Hum. Reprod. Advance Access originally published online on February 15, 2008
Human Reproduction 2008 23(4):878-884; doi:10.1093/humrep/den017
High and low BMI increase the risk of miscarriage after IVF/ICSI and FET
1 Department of Obstetrics and Gynecology, University of Oulu, PO Box 5000, Oulu FIN-90014, Finland 2 Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland 3 Infertility Clinic, Family Federation of Finland, Helsinki, Finland 4 AVA Clinic, Tampere, Finland
5 Correspondence address. Tel: +358-8-3153172; Fax: +358-8-3154310; E-mail: juha.tapanainen{at}oulu.fi
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Abstract |
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BACKGROUND: The extremes of BMI are associated with an increased risk of miscarriage both in spontaneously conceived pregnancies and after fertility treatment. The aim of the present study was to study the effect of BMI on miscarriage rate (MR) in fresh IVF/ICSI, and in spontaneous and hormonally substituted frozen-thawed embryo (FET) cycles.
METHODS: Analysis was carried out on 3330 first pregnancy cycles, performed during the years 1999–2004, of which 2198 were fresh, 666 were spontaneous and 466 were hormonally substituted FET cycles. A categorical, a linear and a quadratic models of the effect of BMI on miscarriage were studied by logistic regression. Factors related to patient characteristics, protocol and embryo parameters were also examined.
RESULTS: MR was higher in hormonally substituted FET (23.0%), compared with the fresh cycles (13.8%) and spontaneous FET (11.4%, P < 0.0001). Multivariate logistic regression revealed that the relationship between BMI and the risk of miscarriage is not linear but quadratic (U-shaped) (P = 0.01), indicating a higher risk of miscarriage in underweight and obese women. Hormonal substitution for FET was also associated with a 1.7-fold higher MR, compared with the fresh cycles (P = 0.002, 95% confidence interval 1.2–2.3).
CONCLUSIONS: Obese and underweight women have an increased risk of miscarriage, and hormonally substituted FET is associated with an even higher MR.
Key words: obesity/underweight/miscarriage/IVF/ICSI/frozen-thawed embryo transfer
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionFundingAcknowledgementReferences |
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Reproductive potential in obese women is decreased as a result of impaired folliculogenesis, ovulation and conception, and obesity is associated with an increased risk of pregnancy complications (Zaadstra et al., 1993
; Hall and Neubert, 2005; Pasquali, 2006). In spontaneous pregnancies, obesity has been found to be an independent cause of miscarriage (Lashen et al., 2004), with miscarriage rates (MRs) varying between 17% (Lashen et al., 1999) and 27% (Wang et al., 2002). A low body mass may also be a risk factor for menstrual disturbances and infertility problems (Frisch, 1978, 1987, 1989, 1996; Scott and Johnston, 1982; Schweiger et al., 1987). Recently, women with a pre-pregnant BMI < 18.5 kg/m2 have been found to have 1.7-fold increased risk of miscarriage in spontaneous pregnancies (Helgstrand and Andersen, 2005; ESHRE, 2006; Maconochie et al., 2007).
In IVF/ICSI, data regarding the risk of miscarriage in pregnancies of obese or underweight women are conflicting (Lashen et al., 1999; Fedorcsák et al., 2000, 2004; Wang et al., 2001, 2002; Winter et al., 2002; Roth et al., 2003) and results are difficult to compare, as studies differ in their definitions of obesity, scope of analysis, stimulation protocols and confounding factors studied.
Frozen-thawed embryo transfer (FET) is becoming more common, mostly as a result of wider use of elective single embryo transfer (eSET). MRs have ranged from 13% to 45% in previous studies on FET (Aytoz et al., 1999; Salumets et al., 2003, 2006), but detailed analyses of the effect of BMI on the MR after FET have not been published.
The aim of this study was to investigate the effect of BMI on MR after IVF/ICSI and FET, while controlling for a number of confounding factors related to patient characteristics, treatment protocols and embryo parameters.
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Materials and Methods |
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During the years 1999–2004, 15 990 assisted conception cycles were performed in the Infertility Clinics of Oulu and Helsinki University Hospitals, the Family Federation of Finland in Oulu and Helsinki, and the AVA Clinic in Tampere. The overall clinical pregnancy rate/embryo transfer was 29.4% (2447/8321) in the fresh cycles, 23.5% (719/3066) in the spontaneous FET and 20.6% (475/2308) in the hormonally substituted FET cycles (P < 0.0001). Analysis was carried out on the first clinical pregnancy cycles of 3330 women, 65.4% (2198 cycles) of which occurred after fresh embryo transfer and 34.6% (1132 cycles) after FET.
Ovarian stimulation was performed using the long GnRH agonist protocol (83.5%, 1835 cycles) or the GnRH antagonist protocol (13.8%, 304 cycles) (Vilska et al., 1999; Tiitinen et al., 2001; Veleva et al., 2005). In 59 cycles (2.7%), other stimulation protocols were used. The starting gonadotrophin dose was determined according to the patient's age, BMI, antral follicular count in the baseline ultrasonographic scan and the outcome of previous infertility treatments. Oocytes/embryos were cultured as previously described (Tomás et al., 1998; Hydén-Granskog et al., 2005). Embryo transfer was carried out on Day 2 or 3 after oocyte retrieval, depending on the day of the week—on Monday if the oocytes were collected on Friday and 2 days after the ovum pickup in all other cases. Such a strategy has been adopted to minimize work during the weekends. A top quality embryo had 4–5 evenly sized cells and <20% of fragmentation, if it was cultured for 2 days, or 
8 cells and <20% of fragmentation if it was cultured for 3 days (Van Royen et al., 1999). Extra embryos were frozen on the day of embryo transfer, using a slow freezing protocol (Hydén-Granskog et al., 2005).
FET after spontaneous ovulation was performed in 666 cycles (56.8% of all FET cycles). The urinary LH surge was measured by means of a home test kit. Depending on the day of freezing of the embryo, embryo transfer was carried out an average of 4 (2–5) days after a positive result. In 562 (84.4%) of these cycles, luteal support with 200 mg/day Lugesteron (Leiras, Helsinki, Finland) was started on the day of embryo transfer and continued for 2 weeks.
In hormonally substituted FET cycles, estradiol valerate or 17β-estradiol (Estrofem, Novo Nordisk, Bagsværd, Denmark; Merimono, Novartis, Basel, Switzerland; Progynova, Schering, Berlin, Germany; Zumenon, Solvay Pharmaceuticals, Hannover, Germany) was administered at a daily dose of 4–6 mg. Vaginal micronized progesterone (400–600 mg Lugesteron/day) or Crinone vaginal gel of 8%, 1.125 g twice a day (Serono, Geneva, Switzerland) was started when the endometrial thickness was 6 mm on cycle Day 11–13 and treatment was continued until 9–12 gestational weeks after a positive pregnancy test result. In cases of a thinner endometrium, the estradiol dose was increased to 6–8 mg/day and progesterone administration was delayed until a thickness of 6 mm was reached. Such a protocol was used in 303 cases of oligo/amenorrhea (61.1%). In 163 cycles (32.2%), GnRH agonist (Suprecur, 450 mg/day, Sanofi-Aventis, Paris, France, or Synarela, 400 mg/day, Pfizer, New York City, USA) was used for pituitary down-regulation before starting endometrial preparation in order to prevent spontaneous ovulation and to control the timing of embryo transfer. In five cases (1.0%), another hormonal substitution protocol was used. Information about the exact hormonal substitution protocol was missing in 25 cases (5.0%). These 30 cases were subsequently excluded from the analysis.
Thawed embryos were graded using the same criteria as in the fresh cycles, although at present there is no consensus of opinion on the definition of a top quality embryo in FET cycles.
Pregnancy was detected by a urinary hCG test (in Oulu) or by serum hCG measurement (in Helsinki and Tampere). Clinical pregnancies were diagnosed by transvaginal ultrasonography at gestational week 6–7 by visualization of a gestational sac and cardiac activity. Miscarriage was defined as a pregnancy lost before 12 full weeks of gestation.
Statistics
The primary outcome measure was the MR after fresh or FETs. Initially, treatment types (fresh cycles, spontaneous and hormonally-substituted FET) were studied independently. Chi-square and two-tailed t-tests were used for comparison of variables in the groups with and without miscarriage. A value of P < 0.05 was taken as the limit of significance.
Univariate logistic regression was used to assess the independent effects of different factors on miscarriage. The effect of BMI was studied by three different approaches. The first one examined whether being obese, compared with being non-obese, affected the MR. Obesity was defined as BMI 27 kg/m2, as this is the threshold value above which insulin sensitivity decreases significantly (Campbell and Gerich, 1990). The second approach studied the validity of a linear relationship using the exact BMI values. The third approach assessed a quadratic, i.e. U-curved, relationship by studying the exact and squared values of BMI together. To prevent possible colinearity between the BMI variables, BMI was centred at 23 kg/m2 (which approximates the mean BMI) before carrying out the ‘quadratic’ regression. Age, diagnosis, secondary infertility, positive history of previous miscarriage, origin of the embryo (IVF versus ICSI), number of embryos transferred and transfer of at least one top quality embryo were the other variables studied in each treatment type.
In the fresh cycles, univariate analysis also included stimulation protocol with a GnRH agonist versus a GnRH antagonist, the number of collected oocytes, eSET and Day 2 versus Day 3 fresh embryo transfer. To date, eSET in the FET cycles is not routinely performed and therefore such data were unavailable as regards the FET cycles. The use of luteal phase progesterone (in spontaneous FET only) and the use of GnRH agonist (in hormonally substituted FET only) were also assessed. Univariate logistic regression was then performed on all studied cycles in order to assess the effect of the treatment type.
Finally, the variables showing independent effects in the univariate analyses were studied by multivariate logistic regression of all cycles. Variables showing non-significant effect were removed from the model in a stepwise manner. The fit of the final logistic model was assessed by means of the Hosmer–Lemeshow test. Statistical analysis was performed with SPSS 14.0.1 software (SPSS Inc., Chicago, IL, USA).
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Results |
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Compared with the fresh (13.8%) and spontaneous FET cycles (11.4%), there was a higher MR in hormonally substituted FET (23.0%, P < 0.0001) (Table I). In all treatment types, women who had a miscarriage were older than those who did not. In the fresh (17.5% versus 12.9%, P = 0.04) and hormonally substituted FET cycles (30.8% versus 13.1%, P < 0.0001), there were more obese women in the miscarriage group, compared with those without miscarriage. However, the mean BMI of women with miscarriage was higher only in the hormonally substituted FET group (25.3 ± 5.4 versus 23.2 ± 3.7, P < 0.0001). A higher incidence of previous miscarriage was observed in the miscarriage group with spontaneous FET. Subjects within the treatment groups were comparable in terms of diagnosis and incidence of secondary infertility in all treatment types.
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The characteristics and outcomes of the treatment cycles are shown in Table II. In IVF/ICSI, fewer oocytes were collected in the miscarriage group than in the group without miscarriage (11.4 ± 7.0 versus 12.5 ± 6.7, P = 0.01). The number of embryos transferred was similar in women with or without miscarriage in all treatment types. However, the proportion of embryo transfers with
1 top quality embryo was smaller in the miscarriage group than in spontaneous FET (21.9% versus 35.4%, P = 0.03).
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In spontaneous FET cycles, the proportion of cycles in which luteal phase progesterone had been administered was similar between the groups with and without miscarriage (63/75, 84.0% versus 499/587, 85.0%, P = 0.9). In hormonally substituted FET, the proportion of cycles with GnRHa did not differ between women with and without miscarriage (40/107, 37.4% versus 123/359, 34.3%, P = 0.6).
In univariate logistic regression analysis, obesity was found to affect the MR in all three analyses (categorical, linear and quadratic). Other independent factors were age, secondary infertility, a positive history of previous miscarriage and the transfer of 1 top quality embryo. A lower number of oocytes predicted miscarriage but its independent effect was lost in the multivariate analysis of the fresh cycles. When all treatment types were analysed together, hormonally substituted FET was associated with an increased MR.
In the final multivariate analyses, all treatment cycles were studied together. Age, the type of cycle and the transfer of 1 top quality embryo were included in three multivariate models: obese versus non-obese (categorical), a model using BMI as a continuous variable (linear) and a model with BMI and its squared value (quadratic). Given the correlation between the type of infertility (primary versus secondary) and a positive history of previous miscarriage, only the latter variable was kept in the analyses, as it was considered to be clinically more relevant.
In the categorical and linear multivariate regression models, BMI did not independently affect the MR, but it did in the quadratic model (Table III). This showed that the relationship between BMI and the MR is quadratic (a U-shaped curve), rather than linear (a straight line), meaning that not only being obese, but also being underweight is associated with a higher risk of miscarriage.
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The other variables with an independent effect on the risk of miscarriage in the multivariate models were age, a positive history of previous miscarriage and the type of cycle. The final model showed different age categories from a clinical point of view; age as a categorical variable is more informative than age as continuous variable. The reference category was age <35 years. If the age of the woman was 35–39 years, the MR increased 1.5-fold, and if the age was
40 years, the MR increased 2.6-fold. A positive history of miscarriage was associated with a 1.5-fold higher MR. Compared with the fresh cycles, spontaneous ovulation in FET was associated with a similar risk of miscarriage but hormonal substitution increased the risk 1.7 times. Compared with hormonally substituted FET, both fresh [P = 0.001, odds ratio (OR) 0.58, 95% confidence interval (CI) 0.42–0.79] and spontaneous FET cycles (P < 0.0001, OR 0.48, 95% CI 0.33–0.71) halved the MR. Figure 1 shows the modelled risk of miscarriage in different age groups and treatment types. The risk of miscarriage of a 36-year-old woman with no previous miscarriages and a BMI of 18 kg/m2 is 15.9% in the fresh cycle and 23.8% in a hormonally substituted FET cycle. If the same woman gains weight and her BMI is 24 kg/m2, her risk of miscarriage decreases to 12.4% in the fresh cycle and to 19.0% in the hormonally substituted FET cycle. If she continues to gain weight and her BMI increases to 32 kg/m2, the risk of miscarriage will be 15.9% in the fresh cycle and 23.8% in a hormonally substituted FET, equal to the risk she had when her BMI was only 18 kg/m2.
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Discussion |
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The present study, in which the 3330 pregnancy cycles out of nearly 16 000 treatment cycles were analysed, showed that the relationship between BMI and the MR after IVF/ICSI or FET is not linear but U-shaped. This means that women with both low and high BMI have an increased risk of miscarriage. In addition, hormonal substitution for FET was independently associated with an increased MR, regardless of the woman's BMI.
This analysis clarifies the long-lived controversy on the effect of BMI on MR after IVF/ICSI. Data from earlier studies support the present findings. It has been suggested that underweight and obese women have lower PR (Wang et al., 2000) and higher rates of early pregnancy loss (Winter et al., 2002) and miscarriage (Fedorcsák et al., 2004), but the results of these studies did not reach statistical significance. This may be due at least partly to the statistical methodology used as the authors have compared different BMI groups. Similarly, in the present analysis, no difference was observed by comparing five BMI groups, whereas the quadratic analysis showed a clear effect of low and high BMI on MR.
In the present study, a relatively high number of subjects were underweight. There were 327 fresh treatment cycles of women with BMI < 20 kg/m2 and 78 cycles of women with BMI < 18.5 kg/m2. A low number of subjects might be the reason for controversial results in previous studies (Wang et al., 2001, 2002; Fedorcsák et al., 2004). Similarly, an insufficient number of cases as well as statistics used may also explain why earlier reports have failed to demonstrate an independent effect of obesity on MR (Lashen et al., 1999; Fedorcsák et al., 2000).
Multivariate analysis indicated that embryo morphology was not related to the MR in any of the treatment modalities studied. Likewise, women who had an eSET in their fresh cycles had a MR (17%) similar to those who did not (15%, P = 0.1). These findings are in line with previously published results showing that embryo morphology at the time of freezing does not affect the MR after FET (Salumets et al., 2006). Another analysis indicated that age-related characteristics, rather than transfer of a single top quality embryo, determine first trimester pregnancy loss in the fresh cycle (De Neubourg et al., 2004). Furthermore, a recent study revealed that embryo quality determines implantation but that continuation of pregnancy depends on the combination of uterine factors and the presence of embryos suitable for cryopreservation (Lambers et al., 2007).
The present results suggest that in FET, the increased MR after hormonal substitution is associated with impaired endometrial function, rather than with poor embryo quality. The endometrial thickness on the day of embryo transfer was higher in the hormonally substituted cycles, compared with spontaneous FET (10.8 ± 2.3 versus 9.6 ± 1.7 mm, P < 0.0001). However, endometrial thickness may not be the optimal indicator of endometrial receptivity (Remohí et al., 1997). This hypothesis is supported by the results of a study on oocyte donation cycles in which only top quality embryos and blastocysts were transferred (Bellver et al., 2003). The MR was 18% in underweight patients, 13% in normal weight ones and 38% in obese women.
The higher MR in subjects with low and high BMI may be explained by the action of leptin, a hormone which is produced predominantly in the adipose tissue (Gonzalez et al., 2000b; Mitchell et al., 2005). Plasma levels of leptin correlate with BMI in non-pregnant women (Andrico et al., 2002), during ovarian stimulation (Wunder et al., 2005) and in pregnancy (Lage et al., 1999; Stock et al., 1999). Leptin and its receptor are expressed in the secretory endometrium (Alfer et al., 2000; Gonzalez et al., 2000a; Kitawaki et al., 2000; Cervero et al., 2004), in which they may regulate uterine angiogenesis (Bouloumie et al., 1998) and embryo implantation (Gonzalez et al., 2000a; Cervero et al., 2004). Low plasma leptin levels have been associated with early miscarriage (Lage et al., 1999) and with recurrent miscarriage (Lage et al., 1999; Laird et al., 2001) and may explain why underweight women have an increased MR.
Obesity is characterized by high leptin levels and, possibly, leptin resistance (Dyck et al., 2006; Enriori et al., 2006). High leptin levels may lead to insulin resistance through an altered fatty acid metabolism in skeletal muscle (Steinberg et al., 2002; Dyck et al., 2006) and a pro-inflammatory shift of the immune system (Loffreda et al., 1998; Bastard et al., 2006). Insulin resistance is typical for obese women (Pasquali et al., 2003) and may be involved in miscarriage through several mechanisms such as diminished endometrial production of the adhesion factors, insulin-like growth factor-binding protein-1 and uterine 
vβ3 integrin (Apparao et al., 2002; Jakubowicz et al., 2004; Giudice, 2006). Lower serum levels of the immunosuppressive protein, glycodelin, that is of importance during the first trimester of pregnancy (Seppälä et al., 2002), have also been described in obese women with polycystic ovary syndrome (PCOS) (Jakubowicz et al., 2001) and in women with miscarriage (Jakubowicz et al., 2004; Salim et al., 2007).
The high MR in hormonally substituted FET can be explained by the observation that many subjects had irregular cycles as a result of PCOS. Although it is not well understood, possible causes for the higher MR in PCOS women include obesity, hyperinsulinemia and hypersecretion of LH (Homburg, 2006). However, recent research has shown that in IVF, insulin resistance alone increases the risk of miscarriage independently of BMI or PCOS (Tian et al., 2007). The effect of the hormonal substitution for FET on PCOS patients has not been investigated. Several earlier studies have involved comparison of outcome in spontaneous versus hormonally substituted FET cycles, but owing to small study groups, the analysis of MR has been limited (Schmidt et al., 1989; Sathanandan et al., 1991; Al-Shawaf et al., 1993; Gelbaya et al., 2006).
In the present analysis, a large number of potential confounding factors were studied in relation to miscarriage. To our knowledge, the effect of progesterone supplementation in spontaneous FET has not been investigated. The multivariate analysis showed that progesterone supplementation did not result in lower MR (12/100, 12.0%) compared with cycles without progesterone supplementation (63/562, 11.2%, P = 0.9). As expected, higher age increased the risk of miscarriage in both fresh and FET cycles. The detrimental effect of increased maternal age on embryo quality is well documented (Magli et al., 1998; Gianaroli et al., 1999, 2000) and is the main cause of the increased MR in older infertility patients (Schieve et al., 2003).
The reproductive history of the woman was also important. Women who had previously experienced miscarriage were at a 1.5-fold higher risk of miscarriage after FET. A similar impact (OR 1.3) of previous miscarriage on the MR after IVF/ICSI has been observed previously (Wang et al., 2001). Furthermore, the risk of miscarriage seems to increase slightly with the number of miscarriages (Schieve et al., 2003).
The present results underline the clinical importance of obesity, especially in FET cycles. Even moderate weight reduction before a hormonally substituted FET cycle might be beneficial (Clark et al., 1995, 1998). Another option could be the use of metformin treatment, which has been shown to increase glycodelin levels (Jakubowicz et al., 2001) and to reduce first trimester miscarriages in women with PCOS (Jakubowicz et al., 2002; Pasquali et al., 2003; Budak et al., 2006). It is equally important to counsel underweight women about the importance of adequate food intake. The effect of physical activity should also be considered as it has been associated with both lower leptin levels (Franks et al., 2003; Dyck, 2005) and improved insulin sensitivity (Black et al., 2005; Franks et al., 2007), most probably through changes in the action of skeletal muscle AMP-activated protein kinase (Steinberg and Jorgensen, 2007).
In conclusion, the present study showed that BMI affected the MR in a non-linear manner. Underweight and obese women are at a higher risk of miscarriage than women with normal weight. The results also suggest that the hormonal environment in fresh IVF/ICSI and in spontaneous ovulatory cycles is associated with better endometrial function than in hormonally substituted FET.
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Funding |
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Sigrid Jusélius Foundation; Academy of Finland.
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Acknowledgement |
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The authors wish to thank Professor Esa Läärä (Department of Mathematical Sciences, University of Oulu) for his advice in data analysis.
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References |
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Submitted on July 30, 2007; resubmitted on October 25, 2007; accepted on November 21, 2007.
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