. Nevertheless, they failed to comment on the age and the basal FSH concentrations of the patients in the various BMI strata. Considering the small sample size in their study these factors could significantly influence the outcome. We did observe, however, significantly lower peak oestradiol concentrations in the obese patients, in contrast to the findings of Lewis et al. (1991). This was despite there being no difference in the amount of gonadotrophin stimulation given, when assessed both by the total dose or the number of days of stimulation. Deslypere et al. (1985) reported that fat tissue is both a steroid reservoir and a site of steroid metabolism. They noticed a positive plasma tissue gradient for all the steroids except for dihydroepiandrosterone sulphate. Therefore, the difference in peak oestradiol concentration between the obese patients and their controls could be due to the uptake of oestradiol by the adipose tissue, which may be aided by the relatively higher free oestradiol due to the low sex hormone binding globulin associated with obesity.

In all other respects, the obese and the underweight IVF patients performed as well as the carefully matched normal control patients which is counter-intuitive, and is at odds with the well documented adverse effects of over- and underweight on fertility outcome with assisted conception.

In our clinic, IVF is regarded as one of a selection of possible treatments for infertility, and all patients who enter the IVF programme are counselled regarding the relation between obesity or underweight and infertility as well as the adversities of abnormal body weight on obstetric outcome. It may therefore be that we have observed the responses of a group of patients who have already begun to normalize their body mass – we know that relatively small alterations in BMI can alter the chances of spontaneous conception in overweight women (Clark et al., 1995Go, 1998Go), and that most obese subjects will presumably attempt to lose weight before entering the IVF programme.

Our study may therefore not represent the responses of a randomly selected group of obese and underweight infertile women to IVF treatment. We would suggest that infertile women with abnormal body mass should be encouraged and helped to lose weight and improve exercise tolerance, in order both to improve the outcome of their infertility treatment and to prepare for the stresses of pregnancy and labour. Extreme maternal underweight at the start of pregnancy is known to be associated with low birth weight (van der Spuy et al., 1988Go), and obesity predisposes to a high rate of gestational diabetes and delivery by Caesarean section (Isaacs et al., 1994Go), miscarriage (Hamilton-Fairley et al., 1992Go), and congenital abnormalities (Waller et al., 1994Go) among many other complications.

Although our findings do not support a policy of excluding obese and underweight women from IVF treatment on the grounds of likely failure of ovulation induction or IVF, we recommend counselling these patients regarding the obstetric risk and the risk to their offspring of their abnormality in BMI, and the institution of a process of weight loss or gain where appropriate. However, the adverse impact of advancing female age on assisted conception outcome must be taken into account, and many units will offer treatment to women who remain at the extreme ends of the body mass spectrum after a period of attempted weight modification if female age is deemed to be a significant adverse factor. Given that this policy is widespread, we feel that our data may be of use in designing protocols for the management of IVF cycles in such patients. Finally, the small numbers in the study will inevitably affect the power of the study and confirmation by other groups is necessary before obesity and underweight can be disregarded as factors that can influence IVF outcome.


    Notes
 
3 To whom correspondence should be addressed Back


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Submitted on August 3, 1998; accepted on December 9, 1998.