Early Fetal Growth Research Articles

Challenges in defining and classifying the preterm birth syndrome

In 2009, the Global Alliance to Prevent Prematurity and Stillbirth Conference charged the authors to propose a new comprehensive, consistent, and uniform classification system for preterm birth. This first article reviews issues related to measurement of gestational age, clinical vs etiologic phenotypes, inclusion vs exclusion of multifetal and stillborn infants, and separation vs combination of pathways to preterm birth. The second article proposes answers to the questions raised here, and the third demonstrates how the proposed system might work in practice.

RUMINANT NUTRITION SYMPOSIUM: OPTIMIZING PERFORMANCE OF THE OFFSPRING: Nourishing and managing the dam and postnatal calf for optimal lactation, reproduction, and immunity1,2

For several mammalian species, it has been shown that fetal and early postnatal nutrition has a role in long-term lipid and glucose metabolism of the offspring, and it thus also may have consequences on milk yield in the dairy cow. For instance, high-energy diets during the last weeks of pregnancy may result in increased glycemia, which in turn, may alter fetal adipose tissue development. However, most research efforts on management and nutrition of dry cows have focused on minimizing metabolic disorders of the postpartum cow without devoting much attention to potential consequences for the offspring. Similarly, nutritional needs for proper placental development and early fetal growth have received little attention, despite the fact that alterations in placental and fetal development may alter expression of genes participating in homeorhesis of the offspring. Therefore, nutrition of the pregnant cow, both while lactating and dry, should also consider aspects of placental and fetal development that may affect health and performance of the progeny. Similarly, newborn calves and young heifers are fed to ensure a particular growth target without compromising mammary development, although data linking postnatal growth targets with future milk yield are scarce. However, milk yield not only depends on mammary development, but also on nutrient partitioning, which is regulated by the endocrine milieu. There are some periods of time during development where nutrition may have long-lasting effects on metabolic function and milk production. For instance, the first months of postnatal life seem to be critical because recent data from both retrospective and controlled studies indicate that increased growth rate or plane of nutrition during this phase is positively associated with future milk production. Postnatal growth rate depends on nutrition (a necessary but not sufficient condition) and management (i.e., grouping strategies and housing systems), and thus optimal rearing programs should be designed considering long-term consequences on milk yield.

OP25.09: Early fetal growth in malaria infected pregnancies

pregnancy outcomes. The current sensitivity and positive predictive value of this association has, however, not yet justified initiation of increased antenatal surveillance in these patients. This study was carried out to identify if 3D placental evaluation enhances the performance of this serum marker as a predictor of adverse pregnancy outcomes. Methods: 62 patients with PAPP-A levels lower than 0.4 multiples of median (MoM) were evaluated between 11 weeks to 13 weeks 6 days of gestation with 3D power Doppler studies in this prospective study. Placental volume, Vascularisation Index (VI), Flow Index and Vascularisation Flow Index (VFI) were computed with standardised equipment settings and correlated with pregnancy outcomes. Results: 38 patients had an uneventful pregnancy outcome. 29 of these had normal 3D placental parameters. Of the 24 patients with adverse outcomes 19 had a small volume placenta, impaired 3D placental vascularisation indices or both. Conclusions: 3D and 3D power Doppler evaluation of the placenta in the late first trimester improves the prediction of adverse outcomes in patients with low PAPP-A levels.

Comparative Efficiency of Measures of Early Fetal Growth Restriction for Predicting Adverse Perinatal Outcomes

To estimate the comparative efficiency of first-trimester fetal growth restriction, second-trimester fetal growth restriction, and first-to-second-trimester growth lag for predicting adverse perinatal outcomes. This is a retrospective cohort study of pregnancies with reliable dating based on last menstrual periods and first-trimester ultrasound examinations. Pregnancies with multiple fetuses, aneuploidy, and major structural anomalies were excluded. Fetal crown-rump lengths at 10-14 weeks, estimated fetal weights based on fetal biometry at 18-22 weeks, and interval growth were measured and converted to gestational age-adjusted Z-scores. The primary outcome was small for gestational age (SGA) at delivery. Secondary outcomes were low birth weight, preterm delivery, stillbirth, and preeclampsia. Receiver-operating characteristics curves were used to identify the optimal definitions of early fetal growth restriction associated with SGA and to compare screening efficiencies. Multivariable logistic regression was used to adjust for confounders. Among 8,978 pregnancies meeting inclusion criteria, 551 (6.5%) neonates were SGA. Crown-rump length Z-score less than -1.0, estimated fetal weights Z-score less than -1.0, and growth Z-score less than -1.0 were identified as the optimal definitions of early fetal growth restriction associated with SGA (adjusted odds ratio 1.41 [95% confidence interval (CI) 1.13-1.74], 3.44 [95% CI 2.85-4.15] and 2.61 [95% CI 2.09-3.25], respectively). The sensitivity and specificity of first- and second-trimester fetal growth restriction for predicting SGA were 21.4% and 83.4%, and 37.2% and 85.5%, respectively. The area under the receiver-operating characteristics curve for second-trimester fetal growth restriction was greater than that for first-trimester fetal growth restriction and first-to-second-trimester growth lag (0.70 compared with 0.59 and 0.66, P<.001). Second-trimester fetal growth restriction is superior to first-trimester fetal growth restriction and first-to-second-trimester growth lag for predicting SGA.

First-trimester crown-rump length as a predictor of fetal LGA and SGA at term

Objective. To determine whether first-trimester crown-rump length (CRL) is associated with birthweight extremes at term.Methods. Included in this study were all term, small for gestational age (SGA), and large for gestational age (LGA) neonates with no other obstetric complications and no abnormal outcomes of pregnancy. CRL at 12.0 to 12.6 weeks of estimated gestational age obtained during nuchal translucency screening was selected as an estimate of early fetal growth. Mean first-trimester CRL of the LGA noenates at term was compared via student’s t-test with mean first-trimester CRL of SGA neonates at term.Results. In all, 121 neonates were included in the study. Mean first-trimester CRL of the 63 LGA-term neonates was 62.7 ± 6.0 mm (95% confidence interval, ±1.49 mm; range, 61.21–64.19), while that of the 58 SGA-term neonates was smaller at 58.8 ± 6.9 mm (95% confidence interval, ±1.79 mm; range, 57.01–60.59 mm). This 3.9 mm difference between the means was statistically significant (P = 0.01).Conclusion. We found that birthweights of LGA and SGA neonates at term were associated with their first-trimester CRL measurements, thus, indicating that fetal growth patterns apparent early in pregnancy continue through term.

Early fetal growth, PAPP‐A and free β‐hCG in relation to risk of delivering a small‐for‐gestational age infant

To examine early fetal growth, pregnancy-associated plasma protein-A (PAPP-A) and free β-human chorionic gonadotropin (β-hCG) in relation to the risk of delivering a small-for-gestational age (SGA) infant. Included in the study were 9450 singleton pregnant women who attended the prenatal screening program at Aarhus University Hospital, Denmark, between January 2005 and December 2007. Maternal serum levels of PAPP-A and free β-hCG were measured between gestational weeks 8 and 13. Two ultrasound examinations were performed, the first at 11-13 weeks and the second at 18-22 weeks, from which gestational age was estimated based on crown-rump length and biparietal diameter, respectively. Early fetal growth was expressed as an index: the ratio between the estimated number of days from the first to the second scan and the actual calendar time elapsed in days. SGA was defined as birth weight < 5(th) centile for gestational age, and the risk of SGA was evaluated according to different cut-offs of the early fetal growth index and the serum markers. PAPP-A < 0.4 MoM combined with an early fetal growth index < 10(th) centile resulted in an increased risk of SGA (odds ratio (OR), 5.8; 95% CI, 2.7-12.7). Low PAPP-A, low free β-hCG and slow early fetal growth were statistically, independently associated with SGA, and the association between free β-hCG < 0.3 MoM and SGA was as strong as that between PAPP-A < 0.3 MoM and SGA (OR, 3.1 and 3.0, respectively). The combination of slow early fetal growth and low PAPP-A resulted in a nearly six-fold increased risk of delivery of an SGA infant. These findings might improve our chances of early identification of fetuses at increased risk of growth restriction.

Early Biometric Lag in the Prediction of Small for Gestational Age Neonates and Preeclampsia

An early fetal growth lag may be a marker of future complications. We sought to determine the utility of early biometric variables in predicting adverse pregnancy outcomes. In this retrospective cohort study, the crown-rump length at 11 to 14 weeks and the head circumference, biparietal diameter, abdominal circumference, femur length, humerus length, transverse cerebellar diameter, and estimated fetal weight at 18 to 24 weeks were converted to an estimated gestational age using published regression formulas. Sonographic fetal growth (difference between each biometric gestational age and the crown-rump length gestational age) minus expected fetal growth (number of days elapsed between the two scans) yielded the biometric growth lag. These lags were tested as predictors of small for gestational age (SGA) neonates (≤10th percentile) and preeclampsia. A total of 245 patients were included. Thirty-two (13.1%) delivered an SGA neonate, and 43 (17.6%) had the composite outcome. The head circumference, biparietal diameter, abdominal circumference, and estimated fetal weight lags were identified as significant predictors of SGA neonates after adjusted analyses (P < .05). The addition of either the estimated fetal weight or abdominal circumference lag to maternal characteristics alone significantly improved the performance of the predictive model, achieving areas under the curve of 0.72 and 0.74, respectively. No significant association was found between the biometric lag variables and the development of preeclampsia. Routinely available biometric data can be used to improve the prediction of adverse outcomes such as SGA. These biometric lags should be considered in efforts to develop screening algorithms for adverse outcomes.

367: Early fetal growth restriction (FGR) for predicting adverse perinatal outcomes

367: Early fetal growth restriction (FGR) for predicting adverse perinatal outcomes

Patterns of fetal and infant growth are related to atopy and wheezing disorders at age 3 years

BackgroundLittle is known about whether patterns of early growth are associated with altered respiratory and immune development. This study relates prenatal and infant growth patterns to wheeze and atopy at...

PAPP‐A, free β‐hCG, and early fetal growth identify two pathways leading to preterm delivery

To evaluate early fetal growth and the biomarkers, pregnancy-associated plasma protein A (PAPP-A) and free β-human chorionic gonadotrophin (β-hCG), in relation to preterm delivery. A cohort study of 9450 singleton pregnant women who attended the prenatal screening program at Aarhus University Hospital between January 2005 and December 2007, was conducted. PAPP-A and free β-hCG were measured in the first trimester. Early fetal growth was estimated by (GA(20)- GA(12))/Days(calendar), where GA(12) reflects the gestational age in days calculated from the crown-rump length at a 12-week scan, GA(20) reflects the gestational age in days calculated from the biparietal diameter at a 20-week scan, and Days(calendar) is the number of calendar days between the two scans. Low PAPP-A and low free β-hCG were significantly associated with preterm delivery (<37 weeks). The association was even stronger when low PAPP-A and slow early fetal growth were combined, resulting in an adjusted odds ratio of 3.8 (95% CI, 1.6-8.7). Fast early fetal growth, but neither high PAPP-A nor high free β-hCG, was significantly associated with preterm delivery. Two different biological pathways leading to spontaneous preterm delivery are suggested: fast early fetal growth and the combination of low PAPP-A and slow early fetal growth.

No influence of body mass index on first trimester fetal growth

Our objective was to determine what effect maternal BMI has on fetal growth rate in the early first trimester. This was a prospective observational study of singleton pregnancies with certain dates, initially presenting for a transvaginal scan (TVS) before 12 weeks of gestation. Maternal characteristics (BMI, ethnicity, maternal age, obstetric history, abdominal pain and vaginal bleeding) were recorded. Fetal crown-rump length (CRL) was measured at the initial scan, and at subsequent ultrasound assessments. In order to assess the fetal growth rates, women with at least two CRL measurements were included in the analysis. A mixed-linear effects model analysis was performed to determine whether BMI influences the rate of change in CRL. A total of 264 pregnancies were analysed. The median BMI was 23.55 (range 16-45), median age was 32 (17-44) and the proportion of white, black and Asian women was 61.0, 15.5 and 5.3%, respectively. Mean gestational age (GA) at first TVS was 56 (range 33-84) days. Studying CRL as a function of GA with a mixed-linear effects model showed that this relationship was neither significantly influenced by BMI when modelling BMI as a continuous variable (P = 0.7529), nor when modelling it as a categorical variable using the WHO criteria (P = 0.8904). Dating by CRL influences subsequent growth assessment and previous studies have suggested that first trimester fetal growth rates may be influenced by ethnicity and age. Our data however suggest that maternal BMI does not significantly influence early fetal growth.

Risk Factors and Outcomes Associated With First-Trimester Fetal Growth Restriction

ABSTRACT Exposure of the fetus to an adverse environment may result in developmental adaptations that lead to fetal growth restriction. It has been suggested that fetal growth restriction may increase the risk of metabolic and cardiovascular diseases and other adverse outcomes in adulthood. Previous studies have shown that first trimester fetal growth restriction increased the risks of low birth weight and small size for gestational age. The effects of maternal lifestyle habits and physical characteristics on first trimester growth and postnatal outcomes are not known. This population-based prospective cohort study investigated the associations of first trimester growth restriction with adverse birth outcomes and postnatal outcomes in early childhood. The effect of several maternal physical characteristics and lifestyle habits on postnatal outcomes was also investigated. A self-administered questionnaire was completed by the mothers at enrollment. First trimester fetal growth in singleton mothers was assessed sonographically by measuring fetal crown rump length between the gestational age of 10 weeks 0 days and 13 weeks 6 days, and then performing follow-up growth scans in the second and third trimesters. The primary birth outcomes examined were preterm birth, low birth weight, and small size for gestational age at birth. Postnatal outcomes were studied up to the age of 2 years. Multivariate analysis showed that maternal age was positively associated with fetal crown rump length; the difference was 0.79 mm (95% confidence interval [CI]: 0.41–1.18) per 1 standard deviation (4.68 maternal years of age) increase. Both diastolic blood pressure and the hematocrit were negatively associated with first trimester crown to rump growth (shorter length) (differences, −0.40 mm; 95% CI: −0.74 to −0.06, and −0.52 mm; 95% CI: −0.90 to −0.14 per standard deviation increase, respectively). Mothers who smoked and did not use folic acid supplements had shorter crown rump lengths than nonsmoking mothers who used folic acid supplements; the difference was 3.84 mm; 95% CI: −5.71 to −1.98. In comparison to normal first trimester growth, restricted first trimester growth was associated with increased risks of prematurity (4.0% vs. 7.2%; adjusted odds ratio [OR]: 2.12; 95% CI: 1.24–3.61), small size for the gestational age at birth (4.0% vs.10.6%; OR: 2.64; 95% CI: 1.64–4.25), and low birth weight (3.5% vs. 7.5%; OR: 2.42; 95% CI: 1.41–4.16). Over the first 2 years of postnatal growth, each standard deviation decrease in first trimester fetal crown rump length was associated with an accelerated growth rate in weight and height; the increase in the standard deviation score was 0.139 per 2 years; 95% CI: 0.097 to 0.181. These findings demonstrate that first trimester fetal growth is independently associated with a number of maternal physical characteristics and lifestyle habits. Early fetal growth restriction is also associated with an increased risk of adverse birth outcomes and accelerated growth rates in early childhood.

Early fetal growth: concepts and pitfalls

Early fetal growth: concepts and pitfalls

Risk Factors and Outcomes Associated With First-Trimester Fetal Growth Restriction

Adverse environmental exposures lead to developmental adaptations in fetal life. The influences of maternal physical characteristics and lifestyle habits on first-trimester fetal adaptations and the postnatal consequences are not known. To determine the risk factors and outcomes associated with first-trimester growth restriction. Prospective evaluation of the associations of maternal physical characteristics and lifestyle habits with first-trimester fetal crown to rump length in 1631 mothers with a known and reliable first day of their last menstrual period and a regular menstrual cycle. Subsequently, we assessed the associations of first-trimester fetal growth restriction with the risks of adverse birth outcomes and postnatal growth acceleration until the age of 2 years. The study was based in Rotterdam, The Netherlands. Mothers were enrolled between 2001 and 2005. First-trimester fetal growth was measured as fetal crown to rump length by ultrasound between the gestational age of 10 weeks 0 days and 13 weeks 6 days. Main birth outcomes were preterm birth (gestational age <37 weeks), low birth weight (<2500 g), and small size for gestational age (lowest fifth birth centile). Postnatal growth was measured until the age of 2 years. In the multivariate analysis, maternal age was positively associated with first-trimester fetal crown to rump length (difference per maternal year of age, 0.79 mm; 95% confidence interval [CI], 0.41 to 1.18 per standard deviation score increase). Higher diastolic blood pressure and higher hematocrit levels were associated with a shorter crown to rump length (differences, -0.40 mm; 95% CI, -0.74 to -0.06 and -0.52 mm; 95% CI, -0.90 to -0.14 per standard deviation increase, respectively). Compared with mothers who were nonsmokers and optimal users of folic acid supplements, those who both smoked and did not use folic acid supplements had shorter fetal crown to rump lengths (difference, -3.84 mm; 95% CI, -5.71 to -1.98). Compared with normal first-trimester fetal growth, first-trimester growth restriction was associated with increased risks of preterm birth (4.0% vs 7.2%; adjusted odds ratio [OR], 2.12; 95% CI, 1.24 to 3.61), low birth weight (3.5% vs 7.5%; adjusted OR, 2.42; 95% CI, 1.41 to 4.16), and small size for gestational age at birth (4.0% vs 10.6%; adjusted OR, 2.64; 95% CI, 1.64 to 4.25). Each standard deviation decrease in first-trimester fetal crown to rump length was associated with a postnatal growth acceleration until the age of 2 years (standard deviation score increase, 0.139 per 2 years; 95% CI, 0.097 to 0.181). Maternal physical characteristics and lifestyle habits were independently associated with early fetal growth. First-trimester fetal growth restriction was associated with an increased risk of adverse birth outcomes and growth acceleration in early childhood.

Effects of heat stress on mammalian reproduction

Heat stress can have large effects on most aspects of reproductive function in mammals. These include disruptions in spermatogenesis and oocyte development, oocyte maturation, early embryonic development, foetal and placental growth and lactation. These deleterious effects of heat stress are the result of either the hyperthermia associated with heat stress or the physiological adjustments made by the heat-stressed animal to regulate body temperature. Many effects of elevated temperature on gametes and the early embryo involve increased production of reactive oxygen species. Genetic adaptation to heat stress is possible both with respect to regulation of body temperature and cellular resistance to elevated temperature.

OP27.07: The relationship between abdominal circumference and umbilical artery Doppler z-scores in severe early onset fetal growth restriction

A. J. Talmor1, A. Daemen4, E. Murdoch5, B. De Moor4, H. Missfelder-Lobos1, D. Timmerman2, T. Bourne3,2, C. Lees1 1Department of Fetal Medicine, Obstetrics and Gynaecology, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Trust, Cambridge, United Kingdom; 2Department of Obstetrics and Gynaecology, University Hospitals, KU Leuven, Leuven, Belgium; 3Imperial College London, Imperial College London, Hammersmith Campus, Du Cane Road, London, United Kingdom; 4Department of Electrical Engineering (ESAT), Katholieke Universiteit Leuven, Leuven, Belgium; 5Department of Neonatology, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Trust, Cambridge, United Kingdom

P20.02: The relationship between abdominal circumference and middle cerebral artery Doppler z-scores in severe early onset fetal growth restriction

P20.02: The relationship between abdominal circumference and middle cerebral artery Doppler z-scores in severe early onset fetal growth restriction

OC28.01: Early fetal growth rate, PAPP-A and free β-hCG in relation to preterm delivery

OC28.01: Early fetal growth rate, PAPP-A and free β-hCG in relation to preterm delivery

Twin growth discrepancy in early pregnancy

To assess whether early fetal growth restriction in a twin, expressed as the intertwin discrepancy in crown-rump length (CRL) between two viable twins at 7 + 0 to 9 + 6 weeks' gestation, is predictive of subsequent single fetal loss. This was a retrospective analysis of data collected prospectively over 3 years. Women attending an early pregnancy unit underwent a transvaginal ultrasound examination. In women with a viable twin pregnancy between 7 + 0 and 9 + 6 weeks of gestation, the CRL ratio between the two embryos was calculated. Women were followed up and the intertwin discrepancy in CRL at the 7 + 0 to 9 + 6-week scan was compared between cases in which there was spontaneous reduction to a singleton and those in which both twins remained viable at the 11-14-week scan. There were 77 women included in the study and nine (12%) of these had a single fetal loss. Pregnancies with subsequent single fetal loss were more likely to have a larger median CRL discrepancy (42.0%; interquartile range (IQR), 23.8-64.3%) than were those which retained two viable fetuses (6.1%; IQR, 2.2-12.5%) (P < 0.0001). The median CRL discrepancy in subsequently viable monochorionic diamniotic twins (10.9%; IQR, 1.9-17.5%) was no different from that in dichorionic diamniotic twin pregnancies (5.9%; IQR, 2.1-12.3%) (P = 0.305). Regardless of chorionicity, there was a relationship between increasing CRL discrepancy and single fetal loss; the likelihood of a subsequently viable twin pregnancy was 97% if the discrepancy was < 20%, while if the discrepancy was > 60% there were no cases of both twins remaining viable (P < 0.0001). Receiver-operating characteristics curve analysis of CRL discrepancy in predicting single fetal loss gave an area under the curve of 0.93, with an optimum cut-off point of 16.9% discrepancy (sensitivity, 88.9%; 95% CI, 51.8-99.7; and specificity, 86.7%; 95% CI, 76.3-93.8). There is a significant relationship between CRL discrepancy at 7 + 0 to 9 + 6 weeks and the likelihood of subsequent single intrauterine fetal loss. This suggests that spontaneous fetal demise of one twin may be preceded by growth restriction in the first trimester.

Dating and growth in the first trimester

Measurement of embryonic or foetal size using the greatest length of the embryo or foetal crown rump length can be used to accurately determine the gestational age of a normal first trimester pregnancy to within three to five days. Transvaginal ultrasound scan can be used to measure the size of an embryo and gestation sac earlier than transabdominal ultrasound. The original Robinson curve used for dating pregnancies is still valid in most cases. Ultrasound dating in the first trimester is now recommended for all women with spontaneous pregnancies, even those with certain menstrual dates. First trimester growth in normal pregnancy is not uniform and is influenced by both maternal and foetal factors. Early foetal growth restriction is demonstrated in many pregnancies that subsequently end in first trimester miscarriage and is also demonstrated in fetuses with triploidy, trisomy 18 and possibly trisomy 13. Pregnancies which are small at the 11-14 week ultrasound scan appear to be at risk of later intrauterine growth restriction, preeclampsia and preterm delivery. Cross-sectional and serial measurement of foetal growth in the first trimester may be helpful in predicting both miscarriage and adverse late pregnancy outcomes.