Martijn J.J. Finken

Microalbuminuria and Lower Glomerular Filtration Rate at Young Adult Age in Subjects Born Very Premature and after Intrauterine Growth Retardation

This prospective follow-up study of 422 19-yr-old subjects born very preterm in The Netherlands was performed to determine whether intrauterine growth retardation (IUGR) predisposes to abnormal GFR and microalbuminuria in adolescents. GFR (ml/min per 1.73 m2) was estimated using the Cockcroft-Gault equation, and albumin-creatinine ratio (mg/mmol) was calculated in a cohort of 19-yr-old subjects born very preterm (gestational age <32 wk) in 1983. Birth weights were adjusted for gestational age and expressed as standard deviation scores (sds) as a measure of IUGR. All subjects had normal renal function. Birth weight (sds) was associated negatively with serum creatinine concentration (micromol/L) (beta = -1.0 micromol/L, 95% confidence interval [CI]: -1.9 to -0.2), positively with GFR (beta = 3.0, 95% CI: 1.7 to 4.2), and negatively with the logarithm of albumin-creatinine ratio (beta = -0.05, 95% CI: -0.09 to -0.01) in young adults born very preterm. IUGR is associated with unfavorable renal functions at young adult age in subjects born very premature. These data suggest that intrauterine growth-retarded subjects born very premature have an increased risk to develop progressive renal failure in later life.

Is Blood Pressure Increased 19 Years After Intrauterine Growth Restriction and Preterm Birth? A Prospective Follow-up Study in the Netherlands

Objective. To determine whether intrauterine growth restriction (IUGR) is a predisposing factor for high blood pressure (BP) in 19-year-olds who were born (very) preterm. Methods. A prospective follow-up study was conducted at age 19 in individuals who born preterm in the Netherlands in 1983. Systolic, diastolic, and mean BP values and plasma renin activity concentration were obtained in 422 young adults who were born with a gestational age (GA) <32 weeks. BP values were also measured in 174 individuals who born with a GA of ≥32 weeks and a birth weight of <1500 g. Results. An increased prevalence of hypertension and probably also of prehypertensive stage was found. IUGR, birth weight, GA, and plasma renin activity were not associated with BP. Current weight and BMI were the best predicting factors for systolic BP at the age of 19 years. Conclusions. The prevalence of hypertension is high in individuals who were born preterm when compared with the general population. In the individuals who were born very preterm, no support to the hypothesis that low birth weight is associated with increased BP at young adult age can be given.

Growth of preterm born children.

Background: In this review, we describe the growth of (very) preterm infants or (very) low-birth-weight infants from birth until adulthood. Methods: A systematic analysis of growth of these infants is thwarted by different definitions (classification by gestational age or birth weight) used in the literature. Results: The early postnatal period of these individuals is almost invariably characterized by substantial growth failure. In the majority of preterm infants this is followed by a period of catch-up growth, which starts in early infancy and usually stops at 2–3 years of age, although in some cases it may continue into adolescence. Catch-up growth is usually incomplete, so that infants born preterm remain shorter and lighter than term-born peers during childhood, adolescence, and adulthood. Disproportionate catch-up growth in height and weight may lead to an altered body composition in adulthood, especially in females. Conclusion: Though early catch-up growth has shown to be beneficial for neurodevelopmental outcome, it is also associated with adverse metabolic consequences in adulthood. As the first generation of (very) preterm infants is now reaching young adulthood, future follow-up studies on these effects are warranted.

Dna Methylation of Igf2, Gnasas, Insigf and Lep and Being Born Small for Gestational Age

Being born small for gestational age (SGA), a proxy for intrauterine growth restriction (IUGR), and prenatal famine exposure are both associated with a greater risk of metabolic disease. Both associations have been hypothesized to involve epigenetic mechanisms. We investigated whether prenatal growth restriction early in pregnancy was associated with changes in DNA methylation at loci that were previously shown to be sensitive to early gestational famine exposure. We compared 38 individuals born preterm (<32 weeks) and with a birth weight too low for their gestational age (-1SDS) and a normal postnatal growth (>-1SDS at 3 months post term; “AGA”). The SGA individuals were not only lighter at birth, but also had a smaller length (P=3.3x10-13) and head circumference at birth (P=4.1x10-13). The DNA methylation levels of IGF2, GNASAS, INSIGF and LEP were 48.5%, 47.5%, 79.4% and 25.7% respectively. This was not significantly different between SGA and AGA individuals. Risk factors for being born SGA, including preeclampsia and maternal smoking, were also not associated with DNA methylation at these loci. Growth restriction early in development is not associated with DNA methylation at loci shown to be affected by prenatal famine exposure. Our and previous results by others indicate that prenatal growth restriction and famine exposure may be associated with different epigenetic changes or non epigenetic mechanisms that may lead to similar later health outcomes.

Intelligence of very preterm or very low birthweight infants in young adulthood

Objective: To examine the effect of intrauterine and neonatal growth, prematurity and personal and environmental risk factors on intelligence in adulthood in survivors of the early neonatal intensive care era. Methods: A large geographically based cohort comprised 94% of all babies born alive in the Netherlands in 1983 with a gestational age below 32 weeks and/or a birth weight >1500 g (POPS study). Intelligence was assessed in 596 participants at 19 years of age. Intrauterine and neonatal growth were assessed at birth and 3 months of corrected age. Environmental and personal risk factors were maternal age, education of the parent, sex and origin. Results: The mean (SD) IQ of the cohort was 97.8 (15.6). In multiple regression analysis, participants with highly educated parents had a 14.2-point higher IQ than those with less well-educated parents. A 1 SD increase in birth weight was associated with a 2.6-point higher IQ, and a 1-week increase in gestational age was associated with a 1.3-point higher IQ. Participants born to young mothers (<25 years) had a 2.7-point lower IQ, and men had a 2.1-point higher IQ than women. The effect on intelligence after early (symmetric) intrauterine growth retardation was more pronounced than after later (asymmetric) intrauterine or neonatal growth retardation. These differences in mean IQ remained when participants with overt handicaps were excluded. Conclusions: Prematurity as well as the timing of growth retardation are important for later intelligence. Parental education, however, best predicted later intelligence in very preterm or very low birthweight infants.

Maternal hypothyroxinemia in early pregnancy predicts reduced performance in reaction time tests in 5- to 6-year-old offspring.

CONTEXT Overt hypothyroidism in pregnant women is associated with poorer neurodevelopment in their children. Findings from studies investigating the effect of less severe impairments in the maternal thyroid function on cognitive functioning in offspring are difficult to interpret for a number of reasons, including lack of objective cognitive tests, preschool age at assessment, and small sample sizes. OBJECTIVE We aimed to assess the effect of the maternal thyroid status in early pregnancy on their offsprings cognitive performance at 5 to 6 years of age. DESIGN AND PARTICIPANTS This was a prospective study that included the data of 1765 healthy 5- to 6-year-old children from the Amsterdam Born Children and their Development study. Maternal serum free T4 and TSH were obtained at a median gestational age of 90 (interquartile range, 83 to 100) days. MAIN OUTCOME MEASURES Cognitive performance was tested using a computerized assessment program that measured response speed, response speed stability, visuomotor skills, response selection, and response inhibition. RESULTS Maternal hypothyroxinemia (ie, maternal free T4 in the lowest 10% of distribution) was associated with a 41.3 (95% confidence interval, 20.3-62.4) ms slower response speed in a simple reaction time task. In this test, it was also associated with a decreased stability in response speed. The relations found persisted after adjustment for family background and perinatal conditions. The effect of hypothyroxinemia on these outcomes was dependent on its interaction with TSH level. CONCLUSIONS Lower maternal free T4 concentration at the end of the first trimester predicted slower response speed and decreased stability in response speed in offspring at 5 to 6 years of age.

Preterm Growth Restraint: A Paradigm That Unifies Intrauterine Growth Retardation and Preterm Extrauterine Growth Retardation and Has Implications for the Small-for-Gestational-Age Indication in Growth Hormone Therapy

Small for gestational age (SGA) is defined as a birth weight and/or length >2 SDs below the gender-specific population reference mean for gestational age. However, there is confusion about various aspects of this term, as recently discussed.1,2 The term “intrauterine growth retardation” (IUGR) is often used for the same condition but preferably should be restricted to poor growth during pregnancy according to intrauterine growth diagrams used in obstetrics.3 SGA after a normal duration of gestation (37–42 weeks) is usually followed by rapid growth after birth (catch-up growth). It has been demonstrated that almost 90% of term SGA infants catch up in height in the first 2 years of postnatal life.4,5 On average, the human male has a birth length of 51 cm after term gestation and a final height, in the Netherlands, of 184 cm. Thus, in the 9 months before birth, he has reached almost 30% of his adult height potential. Fetal length velocity at midgestation is >10-fold higher than pubertal peak height velocity (Fig 1). Thus, very preterm infants are exposed to extrauterine life during a period that normally is characterized by rapid intrauterine growth. To survive, their energy expenditure shifts from growth-promoting actions to survival strategies to cope with the increased requirements of unintended postnatal life. Extrauterine growth retardation (EUGR) is often the result. Preterm infants whose mothers suffered from conditions such as preeclampsia are usually already growth-retarded at birth. Nonetheless, regardless of whether the child is born SGA, very preterm infants tend to be small at term, and a considerable proportion of them even meet criteria for SGA by that age. A study among 52 … Address correspondence to J.M. Wit, MD, PhD, Department of Pediatrics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, Netherlands. E-mail: j.m.wit{at}lumc.nl

Lipid profile and carotid intima-media thickness in a prospective cohort of very preterm subjects at age 19 years: effects of early growth and current body composition

Cardiovascular disease (CVD) risk is associated with prenatal and infancy growth. However, the relative importance of these time periods for the CVD risk is uncertain. To elucidate this, we tested in a very preterm cohort the effects of birth weight for gestational age and weight gain between birth and 3 mo post-term (early postnatal weight gain) and between 3 mo and 1 y post-term (late infancy weight gain) on the lipid profile and carotid intima-media thickness (CIMT) at age 19 y. A less favorable lipid profile was strongly associated with higher current body mass index (BMI), greater waist circumference, and greater absolute fat mass. CIMT was positively associated with current height, and with low-density lipoprotein (LDL) cholesterol and apolipoprotein B (ApoB) levels, and LDL/high-density lipoprotein (HDL) cholesterol and ApoB/apolipoprotein AI (ApoAI) ratios. Lipid profile and CIMT were unrelated to gestational age, birth weight standard deviation score (SDS) and early postnatal weight gain. CIMT was positively associated with late infancy weight gain, but the relationship disappeared after correction for current height. Our findings in 19 y olds born very preterm argue for an effect of current body composition, rather than of early growth, on the CVD risk. Attempts to reduce the CVD risk in this specific population should focus on weight reduction in young adulthood rather than on optimizing the early growth pattern.

Antenatal glucocorticoid treatment is not associated with long-term metabolic risks in individuals born before 32 weeks of gestation

Background: A single course of maternal glucocorticoid treatment is effective in reducing neonatal mortality after preterm birth. However, in animals, maternal glucocorticoid treatment is associated with lifelong hyperglycaemia and hypertension, and impaired nephrogenesis in offspring. Findings from studies in humans on this topic are highly contradictory due to a number of methodological flaws, and renal function after glucocorticoid exposure has never been assessed. Objectives: To assess in individuals born <32 gestational weeks whether antenatal glucocorticoid treatment for preterm birth is associated with long-term metabolical risks, including renal function, in adulthood. Design: Birth cohort study. Setting: Multicentre study. Patients: 412 19 year olds born <32 gestational weeks from the Project On Preterm and Small-for-gestational-age infants (POPS) cohort. Interventions: Maternal betamethasone 12 mg administered twice with a 24 h interval. Main outcome measures: Body composition, insulin resistance, the serum lipid profile, blood pressure and estimated renal function. Results: We did not find any long-term adverse effects of antenatal betamethasone, with the exception of an effect on glomerular filtration rate (GFR). In 19-year-old survivors, GFR was lower after betamethasone: −5.2 ml/min (95% CI −8.9 to −1.4) per 1.73 m2. Conclusions: The reduction in neonatal mortality associated with a single course of maternal betamethasone is not accompanied by long-term metabolical risks in survivors of preterm birth. The only adverse effect found was lower GFR. Although this difference was not clinically relevant at 19 years, it might predict an increased risk of chronic renal failure in prematurely born individuals who were exposed antenatally to betamethasone.

Intrauterine insemination versus timed intercourse for cervical hostility in subfertile couples.

The postcoital test has poor diagnostic and prognostic characteristics. Nevertheless, some physicians believe it can identify scanty or abnormal mucus that might impair fertility. One way to avoid “hostile” cervical mucus is intrauterine insemination. With this technique, the physician injects sperm directly into the uterine cavity through a small catheter passed through the cervix; the theory is to bypass the “hostile” cervical mucus. Although most gynecologic societies do not endorse use of intrauterine insemination for hostile cervical mucus, some physicians consider it an effective treatment for women with infertility thought the result of cervical mucus problems. The aim of this review was to determine the effectiveness of intrauterine insemination with or without ovarian stimulation in women with cervical hostility who failed to conceive. We searched Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library Issue 2, 2005, MEDLINE (1966 to June 2005), EMBASE (1980 to June 2005), POPLINE (to June 2005), and LILACS (to June 2005). In addition, we contacted experts and searched the reference list of relevant articles and book chapters. We included randomized and quasirandomized, controlled trials comparing intrauterine insemination with intercourse timed at the presumed fertile period. Participants were women with cervical hostility who failed to conceive for at least 1 year. We assessed the titles and abstracts of 386 publications and 2 reviewers independently abstracted data on methods and results from 5 studies identified for inclusion. The main outcome is pregnancy rate per couple. We did not pool the outcomes of the included 5 studies in a meta-analysis resulting from the methodological quality of the trials and variations in the patient characteristics and interventions. Narrative summaries of the outcomes are provided. Each study was too small for a clinically relevant conclusion. None of the studies provided information on important outcomes such as spontaneous abortion, multiple pregnancies, and ovarian hyperstimulation syndrome. There is no evidence from the published studies that intrauterine insemination is an effective treatment for cervical hostility. Given the poor diagnostic and prognostic properties of the postcoital test and the observation that the test has no benefit on pregnancy rates, intrauterine insemination (with or without ovarian stimulation) is unlikely to be a useful treatment for putative problems identified by postcoital testing. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader should be able to recall that there is a lack of adequate studies that support that intrauterine insemination (IUI) is an effective treatment of cervical hostility, explain that the postcoital test has poor diagnostic and prognostic properties, and state that the use of both tests has no benefit on pregnancy rates. Editors Note: Although many assisted reproductive technology (ART) programs no longer perform postcoital tests, many perform intrauterine insemination (IUI), often with gonadotropins or clomiphene citrate, in their subfertile patients. Therefore, this review article will be of value to our readers who treat subfertile patients with IUI, whether or not they perform postcoital tests. For additional explanations of the statistical tests employed in this review, see D. Grimes, KF Schulz, Obstetrical and Gynecologic Survey, 57; Supplement 3: S35, September 2002; and D. Grimes, KF Schulz, Obstetrical and Gynecologic Survey, Supplement 2, S53–S69, September 2005.—RBJ