Mirjam M. van Weissenbruch

Cardiometabolic Differences in Children Born After in Vitro Fertilization: Follow-Up Study

CONTEXT Increasing evidence suggests that adverse conditions during early prenatal life are associated with cardiometabolic dysfunction in postnatal life. In vitro fertilization (IVF) conception may be an early prenatal life event with long-term health consequences. OBJECTIVE Our objective was to investigate several cardiometabolic measures in 8- to 18-yr-old IVF singletons and spontaneously conceived controls born from subfertile parents. DESIGN AND SETTING This follow-up study was conducted at the VU University Medical Center, Amsterdam, The Netherlands. PARTICIPANTS Blood pressure was examined in 225 IVF-conceived children and 225 age- and gender-matched spontaneously conceived control children. Several indicators of insulin resistance were studied in a pubertal subpopulation (131 IVF children and 131 controls). MAIN OUTCOME MEASURES Blood pressure, fasting glucose, and fasting insulin were determined. RESULTS Systolic and diastolic blood pressure levels were higher in IVF children than controls (109 +/- 11 vs. 105 +/- 10 mm Hg, P < 0.001; and 61 +/- 7 vs. 59 +/- 7 mm Hg, P < 0.001, respectively). Children born after IVF were also more likely to be in the highest systolic and diastolic blood pressure quartiles (odds ratio = 2.1, 95% confidence interval 1.4, 3.3; odds ratio = 1.9, 95% confidence interval 1.2, 3.0, respectively). Furthermore, higher fasting glucose levels were observed in pubertal IVF children (5.0 +/- 0.4 vs. 4.8 +/- 0.4 mmol/liter in controls; P = 0.005). Blood pressure and fasting glucose differences could not be explained by current body size, birth weight, and other early life factors or by parental characteristics, including subfertility cause. CONCLUSIONS These findings highlight the importance of continued cardiometabolic monitoring of IVF-conceived children and might contribute to current knowledge about periconceptional influences and their consequences in later life.

Early Insulin Therapy in Very-Low-Birth-Weight Infants

BACKGROUND Studies involving adults and children being treated in intensive care units indicate that insulin therapy and glucose control may influence survival. Hyperglycemia in very-low-birth-weight infants is also associated with morbidity and mortality. This international randomized, controlled trial aimed to determine whether early insulin replacement reduced hyperglycemia and affected outcomes in such neonates. METHODS In this multicenter trial, we assigned 195 infants to continuous infusion of insulin at a dose of 0.05 U per kilogram of body weight per hour with 20% dextrose support and 194 to standard neonatal care on days 1 to 7. The efficacy of glucose control was assessed by continuous glucose monitoring. The primary outcome was mortality at the expected date of delivery. The study was discontinued early because of concerns about futility with regard to the primary outcome and potential harm. RESULTS As compared with infants in the control group, infants in the early-insulin group had lower mean (+/-SD) glucose levels (6.2+/-1.4 vs. 6.7+/-2.2 mmol per liter [112+/-25 vs. 121+/-40 mg per deciliter], P=0.007). Fewer infants in the early-insulin group had hyperglycemia for more than 10% of the first week of life (21% vs. 33%, P=0.008). The early-insulin group had significantly more carbohydrate infused (51+/-13 vs. 43+/-10 kcal per kilogram per day, P<0.001) and less weight loss in the first week (standard-deviation score for change in weight, -0.55+/-0.52 vs. -0.70+/-0.47; P=0.006). More infants in the early-insulin group had episodes of hypoglycemia (defined as a blood glucose level of <2.6 mmol per liter [47 mg per deciliter] for >1 hour) (29% in the early-insulin group vs. 17% in the control group, P=0.005), and the increase in hypoglycemia was significant in infants with birth weights of more than 1 kg. There were no differences in the intention-to-treat analyses for the primary outcome (mortality at the expected date of delivery) and the secondary outcome (morbidity). In the intention-to-treat analysis, mortality at 28 days was higher in the early-insulin group than in the control group (P=0.04). CONCLUSIONS Early insulin therapy offers little clinical benefit in very-low-birth-weight infants. It reduces hyperglycemia but may increase hypoglycemia (Current Controlled Trials number, ISRCTN78428828.)

Body Mass Index, Body Composition, and Leptin at Onset of Puberty in Male and Female Rats after Intrauterine Growth Retardation and after Early Postnatal Food Restriction

In this study we examined the body composition at onset of puberty in intrauterine growth retarded (IUGR), postnatal food restricted (FR), and control male and female rats. IUGR was induced by ligation of the uterine artery on d 17 of gestation and FR by litter enlargement to 20 pups per mother from d 2 after birth until weaning (d 24). We defined onset of puberty as balanopreputial separation in male rats and vaginal opening in female rats. We calculated body mass index, measured body composition with dual-energy x-ray absorptiometry, and measured leptin concentrations in serum. It was reported previously that early malnutrition, either during late gestation or immediately postnatally, results in a delayed onset of puberty in IUGR and FR male rats and in IUGR female rats, but not in FR female rats. In IUGR male rats at balanopreputial separation and in IUGR female rats at vaginal opening no differences were found in body mass index, body composition, and leptin levels compared with controls. FR male rats had a significantly lower percentage of fat and serum leptin concentrations at balanopreputial separation. FR female rats had a significantly lower body mass index, percentage of fat, and serum leptin concentrations at vaginal opening. We conclude that the onset of puberty in the rat is not dependent on a certain percentage of body fat or a certain threshold of circulating levels of leptin and that food deprivation during different “critical” time periods around birth results in different effects in later life.

Growth and development of children born after in vitro fertilization

OBJECTIVE To evaluate growth and development of children born after IVF treatment. DESIGN Literature review. CONCLUSION(S) At present there is substantial evidence that children born after IVF are at increased risk for adverse perinatal outcome, congenital malformations, and rare epigenetic defects. It is still unclear whether observed health problems originate from the IVF procedure itself or the underlying subfertility problems of the parents. Current follow-up studies regarding postnatal growth and morbidity rates are scarce with conflicting results and other areas of long-term research in children born after IVF are still in its infancy. The importance of the worldwide continuing monitoring of children born after IVF to investigate potential long-term consequences including the development of cardiovascular diseases is therefore highlighted.

Growth during infancy and early childhood in relation to blood pressure and body fat measures at age 8–18 years of IVF children and spontaneously conceived controls born to subfertile parents

BACKGROUND Little is known about post-natal growth in IVF offspring and the effects of rates of early post-natal growth on blood pressure and body fat composition during childhood and adolescence. METHODS The follow-up study comprised 233 IVF children aged 8-18 years and 233 spontaneously conceived controls born to subfertile parents. Growth data from birth to 4 years of age, available for 392 children (n = 193 IVF, n = 199 control), were used to study early post-natal growth. Furthermore, early post-natal growth velocity (weight gain) was related to blood pressure and skinfold measurements at follow-up. RESULTS We found significantly lower weight, height and BMI standard deviation scores (SDSs) at 3 months, and weight SDS at 6 months of age in IVF children compared with controls. Likewise, IVF children demonstrated a greater gain in weight SDS (P < 0.001), height SDS (P = 0.013) and BMI SDS (P = 0.029) during late infancy (3 months to 1 year) versus controls. Weight gain during early childhood (1-3 years) was related to blood pressure in IVF children (P = 0.014 systolic, 0.04 diastolic) but not in controls. Growth during late infancy was not related to skinfold thickness in IVF children, unlike controls (P = 0.002 peripheral sum, 0.003 total sum). Growth during early childhood was related to skinfold thickness in both IVF and controls (P = 0.005 and 0.01 peripheral sum and P = 0.003 and 0.005 total sum, respectively). CONCLUSIONS Late infancy growth velocity of IVF children was significantly higher compared with controls. Nevertheless, early childhood growth instead of infancy growth seemed to predict cardiovascular risk factors in IVF children. Further research is needed to confirm these findings and to follow-up growth and development of IVF children into adulthood.

Low Birth Weight Is Associated With Increased Sympathetic Activity Dependence on Genetic Factors

Background—Low birth weight may be associated with high blood pressure in later life through genetic factors, an association that may be explained by alterations in sympathetic and parasympathetic activity. We examined the association of birth weight with cardiac pre-ejection period and respiratory sinus arrhythmia (indicators of cardiac sympathetic and parasympathetic activity, respectively) and with blood pressure in 53 dizygotic and 61 monozygotic adolescent twin pairs. Methods and Results—Birth weight of the twins was obtained from the mothers. Pre-ejection period and respiratory sinus arrhythmia were measured with electrocardiography and impedance cardiography at rest, during a reaction time task, and during a mental arithmetic task. In the overall sample, lower birth weight was significantly associated with shorter pre-ejection period at rest, during the reaction time task, and during the mental arithmetic task (P =0.0001, P <0.0001, and P =0.0001, respectively) and with larger pre-ejection period reactivity to the stress tasks (P =0.02 and P =0.06, respectively). In within-pair analyses, differences in birth weight were associated with differences in pre-ejection period at rest and during both stress tasks in dizygotic twin pairs (P =0.01, P =0.06, and P =0.2, respectively) but not in monozygotic twin pairs (P =0.9, P =1.0, and P =0.5, respectively). Shorter pre-ejection period explained approximately 63% to 84% of the birth weight and blood pressure relation. Conclusions—Low birth weight is associated with increased sympathetic activity, and this explains a large part of the association between birth weight and blood pressure. In addition, our findings suggest that the association between birth weight and sympathetic activity depends on genetic factors.

Cigarette smoking is associated with an acute impairment of microvascular function in humans.

An effect on microvascular function has been proposed as a possible mechanism explaining the association of acute smoking with increased blood pressure and decreased insulin sensitivity. However, the effects of smoking on microvascular function have not been studied. We have investigated the acute effects of smoking on microvascular function in 12 healthy smokers. Before and after smoking a cigarette, we measured heart rate, blood pressure and capillary recruitment during peak reactive hyperaemia. We also measured endothelium-dependent and endothelium-independent vasodilatation of the skin microcirculation with iontophoresis of acetylcholine and sodium nitroprusside respectively combined with laser Doppler fluxmetry. To exclude non-specific changes, a control study with sham smoking was performed. The smoking and sham smoking studies were conducted in a randomized order. Compared with sham smoking, acute smoking caused increases in heart rate (smoking, 9.3+/-4.1 beats/min; sham, -1.3+/-3.0 beats/min; P < 0.001) and systolic blood pressure (smoking, 6.3+/-8.8 mmHg; sham, 0.8+/-4.4 mmHg; P < 0.05); decreases in absolute (smoking, -4.9+/-6.9 per mm(2); sham, 0.8+/-2.1 per mm(2); P = 0.01) and relative (smoking, -13.8+/-21.4%; sham, 1.9+/-6.9%; P = 0.02) capillary recruitment during peak reactive hyperaemia; and decreases in absolute [smoking, -62.4+/-47.7 perfusion units (PU); sham, -30.8+/-32.6 PU; P = 0.04] and relative (smoking, -147+/-163%; sham, 32+/-225%; P = 0.07) vasodilatation caused by acetylcholine. Absolute (smoking, -31.6+/-58.5 PU; sham, -8.4+/-44.0 PU; P = 0.3) and relative (smoking, -50.2+/-219.0%; sham, -17.1+/-139%; P = 0.7) vasodilatation caused by sodium nitroprusside were not affected. Thus acute smoking is associated with impaired capillary recruitment during peak reactive hyperaemia and impaired microvascular endothelium-dependent vasodilatation. These findings may explain the increased blood pressure and decreased insulin sensitivity that have been observed after acute smoking.

Pubertal development in children and adolescents born after IVF and spontaneous conception

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 Tanners 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 micromol/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.

Diffusion-weighted and Conventional MR Imaging in Neonatal Hypoxic Ischemia: Two-year Follow-up Study

PURPOSE To establish the supplemental value of diffusion-weighted (DW) magnetic resonance (MR) imaging beyond conventional MR to predict clinical outcome after neonatal hypoxic ischemia (HI) at 2 years of age. MATERIALS AND METHODS Forty-six infants with neonatal HI were enrolled in this prospective study, after approval by the local ethical committee and informed consent of the parents. Neonatal MR imaging ranged from 1 to 45 days after birth. Apparent diffusion coefficient (ADC) was measured in 14 brain regions. DW and conventional images were qualitatively scored for abnormalities, resulting in cumulative scores and patterns of damage. Surviving infants were scored for motor outcome at the age of 2 years, and outcome was classified as poor if the motor score was less than 70 or in case of death. Analyses were performed for the whole group, with additional analyses for the early (0-4 days after birth) and late (>4 days after birth) imaging groups. RESULTS Twenty-five infants had a good outcome and 21 had a poor outcome. Only in the early imaging group, the infants with poor outcome had significantly lowered ADC values in several brain areas, with the posterior limb of the internal capsule being the most predictive (Wald score = 5.7; P = .017). Cumulative scores of DW imaging were the best predictor of poor motor outcome at the age of 2 years (Wald score = 7.2, P < .01). The basal ganglia and central cortex and the diffuse pattern of brain damage were highly associated with poor outcome (Fisher exact test = 29.8; P < .001). CONCLUSION In neonatal HI, DW imaging is a useful additional MR technique to predict the motor outcome at 2 years. Local ADC values had a limited value. Recognition of the patterns of brain damage with DW and conventional MR imaging can be used as a diagnostic tool in neonatal HI.

Maturity of the adrenal cortex in very preterm infants is related to gestational age

To study the maturity of the adrenal cortex in preterms born before 33 wk of gestation, basal levels of cortisol and cortisone and the cortisol and 17-hydroxyprogesterone (17-OHP) response to 1 μg/kg adrenocorticotropic hormone stimulation were measured in 24 appropriate-for-gestational age preterm infants (26-33 wk; 690-1985 g). Gestational age influenced the response of cortisol, 17-OHP, and the ratio between cortisol/17-OHP in the studied infants. In preterms born <30 wk of gestation, levels of cortisol, and the ratio between cortisol/17-OHP were lower compared with preterms born between 30 and 33 wk. Levels of cortisone were higher in preterms born <30 wk, suggesting a lower activity of 11β-hydroxysteroid dehydrogenase that may be related to maturity as well. These findings indicate that the adrenal cortex function in preterm infants is closely related to the duration of gestation and may be important in neonatal morbidity.