Search

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.

Context: Recent studies showed that male reproductive health problems, such as cryptorchidism, hypospadias, testicular cancer, and low sperm quality, are more prevalent in Denmark than in Finland., Objectives: We hypothesized that, if fetal testicular dysgenesis contributed to these observations, differences in gonadal development and the hypothalamus-pituitary-testis axis would already be detectable perinatally. Thus, we investigated healthy newborn boys in both countries., Design: This was a prospective, longitudinal population-based study., Setting: Two primary obstetric centers were included at the University Hospitals of Copenhagen, Denmark, and Turku, Finland., Participants: The participants of the study included 633 Danish and 1044 Finnish boys, born at term with appropriate weight for gestational age., Interventions: Ultrasound determination of testis size at 0, 3, and 18 months and blood sampling (n = 727) at 3 months were analyzed., Main Outcome Measures: Testicular volume and reproductive hormones were measured., Results: Testis volume was significantly higher at all ages in Finnish than in Danish boys (medians, 98 vs. 95, 185 vs. 119, and 188 vs. 136 mm(3), respectively; P < 0.00001). Testis growth from birth to 3 months was larger in Finnish than in Danish boys (mean, 75 vs. 26 mm(3); P < 0.0001). Serum hormone levels were higher in Finnish than Danish boys for inhibin B (median, 456 vs. 385 pg/ml; P < 0.0001), FSH (1.33 vs. 1.21 IU/liter; P < 0.036), and SHBG (143 vs. 136 nmol/liter; P < 0.022). Inhibin B was significantly positively correlated to testicular volume (r = 0.25; P < 0.006)., Conclusions: The larger testes and higher inhibin B levels most likely represent a bigger volume of seminiferous tubules in Finnish compared with Danish boys. Although this phenomenon may be attributable to a genetic difference between the two countries, it may also reflect environmental factors influencing testicular development.

Context: Many aspects of hormonal regulation and mechanisms of normal infancy growth are poorly understood., Objective: The objective of this study was to establish the determinants of serum growth factor levels in infancy and their association with growth., Design: A prospective, longitudinal, population-based birth cohort between 1997-2001 was studied., Participants: Study participants were 942 healthy appropriate weight for gestational age (AGA) infants (538 boys and 404 girls) and 49 small for gestational age (SGA) children (29 boys and 20 girls)., Interventions: INTERVENTIONS were anthropometrical measurements (0, 3, 18, and 36 months) and serum samples (3 months)., Main Outcome Measures: Height, weight, and serum IGF-I and IGF-binding protein-3 (IGFBP-3) were the main outcome measures., Results: IGF-I levels showed no gender difference [boys, 92 ng/ml (confidence interval, 49, 162); girls, 91 ng/ml (47, 149); P = 0.50]. IGFBP-3 levels were significantly higher in females [2174 ng/ml (1295, 3330)] than in males [2103 ng/ml (1266, 3143); P = 0.04]. Infants receiving breast milk had lower IGF-I levels [90 ng/ml (48, 154)] than infants receiving formula [n = 62; 97 ng/ml (58, 165)] or both [n = 123; 94 ng/ml (48, 169); P < 0.001]. IGF-I and IGFBP-3 levels were positively associated with weight gain and height gain from birth to 3 months of age in AGA, but not in SGA, children. SGA children had significantly lower IGF-I [88.0 ng/ml (28, 145); P = 0.05] and IGFBP-3 [1835 ng/ml (1180, 2793); P < 0.001] levels than AGA children., Conclusion: We found a significant, but weak, association between IGF-I and IGFBP-3 levels at 3 months and postnatal growth in AGA, but not SGA, children. Factors other than IGF-I must contribute to the regulation of normal postnatal growth, and these may differ between AGA and SGA children. IGFBP-3, but not IGF-I, showed a gender difference, which may reflect an influence of the postnatal activation of the pituitary-gonadal axis on binding protein levels.

Context: Hormonal dysregulation has been suggested to be one of many etiological factors of cryptorchidism., Objectives: The objective of this study was to assess the hypothalamic-pituitary-testicular axis in cryptorchid boys during the postnatal hormonal surge., Design: This was a prospective, longitudinal, population-based study., Setting: The study was performed at two primary obstetric centers., Participants: Study participants included 388 Finnish and 433 Danish boys (88 and 34 with cryptorchidism, respectively)., Interventions: Clinical examinations were performed at 0 and 3 months. Blood samples were taken at 3 months., Main Outcome Measures: The main outcome measures were testis position and reproductive hormone levels., Results: Finnish cryptorchid boys had significantly higher FSH [1.59 (0.50-3.53) vs. 1.30 (0.49-2.92) IU/liter; P < 0.0001] and lower inhibin B [426 (254-770) vs. 459 (266-742) pg/ml; P < 0.015] levels than Finnish control boys [median (2.5th-97.5th percentiles)]. Danish cryptorchid boys had higher FSH levels than controls [1.47 (0.54-3.89) vs. 1.18 (0.41-3.04) IU/liter; P = 0.018]. Inhibin B levels in healthy Danish boys were lower than those in Finnish boys [380 (233-637) pg/ml; P < 0.0001] and were not reduced in Danish crypt-orchid boys [392 (236-672) pg/ml; P = 0.851]. Changes in hormone levels were strongest in boys with severe, persistent cryptorchidism, but were also detectable in mild and transient cryptorchidism. Effects on Leydig cell function were subtle, with an increase in LH in Finnish (but not Danish) cryptorchid boys vs. controls [1.97 (0.77-5.91) vs. 1.75 (0.58-4.04) IU/liter; P < 0.021], but testosterone levels remained within the normal range., Conclusions: Our results support the hypothesis that cryptorchidism is associated with a primary testicular disorder, which could be a cause or a consequence of cryptorchidism. This malfunction is reflected by low inhibin B production in the Finnish cohort and high gonadotropin drive in both the Finnish and Danish cohorts.

Context: Hypospadias is one of the most frequent male congenital malformations and may be part of the testicular dysgenesis syndrome., Objective: The aim of the study was to investigate the prevalence of hypospadias in Denmark and evaluate the relationship to anthropometrical measurements at birth and reproductive hormone levels at 3 months of age., Design: A prospective cohort study was conducted with 3-yr follow-up (1997-2004)., Setting: The population-based study was conducted at the University Hospital of Copenhagen., Participants: A total of 1072 Danish boys were consecutively recruited antenatally, with 74.4% completing the study., Main Outcome Measures: The study examined the position of the urethral meatus, anthropometrical measurements, placental weight, and reproductive hormone levels., Results: The Danish birth prevalence of hypospadias was significantly higher than in a concomitant Finnish study (1.03 vs. 0.27%; P = 0.012). At 3 yr, the true prevalence was found to be 4.64% because additional mild cases were detected when physiological phimosis dissolved. Weight for gestational age (percentage deviation from expected mean) (-5.00 vs. -0.59%; P = 0.030) and placental weight (567 vs. 658 g; P = 0.023) were significantly lower, and FSH was significantly higher (1.48 vs. 1.15 IU/liter; P = 0.007) in boys with hypospadias, compared with healthy boys., Conclusions: We found a surprisingly high total rate of hypospadias of 4.6% in this large prospective cohort study. Seventy-two percent of the cases were apparent only after the prepuce could be retracted. Hypospadias were associated with elevated serum FSH levels at 3 months. We also confirmed an association between fetal growth impairment and hypospadias; however, it is yet unknown whether this indicates a causal relationship or a shared pathogenic factor.

The aim of the study was 1) to evaluate the association of maternal serum levels of placental GH and IGF-I with fetal growth, and 2) to establish reference data for placental GH, IGF-I, and IGF-binding protein-3 (IGFBP-3) in normal pregnancies based on longitudinal measurements. A prospective longitudinal study of 89 normal pregnant women was conducted. The women had, on the average, seven blood samples taken and three ultrasound examinations performed. All had normal umbilical artery pulsatility indexes during pregnancy and gave birth to singletons between 37 and 42 wk gestation with birth weights above -2 SD. Placental GH levels were detectable in all samples from as early as 5 wk gestation and increased significantly throughout pregnancy to approximately 37 wk when peak levels of 22 ng/ml (range, 4.64-69.22 ng/ml) were reached. Subsequently, placental GH levels decreased until birth. The change in placental GH during 24.5-37.5 wk gestation was positively associated with fetal growth rate (P = 0.027) and birth weight (P = 0.027). Gestational age at peak placental GH values (P = 0.007) was associated with pregnancy length. A positive association between the change in placental GH and the change in IGF-I levels throughout gestation was found in a multivariate analysis (r(2) = 0.42; P < 0.001). There was no association between placental GH and IGFBP-3 levels. The change in IGF-I throughout gestation (P = 0.039), but not placental GH, was significantly positively associated with placental weight at birth. We found a significant association between placental GH and fetal growth. In addition, we found a highly significant association between the increase in placental GH and the increase in IGF-I. The gestational age at peak placental GH levels was associated with pregnancy length.

The early postnatal regulation of reproductive hormones seems to be more complex in girls than in boys. The aim of this study was to describe inhibins A and B, FSH, LH, estradiol, and SHBG in a large prospective cohort of 473 unselected, healthy, 3-month-old girls. In full term, appropriate-for- gestational-age girls (n = 355) hormones showed a marked interindividual variation, with concentrations up to pubertal values [medians (95% confidence intervals): inhibin B, 82 pg/ml (<20-175); FSH, 3.8 IU/liter (1.2-18.8); LH, 0.07 IU/liter (<0.05-1.07); estradiol, 31 pM (<18-83); SHBG, 137 nM (72-260)]. In 38%, FSH levels exceeded 4.5 IU/liter. Weight at 3 months had significant inverse relationships with estradiol and SHBG (P = 0.048 and P = 0.001, respectively). Gestational age was negatively correlated to estradiol (P = 0.001), with a similar trend for LH, FSH, and inhibin B. Inhibin B was higher in premature girls [126 pg/ml (<20-265)] than in term [80 pg/ml (<20-181), P = 0.002] and postmature girls [59 pg/ml (<20-152), P = 0.012]. Likewise, estradiol levels in prematures were higher than in mature girls [51 pM (<18-128) vs. 31 pM (<18-85), P = 0.009]. Estradiol was also higher in small-for-gestational-age than in appropriate-for-gestational-age girls (P = 0.046), with inhibin B and LH, but not FSH, showing a similar trend. In conclusion, reproductive hormones showed a large variation, and concentrations corresponded to those observed in puberty. Our findings support the concept of a minipuberty in infant girls similar to that in boys.

Placental GH is thought to be responsible for the rise in maternal IGF-I during pregnancy and is considered to be important for fetal growth. In this prospective longitudinal study of healthy pregnant women, we investigated determinants of placental GH in maternal serum. Serum was obtained from 455 women with normal singleton pregnancies at approximately 19 and 28 wk gestation. Serum placental GH concentrations were measured by a highly specific immunoradiometric assay, and fetal size was measured by ultrasound. Data on birth weight, gender, prepregnancy body mass index (BMI), parity, and smoking habits were obtained from medical records. Serum placental GH concentrations were detectable in serum from all women as early as 14 wk gestation and increased during pregnancy in all individuals (P < 0.001). Placental GH levels at second examination were found to be higher in women carrying female fetuses [median, 9.0 ng/ml; 95% confidence interval (CI), 4.7-23.0] compared with women carrying male fetuses (median, 8.2 ng/ml; 95% CI, 3.96-19.4; P = 0.004). Similarly, the increase in placental GH between 19 and 28 wk gestation was significantly larger in female fetus bearers than in male fetus bearers (P = 0.002). Placental GH at second examination was positively correlated with gestational age (P = 0.002) and negatively correlated with prepregnancy BMI (P = 0.039). Placental GH correlated with fetal weight at approximately 28 wk gestation (P = 0.002) but did not predict birth weight at term. Our study supports the role of maternal placental GH in the regulation of fetal growth. In conclusion, we found that 1) placental GH levels correlated significantly with fetal size at 28 wk gestation; 2) GH levels were measurable in serum from all women as early as 14 wk gestation; 3) maternal prepregnancy BMI and smoking were determinants of placental GH levels, although their specific effects on the serum maternal levels of placental GH remain to be seen; and 4) women carrying female fetuses have significantly higher placental GH levels compared with women carrying male fetuses at 28 wk gestation.