Hum. Reprod. Advance Access published online on August 9, 2008
Human Reproduction, doi:10.1093/humrep/den309
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Pubertal development in children and adolescents born after IVF and spontaneous conception
1 Department of Paediatrics, Institute for Clinical and Experimental Neuroscience. VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands 2 Department of Obstetrics and Gynaecology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands 3 Department of Epidemiology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
4 Correspondence address. E-mail: m.vanweissenbruch{at}vumc.nl
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Abstract |
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BACKGROUND: Previous studies demonstrated a link between adverse conditions during prenatal life and the development of diseases in adult life. It is still unclear whether IVF conception could permanently affect early prenatal development in humans, with post-natal health consequences. The objective of the present study is to examine pubertal development in 8–18-year-old IVF singletons and controls born from subfertile parents who attended one Dutch fertility clinic were included.
METHODS: IVF singletons and controls born from subfertile parents who attended one clinic in the Dutch OMEGA study were included. Pubertal stage by Tanner’s classification, age at menarche and menstrual cycle characteristics were studied in the total population (n = 233: 115 IVF-conceived boys and 118 IVF-conceived girls, each with age-matched comparison groups). Bone age and sex hormone levels were examined in two distinct pubertal subpopulations.
RESULTS: Pubertal stage and age at menarche were not significantly different between IVF and control children. In the pubertal subpopulation, a higher bone age–chronological age (BA–CA) ratio and a larger BA–CA difference were observed in IVF-conceived girls compared with controls (1.04 ± 0.07 versus 1.02 ± 0.08, P = 0.022; 0.54 ± 0.82 versus 0.18 ± 1.00 year, P = 0.021, respectively). Furthermore, dehydroepiandrosterone sulphate (DHEAS) and LH levels were significantly higher in IVF-conceived girls than in control subjects (2.5 versus 1.9 µmol/l, P = 0.017, and 1.5 versus 0.6 U/l, P = 0.031, respectively).
CONCLUSIONS: Bone age appeared to be advanced in pubertal IVF-conceived girls, but not in boys, compared with controls. Increased DHEAS and LH concentrations were found among IVF girls.
Key words: IVF children/follow-up/pubertal development/bone age
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Introduction |
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Application of IVF has rapidly increased since the first IVF birth in 1978. Approximately 1.6% of the current births in the Netherlands are established after assisted reproduction technologies (ART) (Kremer et al., 2002
), and it is estimated that worldwide over a million children have been born after assisted conception (Schultz and Williams, 2002). There is an accumulating body of evidence that IVF children are at increased risk for adverse perinatal outcome, including low birthweight, preterm birth and other complications (Helmerhorst et al., 2004; Jackson et al., 2004). In addition, concerns about potential lifelong health implications after IVF conception in humans have recently been expressed (Maher et al., 2003; Horsthemke and Ludwig, 2005; Painter and Roseboom, 2007). The manipulation of gametes and embryos inherent to ART has been suggested to influence developmental pathways with post-natal consequences (Johnson, 2005). Recently, higher blood pressure and fasting glucose, and altered body fat composition have been reported among 8–18-year-old IVF children when compared with controls born to subfertile parents (Ceelen et al., 2007, 2008). These findings highlight the importance of the continuing worldwide monitoring of post-natal development of IVF offspring.
Despite the fact that the number of adolescents born after IVF treatment is steadily increasing, sexual maturation in IVF children has not yet been examined. Rojas-Marcos et al. (2005) specifically highlighted the need for monitoring IVF children throughout childhood into adolescence to investigate pubertal development. Although epidemiological data are scarce and inconclusive, an association between prenatal development and timing and progression of puberty in humans has been suggested over the last decade (Hokken-Koelega, 2002; van Weissenbruch et al., 2005). Furthermore, in view of the early embryonic programming influences on several body systems which have been described (Kwong et al., 2000; Edwards and McMillen, 2002; Sjoblom et al., 2005), it can be questioned whether developmental processes related to the hypothalamic–pituitary–gonadal axis can also be impaired by periconceptional events, such as IVF, resulting in a disturbed pubertal development. Hence, we investigated anthropometric, radiological and biochemical characteristics of pubertal development in IVF children and spontaneously conceived control children born from subfertile couples.
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Subjects and Methods |
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Study population
The OMEGA study is a Dutch retrospective cohort study aimed at examining the long-term health effects of hormone stimulation. The cohort consists of 26 428 women diagnosed with subfertility problems in one of the 12 IVF clinics between 1980 and 1995; 19 840 women received IVF treatment and 6588 women did not (Klip et al., 2001
, 2003; de Boer et al., 2003). Eligible women had not achieved conception after at least 1 year of frequent unprotected intercourse at the time of their first visit to the fertility clinic. Risk factor questionnaires to the women and detailed data collection from the medical records provided information on the children born from the OMEGA-participants up to 1996–1997. The questionnaire response rate was 73% among subfertile women with children. The present study was restricted to IVF and spontaneously conceived children born from OMEGA-participants who visited the fertility clinic of the VU University medical center (VUmc). Mothers of the spontaneously conceived children were subfertile but did not receive hormonal stimulation prior to conception. IVF children born from women treated in the VUmc who did not participate in the OMEGA study were also eligible for recruitment.
From the 553 eligible singletons born after standard IVF treatment, we invited 95% of IVF children born between 1986 and 1991, 74% of IVF children born between 1992 and 1993 and 41% of IVF children born between 1994 and 1995 in order to achieve equal representation of all age categories. For each participating IVF child, one spontaneously conceived child of similar gender and age (
3 months age difference) born from subfertile parents was searched. In case this control child did not want to participate, the control recruitment process was repeated until an appropriate control child was found which agreed to participate. The study protocol was approved by the ethics committee of the VUmc and by the National Medical Ethics Committee known as the ‘Centrale Commissie Mensgebonden Onderzoek’ located in The Hague, the Netherlands.
Approach of eligible study subjects
Between March 2003 and March 2006, children and their parents were informed by letter about our study on growth and development of IVF children (n = 354 IVF children and n = 454 control children). By means of a reply form and a pre-stamped envelope, parents were able to inform us whether they were willing to participate in our study. Address information of the families was checked and/or obtained using extensive tracing techniques. After 4–8 weeks, non-responders were approached by telephone. Inclusion results are summarized in Fig. 1. In total, 69% of the IVF-responders (n = 246) and 51% of the control-responders (n = 233) agreed to participate, resulting in 233 matched pairs.
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Anthropometric measurements of all participating children were obtained. Pubertal children [as assessed according to Tanner criteria (Tanner and Whitehouse, 1976
)] were recruited for additional research including the assessment of skeletal maturation and a fasting blood test. Hormonal concentrations were determined in pubertal premenarcheal girls (B2-3 Tanner stage) and pubertal boys (G3-5 Tanner stage). All children and their parents gave written informed consent to participate in the study. Families who refused to participate in the study received a single questionnaire regarding health, education and other characteristics of the respective child (n = 283). Non-participation analysis yielded no significant differences between participants and non-participants regarding children’s current height, weight and BMI. On average, non-participating children were significantly older (12.9 ± 2.6 versus 12.0 ± 2.6 year, P = 0.002) and their mothers were less often highly educated (26 versus 37%, P = 0.015), but these values were similar in the IVF and control population.
Data collection and measurements
Pubertal development using breast or genital developmental stages and pubic hair growth were recorded according to Tanner and Whitehouse (1976). In boys, testicular volume was determined by means of a Prader orchidometer. Body weight and height were assessed to the nearest 0.1 kg and 0.1 cm using an electronic scale (SECA) and a stadiometer (Holtain Ltd, Crymych, Dyfed, UK), respectively, with children dressed only in underwear. From these measurements, the BMI was calculated as kg/m2. Height was expressed as standard deviation score (SDS) for chronological age and bone age using Dutch references (Fredriks et al., 2000). Target height was calculated as midparental height corrected for sex and Dutch secular trend (Finken et al., 2006) and was expressed as SDS using Dutch references (Fredriks et al., 2000). Corrected height SDS was defined as height SDS minus target height SDS. Skinfold thickness measurements (triceps, biceps, subscapular and supra-iliac) were collected in triplicate on the non-dominant side of the body by means of a Harpenden caliper. A tape measure was used to measure waist and hip circumference and waist-hip ratio was calculated. The majority (94%) of the anthropometric measurements were performed by one observer (M.C.).
Bone age was estimated from left-hand radiographs, using the Greulich and Pyle standards, by one observer (M.C.) (Greulich et al., 1959). To validate accuracy, skeletal age of 45 randomly selected children was determined by an experienced paediatric endocrinologist as well. The Spearman correlation coefficient between the measurements was 0.987 (P < 0.001). The difference between bone age and chronological age and the bone age–chronological age (BA–CA) ratio were calculated.
Blood samples were drawn between 9:00 and 10:00 a.m. Plasma levels of LH and FSH were determined by immunofluorometric assays (Delfia, Wallac, Turku, Finland). For the LH assay, the detection limit was 0.3 U/l and for the FSH assay, the limit of detection was 0.5 U/l. Serum estradiol (E2) concentrations were measured with the use of a double-antibody radioimmunoassay (Diasorin, Saluggia, Italy). The detection limit was 18 pmol/l. Serum concentrations of testosterone and dehydroepiandrosterone sulphate (DHEAS) were analysed by the Coat-A-Count radioimmunoassay (DPC, Los Angeles, USA). For the testosterone assay, the detection limit was 1 nmol/l. For the DHEAS assay, the limit of detection was 0.2 µmol/l. All methods had intra- and inter-assay coefficients of variation from 3 to 20% within the relevant concentration ranges. All laboratory measurements were performed in the endocrinological laboratory at the Department of Clinical Chemistry of the VUmc.
Prior to the follow-up visit in the VUmc, a questionnaire was sent to the parents in order to gather information on various demographic, lifestyle and medical factors including cause of subfertility, duration, parental education level, maternal smoking during pregnancy and birthweight and gestational age of the respective child. Birthweight was expressed as SDS to correct for gestational age and gender (Niklasson et al., 1991). Information regarding girls’ menstrual cycle pattern was obtained during the visit by means of an interview. An average length of the menstrual cycle between 22 and 41 days was classified as ‘regular’ (van Hooff et al., 1998). Other relevant outcomes, such as blood pressure levels and body composition, have been reported elsewhere (Ceelen et al., 2007, 2008).
Statistical analysis
Characteristics of 233 matched IVF–control pairs were compared using the paired t-test for continuous variables and the McNemar test for dichotomous variables (Statistical Package for the Social Sciences version 12.0; SPSS Inc., Chicago, IL, USA). Girls with Tanner breast stage 
B2 and boys with Tanner genital stage G2 and/or a testis volume 4 ml were classified as pubertal children. The proportion of pubertal IVF and control children and the proportion of IVF and control children in the distinct Tanner stages were tested. Furthermore, per Tanner stage, mean age of IVF and control children was calculated and compared. Differences in skeletal maturation and sex hormone levels between the pubertal IVF and control subjects were tested by using Student's t-test or Mann–Whitney U-test when appropriate. P-value of <0.05 was considered to be statistically significant, based on two-sided testing.
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Results |
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Perinatal outcome and anthropometry at follow-up
Birthweight, birthweight SDS and gestational age were significantly lower in children conceived by IVF when compared with controls (3.2 ± 0.6 versus 3.4 ± 0.6 kg, P < 0.001; –0.15 ± 1.00 versus 0.08 ± 1.08, P = 0.025; 38.9 ± 2.5 versus 39.5 ± 1.8 weeks, P = 0.004, respectively). Anthropometric characteristics of the study subjects are listed in Table I. Age at follow-up of IVF children and controls was 12.2 ± 2.6 years. Total sum of skinfold thickness of IVF children tended to be higher when compared with controls (40.4 ± 20.3 versus 37.1 ± 17.5 mm; P = 0.054). No significant differences in anthropometric measurements, such as height, weight and BMI between IVF children and control children were found. Also height SDS was not statistically significant between the IVF and control population.
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Physical signs of puberty
Although the proportion of pubertal IVF boys and control boys was similar (65 versus 67%, respectively, P = 0.69), a trend towards a higher proportion of pubertal IVF girls was demonstrated (80 versus 73% in controls, P = 0.064). On the other hand, comparison of the proportion of children in the distinct Tanner stages revealed no significant differences between IVF and control population (Fig. 2A). Furthermore, mean age of IVF children and controls in the distinct pubertal stages was comparable (Fig. 2B). In IVF subjects, mean age of boys in G2 stage and boys with testicular volume of 4 ml was 11.0 ± 1.3 and 12.0 ± 1.5 year, respectively, whereas mean age of girls in B2 stage was 10.4 ± 1.2 year. In control subjects, mean age of boys in G2 stage and boys with testicular volume of 4 ml was 11.1 ± 1.1 and 12.2 ± 1.2 year, respectively, whereas mean age of girls in B2 stage was 10.6 ± 0.8 year. Height, weight and BMI at onset of puberty did not differ between the IVF and control population (data not shown). On average, testicular volume of IVF-conceived boys tended to be higher when compared with controls (8.0 ± 7.6 versus 7.1 ± 6.4 ml, P = 0.059). No difference was found with respect to the proportion of children with pubic hair development (69% of IVF girls versus 66% of control girls, P = 0.69; 48% of IVF boys versus 45% of control boys, P = 1.0).
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Menses
The same proportion of IVF girls and control girls had reached menarche (42 versus 42%, P = 1.0). Menstrual cycle characteristics of these girls are presented in Table II. Reported age at menarche of IVF girls and control girls was 12.5 ± 1.2 and 12.6 ± 1.2 year, respectively (P = 0.53). The difference in reported age at menarche of IVF mothers and their daughters did not reach statistical significance (P = 0.054). No differences were found between IVF and control girls in terms of actual menstrual cycle pattern, bleeding time and prevalence of dysmenorrhoea. In addition, height SDS, weight SDS and BMI SDS of menarcheal IVF and control girls did not differ (data not shown).
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Bone age
In the pubertal subpopulation, a higher BA–CA ratio and a larger BA–CA difference were found among IVF-conceived girls compared with control girls (1.04 ± 0.07 versus 1.02 ± 0.08, P = 0.022; 0.54 ± 0.82 versus 0.18 ± 1.00 year, P = 0.021, respectively) (Table III). Height and weight were significantly correlated with chronological age (R = 0.734, P < 0.001; R = 0.672, P < 0.001, respectively) and bone age (R = 0.762, P < 0.001; R = 0.764, P < 0.001, respectively). No differences in corrected height measures between the two study groups were noted.
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Sex hormones
Table IV presents sex hormone concentrations in pubertal IVF-conceived subjects and control subjects. IVF-conceived girls showed significantly higher DHEAS concentrations than controls [2.5 (2.0–2.9) versus 1.9 (1.2–2.2) µmol/l, P = 0.017]. In addition, LH levels were significantly increased in IVF girls when compared with control girls (1.5 ± 1.6 versus 0.6 ± 0.7 U/l, P = 0.031). No significant differences in FSH and E2 were found between IVF girls and controls. Similar levels of LH, FSH, DHEAS and testosterone were found in IVF and control boys. DHEAS levels were not correlated with birthweight, birthweight SDS, gestational age and sum of skinfolds. A weak but significant correlation was found between DHEAS concentrations and BA–CA ratio and BA–CA difference (R = 0.257, P = 0.006; R = 0.317, P = 0.001, respectively).
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Discussion |
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This is the first report that assessed clinical signs related to pubertal development, adrenarche, skeletal maturation and sex hormone levels in IVF children compared with controls. Despite a trend towards a higher proportion of pubertal IVF girls, chronological age at important pubertal milestones, including age at menarche, appeared to be similar in IVF and control girls. Similarly, the proportion of post-menarcheal IVF and control girls and their menstrual cycle characteristics did not differ. Between IVF and control boys, no differences in chronological age at distinct genital stages and subsequent categories of testicular volume were found. Furthermore, the proportion of pubertal IVF and control boys was similar. In contrast, mean testicular volume tended to be higher in IVF boys. Testicular volume has been suggested to be a more finely graduated indicator of development than other measures (Manasco et al., 1995
). On the other hand, others stated that testicular volume is not without its own measurement issues, as systematic overestimation of testicular volume has been reported and testicular volume measurement is subject to great inter-observer variation (Rivkees et al., 1987; Papadimitriou, 2004). In the current study, the vast majority of the boys were examined by a single investigator, which reduces misclassification bias.
Bone age of IVF girls was advanced when compared with control girls. In the literature, accelerated skeletal maturation has been associated with compromised adult stature due to premature closure of epiphyseal junctions (Feuillan et al., 1999). Nevertheless, height SDS of menarcheal IVF and control girls did not differ. As post-menarcheal growth in height is limited, it is therefore unlikely that final height is substantially reduced in IVF girls.
Among pubertal IVF girls, higher DHEAS levels were found when compared with controls. In accordance with these findings, some studies showed higher serum DHEAS levels in girls born following prenatal growth restraint, which may be linked to an exaggerated adrenarche. Increased DHEAS levels have been reported in asymptomatic non-obese, post-menarcheal girls born small for gestational age (SGA) (Ibanez et al., 1999, 2002). Ghirri et al. (2001) demonstrated that DHEAS levels were significantly higher in SGA girls than in control subjects despite the lack of differences in clinical signs of puberty. In addition, elevated DHEAS levels have also been found in low birthweight boys (van Weissenbruch and Delemarre-Van de Waal, 2006). Although several other studies did not find such an association (Dahlgren et al., 1998; Boonstra et al., 2004), these described increased DHEAS levels in children born SGA suggest that birthweight is an important factor that has to be taken into account when investigating DHEAS levels in children. Nonetheless, in the present study increased DHEAS concentrations found in IVF girls could not be explained by the observed difference in birthweight. It is important, however, to realize that birthweight is just an indicator of fetal growth and that developmental adaptations to prenatal environmental insults are not necessarily reflected in birthweight (Bloomfield et al., 2006). Likewise, other studies demonstrated that serum DHEAS levels are positively correlated with weight, particularly weight gain and adiposity (Remer and Manz, 1999). In the current study, no correlations were found between DHEAS levels and body fat measures including BMI and sum of skinfolds. A possible explanation might be the low number of obese children in our study population.
The cause of the increased LH levels observed in pubertal IVF girls is not yet clear. Previous studies have shown that during puberty nocturnal increases in LH pulse amplitude and frequency are followed by a diurnal pattern of LH pulsatility (Wennink et al., 1990). It cannot be excluded that comparison of LH concentrations between midpubertal IVF and control girls is hindered due the large variation in LH secretory activity.
Growing evidence has emerged on the relation between prenatal growth restraint, premature adrenarche, early puberty and polycystic ovary syndrome (PCOS) (van Weissenbruch, 2007). PCOS is characterized by hyperandogenaemia, elevated plasma LH concentrations, insulin resistance, menstrual abnormalities with anovulation, obesity and ultrasonographic evidence of polycystic ovaries (Franks, 1995). The clinical relevance of the higher DHEAS concentrations and the increased LH levels found in pubertal IVF girls in comparison with control children has to be further established.
In order to be able to adequately examine post-natal growth and development in IVF children, an appropriate comparison group of unexposed children was needed. It is generally known that IVF parents differ from the general reproductive population with regard to age, parity and other important characteristics. To avoid confounding due to these known differences, comparison with children born to subfertile parents after spontaneous conception was preferred. Our study was based on 58% (n = 466) of the total number of subjects approached (n = 808). No differences in anthropometric measures, such as height, weight and BMI, were found between the participants and non-participants who returned the questionnaire. On the other hand, there appeared to be a significant difference in maternal education between the non-participating and participating children. This phenomenon was found in both the IVF and the control population. Therefore, it did not confound the comparisons performed between IVF and control children in the present study, but it might have implications for the generalizability of our results. Selection bias could have occurred when the relationships between parental education and studied outcome variables are different among children who participated and those who did not participate. It would be interesting to follow the current study population prospectively to further investigate sexual development and subsequent reproductive functioning of IVF offspring. Longitudinal series can be used to characterize the various pubertal events in more detail than cross-sectional series (Karlberg, 2002). For logistical reasons, it was not possible in the present study to plan the blood withdrawal of menarcheal girls within a specific phase of their menstrual cycle. Therefore, we did not measure hormonal levels in these girls, as variation in hormone levels due to differences in menstrual cycle would hamper the comparison between IVF and control subjects. Nevertheless, it would be worthwhile to examine hormonal levels, including LH and DHEAS concentrations, during late adolescence. It remains to be elucidated whether the slight differences in DHEAS and LH levels between IVF and control girls will persists during pubertal development.
In conclusion, in IVF girls bone age was advanced and increased LH and DHEAS concentrations were found. Conversely, no differences in pubertal stage between IVF and control children were observed. Differences in LH levels between IVF and control girls might be the consequence of the major variation in pulsatile LH secretion. However, it is important to realize that these findings did not follow from a specific hypothesis being tested and that multiple significance testing was performed which can lead to chance findings. Before definitive conclusions can be drawn, our findings need to be reproduced by other prospective follow-up studies.
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Submitted on April 24, 2008; resubmitted on July 12, 2008; accepted on July 16, 2008.
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