Hum. Reprod. Advance Access originally published online on August 6, 2008
Human Reproduction 2008 23(11):2549-2554; doi:10.1093/humrep/den286
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Ovarian stimulation for IVF has no quantitative association with birthweight: a registry study
1 Department of Obstetrics and Gynecology, Campus Luebeck, University Clinic of Schleswig-Holstein, Luebeck, Germany 2 Unit for Human Reproduction, First Department of Obstetrics and Gynaecology, Aristotle University of Thessaloniki, Thessaloniki, Greece 3 ENDOKRINOLOGIKUM Hamburg, Lornsenstrasse 4-6, 22767 Hamburg, Germany
4 Correspondence address. UK-SH, Campus Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany. Tel: +49-451-500-2134; Fax: +49-451-500-2170; E-mail: georg.griesinger{at}frauenklinik.uni-luebeck.de
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Abstract |
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BACKGROUND: Singleton children born after IVF are of lower birthweight compared with their naturally conceived peers. It has been hypothesized that ovarian stimulation might be associated with low birthweight in children born after IVF. The aim of the present study was to explore whether or not a dose relationship exists between ovarian stimulation and birthweight in singletons born after ovarian stimulation for IVF.
METHODS: Using a national IVF registry database with a coverage of 65–70%, parental demographic variables, treatment cycle variables and neonatal variables were retrieved from all IVF treatment cycles in women between 25 and 35 years of age in which gonadotrophins were used for ovarian stimulation and a fresh embryo transfer resulting in singleton live birth was performed. Birthweight was standardized as a z-score, adjusting for gestational week at delivery and fetal sex, using data from a large reference population. Multivariate regression analysis was used to investigate the association between the dependent variable z-score and the independent predictor variables maternal age (years), maternal weight (kg), maternal height (cm), maternal body mass index (BMI) (kg/m2), duration of infertility (years), number of embryos transferred (n), duration of stimulation (days), consumption of gonadotrophins (ampoules) and number of oocytes retrieved (n).
RESULTS: Data retrieval yielded 32 416 singleton live births after IVF, with a mean (±SD) z-score of –0.25 (±1.0) and –0.23 (±1.0) for male and female neonates, respectively. Regression analysis indicated that maternal weight, maternal height, duration of infertility and the number of embryos transferred were statistically significant determinants of the birthweight of singletons after ovarian stimulation IVF. Parameters of ovarian stimulation (duration of stimulation, consumption of gonadotrophins, number of oocytes retrieved), maternal BMI and maternal age did not significantly predict birthweight.
CONCLUSIONS: Features reflecting ovarian stimulation do not correlate with birthweight. Therefore, ovarian stimulation is unlikely to be a factor affecting birthweight of IVF pregnancies.
Key words: birthweight/ovarian stimulation/adverse outcome/child health/IVF
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Introduction |
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Singleton children born after in vitro fertilization (IVF) have a significantly lower birthweight compared with their spontaneously conceived peers (summarized by Helmerhorst et al., 2004
; Jackson et al., 2004; Sutcliffe and Ludwig, 2007), even after adjustment for maternal age and parity. This phenomenon has generated a lot of concern, because low birthweight is associated with morbidity in both the short and long term (Gutbrod et al., 2000; Hack et al., 2003; Lau and Rogers, 2004) and speculations about possible causes, including epigenetic alterations by ovarian stimulation, have been published (Horsthemke and Ludwig, 2005). Theoretically, the lower birthweight in IVF singletons could be attributed to (i) maternal and/or paternal characteristics associated with infertility; (ii) the effects of ovarian stimulation on oocytes, endometrium or the endocrinology of the luteal phase or early pregnancy or (iii) IVF laboratory procedures such as ICSI or embryo culture (Williams et al., 1991; Thomson et al., 2005; Fernandez-Gonzalez et al., 2007).
Recent studies have indicated a link between ovarian stimulation and the occurrence of adverse outcome in IVF children, including low birthweight, since the risk of low birthweight in IVF singletons appears to be significantly higher in fresh embryo transfer cycles (following ovarian stimulation) than in frozen cycles (Wennerholm et al., 1997; Källen et al., 2005; Wang et al., 2005). Furthermore, it has been suggested that birthweight is reduced in cases of ovarian stimulation IVF compared with natural cycle IVF (Keizer et al., 2004), ovarian stimulation IVF compared with minimal stimulation IVF (Keizer et al., 2005) or conception after ovarian stimulation compared with spontaneous conception (Kapiteijn et al., 2006). A negative correlation between follicular phase estradiol levels under ovarian stimulation for IVF and birthweight has also been described (Mitwally et al., 2004). Finally, animal studies have linked ovarian stimulation to birthweight alterations and epigenetic changes. In the mouse, ovulation induction induces fetal growth retardation (Ertzeid and Storeng, 2001; van der Auwera and D’Hooghe, 2001), and ovarian stimulation has been associated with aberrant DNA methylation patterns in murine oocytes and embryos (Shi and Haaf, 2002; Fauque et al., 2007; Sato et al., 2007).
However, the evidence supporting the hypothesis that ovarian stimulation and birthweight have an association cannot be considered sufficient for the following reasons. Studies with normally fertile patients as a control group suggesting that ovarian stimulation is associated with low birthweight are generally prone to confounding by the infertility background of the study population. More specifically, in studies on children born after frozen–thawed cycles, the risk of confounding stems from a selection bias of women, who are able to undergo a frozen-thawed cycle (Wennerholm et al., 1997; Källen et al., 2005; Wang et al., 2005), compared with those having only fresh embryo transfers. Other previous studies show lack of adjustment for multiplicity, gestational age and gender (Keizer et al., 2004, 2005), risk of selection bias (Keizer et al., 2004, 2005), in addition to very small sample sizes (Keizer et al., 2004, 2005; Mitwally et al., 2004), including both singletons and twins. Animal studies stem exclusively from the mouse (a polyovulatory species) (Ertzeid and Storeng, 2001; van der Auwera and D’Hooghe, 2001; Shi and Haaf, 2002), and the results might not be valid in the human (a mono-ovulatory species).
The purpose of this study was therefore to test the hypothesis that a quantitative association exists between birthweight of IVF singletons after fresh embryo transfer and parameters of ovarian stimulation. Conventional IVF follow-up studies that compare outcomes in IVF children with those in spontaneously conceived children are usually confounded by the infertility background of the study population. To exclude such confounding, here in the case of birthweight, there is a need for examining a large population of IVF children for the occurrence of birthweight alterations that might have a quantitative relationship with the procedures and techniques involved in IVF.
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Materials and Methods |
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The present study was a retrospective exploratory analysis of prospectively collected data from a national IVF registry (recdate®). The protocol for this study was established in October 2006 prior to data retrieval and analysis, after consensus about methodological issues had been reached between the investigators. Data of a cohort of singleton children after IVF or ICSI were examined. Parental demographic variables, treatment cycle variables and neonatal variables were retrieved from all IVF or ICSI treatment cycles with gonadotrophin stimulation and fresh embryo transfer resulting in singleton birth. The data set retrieved was explored by multivariate regression analysis.
Data origin and retrieval
The recdate IVF registry has existed since 2001 in parallel with the national German IVF registry (DIR, 2006). In contrast to the national German IVF registry, which is believed to have a coverage close to 100% for the treatment reports, participation in the recdate data collection is voluntary, and a larger array of data are collected than what is mandatory in the context of the national registry. When comparing the national IVF registry and the recdate registry, the coverage of IVF treatment cycles performed in Germany, recorded in recdate, is 
65–70% (38 000–81 000 treatment cycles reported per year) per year, and 73–79 treatment centres have been exporting data at regular intervals since 2001 (DIR registry: 109–120 centres).
In November 2006, data on all documented live births were retrieved from the registry in cases where the following criterion was fulfilled: singleton live birth, following ovarian stimulation with gonadotrophins for IVF/ICSI and fresh embryo transfer, in women between 25 and 35 years of age. For each case, demographic variables (assessed at the onset of treatment), neonatal variables and variables of the treatment cycle that resulted in live birth were retrieved: maternal age (years), maternal height (cm), maternal weight (kg), maternal body mass index (BMI) (kg/m2), duration of infertility (years), birthweight of the neonate (g), duration of gestation (weeks), fetal sex, number of embryos transferred (n), duration of stimulation (days), gonadotrophin consumption (75 IU ampoules) and number of oocytes retrieved (n).
Outcome measure
Birthweight was recorded in grams, with information on fetal sex and gestational age at delivery for every singleton live birth after IVF. Birthweight data were retrieved from hospital reports or information from the parents. To correct for the high physiological variation of birthweight occurring as a consequence of multiple pregnancy, it had been an a priori decision to include only singleton live births in the present analysis. Furthermore, to reduce variation in both birthweight (Wang et al., 2005) and ovarian response to stimulation (Toner et al., 1991; Rosenwaks et al., 1995) as a consequence of maternal age, it had been an a priori decision to include only live births in women between the ages of 25 and 35 years. It was decided to customize birthweight of each case by comparison with a German reference population (Voigt et al., 2006). This was done by calculating z-scores (Oken et al., 2003). The z-score of each individual case was calculated using the following formula: (weight of individual case at given gestational age–mean weight of reference population at same gestational age)/standard deviation in the reference population) (Land, 2006). The z-score indicates how many standard deviations an observation is above or below the reference population mean. The reference population consisted of all 1 184 624 singleton male neonates and 1 117 742 singleton female neonates born between 1995 and 2000 in Germany (Voigt et al., 2006), for whom arithmetic means (and standard deviations) of birthweight stratified for fetal sex and gestational age were available. This reference population represents the latest available birthweight data for Germany at the time of data analysis. The reference population includes children born after IVF.
Statistical analysis
Multivariate linear regression was used to investigate the association between the (dependent) variable z-score and the (independent) predictor variables maternal age, height, weight and BMI, duration of infertility, number of embryos transferred, duration of stimulation, gonadotrophin consumption and number of oocytes retrieved. As this was an exploratory analysis, all the independent variables were entered into the analysis, regardless of any findings in univariate analyses. A P-value of 
0.01 was considered to indicate statistical significance, representing a conservative threshold for rejecting the null hypothesis (no association between dependent and independent variable). The software program used for the calculations was SAS (version 9.1.3).
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Data retrieval from the IVF registry yielded 32 416 singleton live births after IVF or ICSI born to women between 25 and 35 years of age at the onset of treatment, of whom 16 510 were of male sex and 15 906 were of female sex. Mean (±SD) birthweight of male and female IVF neonates was 3297.8 g (±625.2) and 3197.3 g (±601.7), respectively. In 11 294 cases, 3 embryos had been transferred; in 19 362 cases, 2 embryos had been transferred, whereas 1735 cases resulted from single embryo transfer.
z-Score
The mean z-score was –0.24 (–0.25 ± 1.0 and –0.23 ± 1.0 for male and female neonates, respectively). Figure 1 depicts mean z-scores stratified for gestational age at delivery. A consistently lower birthweight can be observed throughout all gestational ages in children born after IVF. Table I shows mean z-scores according to arbitrarily defined categories of duration of stimulation, gonadotrophin consumption and number of oocytes retrieved. The distribution of z-scores did not vary substantially across categories of characteristics of ovarian stimulation.
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Multivariate regression analysis
In the regression analysis, the z-score translated into an intercept of –2.98 (P < 0.01). Regression analysis indicated that maternal weight, maternal height, duration of infertility and the number of embryos transferred were statistically significant determinants of the birthweight of singletons after ovarian stimulation IVF, although the associations were weak. Parameters of ovarian stimulation (duration of stimulation, consumption of gonadotrophins, number of oocytes retrieved), maternal BMI and maternal age did not significantly predict birthweight (Table II).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionFundingAcknowledgementsReferences |
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Here we aimed to investigate whether or not a quantitative association between various parameters of ovarian stimulation and neonatal birthweight after IVF exists. No such association was found for the duration of stimulation, the gonadotrophin consumption or the number of oocytes retrieved. As expected (Martin et al., 2004
; Xue et al., 2008), maternal height and weight were found to be significant predictors of birthweight in our cohort of subjects, as both are highly heritable. In contrast to previous publications (Wang et al., 2005), maternal age was not associated with birthweight; however, this is likely to result from the narrow maternal age limits (25–35 years) chosen for the present analysis. The results from the present study should therefore only be extrapolated to women of 25–35 years. Duration of infertility was positively associated with birthweight (i.e. the longer the duration of infertility, the higher the birthweight), which is an unexpected finding. In contrast, previous studies have reported maternal infertility as a risk factor for low birthweight (Martin et al., 2004; Thomson et al., 2005; Wang et al., 2005; Xue et al., 2008). The association found in our study was, however, very weak, with a regression estimate of 0.006, and we therefore think that this result represents a chance finding of doubtful external validity.
The number of embryos transferred was negatively, and statistically significantly, associated with birthweight, i.e. the higher the number of embryos transferred, the lower the birthweight of the singleton. Previous publications have indicated that ‘vanishing twin syndrome’ (Pinborg et al., 2005, 2007; Shebl et al., 2007) and a higher number of embryos transferred (Rombauts et al., 2004) are associated with low birthweight after IVF. It is likely that vanishing twins were a common phenomenon in our cohort of singleton cases, because the majority of cases resulted from multiple embryo transfers. Our study finding supports the contention of an association of multiple embryo transfer with lower birthweight in singletons.
In the regression model, the group of independent variables when used together predict the dependent variable z-score with statistical significance; however, only 4.3% of the total variation in z-score observed could be explained by the predictor variables used. We are left to speculate about the extent of variation in birthweight observed resulting from predictor variables (which were not available for this analysis), such as occurrence of gestational disease or fetal or placental chromosomal abnormalities, etc. A recently published prediction model of birthweight (Xue et al., 2008), which included socio-economic factors, nutritional factors and pregnancy-related disease factors in addition to parental anthropomorphic variables, predicted only 23.3% of the observed variance in birthweight. Therefore, it is likely that a significant proportion of the variation in birthweight in humans results from random fluctuation.
Ideally, a prospective clinical study should be conducted to assess predictors of birthweight in IVF children. Such a study would need to closely monitor a large cohort of women from preconception throughout pregnancy to live birth. We are not aware of any database from a prospective clinical trial, large enough to answer our question of interest; therefore, we chose the current approach, involving a registry database, as currently the best approximation of the truth.
Conventionally, follow-up studies in assisted reproduction have compared children after IVF with spontaneously conceived children for the outcomes of interest, such as birthweight (Dhont et al., 1999; Katalinic et al., 2004; Ludwig et al., 2004; Hansen et al., 2005). Any finding from such studies is however subject to potential confounding by infertility, because ovarian stimulation and IVF are performed in subfertile couples only, whereas the control couples are normally fertile. The present study circumvents the problem of such confounding, as all cases were subfertile, with an indication for ovarian stimulation IVF. In biological systems, associations between continuous variables are often quantitative, and therefore, our hypothesis was that if an association between ovarian stimulation and birthweight existed, that this would be a quantitative one, and therefore detectable in an uncontrolled study. If, however, low birthweight was associated with gonadotrophin stimulation per se, regardless of the extent, then such an association would be missed with such a study design. Nevertheless, ovarian stimulation is still a standard procedure in IVF, and therefore our study results are practically relevant. For the clinician, it is re-assuring that the birthweight of an IVF neonate will not be affected by, e.g. the size of the oocyte pool from which the conception originates. Further evidence to support our hypothesis of no association between ovarian stimulation and birthweight stems from a recently published randomized trial (Heijnen et al., 2007), in which a mild ovarian stimulation regimen (with single-embryo transfer) (Hohmann et al., 2003) was compared with a conventional stimulation regimen (with double-embryo transfer), and from a recent prospective cohort study, in which no differences in z-scores for birthweight were observed when comparing singletons resulting from ovarian stimulation IVF, modified natural cycle IVF and spontaneous conception in subfertile couples (Middelburg et al., 2007). Furthermore, Shih et al. (2008) failed to find an impact of the number of oocytes and FSH stimulation on birthweight in singletons after IVF in a large retrospective analysis.
It is important to state that the aim of the study was to explore whether or not an association between ovarian stimulation and birthweight exists, and not to construct a prediction model for birthweight in IVF singletons. Therefore, we chose to use a multivariate analysis including all a priori confounders that were available in the recdate registry, rather than backward or forward selection, which would allow the detection of co-linearity (e.g. age and oocyte yield). Limitations of this study result mostly from the fact that a number of well-known a priori confounders, such as gestational diseases, were not available for analysis. Other limitations stem from the fact that the reference and the study population refer to different time periods, and that the reference population will include birthweight data from children after IVF. The effect of the latter on mean birthweight of the reference population is, however, likely to be negligible. It can be estimated from the report in the German IVF registry (DIR, 2006) that approximately 30 000 singleton live births happened after IVF, ICSI or frozen–thawed embryo transfer cycles in the time span 1995–2000. This number is dwarfed by the total number of 2 302 366 singleton children in the reference population for the same time period.
In conclusion, the present study provides robust evidence from a large sample of IVF singletons that ovarian stimulation and birthweight have no apparent quantitative (e.g. dose–response) association. Although this is re-assuring to the clinician, it does not invalidate the need for studying the effect of ovarian stimulation on outcomes other than birthweight, such as epigenetic alterations, and associated health disorders.
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None of the authors has received funding for this work.
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The authors acknowledge PD DDr M. Voigt, pediatrician, for providing the birthweight data of the German newborns used as a reference population. We would like to thank Dr E. Beck, Anfomed, Germany, for his help with data retrieval from the recdate registry and statistical advice. Finally, we thank all the doctors working in the German IVF centres who participate in the ongoing data collection for the recdate registry.
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Submitted on January 16, 2008; resubmitted on June 23, 2008; accepted on June 30, 2008.
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