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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2006-0701
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 11 4352-4360
Copyright © 2006 by The Endocrine Society

Serum Insulin-Like Growth Factor-I (IGF-I) and Growth in Children Born after Assisted Reproduction

Claudia Mau Kai, Katharina M. Main, Anders Nyboe Andersen, Anne Loft, Marla Chellakooty, Niels E. Skakkebæk and Anders Juul

University Department of Growth and Reproduction (C.M.K., K.M.M., M.C., N.E.S., A.J.) and The Fertility Clinic (A.N.A., A.L.), Copenhagen University Hospital Rigshospitalet, DK-2100 Copenhagen, Denmark

Address all correspondence and requests for reprints to: Claudia Mau Kai, M.D., University Department of Growth and Reproduction GR, Rigshospitalet Section 5064, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. E-mail: claudia.mau{at}rh.hosp.dk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Concern has been raised about the safety of assisted reproduction techniques for the offspring.

Objectives: The objective of the study was to investigate postnatal growth and growth factors in children born after intra-cytoplasmatic sperm injection (ICSI) and in vitro fertilization (IVF).

Design: The study had two cohorts: a population-based longitudinal infant cohort 0–36 months [236 ICSI, 173 IVF, 1530 naturally conceived (NC)], and a cross-sectional child cohort at 5 yr (68 ICSI, 67 IVF, 70 NC).

Intervention: Anthropometrical measurements were made at birth, 3, 18, 36 (infant cohort), and 60 months (child cohort), and blood samples were collected at 3 or 60 months.

Main Outcome Measures: Serum IGF-I, IGFBP-3, height, weight, head and abdominal circumference, body mass index, and fat folds were the main outcome measures.

Results: Anthropometrical measurements showed no significant differences between ICSI and IVF children and controls in either cohort. However, singleton ICSI girls [3.4 (0.6) kg, P = 0.008] had a slightly lower birth weight than IVF [3.5 (0.5) kg] and NC girls [3.5 (0.5) kg]. Birth weights of singleton boys [3.6 (0.5) kg], twin boys [2.6 (0.6) kg], and twin girls [2.4 (0.5) kg] did not differ between types of conception. In the infant cohort in 3-month-old singletons, serum IGF-I was lower in ICSI [78 (26) ng/ml] than NC boys [94 (27) ng/ml, P < 0.001] and IVF [74 (34) ng/ml], compared with NC girls [93 (43) ng/ml, P = 0.011]. ICSI children were also smaller than their target height (SD score) at 3 yr of age [mean –0.91 (1.2)], compared with NC children [–0.61 (0.9), P = 0.033]. In the child cohort, target height attainment (SD score) and growth factors did not differ among the three groups.

Conclusions: The overall growth pattern of ICSI and IVF children in both cohorts was normal. Our findings of subtle differences in target height attainment and serum IGF-I levels between infants born after assisted reproduction techniques and controls may not be clinically significant. However, these observations indicate that further systematic follow-up of growth and puberty in these children is needed.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
DURING THE LAST 25 yr, assisted reproduction has become increasingly available for infertile couples. The first child conceived by in vitro fertilization (IVF) was born in 1978. Approximately 10 yr later intra-cytoplasmic sperm injection (ICSI) was developed for severe male infertility and led to the first delivery of a healthy child in 1992 (1). Using ICSI, one single spermatozoon is injected into the ooplasma of a metaphase II oocyte. The spermatozoon is derived from ejaculated or surgically retrieved sperm from the epididymis or testis. The especially invasive nature of this technique and IVF led to concerns about the potential risks for the offspring. Previous studies found higher maternal age at delivery, shorter gestational age (GA), lower birth weight, and higher prevalence of small for GA (SGA) in singleton children conceived by ICSI and IVF, compared with naturally conceived (NC) children (2, 3, 4, 5). A recent metaanalysis found a 30–40% increased incidence of congenital malformation in children conceived by ICSI and IVF (6). Postnatal growth in children conceived by ICSI and IVF has been poorly studied with small samples sizes and without reporting the precise heights for each gender (7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17). Serum levels of IGF-I play an important role for postnatal growth (18) but have not previously been studied in children born after ICSI and IVF. Here we report serum IGF-I and its major binding protein (IGFBP-3) and auxological measurements in children conceived by ICSI and IVF in comparison with a reference group of NC children.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study participants and design

Infant cohort. At a public fertility clinic in the Copenhagen area (Rigshospitalet), 397 families who conceived by ICSI were consecutively contacted in the period 1998–2004, and 219 (55.2%) participated in the study. Only families with children examined until August 2004 and aged 2.5–4.5 months at the first examination were included in this study, leaving 236 eligible ICSI children (n = 107 males, n = 129 females). Likewise, 515 families who conceived by IVF were consecutively contacted in the same period, and 169 (32.8%) participated in the study. The same inclusion criteria as for the ICSI group were applied for children born after IVF, leaving 173 eligible IVF children (n = 97 males, n = 76 females).

There were no differences in maternal age at delivery (P = 0.414), number of twins (30 and 36%, respectively, P = 0.07), and prevalence of SGA children (8.3 and 10.9%, respectively, P = 0.206) between participants and nonparticipants. However, participants were heavier and longer at birth (3.28 and 3.08 kg, P < 0.001; 51 and 50 cm, P < 0.001, respectively). There was a difference in weight for GA (WGA) (–3.6% and –5.9%, respectively, P = 0.016), GA (274 and 268 d, P < 0.001), and prevalence of prematurity (GA < 37 wk; 10.8 and 26.4%, respectively, P < 0.001). The assessment of congenital malformation rates was not the main aim of the present paper, but major malformations were registered at birth. The malformation rates of participants and nonparticipants were comparable [ICSI: 1.6%, IVF: 1.4%, NC: 0.6%, and ICSI: 1.8%, IVF: 2.4%; background population: 6.3% (data from the Danish Health Council, http://www.sst.dk)] and in agreement with a large Danish register study (19).

All families were Caucasians (ICSI: 96.6% Danish and 3.4% of other origin, IVF: 97.7% Danish and 2.3% of other origin). No donor semen was used. Six ICSI children (2.5%) and three IVF children (1.7%) were conceived after frozen embryo transfer.

The reference group consisted of naturally conceived 2229 pregnant mothers (22% of eligible pregnant mothers with a Danish surname contacted during the first trimester) who entered the study (20). A total of 1507 Caucasian families of Danish origin with children aged 2.5–4.5 months at 3-month examination were included in this study, leaving 1530 NC children (n = 877 males, n = 653 females). They were born from 1997–2001 and participated in a longitudinal prospective birth cohort study of pregnant mothers and their offspring up to the age of 3 yr investigating genital development (21), kidney size (22), occurrence of genital malformations (20, 23), and IGF-I (24). Anthropometric data at birth were registered, and all children were examined at 3 months [3.1 months (2.9, 3.4)], 18 months [18.4 months (18.0, 19.0)], and 36 months [36.4 months (36.0, 37.1)] of age. All included children in this study were born after GA longer than 32 wk. The percentages of twins were 33.2% in the ICSI group, 33.5% in the IVF group, and 3.2% in the NC group. At each visit one of a team of seven doctors examined the child.

Child cohort. As part of an international multicenter cohort study (15, 17, 25, 26), 205 first- or second-born, singleton Caucasian children of Danish origin at the age of 5 yr [4.8 yr (4.7, 5.1)] with a GA longer than 32 wk at birth were examined. One hundred families who conceived by ICSI were contacted, and 68 (68%) (n = 38 males, n = 30 females) participated in the study. One hundred twenty families who conceived by IVF were contacted, and 67 (56%) (n = 37 males, n = 30 females) participated. There were no significant differences in minor malformations (ICSI = 47.1%, IVF = 47.8%, NC = 47.1%, P = 0.384) or major malformations (ICSI = 5.9%, IVF = 4.5%, NC = 1.4%, P = 0.996). The mothers had been treated at one of two public fertility clinics in the Copenhagen area (Rigshospitalet and Herlev University Hospital) or at one of two private clinics in the same area (The Fertility Clinic Trianglen and Danish Fertility Clinic). No donor semen was used. Two ICSI children (3%) and two IVF children (3%) were conceived after frozen embryo transfer. Two hundred six families who conceived naturally were contacted, and 70 (34%) (n = 37 males, n = 33 females) participated. They were born in 1996–1997 at the primary obstetric unit of the Copenhagen University Hospital, Rigshospitalet, Denmark, and selected from the hospital’s birth registry and matched for date of birth, gender, and maternal age at delivery. One doctor (C.M.K.) examined all children.

Blood samples

Nonfasting peripheral venous blood samples were taken from an antecubital vein after local anesthesia from the children between 0900 and 1815 h. Only one attempt to draw a blood sample was made in each child. Thus, blood samples could not be obtained from all children due to unsuccessful procedure or denial. Samples were separated by centrifugation and stored at –20 C until analysis. The blood samples were analyzed consecutively over a 5-yr period and blinded for the type of conception for the technician. The final numbers of blood samples at 3 months of age were 141 (60%) from children conceived by ICSI (n = 68 males, n = 73 females), 110 (63%) from children conceived by IVF (n = 70 males, n = 40 females), and 1030 (67%) from NC children (n = 599 males, n = 431 females). At 5 yr of age, 167 children (81%) had a blood sample taken [53 ICSI (n = 30 males, n = 23 females), 55 IVF (n = 32 males, n = 23 females), 59 NC (n = 31 males, n = 28 females)].

Anthropometrical measurements

Birth data and obstetric history in both cohorts were obtained from medical records. WGA was expressed as percentage deviation from the expected mean weight for GA. A sex-differentiated fourth-degree polynomia was used for this calculation (27, 28). Appropriate weight for gestational age was defined as a birth weight deviation from mean between –22 and 22% equivalent to –2 SD and +2 SD, respectively (27).

The length of the children was measured in the supine position with a portable infantometer until 18 months of age (Kidimeter; Raven Equipment Ltd., Essex, UK) to the nearest 0.01 cm; the mean of three was calculated. At the ages of 3 and 5 yr, an electronic stadiometer to the nearest 0.01 cm was used (Force Technology, Brøndby, Denmark, and Holtain Ltd., Crymych, Dyfed, UK). Weight was measured on a digital scale (baby scale model; Solotop Oy, Helsinki, Finland) to the nearest 0.005 kg and the mean of three calculated. At 5 yr of age, a digital scale (Seca Delta, model 707; SECA, Bradford, MA) to the nearest 0.1 kg was used and the mean of three calculated. The intraobserver variation for anthropometrical measurements was determined from the averages of triple measurements of each child in the infant cohort. The interobserver variation was determined in a subgroup of 72 children. Confidence intervals (95%) for intra- and interobserver variations for height were less than ± 1.4 mm and for weight less than ± 25 g (24). Head and abdominal circumference was measured with a tape lasso (Child Growth Foundation, London, UK) to the nearest 0.01 cm. Skin-fold measurements were done in triceps, subscapular, flank, and quadriceps position to the nearest 0.1 mm using a skin-fold caliper (Harpenden, British Indicators Ltd., London, UK). Parental height was obtained from questionnaires (self-reported).

Assays

IGF-I was measured in all subjects with a RIA originally described by Bang et al. (29) with some modifications. Serum was extracted by acid/ethanol and cryoprecipitated before analyses to remove interfering binding proteins, and monoiodinated Tyr31[125I]des-(1–3) IGF-I was used as radioligand (30). Interassay variations were 9.4%, intraassay variations were 10.3%, and limit of detection was 21 ng/ml. IGFBP-3 was determined by RIA as described by Blum et al. (31). IGFBP-3 was measured on unprocessed serum using a polyclonal rabbit antiserum and a purified human IGFBP-3 fragment as standard and radioligand. Reagents for the analyses were obtained from Mediagnost GmbH (Tübingen, Germany). Interassay variations were 8.4%; in our hands, intraassay variations were 5.9% and limit of detection 300 ng/ml (32).

Statistics

Descriptive statistics are given as mean and SD. Ages at examinations are given as median and 25th and 75th percentiles. Singletons and twins were analyzed separately, and twins were counted as individuals. All continuous variables [GA, birth weight and length, WGA, age at examination, weight, length, head and abdominal circumference, body mass index (BMI), skinfold thickness, and levels of IGF-I and IGFBP-3] were analyzed by ANOVA for differences between the types of conception (ICSI/IVF/NC). When statistical significance was found (P < 0.05), variables were analyzed with independent t test comparing children conceived by ICSI and IVF with NC children, respectively. Rates were analyzed by {chi}2 test for differences between types of conception. To determine factors of influence on birth length, height, head circumference, BMI, and IGF-I, each factor was used as dependent variable in general linear model (GLM). The models included as explanatory variables type of conception (fixed factor with NC as reference); gender (females = 1, males = 2); number of children (singleton = 1, twins = 2); nutrition at 3 months of age (formula = 1, mixed breast milk and formula = 2, breast milk = 3); GA; parity (fixed factor with primipara as reference); birth weight (depending on model); age at examination; target height; serum levels of IGF-I and IGFBP-3; and maternal age at delivery. For post hoc comparison, Scheffé’s test was used. Height SD score (SDS) was calculated from Andersen et al. (33): (participant’s height – mean height for sex and age)/ SD. Target height (SDS) was calculated by the equation, [maternal height (SDS) + paternal height (SDS)]/2, and converted to centimeters using national references (33). The individual difference between height (SDS) at 3 yr (infant cohort) and 5 yr (child cohort) and target height (SDS) was calculated by simple subtraction. The statistical analyses were carried out using SPSS (version 14; SPSS, Inc., Chicago, IL).

Ethical aspects

The study was performed according to the Helsinki Declaration II and approved by the local ethical committee [(KF) 01-030/97; (KF) 01-090/98; (KF) 01-069/01) and the Danish Registry Agency (1997-1200-074; 1998-1200-262; 2001-41-0782].


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Descriptives

Detailed auxological findings are shown in Tables 1Go and 2Go. From these tables, sporadically, statistically significant differences between conception groups were apparent, but they were not persistent throughout successive age groups.


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  		TABLE 1. Auxological characteristics at birth and in 3-month-old children conceived by ICSI and IVF, compared with NC children and serum levels of IGF-I and IGFBP-3 at 3 months of age

 

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  		TABLE 2. Auxological characteristics of 18- to 60-month-old children conceived by ICSI and IVF, compared with NC children, and serum levels of IGF-I and IGFBP-3 at 60 months of age

 
Mothers of singleton children and mothers of twin boys conceived by ICSI and IVF were significantly older at delivery, compared with NC mothers (P < 0.001 and P < 0.02, respectively). Singleton boys conceived by ICSI and IVF had a shorter GA at birth, compared with NC children (P = 0.018 and P = 0.04, respectively), and singleton ICSI-conceived girls had a shorter GA (P = 0.014). Birth weights of singleton boys [3.6 (0.5) kg], twin boys [2.6 (0.6) kg], and twin girls [2.4 (0.5) kg] did not differ between types of conception, but singleton girls conceived by ICSI had a lower birth weight, compared with NC girls (P = 0.013). No significant differences in WGA were found between groups. In subsequent multivariate analyses, the type of conception had no effect on birth weight, birth length, or WGA after controlling for confounders. The prevalence of being born SGA in the entire singleton cohort (n = 1971) was 1.7% for NC singletons and 4.3% for singletons conceived by ICSI (ICSI vs. NC, P = 0.025); 2.7% of singletons conceived by IVF were SGA (IVF vs. NC, P = 0.144). In the twin cohort (n = 170), the percentage of children born SGA was 8.7% (NC twins), 22.2% of twins conceived by ICSI (ICSI vs. NC, P = 0.056), and 21.2% of twins conceived by IVF were born SGA, respectively (IVF vs. NC, P = 0.087).

The percentage of breast-feeding was 74.6% in the singleton NC cohort and 64.6% in the singleton ICSI cohort, respectively (P = 0.002). In the IVF singleton cohort, 71.1% were breast-fed (IVF vs. NC, P = 0.553). Within the twin cohort, the percentage of breast-feeding was 37.0% (NC twins), and 22.2% of ICSI twins (ICSI vs. NC, P = 0.169) and 28.8% of IVF twins (IVF vs. NC, P = 0.3) were breast-fed, respectively. Target height and target height (SDS) were not significantly different between types of conception.

Height

Individual growth charts for height in ICSI and IVF boys and girls in comparison with NC children are presented in Fig. 1Go, A and B. The type of conception did not have an effect on height at 3 (Table 3Go), 18, or 36 months of age (data not shown).


Figure 1
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  		FIG. 1. Height in singleton children conceived after assisted reproductive techniques [ICSI (•) and IVF ({circ})] from birth to 60 months of age, compared with NC children. Solid lines represent mean and ± 1 and 2 SD of data on healthy (NC) children examined longitudinally from birth to 36 months of age, and dashed lines interpolate height at 36 months with height in the 60-month-old children (cross-sectional study). A, Boys; B, girls.

 

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  		TABLE 3. GLMs examining the influence of different confounding variables on serum IGF-I and height at 3 months of age

 
Height (SDS) at 3 yr (P = 0.482) did not differ significantly between types of conception (singleton and twins combined). The differences between height (SDS) at 3 yr and target height (SDS) were –0.91 (1.2) (ICSI), – 0.61 (1.1) (IVF), and –0.61 (0.9) (NC). ICSI children were significantly smaller than their target height (SDS), compared with NC children (P = 0.033) at 3 yr of age.

Height (SDS) at 5 yr did not differ significantly between groups (P = 0.349), and the differences between height (SDS) and target height (SDS) were not different between ICSI and NC.

Serum IGF-I and IGFBP-3 levels

Serum IGF-I was significantly lower in singleton boys conceived by ICSI and singleton girls conceived by IVF, compared with NC children at 3 months of age (P < 0.02) (Tables 1Go and 3Go and Fig. 2Go). Further analysis showed that breast-fed children had lower IGF-I than formula-fed children (P < 0.001) independent of the type of conception. Singleton girls conceived by IVF had lower IGFBP-3 than NC girls (P = 0.001) (Table 1Go and Fig. 3BGo). In a subsequent multivariate analysis (R2 = 0.028), girls had higher serum IGFBP-3 than boys [parameter estimate (B) = 73.999, P = 0.013, boys = reference], birth weight was positively associated with serum IGFBP-3 (B = 104.935, P = 0.002), and IVF children had lower serum IGFBP-3, compared with NC children (B = –158.679, P = 0.005).


Figure 2
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  		FIG. 2. Serum IGF-I in relation to postnatal age in children conceived after assisted reproductive techniques [ICSI (•) and IVF ({circ})], compared with NC children. Lines represent fifth, 50th, and 95th percentiles in healthy (NC) children. A, Boys; B, girls.

 

Figure 3
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  		FIG. 3. Serum IGFBP-3 in relation to postnatal age in children conceived after assisted reproductive techniques [ICSI (•) and IVF ({circ})], compared with NC children. Lines represent fifth, 50th, and 95th percentiles in healthy (NC) children. A, Boys; B, girls.

 
At 5 yr of age, no significant differences in IGF-I or IGFBP-3 serum levels were found between conception methods (Table 2Go; for boys P = 0.611 and P = 0.994, respectively; for girls P = 0.648 and P = 0.642, respectively).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This large prospective study is the first to describe serum levels of IGF-I and its binding protein, IGFBP-3, in relation to growth in children conceived by ICSI and IVF, compared with a representative, large contemporary control group of NC children. In general, our findings are reassuring with regard to height and weight. However, we found that singleton ICSI boys and singleton IVF girls had slightly but statistically significantly lower serum IGF-I than NC children.

Auxological findings

In accordance with earlier findings (2, 3, 4, 5), we found higher maternal age at delivery, shorter GA, lower birth weight, and higher prevalence of SGA in singleton children conceived by ICSI and IVF, compared with NC children. This may be the consequence of an early twin pregnancy (vanished twin phenomenon). Pinborg et al. (34) reported that one in 10 IVF singletons originates from a twin pregnancy. They showed that spontaneous reductions that occur at longer than 8 wk of gestation result in a lower mean birth weight and GA in the survivor. Pinborg (35) recently reported assisted reproduction to account for more than 40% of twin births in Denmark, which is in line with our findings of a higher prevalence of twins in the ICSI and IVF group.

The sporadic significant differences in anthropometrical measures (head and abdominal circumference, skinfold) were not persistent throughout ages and could not be explained by interobserver variations. Three-month-old singleton ICSI and IVF boys were slightly heavier, compared with NC boys, and singleton ICSI boys were slightly longer at 3 months of age. However, we cannot explain why these children at the same time have lower serum IGF-I levels. In a GLM model explaining 43.8% of factors influencing height at 3 months of age, we found that parity had a positive effect. This is in accordance with Ong et al. (36), who showed that first-born infants are smaller and thinner at birth but catch up in weight and height during the first year of life. All other factors (gender, singleton/twin, GA, age at examination, target height SDS, IGF-I) have a well-known significant effect on height. Overall, children conceived by ICSI and IVF had comparable lengths with those of NC children.

We cannot exclude that a selection bias may have influenced our otherwise reassuring results because we found minor differences in birth weight and length, GA, and fewer premature births (GA < 37 wk) between participants and nonparticipants.

Our findings are in line with earlier studies examining postnatal growth in children born after assisted reproduction techniques (9, 10, 11, 12, 16). However, these studies are based on small sample sizes (52–75 children) in each group and report heights within the normal range but not the exact height in centimeters. In contrast, Brandes et al. (7) reported lower percentiles of weight and length in 116 IVF children (aged 22 months), compared with 116 matched controls. Similarly, Koivurova et al. (13) examined 299 children conceived by IVF, who were shorter, compared with 558 NC children, during a follow-up period from birth to 3 yr of age. However, Saunders et al. (8) examined 314 children conceived by IVF at 2 yr of age and found their height significantly larger than a group of 150 matched NC children. Two large cross-sectional European studies (15, 17), of which the present child cohort is part, included 540 5-yr-old children conceived by ICSI from five countries and compared them with 437 children conceived by IVF and 538 NC children. They found no differences in height, weight, and head circumference at 5 yr of age between the different conception groups and no indication that growth differed, depending on paternal sperm concentration. We found no differences in growth in 5-yr-old children in the present study. Bonduelle et al. (14) made similar observations in the same age group in another cross-sectional multicenter study of 560 children conceived by ICSI, compared with 560 NC children.

In our infant cohort, the 3-yr-old children conceived by ICSI had not achieved their genetic height potential, whereas the 5-yr-old children conceived by ICSI did not differ from their genetic potential. Because children up to approximately 2 yr of age can show considerable catch-up and catch-down growth curves (as a regression toward the mean), target height SDS was only evaluated at the ages of 3 and 5 yr. Parental height was collected by questionnaire in both cohorts; thus, the findings may be random. However, both the strict inclusion criteria in the cross-sectional study and the smaller number of participants may have introduced a selection bias.

Serum IGF-I and IGFBP-3 levels

We found an association between serum IGF-I and conception method at 3 months of age in a GLM model. There is a strong genetic influence on serum IGF-I levels (37). Thus, common genetic polymorphisms in the gene encoding IGF-I (or in the promoter region) are associated with levels of circulating serum IGF-I (38). Hypothetically, lower serum IGF-I levels in the parents may be related to their infertility because IGF-I has a stimulating effect on gonadotropin secretion, which in turn increases testicular testosterone secretion in males (30, 39). In women serum IGF-I plays a role in the regulation of ovarian function (40). Lower serum IGF-I levels could thus be inherited by the offspring. The lower IGF-I in boys born after ICSI could be inherited from their father because ICSI is predominantly used to treat male factor infertility. Similarly, low IGF-I levels in girls born after IVF could be inherited from their mother because IVF is predominantly used to treat female factor infertility.

Singleton girls conceived by IVF had lower IGFBP-3 than NC girls matching their lower serum IGF-I levels, whereas singleton ICSI boys had lower serum IGF-I without lower levels of serum IGFBP-3. Our failure to show similar statistically significant differences in serum IGF-I and IGFBP-3 at 5 yr of age may be related to a smaller number of 5-yr-old children in our study.

We also found an association between breast-feeding and lower serum IGF-I in children, compared with children fed with formula or formula combined with breast-feeding. This is in accordance with our previous findings in healthy naturally conceived children (24) .

Limitations of the study

We cannot exclude a possible selection bias due to the 30–50% participation rates as well as the found differences between participants and nonparticipants. However, we found the clinical value of the data to be important enough to supersede this. We also suspect the sporadic significant differences in anthropometrical measures to be chance findings possibly due to mass significance.

In conclusion, the overall growth pattern of children conceived by ICSI and IVF was within normal range. However, in the systematically followed large infant cohort ICSI children had not fully achieved their genetic height potential at 3 yr, and there were subtle differences in growth factor levels in both ICSI and IVF children. We did not confirm these observations in the smaller cross-sectional cohort of 5-yr-old children. However, this may be due to differences in inclusion criteria, introducing a bias. We recommend that children born after ICSI or IVF should also be systematically followed throughout childhood and adolescence.


   Acknowledgments
 
The Nordic Cryptorchidism Study Group was involved in examination of the children and consisted of doctors Malene Boas, Kirsten Boisen, Ida Norgil Damgaard, Ida Maria Schmidt, and Anne-Maarit Suomi (University Department of Growth and Reproduction, Copenhagen, Denmark). We are grateful to all the families, especially the children who participated in this study. We appreciate the skilled help of nurse Helle Kelkeland, students, and the technicians (University Department for Growth and Reproduction). We also thank secretary Bente Wedel Larsen and the staff of the Fertility Clinic for practical help and support in conducting the study.


   Footnotes
 
This work was supported by The University of Copenhagen, The Danish Medical Research Council (9700833 and 9700909), The European Commission (QLK4-CT1999-01422, QLK4-2001-00269, and QLG4-CT-2000-00545), Turku University Central Hospital, the Academy of Finland, and the Novo Nordisk Foundation. The authors are solely responsible for the study design and the interpretation of data. The funding source had no responsibility therein.

First Published Online August 15, 2006

Abbreviations: B, Parameter estimate; BMI, body mass index; GA, gestational age; GLM, general linear model; ICSI, intra-cytoplasmic sperm injection; IGFBP, IGF binding protein; IVF, in vitro fertilization; NC, naturally conceived; SDS, SD score; SGA, small for GA; WGA, weight for GA.

Received March 30, 2006.

Accepted August 4, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Palermo G, Joris H, Devroey P, Van Steirteghem AC 1992 Pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte. Lancet 340:17–18[CrossRef][Medline]
  2. Westergaard HB, Johansen AM, Erb K, Andersen AN 1999 Danish National In-Vitro Fertilization Registry 1994 and 1995: a controlled study of births, malformations and cytogenetic findings. Hum Reprod 14:1896–1902[Abstract/Free Full Text]
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