Sex-specific differences in fetal and infant growth patterns: a prospective population-based cohort study.

BACKGROUND: The objective of this study was to assess whether sex-specific differences in fetal and infant growth exist. METHODS: This study was embedded in the Generation R Study, a population-based prospective birth cohort. In total, 8556 live singleton births were included. Fetal growth was assessed by ultrasound. During the first trimester, crown-rump-length (CRL) was measured. In the second and third trimester of pregnancy head circumference (HC), abdominal circumference (AC) and femur length (FL) were assessed. Information on infant growth during the first 2 years of life was obtained from Community Health Centers and included HC, body weight and length. RESULTS: In the first trimester, male CRL was larger than female CRL (0.12 SD [95% CI 0.03,0.22]). From the second trimester onwards, HC and AC were larger in males than in females (0.30 SD [95% CI 0.26,0.34] and 0.09 SD [95% CI 0.05,0.014], respectively). However, FL in males was smaller compared to female fetuses (0.21 SD [95% CI 0.17,0.26]). Repeated measurement analyses showed a different prenatal as well as postnatal HC growth pattern between males and females. A different pattern in body weight was observed with a higher body weight in males until the age of 12 months where after females have a higher body weight. CONCLUSIONS: Sex affects both fetal as well as infant growth. Besides body size, also body proportions differ between males and females with different growth patterns. This sexual dimorphism might arise from differences in fetal programming with sex specific health differences as a consequence in later life.

In utero origin of sex-related differences in future cardiovascular disease.

BACKGROUND: There are sex differences in the risk of development of cardiovascular disease (CVD). According to the developmental origins of health and disease paradigm (DOHaD), CVD originates in fetal life. This study examines fetal sex differences in cardiovascular development in utero. METHODS: In 1028 pregnant women, we assessed fetal circulation using pulsed wave Doppler examinations between 28 and 34 weeks gestation. To test associations between fetal sex and fetal circulation measurements, linear regression models were used adjusting for fetal size, gestational age, and fetal heart rate. RESULTS: A higher pulsatility index in the ductus venosus was observed in male fetuses compared to female fetuses (difference 0.02, 95 % CI 0.01; 0.05) with a lower E/A ratio of the tricuspid (difference -0.01, 95 % CI -0.03; -0.00) and mitral (difference -0.02, 95 % CI -0.03; -0.01) valves. This was mainly determined by differences in the E wave of the tricuspid and mitral valves (differences -1.02, 95 % CI -1.81; -0.24 and -1.28, 95 % CI -2.11; -0.46, respectively). Also in males, a lower peak systolic velocity was seen in the pulmonary artery (difference -1.33, 95 % CI -2.63; -0.03) with a similar lower trend regarding peak systolic velocity in the ascending aorta. CONCLUSIONS: Male fetuses exhibit an increased preload and reduced afterload conditions compared to females. While it is difficult to relate these measurements to exact cardiac function, our findings strongly suggest that the known differences in cardiovascular performance between the sexes already start in utero.

Third trimester fetal hemodynamics and cardiovascular outcomes in childhood: the Generation R study.

OBJECTIVE: Low birth weight is associated with cardiovascular disease in adulthood. Hemodynamic adaptations related to fetal growth restriction may underlie these associations, through persistent influences on cardiovascular development. We examined the associations of third trimester fetal hemodynamics with cardiovascular outcomes in childhood. METHODS: In a prospective cohort study among 917 pregnant women and their children, we measured fetal growth, and fetal arterial and cardiac hemodynamic variables with ultrasound and Doppler examinations at a gestational age of 30.3 (95% range 28.8-32.3) weeks. At the age of 6 years, we measured blood pressure, carotid-femoral pulse wave velocity, and left cardiac structures and function. RESULTS: We observed that fetal hemodynamics were not associated with childhood blood pressure and carotid-femoral pulse wave velocity. The fetal aorta ascendens diameter and left cardiac output were positively associated with childhood aortic root diameter [0.14 standard deviation score (SDS), 95% confidence interval (CI) 0.07-0.22 and 0.08 SDS, 95% CI 0.01-0.15 per SDS change in diameter and output, respectively]. Fetal left ventricular diastolic filling pattern was inversely associated with aortic root diameter (-0.07 SDS, 95% CI -0.13 to 0.00 per SDS change in E/A ratio) at 6 years. Analyses adjusted and stratified for estimated fetal weight showed no differences in results. CONCLUSION: Our results suggest that third trimester fetal vascular resistance parameters do not affect blood pressure or arterial stiffness in childhood. Fetal cardiac functional and structural measures are associated with cardiac outcomes in childhood. Whether these early adaptations lead to greater risks of cardiovascular disease should be further studied.

Individually customised fetal weight charts derived from ultrasound measurements: the Generation R Study.

Maternal and fetal characteristics are important determinants of fetal growth potential, and should ideally be taken into consideration when evaluating fetal growth variation. We developed a model for individually customised growth charts for estimated fetal weight, which takes into account physiological maternal and fetal characteristics known at the start of pregnancy. We used fetal ultrasound data of 8,162 pregnant women participating in the Generation R Study, a prospective, population-based cohort study from early pregnancy onwards. A repeated measurements regression model was constructed, using backward selection procedures for identifying relevant maternal and fetal characteristics. The final model for estimating expected fetal weight included gestational age, fetal sex, parity, ethnicity, maternal age, height and weight. Using this model, we developed individually customised growth charts, and their corresponding standard deviations, for fetal weight from 18 weeks onwards. Of the total of 495 fetuses who were classified as small size for gestational age (<10th percentile) when fetal weight was evaluated using the normal population growth chart, 80 (16%) were in the normal range when individually customised growth charts were used. 550 fetuses were classified as small size for gestational age using individually customised growth charts, and 135 of them (25%) were classified as normal if the unadjusted reference chart was used. In conclusion, this is the first study using ultrasound measurements in a large population-based study to fit a model to construct individually customised growth charts, taking into account physiological maternal and fetal characteristics. These charts might be useful for use in epidemiological studies and in clinical practice.

Employment status and the risk of pregnancy complications: the Generation R Study.

OBJECTIVES: This study explored the relationships of employment status, type of unemployment and number of weekly working hours, with a wide range of pregnancy outcomes. METHODS: Information on employment characteristics and pregnancy outcomes was available for 6111 pregnant women enrolled in a population-based cohort study in the Netherlands. RESULTS: After adjustment for confounders, there were no statistically significant differences in risks of pregnancy complications between employed and unemployed women. Among unemployed women, women receiving disability benefit had an increased risk of preterm ruptured membranes (OR 3.16, 95% CI 1.49 to 6.70), elective caesarean section (OR 2.98, 95% CI 1.21 to 7.34) and preterm birth (OR 2.64, 95% CI 1.32 to 5.28) compared to housewives. Offspring of students and women receiving disability benefit had a significantly lower mean birth weight than offspring of housewives (difference: -93, 95% CI -174 to -12; and -97, 95% CI -190 to -5, respectively). In employed women, long working hours (>or=40 h/week) were associated with a decrease of 45 g in offspring's mean birth weight (adjusted analysis; 95% CI -89 to -1) compared with 1-24 h/weekly working hours. CONCLUSIONS: We found no indications that paid employment during pregnancy effects the health of the mother and child. However, among unemployed and employed women, women receiving disability benefit, students and women with long working hours during pregnancy were at risk for some adverse pregnancy outcomes. More research is needed to replicate these results and explain these findings. Meanwhile, prenatal care providers should be made aware of the risks associated with specific types of unemployment and long working hours.

Cardiac structures track during the first 2 years of life and are associated with fetal growth and hemodynamics: the Generation R Study.

BACKGROUND: The aim of this study is to examine whether cardiac size and function track in early childhood and are associated with fetal and early postnatal growth and blood flow characteristics. METHODS: This study was embedded in a population-based prospective cohort study from fetal life onward. Fetal growth and fetal and placental blood flow parameters in second and third trimester of pregnancy were measured by ultrasound and Doppler. Left cardiac structures and shortening fraction were measured postnatally at the ages of 1.5, 6, and 24 months. Analyses were based on 1,001 children. RESULTS: Left ventricular mass tended to remain in the lowest and highest quartiles from the age of 1.5 to 24 months (odds ratio 1.70, 95% confidence interval [CI] 1.10-2.63) and 2.15 (95% CI 1.41-3.30), respectively. Similar results were found for aortic root diameter and left atrial diameter. Birth weight was positively associated with aortic root diameter (0.08 mm, 95% CI 0.01-0.17; per SD increase) and left ventricular mass (0.65 g, 95% CI 0.09-1.21; per SD increase). Resistance indices of the umbilical and uterine arteries showed weak tendencies toward inverse associations with left cardiac structures. Fetal cardiac output was positively associated with both left atrial diameter (increase of 1.96 mm, 95% CI 1.28-2.64; per mL/min increase) and left ventricular mass (increase of 1.79 g, 95% CI 0.35-3.22; per mL/min increase). CONCLUSIONS: This study suggest moderate tracking of left cardiac structures during the first 2 years and that small size and hemodynamic variations in fetal life have consequences for postnatal cardiac size and function.

Tracking and determinants of kidney size from fetal life until the age of 2 years: the Generation R Study.

BACKGROUND: An adverse fetal environment may lead to smaller kidneys and subsequently kidney disease and hypertension in adulthood. The aims of this study are to examine whether kidney size tracks from fetal life to childhood and whether maternal and fetal characteristics are associated with kidney size at the age of 2 years. STUDY DESIGN: Prospective cohort study from fetal life onward. SETTING & PARTICIPANTS: The study was conducted in a group of 688 infants in Rotterdam, The Netherlands. Entry criteria were singleton, noncomplicated pregnancies, and Dutch ethnicity. PREDICTORS: The maternal characteristics age, height, and prepregnancy weight were measured in early pregnancy. Fetal growth, head circumference, abdominal circumference, femur length and estimated fetal weight, and placental characteristics were assessed in the second and third trimesters. OUTCOMES & MEASUREMENTS: Kidney size, defined as length, width, depth, and volume, was measured in the third trimester of pregnancy and at postnatal ages 6 and 24 months. RESULTS: Overall median gestational age was 40.3 weeks (95% range, 36.0 to 42.3 weeks), and mean birth weight was 3,536 +/- 524 (SD) g. Children tended to remain in the lowest and highest quartiles of kidney volume from the third trimester to the age of 2 years (odds ratio, 2.05; 95% confidence interval, 1.38 to 3.06; odds ratio, 3.29; 95% confidence interval, 2.22 to 4.87, respectively). Maternal height and prepregnancy weight were associated positively with kidney volume at the age of 2 years. Third-trimester fetal head circumference, abdominal circumference, and estimated weight and postnatal length were associated positively with kidney volume at the age of 2 years. Preferential fetal blood flow to the brain was associated with smaller kidneys. LIMITATIONS: Kidney measurements successfully performed in only 86% of children. CONCLUSIONS: Small kidney size in fetal life tends to persist in early childhood. Maternal anthropometrics and fetal biometrics and blood flow patterns are associated with kidney size in childhood. Follow-up studies are needed to examine whether these variations in kidney size are related to kidney function and blood pressure in later life.

What is spared by fetal brain-sparing? Fetal circulatory redistribution and behavioral problems in the general population.

Intrauterine growth restriction has been linked to infant behavioral problems. While typically only birth weight is examined, here the authors assessed fetal circulatory redistribution, also called the "brain-sparing effect," which is a fetal adaptive reaction to placental insufficiency. They aimed to investigate whether fetal circulatory redistribution protects against behavioral problems. Within the Generation R Study (Rotterdam, the Netherlands, 2003-2007), fetal circulation variables for the umbilical artery and the middle and anterior cerebral arteries were assessed with Doppler ultrasound in late pregnancy. Ratios between placental resistance and cerebral resistance were related to behavioral problems, as measured by the Child Behavior Checklist, in 935 toddlers aged 18 months. The umbilical/anterior cerebral ratio was associated with the Total Problems summary score from the Child Behavior Checklist (per standard-deviation increase, odds ratio = 1.2, 95% confidence interval: 1.0, 1.5). Children with higher umbilical/anterior cerebral ratios had higher risks of internalizing problems, emotional reactivity, somatic complaints, and attention problems. A high umbilical/middle cerebral ratio was related to higher scores on the Internalizing and Somatic Complaints scales. The authors conclude that infants with circulatory redistribution in gestation are more likely to have behavioral problems. This suggests that "brain-sparing" does not completely spare the brain and indicates underlying pathology with consequences for later behavior.

Intra- and interobserver reproducibility study of early fetal growth parameters.

OBJECTIVE: To assess the intra- and interobserver reproducibility of fetal biometry measurements by transabdominal ultrasound in early pregnancy. METHODS: The study consisted of 21 singleton pregnancies with a gestational age between 9 and 14 weeks. Intraclass correlation coefficients (ICCs) and coefficients of variation (CVs) were calculated. Bland and Altman plots were computed to analyze agreement for measurements between and among observers. Limits of agreement +/- 2 SD for the differences in fetal biometry measurements in proportions of the mean of the measurements were derived. RESULTS: High intra- and interobserver ICCs were found, ranging from 0.998, crown-rump length (CRL) to 0.982, femur length (FL) and CVs ranging from 1.4% (CRL) to 5.9% (FL). Limits of agreement in the Bland and Altman plots ranged from - 2.7 to 2.3% (CRL) difference from the mean to - 13 to 23% (FL) difference. Agreement for fetal biometry increased with fetal size. CONCLUSIONS: This study demonstrated good reproducibility of most measurements of fetal biometry in early pregnancy by abdominal ultrasound. CRL and biparietal diameter (BPD) showed high reproducibility and agreement, and head circumference (HC) to a lesser extend, from 9 weeks of gestational age onwards. abdominal circumference (AC) is only reliable from circa 11 weeks onwards. FL has a poor reproducibility before 14 weeks of gestational age.

Fetal hemodynamic adaptive changes related to intrauterine growth: the Generation R Study.

BACKGROUND: It has been suggested that an adverse fetal environment increases susceptibility to hypertension and cardiovascular disease in adult life. This increased risk may result from suboptimal development of the heart and main arteries in utero and from adaptive cardiovascular changes in conditions of reduced fetal growth. The aim of the present study was to evaluate whether reduced fetal growth is associated with fetal circulatory changes and cardiac dysfunction. METHODS AND RESULTS: This study was embedded in a population-based, prospective cohort study starting in early fetal life. Fetal growth characteristics and fetal circulation variables were assessed with ultrasound and Doppler examinations in 1215 healthy women. The fetal circulation was examined in relation to estimated fetal weight. Higher placental resistance indices were strongly associated with decreased fetal growth. Cerebral resistance showed a gradual decline with reduced fetal growth. Cardiac output, peak systolic velocity of the outflow tracts, and cardiac compliance showed a gradual reduction with diminished fetal growth, whereas intraventricular pressure gradually increased. CONCLUSIONS: Decreased fetal growth is associated with adaptive fetal cardiovascular changes. Cardiac remodeling and cardiac output changes are consistent with a gradual increase in afterload and compromised arterial compliance in conditions of decreased fetal growth. These changes have already begun to occur before the stage of clinically apparent fetal growth restriction and may contribute to the increased risk of cardiovascular disease in later life.

Maternal anthropometrics in pregnancy are associated with left ventricular mass in infancy. The generation R study.

Pregnancy and early life factors may permanently affect left ventricular growth and development in the offspring. The aim of this study was to examine the associations of maternal anthropometrics during pregnancy with left ventricular mass (LVM) in infancy. This study was embedded in the Generation R Study, a population-based prospective cohort study from fetal life onwards. Maternal anthropometrics were obtained in early (gestational age <18 wk), mid- (gestational age 18-25 wk), and late (gestational age >25 wk) pregnancy. Echocardiographic follow-up measurements were performed in 791 infants aged 6 wk and 6 mo. We found no associations of maternal height, weight, or body mass index (BMI) measured in early, mid-, and late pregnancy with longitudinally measured left ventricular mass (LVM) from 6 wk to 6 mo. Maternal weight gain until late pregnancy was associated with an increased growth of LVM from 6 wk to 6 mo [difference 0.46 g per week for the highest tertile of weight gain compared with the lowest tertile (p value <0.05)]. We concluded that maternal weight gain until late pregnancy is associated with larger LVM at the age of 6 mo, suggesting that maternal health status during pregnancy may have permanent consequences for LVM in their children. Further studies are needed to identify the underlying causal mechanisms and the long-term consequences.

Maternal smoking and fetal growth characteristics in different periods of pregnancy: the generation R study.

The authors examined the associations of maternal smoking in pregnancy with various fetal growth characteristics among 7,098 pregnant women participating in the Generation R Study (2002-2006), a population-based prospective cohort study of pregnant women and their children in Rotterdam, the Netherlands. Maternal smoking was assessed by questionnaires administered in early, mid-, and late pregnancy. Fetal growth characteristics evaluated included head circumference, abdominal circumference, and femur length measured repeatedly in mid- and late pregnancy. Maternal smoking during pregnancy was associated with reduced growth in head circumference (-0.56 mm/week; 95% confidence interval (CI): -0.73, -0.40), abdominal circumference (-0.58 mm/week; 95% CI: -0.81, -0.34), and femur length (-0.19 mm/week; 95% CI: -0.23, -0.14). This reduced growth resulted in a smaller femur length from midpregnancy (gestational age 18-24 weeks) onwards and smaller head and abdominal circumferences from late pregnancy (gestational age > or =25 weeks) onwards. Analyses using standard deviation scores for the growth characteristics demonstrated the largest effect estimates for femur length. The authors concluded that maternal smoking during pregnancy is associated with reduced growth in fetal head circumference, abdominal circumference, and femur length. The larger effect on femur length suggests that smoking during pregnancy affects primarily peripheral tissues.

Effects of maternal smoking in pregnancy on prenatal brain development. The Generation R Study.

Nicotine, as has been shown in animal studies, is a neuroteratogen, even in concentrations that do not cause growth retardation. In humans, there is only indirect evidence for negative influences of nicotine on brain development from studies on the association between maternal smoking in pregnancy and behavioural and cognitive development in the offspring. We investigated the associations of maternal smoking in pregnancy with foetal head growth characteristics in 7042 pregnant women. This study was embedded in the Generation R Study, a population-based prospective cohort study from foetal life until adulthood. Maternal smoking was assessed by questionnaires in early, mid- and late pregnancy. Head circumference, biparietal diameter, transcerebellar diameter and atrial width of lateral ventricles were repeatedly measured by ultrasound. When mothers continued to smoke during pregnancy, foetal head circumference showed a growth reduction of 0.13 mm [95% confidence interval (CI): -0.18, -0.09] per week compared to foetuses of mothers who never smoked during pregnancy. Biparietal diameter of foetuses with smoking mothers grew 0.04 mm (95% CI: -0.05, -0.02) less per week than that of foetuses of nonsmoking mothers. Atrial width of lateral ventricle was 0.12 mm (95% CI: -0.22, -0.02) smaller and transcerebellar diameter was 0.08 mm (95% CI: -0.15, -0.00) smaller if mothers smoked, but growth per week of these characteristics was not affected by maternal smoking in pregnancy. In conclusion, continuing to smoke during pregnancy leads to reduced growth of the foetal head. Further research should focus on the causal pathway from prenatal cigarette exposure via brain development to behavioural and cognitive functions.