Association of culture medium with growth, weight and cardiovascular development of IVF children at the age of 9 years.

STUDY QUESTION: Is embryo culture media used during an IVF/ICSI treatment associated with differences in growth, body composition and cardiovascular development as determined in 9-year-old singleton IVF children? SUMMARY ANSWER: The choice of in vitro culture medium for human embryos is associated with differences in body weight, BMI, truncal adiposity, waist circumference and waist/hip ratio at the age of 9, while no significant differences were observed in cardiovascular development. WHAT IS KNOWN ALREADY: Children born after IVF/ICSI have an increased risk of low birthweight, which is correlated with a higher risk of cardiovascular diseases. Some studies show that IVF children exhibit a significantly higher systolic and diastolic blood pressure and higher fasting glucose levels compared to naturally conceived children. After alternating assignment to G1™ Version 3 (Vitrolife) or K-SICM (Cook) embryo culture media, birthweight of the resulting children was significantly higher in the Vitrolife group and they remained heavier during the first 2 years of life. STUDY DESIGN, SIZE, DURATION: In this observational cohort study (MEDIUM-KIDS), parents of singletons from a previous study were approached for further follow-up after the ninth birthday of their child. The singletons were born after fresh embryo transfer of cleavage stage embryos resulting from an IVF/ICSI treatment performed between July 2003 and December 2006 in our clinic, when two different culture media were used alternately: either G1™ Version 3 (Vitrolife) or K-SICM (Cook). Follow-up measurements were performed between March 2014 and December 2016. PARTICIPANT/MATERIALS, SETTINGS, METHODS: Parents were invited to attend our clinic with their child for a single visit lasting ~2.5 h. Two experienced clinicians performed all measurements as part of the MEDIUM-KIDS study in a standardized way. Height and weight of the child was measured using calibrated scales, 4-point skinfold thickness measurements were measured in triplicate and waist and hip circumference were measured using a tape measure. The following cardiovascular parameters were measured in a standardized way: blood pressure, heart rate and endothelial function by skin laser-Doppler with iontophoresis using vasodilatory drugs. Cortisol and cortisone concentrations in hair were measured. A blood sample was taken after an overnight fast for insulin, glucose, TSH and lipid analysis. Blood samples of the IVF children were compared with a non-IVF control group. Differences between culture medium groups were analysed by Student's t-test and effects of confounders were analysed using multivariable regression analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 294 eligible children (168 Vitrolife and 126 Cook), 136 children (75 Vitrolife and 61 Cook) participated in the study. Baseline characteristics of the participating children from the Vitrolife and Cook group were similar. Birthweight was higher in the Vitrolife group, in keeping with the full cohort. After correction for confounders, the difference in weight and BMI attributable to culture medium was 1.58 kg (95% CI: 0.01-3.14) and 0.84 kg/m2 (95% CI: 0.02-1.67), respectively, with the Vitrolife children being heavier. Height and height corrected for age and gender (SDS scores) were similar in both groups. Furthermore, waist circumference was significantly higher in the Vitrolife group with a corrected difference of 3.21 cm (95%CI: 0.60-5.81) leading to a 0.03 increase (95% CI: 0.01-0.05) in waist/hip ratio. Subscapular skinfolds combined with suprailiacal skinfolds (defined as truncal adiposity), was also significantly higher in Vitrolife children (adjusted difference 3.44 cm [95% CI: 0.27-6.62]). Both systolic (adj. beta 0.364 [95% CI: -2.129 to 2.856],) and diastolic (adj. beta 0.275 [95% CI: -2.105 to 2.654]) blood pressures (mmHg) were comparable for the two groups. After an overnight fast, cholesterol, glucose, insulin, low and high-density lipoprotein, triglycerides and TSH were normal and similar in the two groups. Endothelial function in the microcirculation was compared by using maximum perfusion units corrected for the baseline value as a measure for vasodilatory capacity. There were no significant differences between the two groups. Cortisol and cortisone concentration in hair samples were comparable. LIMITATIONS, REASONS FOR CAUTION: A limitation of the original study was its pseudo-randomized design. This and the dwindling enthusiasm of families for participation (47.7% after 9 years) prevent us from drawing robust causal conclusions from the observed association. Nevertheless, to date this is oldest cohort of IVF/ICSI children where culture medium was allocated alternatingly and used in a blinded setting, to be studied. We believe that our participants are representative for the full cohort. The current number of participants was sufficient to rule out differences as little as 3 mmHg in systolic and diastolic blood pressures. WIDER IMPLICATIONS OF THE FINDINGS: This study underlines the importance of structured follow-up of IVF/ICSI children to further elucidate possible long-term health effects. Health professionals and culture medium manufacturers should be aware that small changes in culture conditions and culture medium composition for the early embryo can have long-term health effects. The similar cardiovascular results for the two groups are reassuring but the children may still be too young to detect differences in cardiovascular development. Prolonged follow-up and structured investigations up until adulthood are necessary to gain more insight and reassurance in the cardiovascular development of IVF offspring, although long-term follow-up will become more complicated by confounding life-style and environmental factors possibly influencing development. STUDY FUNDING/COMPETING INTEREST(S): The study was financially supported by the March of Dimes (Grant number #6-FY13-153). The sponsor of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: NTR4220.

Using vaginal Group B Streptococcus colonisation in women with preterm premature rupture of membranes to guide the decision for immediate delivery: a secondary analysis of the PPROMEXIL trials.

OBJECTIVE: To investigate whether vaginal Group B Streptococcus (GBS) colonisation or other baseline characteristics of women with preterm premature rupture of membranes (PPROM) can help in identifying subgroups of women who would benefit from immediate delivery. DESIGN: Secondary analysis of the PPROMEXIL trials. SETTING: Sixty hospitals in the Netherlands. POPULATION: Women with PPROM between 34 and 37 weeks of gestation. METHODS: Random assignment of 723 women to immediate delivery or expectant management. MAIN OUTCOME MEASURES: Early onset neonatal sepsis. RESULTS: Vaginal GBS colonisation status was the only marker which was significantly associated with the benefit of immediate delivery (P for interaction: 0.04). GBS colonisation was observed in 14% of women. The risk of early onset neonatal sepsis in GBS-positive women was high (15.2%) when they were managed expectantly but this risk was reduced to 1.8% with immediate delivery. The early onset neonatal sepsis risk was much lower in neonates of GBS-negative women: 2.6% after expectant management and 2.9% with immediate delivery. We estimated that by inducing labour only in GBS-positive women, there would be a 10.4% increase in term delivery rate, while keeping neonatal sepsis and caesarean delivery rates comparable to a strategy of labour induction for all. CONCLUSIONS: Our post hoc findings suggest that women with PROM between 34 and 37 weeks might benefit from immediate delivery if they have GBS vaginal colonisation, while in GBS-negative women labour induction could be delayed until 37 weeks.

Clinical practice: neonatal resuscitation. A Dutch consensus.

The updated Dutch guidelines on Neonatal Resuscitation assimilate the latest evidence in neonatal resuscitation. Important changes with regard to the 2004 guidelines and controversial issues concerning neonatal resuscitation are reviewed, and recommendations for daily practice are provided and argued in the context of the ILCOR 2005 consensus.

Longitudinal growth during the first years of life: what is normal?

The anthropometric data of a longitudinal growth study on healthy infants, followed from birth until the age of 4 years and performed during 1995-1999 in The Netherlands, were used to analyze the general growth patterns in terms of height, weight and head circumference, based on z-scores, during the first 4 years of life. The well-known phenomenon where each infant or child tends to decelerate or accelerate its growth velocity depending on its starting position on the reference curve is obvious in this study too. This phenomenon, known as the regression to the mean, is a strong phenomenon especially during the first year. Regression to the mean is calculated for the different age groups as factor. With the given alpha, it is possible to estimate the individual expectation of growth.

Pentalogy of Cantrell: two patients and a review to determine prognostic factors for optimal approach.

Two patients with incomplete pentalogy of Cantrell are described. The first was a girl with a large omphalocele with evisceration of the heart, liver and intestines with an intact sternum. Echocardiography showed profound intracardiac defects. The girl died 33 h after birth. The second patient was a female fetus with ectopia cordis (EC) without intracardiac anomalies; a large omphalocele with evisceration of the heart, stomach, spleen and liver; a hypoplastic sternum and rib cage; and a scoliosis. The pregnancy was terminated. A review of patients described in the literature is presented with the intention of finding prognostic factors for an optimal approach to patients with the pentalogy of Cantrell. In conclusion the prognosis seems to be poorer in patients with the complete form of pentalogy of Cantrell, EC, and patients with associated anomalies. Intracardial defects do not seem to be a prognostic factor.

Functional outcomes and participation in young adulthood for very preterm and very low birth weight infants: the Dutch Project on Preterm and Small for Gestational Age Infants at 19 years of age.

OBJECTIVE: Young adults who were born very preterm or with a very low birth weight remain at risk for physical and neurodevelopmental problems and lower academic achievement scores. Data, however, are scarce, hospital based, mostly done in small populations, and need additional confirmation. METHODS: Infants who were born at < 32 weeks of gestation and/or with a birth weight of < 1500 g in The Netherlands in 1983 (Project on Preterm and Small for Gestational Age Infants) were reexamined at age 19. Outcomes were adjusted for nonrespondents using multiple imputation and categorized into none, mild, moderate, or severe problems. RESULTS: Of 959 surviving young adults, 74% were assessed and/or completed the questionnaires. Moderate or severe problems were present in 4.3% for cognition, 1.8% for hearing, 1.9% for vision, and 8.1% for neuromotor functioning. Using the Health Utility Index and the London Handicap Scale, we found 2.0% and 4.5%, respectively, of the young adults to have > or = 3 affected areas in activities and participation. Special education or lesser level was completed by 24%, and 7.6% neither had a paid job nor followed any education. Overall, 31.7% had > or = 1 moderate or severe problems in the assessed areas. CONCLUSIONS: A total of 12.6% of young adults who were born very preterm and/or with a very low birth weight had moderate or severe problems in cognitive or neurosensory functioning. Compared with the general Dutch population, twice as many young adults who were born very preterm and/or with a very low birth weight were poorly educated, and 3 times as many were neither employed nor in school at age 19.

Hyperechogenic fetal bowel: counseling difficulties.

The detection of echodense fetal bowel on ultrasound examination in the second trimester of pregnancy justifies invasive procedures such as amniocentesis to detect an underlying cause. We present a case in which initial tests identified only one mutation in the cystic fibrosis transmembrane regulator (CFTR)-gene of the fetus, the family history being negative for CF. Strongly reduced intestinal enzyme activities suggested intestinal obstruction and further increased the estimated risk for CF. After the 24th gestational week, a second mutation was found, confirming cystic fibrosis in this child. Problems in counseling in this particular case are discussed.

Sonographic genital ambiguity in a fetus due to a mosaic 45,X/46,X,idic(Y)(qter-p11.32::p11.32-qter) karyotype.

Nowadays, improved ultrasound techniques enable the detection of more subtle congenital abnormalities at an earlier stage of fetal development. Current cytogenetic techniques can characterize a chromosomal abnormality in greater detail. These advancements in both diagnostic possibilities have helped to answer many questions but have also created new issues and dilemmas in counselling. This is illustrated by this case report of a 35-year-old woman, who presented at the end of the second trimester of her first pregnancy. Sonographic examination indicated an abnormal external genital in a male fetus. A differential diagnosis of hypospadia was made. During follow-up, an amniocentesis was performed, and this showed a 45,X/46,X,idic(Y)(qter-p11.32::p11.32-qter) karyotype as the cause of the sonographic findings. Cytogenetic characterization of the isodicentric Y chromosome and pre- and post-natal findings in the child are reported. Cases with a similar karyotype reported in the literature are reviewed.

Intracranial pressure and cerebral blood flow velocity in preterm infants with posthaemorrhagic ventricular dilatation.

AIM: To determine the volume of cerebrospinal fluid (CSF) that should be tapped in preterm infants with posthaemorrhagic ventricular dilatation as guided by intracranial pressure (ICP) and cerebral blood flow velocity (CBFV). METHODS: The total number of measurements was 106 in 22 infants. Birth weights ranged from 630 to 2050 g, gestational age from 24.5 to 30.3 weeks, and age at insertion from 12 to 67 days. A subcutaneous ventricular catheter reservoir for repetitive CSF drainage was placed when the diameter of a ventricle was > 4 mm above the 97th centile. A volume of 5 ml/kg body weight was removed twice daily. ICP and CBFV were determined before and after CSF tapping. RESULTS: If the ICP after tapping exceeded 7 cm H(2)O, tapping did not result in a significant improvement in CBFV. If the ICP before tapping was less than 6 cm H(2)O, tapping also had no effect on CBFV. Longitudinal studies in individual infants showed a slight correlation between ICP and CBFV. CONCLUSION: Volume of repetitive CSF drainage in preterm infants with posthaemorrhagic ventricular dilatation guided by ICP and CBFV may be a useful technique. An ICP of about 6 cm H(2)O is the cut off point for CSF drainage.

Sympathetic control of the cardiovascular response to acute hypoxemia in the chick embryo.

In response to an acute hypoxemic insult, the mammalian fetus shows a redistribution of the cardiac output in favor of the heart and brain. Peripheral vasoconstriction contributes to this response and is partly mediated by the release of catecholamines. Two mechanisms of catecholamine release in the fetus are reported: 1) neurogenic sympathetic stimulation and 2) a nonneurogenic mechanism via a direct effect of hypoxemia on chromaffin tissues. In the present study, the effects of sympathetic blockade on plasma catecholamine release and cardiac output distribution in response to acute hypoxemia were studied in the chick embryo at different stages of incubation. Only at the end of the incubation period, sympathetic blockade markedly attenuated the increase in plasma catecholamine concentrations and resulted in a greater fraction of the cardiac output distributed to the carcass. However, these effects did not prevent a significant increase in cardiac output to the brain and heart during acute hypoxemia. These data imply that in the chick embryo the contribution of neurogenic mechanisms to the catecholaminergic response to acute hypoxemia becomes greater by the end of the incubation period.

Alpha-adrenergic contribution to the cardiovascular response to acute hypoxemia in the chick embryo.

Fetal responses to acute hypoxemia include bradycardia, increase in blood pressure, and peripheral vasoconstriction. Peripheral vasoconstriction contributes to the redistribution of the cardiac output away from ancillary vascular beds toward myocardial, cerebral, and adrenal circulations. We investigated the effect of alpha-adrenergic receptor blockade on this fetal response. Fluorescent microspheres were used to measure cardiac output distribution during basal and hypoxemic conditions with and without phentolamine treatment. Phentolamine altered basal cardiac output distribution, indicating a basal alpha-adrenergic tone, but this was mainly noted at the earlier stages of incubation. During hypoxemia, phentolamine prevented vasoconstriction in the carcass. At day 19 of incubation, the percent cardiac output distributed to the carcass increased by 20% compared with a decrease in the control group by 17%. Phentolamine markedly attenuated the subsequent redistribution of the cardiac output toward the brain (from +102% in the control group to -25% in the phentolamine-treated group) and the heart (from +196% in the control group to +69% in the phentolamine-treated group). In the chick embryo, alpha-adrenergic mechanisms contribute to the maintenance of basal vascular tone and to the redistribution of the cardiac output away from the peripheral circulations toward the brain and heart during hypoxemic conditions.

Developmental changes in plasma catecholamine concentrations during normoxia and acute hypoxia in the chick embryo.

In the mammalian fetus, the cardiovascular responses to acute hypoxaemia include a redistribution of the cardiac output away from the periphery towards the adrenal, myocardial and cerebral circulations. A component of the peripheral vasoconstriction is mediated by increased release of catecholamines into the fetal circulation during acute hypoxaemia. Previously, we have shown that the chick embryo also shows an increase in peripheral vascular resistance during acute hypoxaemia and that this response becomes progressively larger towards the end of the incubation period. However, the ontogeny of the catecholaminergic response to acute hypoxaemia has not been investigated in this species. Fertilised chicken eggs were studied on days 10, 13, 16 and 19 of incubation (hatching is at 21 days). At each stage of incubation, blood samples were obtained from the chorioallantoic artery of the chick embryos during normoxia and after 5 min of hypoxaemia for measurement of plasma concentrations of adrenaline and noradrenaline by HPLC. Basal plasma adrenaline and noradrenaline concentrations by the end of the incubation period were much higher in the chick embryo than values reported for mammalian fetuses during late gestation. During normoxia, basal plasma noradrenaline concentration remained unchanged during development but plasma adrenaline concentration showed a developmental increase from < 25.1 pmol l-1 at day 10 to 3 nmol l-1 at day 19 of incubation. Acute hypoxaemia caused an increase in plasma noradrenaline and adrenaline from day 13 and day 16 of incubation, respectively. In addition, the increase in plasma adrenaline and noradrenaline and in the ratio of plasma adrenaline to noradrenaline during acute hypoxaemia became progressively larger by the end of the incubation period. These data show an ontogenic increase in basal plasma catecholamines and in the catecholaminergic response to acute hypoxaemia in the chick embryo during the last third of the incubation period.

Cardiac output distribution in response to hypoxia in the chick embryo in the second half of the incubation time.

1. The fetus develops cardiovascular adaptations to protect vital organs in situations such as hypoxia and asphyxia. These include bradycardia, increased systemic blood pressure and redistribution of the cardiac output. The extent to which they involve maternal or placenta influences is not known. The objective of the present work was to study the cardiac output distribution in response to hypoxia in the chick embryo, which is independent of the mother. 2. Fertilized eggs were studied at three incubation times (10-13 days, 14-16 days and 17-19 days of a normal incubation time of 21 days). Eggs were placed in a Plexiglass box in which the oxygen concentration could be changed. Eggs were opened at the air cell and a chorioallantoic vein was catheterized. Cardiac output distribution was measured with 15 micron fluorescent microspheres injected during normoxia, during the last minute of a 5 min period of hypoxia and after 5 min of subsequent reoxygenation. 3. Hypoxia caused a redistribution of the cardiac output in favour of heart (+17 to +160 % of baseline) and brain (+21 to +57 % of baseline) at the expense of liver (-3 to -65 % of baseline), yolk-sac (-46 to -77 % of baseline) and carcass (-6 to -33 % of baseline). 4. The magnitude of the changes in cardiac output distribution to the heart, brain, liver and carcass in response to hypoxia increased with advancing incubation time. 5. The data demonstrate the development of a protective redistribution of the cardiac output in response to hypoxia in the chick embryo from day 10 of incubation.

[Childhood hypophosphatasia]. / Hypofosfatasemie op de kinderleeftijd.

Hypophosphatasia was diagnosed in two boys aged four months and two years. This is a rare hereditary bone disease characterized by deficient activity of enzyme alkaline phosphatase. Increased levels of substrates of this enzyme are found: phosphoethanolamine in urine and pyridoxal phosphate in serum. Patients show defective bone mineralization, which results in severe deformities of limbs, thorax and skull and dental abnormalities (loss of teeth and caries). The disease is classified in four age-related forms: perinatal, infantile, childhood and adult hypophosphatasia. The perinatal form is usually lethal. There is no curative therapy. Recognition of the disease is of importance for genetic counselling.

The incidence of male childhood type 1 (insulin-dependent) diabetes mellitus is rising rapidly in The Netherlands.

This study evaluates the cumulative incidence of Type 1 (insulin-dependent) diabetes mellitus in male army conscripts 0-18 (inclusive) years of age in the Netherlands (birth cohorts) over 10 years. Data from 2136 cases were retrieved from files of the conscript registry of the Royal Dutch Army. Ascertainment was sought by the capture-recapture method, achieving an average ascertainment rate of 89.7%. Poisson regression modelling was used to determine the change in incidence over time. A significant non-linear increase in the incidence of insulin-dependency in the birth cohorts of 1960-1970 was found. The cumulative incidences of the early birth cohorts 1.85/1000 (1960), 1.76/1000 (1961), 1.11/1000 (1962) were considerably lower than of the later birth cohorts 1.96/1000 (1968), 2.11/1000 (1969), 2.12/1000 (1970). Overall the risk of Type 1 diabetes increased on the average 4.4% with each annual birth cohort. Only for the 1962 birth cohort was a significant dip in the incidence observed. The results indicate a rapidly increasing incidence of diabetes in males in the Netherlands consistent with the concurrent rapid rise in Northern Europe, found in both sexes.