Supplementary Material for: Survey on the Current Trends in Managing Intrauterine Growth Restriction

<b><i>Objective:</i></b> To provide a snapshot of the current trends in managing intrauterine growth restriction (IUGR) and to assess the agreement on the gestational age and the way of delivery in different clinical scenarios. <b><i>Methods:</i></b> A PubMed search was performed to identify all original articles on IUGR in the last 6 years. The most active 20 authors were selected as experts and were invited to respond to a survey on their preferred gestational age for elective delivery in several IUGR cases depending on Doppler measurements (including umbilical artery (UA), middle cerebral artery, cerebroplacental ratio, uterine artery and ductus venosus), biophysical profile and cardiotocography. <b><i>Results:</i></b> 15 of the 20 selected experts agreed to participate in the survey, of which 3 failed to meet the deadline to complete the survey. Management of IUGR was relatively uniform for abnormal UA, uterine artery or cerebroplacental ratio. Although average gestational age at delivery reflected a clear progression with accepted markers of severity, discrepancies of up to 4 weeks were found for abnormal middle cerebral artery Doppler and absent end-diastolic velocity in the UA, and of up to 8 weeks for reverse end-diastolic velocity in the UA and abnormalities in the ductus venosus Doppler. <b><i>Conclusions:</i></b> Management of IUGR is still far from being uniform among centers, with most controversy surrounding the management of early-onset IUGR. There is a need of prospective studies to address this issue

Supplementary Material for: Chromosomal Microarray Analysis in Fetuses with Growth Restriction and Normal Karyotype: A Systematic Review and Meta-Analysis

<strong><em>Objective:</em></strong> To perform a systematic review of the literature and a meta-analysis to estimate the incremental yield of chromosomal microarray analysis (CMA) over karyotyping in fetal growth restriction (FGR). <b><i>Methods:</i></b> This was a systematic review conducted in accordance with the PRISMA criteria. All articles identified in PubMed, Ovid Medline, and ISI Web of Knowledge (Web of Science) from January 2009 to November 2016 describing pathogenic copy number variants (CNVs) in fetuses with growth restriction were included. Case reports were excluded. Risk differences were pooled to estimate the overall and stratified CMA incremental yield. <b><i>Results:</i></b> Ten studies with full data available met the inclusion criteria for analysis. Combined data from these studies revealed a 4% (95% confidence interval [CI] 1-6%) incremental yield of CMA over karyotyping in nonmalformed growth-restricted fetuses, and a 10% (95% CI 6-14%) incremental yield in FGR when associated with fetal malformations. The most frequently found pathogenic CNVs were 22q11.2 duplication, Xp22.3 deletion, and 7q11.23 deletion (Williams-Beuren syndrome), particularly in isolated FGR. <b><i>Conclusion:</i></b> The use of genomic CMA provides a 4% incremental yield of detecting pathogenic CNVs in fetuses with isolated growth restriction and normal karyotype

Supplementary Material for: Second- to Third-Trimester Longitudinal Growth Assessment for the Prediction of Largeness for Gestational Age and Macrosomia in an Unselected Population

<p><b><i>Background:</i></b> Prenatal detection of excessive growth remains inaccurate. Most strategies rely on a single cross-sectional evaluation of fetal size during the third trimester. <b><i>Objectives:</i></b> To compare second- to third-trimester longitudinal growth assessment with cross-sectional evaluation at the third trimester in the prediction of largeness for gestational age (LGA) and macrosomia. <b><i>Methods:</i></b> A cohort of 2,696 unselected singleton pregnancies scanned at 21 ± 2 and 32 ± 2 weeks was created. Abdominal circumference (AC) measurements were transformed to <i>z</i> values according to the INTERGROWTH-21st standards. Longitudinal growth assessment was performed by calculation of <i>z</i> velocity and conditional growth. Both methods were compared to cross-sectional assessment at 32 ± 2 weeks. Predictive performance for LGA and macrosomia was determined by receiver operating characteristic curve analysis. <b><i>Result:</i></b> A total of 188 (7%) newborns qualified for LGA and 182 (6.8%) for macrosomia. The areas under the curve (AUCs) for 32-week AC <i>z</i> score, AC <i>z</i> velocity, and conditional AC were 0.78, 0.61, and 0.55, respectively, for the prediction of LGA, and 0.75, 0.61, and 0.55, respectively, for the prediction of macrosomia. Both AUCs of AC <i>z</i> velocity and conditional AC were significantly lower (<i>p</i> < 0.001) than the AUC of cross-sectional AC <i>z</i> scores. <b><i>Conclusions:</i></b> In the general population, second- to third-trimester longitudinal assessment of fetal growth is inferior to third-trimester cross-sectional evaluation of size in the prediction of LGA and macrosomia.</p

Supplementary Material for: Gender-Specific Antenatal Growth Reference Charts in Monochorionic Twins

<b><i>Objective:</i></b> To create antenatal gender-specific reference growth charts in uncomplicated monochorionic diamniotic twins. <b><i>Materials and Methods:</i></b> This is a prospective longitudinal study in which uncomplicated monochorionic (MC) twin pregnancies were included from 23 + 4 weeks of gestation onwards. Estimated fetal weight (EFW) and biometric parameters (biparietal diameter, head circumference, abdominal circumference, and femur length) were evaluated in both fetuses every 2 weeks using standardized methodology. Maternal and fetal complications were excluded. Charts were fitted for each biometric parameter and EFW in relation to gestational age and fetal gender using multilevel mixed models. <b><i>Results:</i></b> The final analysis included a total of 456 ultrasound examinations in 62 MC twins, with a mean of 7 scans per pregnancy (range 5–8). The mean as well as 5th and 95th percentiles of each biometric parameter and EFW were adjusted in relation to gender and gestational age between 24 and 37 weeks of gestation. Male fetuses have higher reference values than females, and the disparity is larger in the upper centiles of the distribution. <b><i>Discussion:</i></b> We provide gender-specific reference growth charts for MC twins. We suggest that these charts will improve prenatal MC twin assessment and surveillance, with a more accurate classification of normal or growth-restricted fetuses adjusted per sex

Supplementary Material for: Neurodevelopmental Effects of Undernutrition and Placental Underperfusion in Fetal Growth Restriction Rabbit Models

<p><b><i>Introduction:</i></b> Chronic reduction of oxygen and nutrient delivery to the fetus has been related to neurodevelopmental problems. Placental underperfusion induces a significant reduction in oxygen and nutrient delivery, whereas maternal undernutrition causes mainly nutrient deficiency. A comparison of the neurodevelopmental effects of both situations in pregnant rabbits was performed. <b><i>Materials and Methods:</i></b> The placental underperfusion model was induced after uteroplacental vessel ligation at 25 days of pregnancy. The undernutrition model was induced after a reduction of 70% of the basal maternal intake at 22 days of pregnancy. Neurobehavioral tests were applied in the derived offspring at the neonatal period and over the long term. Structural brain differences were evaluated by brain networks obtained from diffusion magnetic resonance imaging. <b><i>Results:</i></b> Birth weight was significantly lower in both cases. However, stillbirth was only increased in the placental underperfusion model. Cases from both models presented poorer neurobehavioral performance and network infrastructure, being more pronounced in the placental underperfusion model. <b><i>Discussion:</i></b> Prenatal insults during the last third of gestation resulted in functional and structural disturbances. The degree of neurodevelopmental impairment and its association with structural brain reorganization seemed to be related to the type of the prenatal insult, showing stronger effects in the placental underperfusion model.</p

Supplementary Material for: Early Environmental Enrichment Enhances Abnormal Brain Connectivity in a Rabbit Model of Intrauterine Growth Restriction

<p><b><i>Introduction:</i></b> The structural correspondence of neurodevelopmental impairments related to intrauterine growth restriction (IUGR) that persists later in life remains elusive. Moreover, early postnatal stimulation strategies have been proposed to mitigate these effects. Long-term brain connectivity abnormalities in an IUGR rabbit model and the effects of early postnatal environmental enrichment (EE) were explored. <b><i>Materials and Methods:</i></b> IUGR was surgically induced in one horn, whereas the contralateral one produced the controls. Postnatally, a subgroup of IUGR animals was housed in an enriched environment. Functional assessment was performed at the neonatal and long-term periods. At the long-term period, structural brain connectivity was evaluated by means of diffusion-weighted brain magnetic resonance imaging and by histological assessment focused on the hippocampus. <b><i>Results:</i></b> IUGR animals displayed poorer functional results and presented altered whole-brain networks and decreased median fractional anisotropy in the hippocampus. Reduced density of dendritic spines and perineuronal nets from hippocampal neurons were also observed. Of note, IUGR animals exposed to enriched environment presented an improvement in terms of both function and structure. <b><i>Conclusions:</i></b> IUGR is associated with altered brain connectivity at the global and cellular level. A strategy based on early EE has the potential to restore the neurodevelopmental consequences of IUGR.</p