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In Japan, pregnant women are diagnosed as obese if the prepregnancy body mass index (BMI) is ≥25 kg/m2. However, this is different from other countries. The Institute of Medicine (IOM) classifies prepregnancy BMI as underweight (BMI

Background: Preterm birth is the most frequent cause of neonatal death, but its aetiology remains unclear. It has been suggested that the imbalance of immunological mechanisms responsible for maintaining pregnancy is contributing to preterm birth pathogenesis. We aimed to investigate global gene expression and the levels of several complement system components in umbilical cord blood samples from preterm neonates and compare them to term newborns. We sought to examine how differentially expressed genes could affect various immune-related pathways that are believed to be crucial factors in preterm birth. Material and methods: We enrolled 27 preterm infants (37 weeks GA), from which umbilical cord blood samples were collected. From these samples, peripheral blood mononuclear cells were isolated and subsequent RNA isolation was performed. We used Affymetrix Human Gene 2.1 ST Array Strip for microarray experiment and DAVID resources for bioinformatics analysis of the obtained data. Concentrations of C2, C3a, C5/C5a, C9, FactorD, Properdin were measured in umbilical cord blood plasma samples using multiplex fluorescent bead-based immunoassays using Luminex technology. Results: The levels of C3a and C5/5a were significantly elevated in preterm neonates compared to term babies, whereas C9 concentration was evidently increased in term infants. The expression of 250 genes was upregulated at least 2-fold and 3781 genes were downregulated at least 2-fold in preterm neonates in comparison with term infants. Functional annotation analysis revealed that in preterm infants in comparison to term babies there was a significant downregulation of genes encoding several Toll-like receptors, interleukins and genes involved in major signalling pathways (e.g. NF-κB, MAPK, TNF, Notch, JAK) and vital cellular processes (e.g. intracellular signal transduction, protein ubiquitination, protein transport, RNA splicing, DNA-templated transcription). Conclusions: Preterm birth results in immediate and long-term complications. Our results indicate that infants born prematurely show significant differences in complement components concentration and a downregulation of over 3,000 genes, involved mainly in various immune-related pathways, including innate immune response, phagocytosis and TLR function, when compared to full-term babies. Further studies on larger cohorts are needed to elucidate the role of immunity in prematurity.

BackgroundDNA methylation is highly sensitive to in utero perturbations and has an established role in both embryonic development and regulation of gene expression. The fetal genetic component has been previously shown to contribute significantly to the timing of birth, yet little is known about the identity and behavior of individual genes.ObjectivesThe aim of this study was to test the extent genome-wide DNA methylation levels in umbilical cord blood were associated with gestational age at birth (GA). Findings were validated in an independent sample and evidence for the regulation of gene expression was evaluated for cis gene relationships in matched specimens.ResultsGenome-wide DNA methylation, measured by the Illumina Infinium Human Methylation 450K BeadChip, was associated with GA for 2,372 CpG probes (5% false discovery rate) in both the Pregnancy, Race, Environment, Genes (PREG – Virginia Commonwealth University) and Newborn Epigenetic Study (NEST – Duke University) cohorts. Significant probes mapped to 1,640 characterized genes and an association with nearby gene expression measures obtained by the Affymetrix HG-133A microarray was found for 11 genes. Differentially methylated positions were enriched for actively transcribed and enhancer chromatin states, were predominately located outside of CpG islands, and mapped to genes enriched for inflammation and innate immunity ontologies. In both PREG and NEST, the first principal component derived from these probes explained approximately one-half (58.1% and 47.8%, respectively) of the variation in GA. This assessment provides a strong evidence to support the importance of DNAm change throughout the gestational time period.ConclusionsThese results converge on support for the role of variation in DNAm measures as an important genetic regulatory mechanism contributing to inter-individual differences in gestational age at birth. In particular, the pathways described are consistent with the well-known hypothesis of pathogen detection and response by the immune system to elicit premature labor as a consequence of unscheduled inflammation.

When drugs exert their effects in the brain, linear extrapolation of doses from adults could be harmful for children as the blood–brain barrier (BBB) and blood–CSF barrier (BCSFB) function is still immature. More specifically, age-related variation in membrane transporters may impact brain disposition. As human data on brain transporter expression is scarce, age dependent [gestational age (GA), postnatal age (PNA), and postmenstrual age (PMA)] variation in immunohistochemical localization and staining intensity of the ABC transporters P-glycoprotein (Pgp), breast cancer resistance protein (BCRP), and multidrug resistance-associated proteins 1, 2, 4, and 5 (MRP1/2/4/5) was investigated. Post mortem brain cortical and ventricular tissue was derived from 23 fetuses (GA range 12.9–39 weeks), 17 neonates (GA range 24.6–41.3 weeks, PNA range 0.004–3.5 weeks), 8 children (PNA range 0.1–3 years), and 4 adults who died from a wide variety of underlying conditions. In brain cortical BBB, immunostaining increased with age for Pgp and BCRP, while in contrast, MRP1 and MRP2 staining intensity appeared higher in fetuses, neonates, and children, as compared to adults. BCSFB was positively stained for Pgp, MRP1, and MRP2 and appeared stable across age, while BCRP was not detected. MRP4 and MRP5 were not detected in BBB or BCSFB. In conclusion, human BBB and BCSFB ABC membrane transporters show brain location and transporter-specific maturation. Electronic supplementary material The online version of this article (10.1007/s00418-020-01884-8) contains supplementary material, which is available to authorized users.

Objective:The objective was to evaluate maternal Mediterranean diet (MD) pattern adherence during pregnancy and its association with small for gestational age (SGA) and preterm birth. A secondary objective of the current study was to describe the sociodemographic, lifestyle and obstetric profile of the mothers studied as well as the most relevant paternal and newborn characteristics.Design:The current study is a two-phase retrospective population-based study of maternal dietary habits during pregnancy and their effect on newborn size and prematurity. The descriptive first phase examined maternal dietary habits during pregnancy along with the maternal sociodemographic, lifestyle and obstetric profile in a cross-sectional period study. In the second phase, newborn outcomes were evaluated in a nested case–control study. Adherence to MD during pregnancy was measured with the Spanish version of Kidmed index.Setting:Obstetrics ward of the La Fe Hospital in Valencia.Participants:All mother–child pairs admitted after delivery during a 12-month period starting from January 2018 were assessed for eligibility. A total of 1118 provided complete outcome data after signing informed consent.Results:14·5 % met the criteria of poor adherence (PA); 34·8 %, medium adherence (MA); and 50·7 %, optimal adherence (OA). Medium adherence to MD was associated in the adjusted scenarios with a higher risk of giving birth to a preterm newborn. No association was found between MD adherence and SGA.Conclusions:Early intervention programmes geared towards pregnant women, where women were aided in reaching OA to MD, might reduce the risk of preterm newborn.

AIM: To use a sonographic method to determine the usefulness of trans-cerebellar diameter (TCD) as an independent estimator of gestational age (GA). METHODS: A convenience sample of 257 healthy pregnant women of Igbo ethnic origin with singleton normal pregnancy whose GA ranged from 16 to 40 weeks were examined. GA was calculated from the date of onset of the last menstrual period (LMP) and was used as the standard criterion, while the biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC), and femur length (FL) were used to estimate GA. TCD was measured and employed to derive regression models utilized to assess GA. RESULTS: The mean TCD was 32.0 ± 11.6 mm; TCD had a strong positive linear relationship with GA (R = 0.988; R(2) = 0. 975; P =

Objective:Observational studies have linked elevated homocysteine to vascular conditions. Folate intake has been associated with lower homocysteine concentration, although randomised controlled trials of folic acid supplementation to decrease the incidence of vascular conditions have been inconclusive. We investigated determinants of maternal homocysteine during pregnancy, particularly in a folic acid-fortified population.Design:Data were from the Ottawa and Kingston Birth Cohort of 8085 participants. We used multivariable regression analyses to identify factors associated with maternal homocysteine, adjusted for gestational age at bloodwork. Continuous factors were modelled using restricted cubic splines. A subgroup analysis examined the modifying effect of MTHFR 677C>T genotype on folate, in determining homocysteine concentration.Setting:Participants were recruited in Ottawa and Kingston, Canada, from 2002 to 2009.Participants:Women were recruited when presenting for prenatal care in the early second trimester.Results:In 7587 participants, factors significantly associated with higher homocysteine concentration were nulliparous, smoking and chronic hypertension, while factors significantly associated with lower homocysteine concentration were non-Caucasian race, history of a placenta-mediated complication and folic acid supplementation. Maternal age and BMI demonstrated U-shaped associations. Folic acid supplementation of >1 mg/d during pregnancy did not substantially increase folate concentration. In the subgroup analysis, MTHFR 677C>T modified the effect of folate status on homocysteine concentration.Conclusions:We identified determinants of maternal homocysteine relevant to the lowering of homocysteine in the post-folic acid fortification era, characterised by folate-replete populations. A focus on periconceptional folic acid supplementation and improving health status may form an effective approach to lower homocysteine.

Aim: The definition of fetal growth restriction (FGR) refers to the incapability of a fetus to achieve the appropriate estimated growth, with expected fetal weight below the 10th percentile calculated for its gestational age. Placental factors and hypoxemia are considered to be essential elements with influence on intrauterine growth restriction (IUGR) and fetal death. The purpose of the present study was to investigate the macroscopic and microscopic pathological findings regarding the placentas in pregnancies complicated by influence on IUGR. Patients, Materials and Methods: Our study included 42 third-trimester pregnant patients admitted to the Cuza Vodă Hospital of Obstetrics and Gynecology, Iaşi, Romania, in the last three years. Soon after delivery, the 42 placentas were collected and analyzed; 32 placentas came from cases previously diagnosed with influence on IUGR and were included in our study group. Ten other placentas included in the control group were selected from uncomplicated pregnancies. Standard Hematoxylin–Eosin (HE) staining method, as well as Periodic Acid–Schiff (PAS) staining, and immunohistochemical techniques for cluster of differentiation 31 (CD31) and collagen IV were used in order to highlight the morphological features of the studied placentas. Results: Our study revealed that reduced placental dimensions and eccentric umbilical cord insertion are correlated with the birthweight of the fetuses with IUGR (p

Insulin-like growth factor 1 (IGF-1) is a regulator of intrauterine growth, and circulating concentrations are reduced in intrauterine growth-restricted fetuses. The aim of our study was to investigate the relationship between IGF-1 levels in newborns and intrauterine growth, expressed as birth weight (BW). The research was designed as a cross-sectional study. The study included 71 premature newborns, gestational age (GA) ≤33 weeks. Quantitative determination of IGF-1 was performed in the 33rd post-menstrual week (pmw) to make the measurements more comparable. We used an enzyme-bound immunosorbent test for quantitative determination of IGF-1. Our results showed the mean IGF-1 level in premature newborns in 33rd pmw to be 23.1±4.56 (range 15.44-39.75) μg/L. There was no difference in IGF-1 values between male (23.1±4.98 μg/L) and female (23.1±4.87 μg/L) newborns. Tere was no significant difference in the average IGF-1 levels between male and female newborns with BW 50th percentile for GA either (p>0.50). Only BW, Inzulinu sličan faktor rasta (IGF-1) je jedan od čimbenika koji utječu na intrauterini rast. Serumske razine IGF-1 su smanjene u fetusima s intrauterinim zastojem rasta. Cilj našega istraživanja bio je ispitati odnos između razine IGF-1 u nedonoščadi i intrauterinog rasta izraženog kao porođajna težina (PT). Istraživanje je provedeno kao presječna studija. U studiju je bilo uključeno 71 nedonošče gestacijske dobi (GD) ≤33 tjedna. Kvantitativno određivanje IGF-1 provedeno je u 33. postmenstruacijskom tjednu (pmt) radi bolje usporedivosti rezultata. Za kvantitativno određivanje IGF-1 rabili smo enzimski imunosorbentni test. Naši rezultati pokazali su da je srednja razina IGF-1 u nedonoščadi u 33. pmt iznosila 23,1±4,56 (raspon 15,44-39,75) μg/L. Nije bilo razlike u vrijednostima IGF-1 između muške (23,1±4,98 μg/L) i ženske (23,1±4,87 μg/L) nedonoščadi. Također nije bilo značajne razlike u srednjim razinama IGF-1 između nedonoščadi s PT 50. percentila za GD (p>0,50). Nedonoščad s niskom PT (

Introduction: This study aimed to compare the apparent diffusion coefficient (ADC) values of different brain areas between two groups of intrauterine growth restricted (IUGR) foetuses and control cases. Material and methods: A total of 38 foetuses with IUGR and 18 normal control foetuses with similar gestational age were compared using a 3T magnetic resonance scanner. IUGR cases included 23 foetuses with clinical severity signs (group A) and 15 foetuses without clinical severity signs (group B). ADC values were measured in different brain regions and compared among groups. Foetuses with structural brain abnormalities were excluded from the study. Results: All foetuses had normal foetal structural brain anatomy. Head circumference (HC) < 5% was more common in IUGR group A compared to IUGR group B (56.5% vs. 13.3%, p < 0.0001). In comparison to the normal group, the ADC values in IUGR foetuses were significantly lower in cerebellar hemispheres (CH) (1.239 vs. 1.280.5 × 10-3 mm2/s, p = 0.045), thalami (1.205 vs. 1.285 × 10–3 mm2/s, p = 0.031) and caudate nucleus (CN) (1.319 vs. 1.394 × 10-3 mm2/s, p = 0.04). However, there were no significant differences in ADC values between IUGR subtypes. Among all brain regions, pons had the lowest ADC values. Conclusions: ADC values of thalami, CN, and CH were significantly lower in IUGR than control foetuses, while there was no significant difference among IUGR groups. Further studies are needed to evaluate the prognostic value of ADC changes in IUGR foetuses.

Objectives To describe and compare ultrasound and Doppler findings in pregnant women who were positive for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) with findings in those who were SARS‐CoV‐2‐negative, evaluated during the pandemic period. Methods In this retrospective case–control study, we analyzed data from 106 pregnant women who tested positive for SARS‐CoV‐2 at the time of, or within 1 week of, an ultrasound scan between 1 May and 31 August 2020. Scans were either performed for routine fetal evaluation or indicated due to a positive SARS‐CoV‐2 test. Forty‐nine women were symptomatic and 57 were asymptomatic. For comparison, we analyzed data from 103 pregnant women matched for maternal age, parity, body mass index and gestational age at the time of the ultrasound scan. These control women did not report symptoms of SARS‐CoV‐2 infection at the time of the ultrasound scan or at the time of admission for delivery and had a negative SARS‐CoV‐2 test at admission for delivery. Fetal biometry, fetal anatomy, amniotic fluid volume and Doppler parameters, including umbilical and fetal middle cerebral artery pulsatility indices, cerebroplacental ratio and biophysical profile (BPP), were evaluated as indicated. Biometric and Doppler values were converted to Z‐scores for comparison. Our primary outcome, an adverse prenatal composite outcome (APCO) included any one or more of: small‐for‐gestational‐age (SGA) fetus, oligohydramnios, abnormal BPP, abnormal Doppler velocimetry and fetal death. Comorbidities, delivery information and neonatal outcome were compared between the two groups. Results Eighty‐seven (82.1%) women who were positive for SARS‐CoV‐2 had a body mass index > 25 kg/m2. SARS‐CoV‐2‐positive women had a higher prevalence of diabetes (26/106 (24.5%) vs 13/103 (12.6%); P = 0.03), but not of pre‐eclampsia (21/106 (19.8%) vs 11/103 (10.7%); P = 0.08), compared with controls. The prevalence of APCO was not significantly different between SARS‐CoV‐2‐positive women (19/106 (17.9%)) and controls (9/103 (8.7%)) (P = 0.06). There were no differences between SARS‐CoV‐2‐positive women and controls in the prevalence of SGA fetuses (12/106 (11.3%) vs 6/103 (5.8%); P = 0.17), fetuses with abnormal Doppler evaluation (8/106 (7.5%) vs 2/103 (1.9%); P = 0.08) and fetuses with abnormal BPP (4/106 (3.8%) vs 0/103 (0%); P = 0.14). There were two fetal deaths in women who were positive for SARS‐CoV‐2 and these women had a higher rate of preterm delivery ≤ 35 weeks of gestation (22/106 (20.8%) vs 9/103 (8.7%); odds ratio, 2.73 (95% CI, 1.19–6.3); P = 0.01) compared with controls. Conclusions There were no significant differences in abnormal fetal ultrasound and Doppler findings observed between pregnant women who were positive for SARS‐CoV‐2 and controls. However, preterm delivery ≤ 35 weeks was more frequent among SARS‐CoV‐2‐positive women. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Background and objectives Guidelines and indications for exchange transfusion in haemolytic disease of the foetus and newborn (HDFN) have changed drastically in the past decades, causing a decline in exchange transfusion rate. This study aims to evaluate the incidence of exchange transfusions (ETs) in neonates with Rh-mediated HDFN over the past 20 years at our centre, and report potentially ET-related complications as well as indicators for bilirubin encephalopathy.Material and methods In this observational study, 438 neonates were included with HDFN, born >= 35 weeks gestational age at the Leiden University Medical Centre between January 2000 and July 2020. The incidence of ET and procedure-related complications were assessed in three consecutive time periods determined by changes in guidelines and indications for ET.Results The incidence of ET in our centre declined from (104/156) 67% (time period 2000-2005), to (39/181) 22% (2006-2015) and to (10/101) 10% (2015-2020, p < 0 center dot 001). The maximum bilirubin levels in neonates after birth increased from 13 center dot 6 mg/dL (or 233 mu mol/L), to 15 center dot 0 mg/dL (257 mu mol/L) and to 15 center dot 3 mg/dL (263 mu mol/L). The incidence of complications associated with the use of ET (including sepsis, haematologic disorders and respiratory failure) remained stable throughout the years, and no neonates died during the study period.Conclusion Exchange transfusion incidence declined significantly over the past two decades. Decrease in ET incidence, and concomitant decrease in exposure and expertise, was not associated with an increase in procedure-related complications.

Objectives Placental expression of neuropilin‐1 (NRP1), a proangiogenic member of the vascular endothelial growth factor receptor family involved in sprouting angiogenesis, was recently discovered to be downregulated in pregnancies with fetal growth restriction (FGR) and abnormal umbilical artery (UA) Doppler. Soluble NRP1 (sNRP1) is an antagonist to NRP1; however, little is known about its role in normal and FGR pregnancies. This study tested the hypotheses that, first, sNRP1 would be detectable in maternal circulation and, second, its concentration would be upregulated in FGR pregnancies compared to those with normal fetal growth and this would correlate with the severity of the disease as assessed by UA Doppler. Methods This was a prospective case–control pilot study of 40 singleton pregnancies (20 FGR cases and 20 uncomplicated controls) between 24 + 0 and 40 + 0 weeks' gestation followed in an academic perinatal center from January 2015 to May 2017. FGR was defined as an ultrasound‐estimated fetal weight

The first positive genome-wide association study on gestational length and preterm delivery showed the involvement of an Se metabolism gene. In the present study, we examine the association between maternal intake of Se and Se status with gestational length and preterm delivery in 72 025 women with singleton live births from the population-based, prospective Norwegian Mother, Father and Child Cohort Study (MoBa). A self-reported, semi-quantitative FFQ answered in pregnancy week 22 was used to estimate Se intake during the first half of pregnancy. Associations were analysed with adjusted linear and Cox regressions. Se status was assessed in whole blood collected in gestational week 17 (n 2637). Median dietary Se intake was 53 (interquartile range (IQR) 44–62) µg/d, supplements provided additionally 50 (IQR 30–75) µg/d for supplement users (n 23 409). Maternal dietary Se intake was significantly associated with prolonged gestational length (β per sd = 0·25, 95 % CI, 0·07, 0·43) and decreased risk of preterm delivery (n 3618, hazard ratio per sd = 0·92, 95 % CI, 0·87, 0·98). Neither Se intake from supplements nor maternal blood Se status was associated with gestational length or preterm delivery. Hence, the present study showed that maternal dietary Se intake but not intake of Se-containing supplements, during the first half of pregnancy was significantly associated with decreased risk of preterm delivery. Further investigations, preferably in the form of a large randomised controlled trial, are needed to elucidate the impact of Se on pregnancy duration.

Objective:To investigate the hypothesis that folic acid supplementation and dietary folate intake before conception and during pregnancy reduce the risk of small for gestational age (SGA) and to examine the joint effect of folic acid supplementation and dietary folate intake on the risk of SGA.Design:Participants were interviewed by trained study interviewers using a standardized and structured questionnaire. Information on birth outcomes and maternal complications was abstracted from medical records and dietary information was collected via a semi-quantitative FFQ before conception and during pregnancy.Setting:A birth cohort data analysis using the 2010–2012 Gansu Provincial Maternity and Child Care Hospital.Participants:Women (n 8758) and their children enrolled in the study.Results:Folic acid supplementation was associated with a reduced risk of SGA (OR = 0·72, 95 % CI 0·60, 0·86), with the reduced risk seen mainly for SGA at ≥37 weeks of gestational age (OR = 0·70, 95 % CI 0·58, 0·85) and nulliparous SGA (OR = 0·67, 95 % CI 0·54, 0·84). There was no significant association between dietary folate intake and SGA risk.Conclusions:Our study suggested that folic acid supplementation was associated with a reduced risk of SGA and the risk varied by preterm status and parity.

Background: High arterial oxygen saturation (SaO2) is associated with the development of retinopathy of prematurity (ROP), but difficult to avoid. Objective: To assess the association between severe ROP and a burden of cerebral and arterial hyperoxia. Methods: We retrospectively analyzed 225 preterm infants born ≤30 weeks’ gestation. The cerebral oxygen saturation (rcSO2) and SaO2 were measured within the first 96 h after birth. We determined the burden of both cerebral and arterial hyperoxia, which was defined as the percentage of time spent at saturation thresholds exceeding 85 and 90%, respectively. Their association with severe ROP (prethreshold disease type 1) was tested using logistic regression analyses. Results: Median gestational age (GA) was 28.0 weeks (interquartile range 26.7–29.0) and mean birth weight 1,032 g (±281 SD). Eight infants developed severe ROP. Infants with severe ROP spent more time at cerebral hyperoxic levels than infants without severe ROP (medians 30 vs. 16%). Adjusted for GA, for every 10% increase in burden of cerebral hyperoxia, the OR for developing ROP was 1.50 (95% CI 1.09 – 2.06, p = 0.013). A burden of arterial hyperoxia was not associated with ROP. Infants with severe ROP experienced even less arterial hyperoxia, although not statistically significant. Conclusions: Cerebral hyperoxia may be a better early predictor of severe ROP than arterial hyperoxia. Moreover, under strict oxygen management, cerebral hyperoxia in these infants may result from cerebral immaturity rather than a high SaO2. Whether reducing cerebral hyperoxia is feasible and might prevent ROP needs to be further examined.

Highlights • Applicability of GAIA definitions were assessed using medical records in LMICs. • LBW, preterm birth and neonatal death definitions were applicable in the field. • SGA, stillbirth, neonatal infection, congenital microcephaly definitions were less applicable. • Suggestions to the improvement in GAIA definitions were made. • Better documentation of maternal immunization is suggested for vaccine-safety studies., Standardized case definitions strengthen post-marketing safety surveillance of new vaccines by improving generated data, interpretation and comparability across surveillance systems. The Global Alignment of Immunization Safety Assessment in Pregnancy (GAIA) project developed standardized case definitions for 21 key obstetric and neonatal terms following the Brighton Collaboration (BC) methodology. In this prospective cohort study, we assessed the applicability of GAIA definitions for maternal immunization exposure and for low birth weight (LBW), preterm birth, small for gestational age (SGA), stillbirth, neonatal death, neonatal infection, and congenital microcephaly. We identified the missing data elements that prevented identified cases and exposures from meeting the case definition (level 1–3 of BC diagnostic certainty). Over a one-year period (2019–2020), all births occurring in 21 sites (mostly secondary and tertiary hospitals) in 6 Low Middle Income Countries and 1 High Income Country were recorded and the 7 perinatal and neonatal outcome cases were identified from routine medical records. Up to 100 cases per outcome were recruited sequentially from each site. Most cases recruited for LBW, preterm birth and neonatal death met the GAIA case definitions. Birth weight, a key parameter for all three outcomes, was routinely recorded at all sites. The definitions for SGA, stillbirth, neonatal infection (particularly meningitis and respiratory infection) and congenital microcephaly were found to be less applicable. The main barrier to obtaining higher levels of diagnostic certainty was the lack of sonographic documentation of gestational age in first or second trimester. The definition for maternal immunization exposure was applicable, however, the highest level of diagnostic certainty was only reached at two sites. Improved documentation of maternal immunization will be important for vaccine safety studies. Following the field-testing of these 8 GAIA definitions, several improvements are suggested that may lead to their easier implementation, increased standardization and hence comparison across studies.

Background The COVID-19 pandemic has presented obstacles for providers and patients in the maternal health care setting, causing changes to many pregnant women’s birth plans, as well as abrupt changes in hospital labor and delivery policies and procedures. Few data exist on the effects of the COVID-19 pandemic on the maternal health care landscape at the national level in the United States. Objective The aim of this study is to assess the incidence of key obstetrics outcomes (preterm delivery, Cesarean sections, and home births) and length of hospital stay during the COVID-19 pandemic as compared to the 6 months prior. Methods We conducted a retrospective cohort study of women aged 18-44 years in the United States who delivered between October 1, 2019, and September 30, 2020, had singleton deliveries, and completed a birth report in the Ovia Pregnancy mobile app. Women were assigned to the prepandemic cohort if they delivered between October 2019 and March 2020, and the pandemic cohort if they delivered between April and September 2020. Gestational age at delivery, delivery method, delivery facility type, and length of hospital stay were compared. Results A total of 304,023 birth reports were collected, with 152,832 (50.26%) in the prepandemic cohort and 151,191 (49.73%) in the pandemic cohort. Compared to the prepandemic cohort, principal findings indicate a 5.67% decrease in preterm delivery rates in the pandemic cohort (P Conclusions Results suggest a need for continuous monitoring of maternal health trends as the COVID-19 pandemic progresses and underline the important role of digital data collection, particularly during the pandemic.

Objective To estimate the risk of miscarriage associated with chorionic villus sampling (CVS). Methods This was a retrospective cohort study of women attending for routine ultrasound examination at 11 + 0 to 13 + 6 weeks' gestation at one of eight fetal‐medicine units in Spain, Belgium and Bulgaria, between July 2007 and June 2018. Two populations were included: (1) all singleton pregnancies undergoing first‐trimester assessment at Hospital Clínico Universitario Virgen de la Arrixaca in Murcia, Spain, that did not have CVS (non‐CVS group); and (2) all singleton pregnancies that underwent CVS following first‐trimester assessment at one of the eight participating centers (CVS group). We excluded pregnancies diagnosed with genetic anomalies or major fetal defects before or after birth, those that resulted in termination and those that underwent amniocentesis later in pregnancy. We used propensity score (PS) matching analysis to estimate the association between CVS and miscarriage. We compared the risk of miscarriage of the CVS and non‐CVS groups after PS matching (1:1 ratio). This procedure creates two comparable groups balancing the maternal and pregnancy characteristics that are associated with CVS, in a similar way to that in which randomization operates in a randomized clinical trial. Results The study population consisted of 22 250 pregnancies in the non‐CVS group and 3613 in the CVS group. The incidence of miscarriage in the CVS group (2.1%; 77/3613) was significantly higher than that in the non‐CVS group (0.9% (207/22 250); P, This article's abstract has been translated into Spanish and Chinese. Follow the links from the abstract to view the translations.

Background To inform the on-going debate about the use of universal prescriptive versus national intrauterine growth charts, we compared perinatal mortality for small and large-for-gestational-age (SGA/LGA) infants according to international and national charts in Europe. Methods We classified singleton births from 33 to 42 weeks of gestation in 2010 and 2014 from 15 countries (N = 1,475,457) as SGA (birthweight 90th percentile) using the international Intergrowth-21st newborn standards and national charts based on the customised charts methodology. We computed sex-adjusted odds ratios (aOR) for stillbirth, neonatal and extended perinatal mortality by this classification using multilevel models. Findings SGA and LGA prevalence using national charts were near 10% in all countries, but varied according to international charts with a north to south gradient (3.0% to 10.1% and 24.9% to 8.0%, respectively). Compared with appropriate for gestational age (AGA) infants by both charts, risk of perinatal mortality was increased for SGA by both charts (aOR[95% confidence interval (CI)]=6.1 [5.6–6.7]) and infants reclassified by international charts from SGA to AGA (2.7 [2.3–3.1]), but decreased for those reclassified from AGA to LGA (0.6 [0.4–0.7]). Results were similar for stillbirth and neonatal death. Interpretation Using international instead of national charts in Europe could lead to growth restricted infants being reclassified as having normal growth, while infants with low risks of mortality could be reclassified as having excessive growth. Funding InfAct Joint Action, CHAFEA Grant n°801,553 and EU/EFPIA Innovative Medicines Initiative 2 Joint Undertaking ConcePTION grant n°821,520. AH received a PhD grant from EHESP. publishedVersion

To reassess the efficacy of levothyroxine on subclinical hypothyroidism (SCH, 4.0 mIU/L ≤ TSH (thyroid stimulating hormone), Graphical Abstract

Background Chlorhexidine gluconate (CHG) body washes and emollient application may modulate bacterial pathogen colonization and prevent neonatal hospital-acquired infections. Methods This pilot, non-randomized, open-label trial, enrolled preterm neonates (1000-1500g; day 1-3 of life) at a tertiary hospital in Cape Town, South Africa. Participants were sequentially allocated to 4 trial arms (n=20 each): 1% aqueous CHG (CHG), 1% CHG plus emollient (CHG+EM), emollient only (EM) and standard of care (SOC: no antiseptic/emollient). Trial treatment/s were applied daily for 10 days (d) post-enrolment, documenting neonatal skin condition score. Anterior nose, neck, umbilical and perianal swabs for bacterial culture were collected at d1, d3, d10 and d16 post-enrolment, (±1 day), reporting pathogen acquisition rates and semi-quantitative bacterial colony counts. (ClinicalTrials.gov identifier: NCT03896893; trial status: closed). Findings Eighty preterm neonates (mean gestational age 30 weeks [SD 2]) were enrolled between 4 March and 26 August 2019. The bacterial pathogen acquisition rate (comparing d1 and d16 swabs) varied from 33·9% [95%CI 22·9-47·0] at the umbilicus, 39·3% [95%CI 27·6-52·4] at the neck, to 71·4% [95%CI 58·5-81·7] at both the nose and perianal region. At d10, CHG babies had reduced bacterial density detected from neck, umbilicus, and perianal swabs compared to other groups (see Table 3). Following intervention cessation, colonization density was similar across all trial arms, but S. aureus colonization was more prevalent among EM and CHG+EM babies. Neonatal skin condition score improved in babies receiving emollient application (EM: -0·87 [95%CI 0·69-1·06] and CHG+EM: -0·73 [0·45-0·99]), compared to the SOC and CHG arms (Table 2); no CHG-related skin reactions occurred. Interpretation Bacterial colonization density was significantly reduced in babies receiving 1% CHG washes but colonization levels rebounded rapidly post-intervention. Emollient application improved skin condition but was associated with higher rates of S. aureus colonization. Funding South African Medical Research Council; National Institutes of Health (TW010682).

Placenta‐origin pregnancy complications, including preeclampsia (PE), gestational diabetes mellitus (GDM), fetal growth restriction (FGR), and macrosomia (MA) are common occurrences in pregnancy, resulting in significant morbidity and mortality for both mother and fetus. However, despite their frequency, there are no reliable methods for the early diagnosis of these complications. Since cfDNA is mainly derived from placental trophoblasts and maternal hematopoietic cells, it might have information for gene expression which can be used for disease prediction. Here, low coverage whole‐genome sequencing on plasma DNA from 2,199 pregnancies is performed based on retrospective cohorts of 3,200 pregnant women. Read depth in the promoter regions is examined to define read‐depth distribution patterns of promoters for pregnancy complications and controls. Using machine learning methods, classifiers for predicting pregnancy complications are developed. Using these classifiers, complications are successfully predicted with an accuracy of 80.3%, 78.9%, 72.1%, and 83.0% for MA, FGR, GDM, and PE, respectively. The findings suggest that promoter profiling of cfDNA may be used as a biological biomarker for predicting pregnancy complications at early gestational age., Cell free DNA (cfDNA) comprises a nucleosome footprint that carries information of its tissue of origin. Different pregnancy complications show distinct patterns of promoter profiling. Based on promoter profiling and machine learning methods, the prediction classifiers can forecast four types of pregnancy complications, such as macrosomia, fetal growth restriction, gestational diabetes, and preeclampsia at early gestational age.

Objective To explore the effect on perinatal outcome of different fetal monitoring strategies for early‐onset fetal growth restriction (FGR). Methods This was a cohort analysis of individual participant data from two European multicenter trials of fetal monitoring methods for FGR: the Growth Restriction Intervention Study (GRIT) and the Trial of Umbilical and Fetal Flow in Europe (TRUFFLE). All women from GRIT (n = 238) and TRUFFLE (n = 503) who were randomized between 26 and 32 weeks' gestation were included. The women were grouped according to intervention and monitoring method: immediate delivery (GRIT) or delayed delivery with monitoring by conventional cardiotocography (CTG) (GRIT), computerized CTG (cCTG) only (GRIT and TRUFFLE) or cCTG and ductus venosus (DV) Doppler (TRUFFLE). The primary outcome was survival without neurodevelopmental impairment at 2 years of age. Results Gestational age at delivery and birth weight were similar in both studies. Fetal death rate was similar between the GRIT and TRUFFLE groups, but neonatal and late death were more frequent in GRIT (18% vs 6%; P, This article's abstract has been translated into Spanish and Chinese. Follow the links from the http://onlinelibrary.wiley.com/doi/10.1002/uog.20354/abstract to view the translations. This article has been selected for Journal Club. Click https://www.isuog.org/resource/uog-journal-club-January-2020.html to view slides and discussion points.

Objective To investigate the antenatal management and outcome in a large international cohort of monochorionic twin pregnancies with spontaneous or post‐laser twin anemia–polycythemia sequence (TAPS). Methods This study analyzed data of monochorionic twin pregnancies diagnosed antenatally with spontaneous or post‐laser TAPS in 17 fetal therapy centers, recorded in the TAPS Registry between 2014 and 2019. Antenatal diagnosis of TAPS was based on fetal middle cerebral artery peak systolic velocity > 1.5 multiples of the median (MoM) in the TAPS donor and, This article's abstract has been translated into Spanish and Chinese. Follow the links from the abstract to view the translations. A video abstract of this article is available online here.

How neurovascular coupling develops in preterm-born neonates has been largely neglected in scientific research. We measured visually evoked (flicker light) hemodynamic responses (HRs) in preterm-born neonates ( n = 25 , gestational age: 31.71 ± 3.37 weeks, postnatal age: 25.48 ± 23.94 days) at the visual cortex (VC) and left frontotemporal lobe (FTL) using functional near-infrared spectroscopy (fNIRS) neuroimaging. We found that the HR characteristics show a large intersubject variability but could be classified into three groups according to the changes of oxyhemoglobin concentration at the VC [(A) increase, (B) decrease, or (C) inconclusive]. In groups A and B, the HRs at the left FTL were correlated with those at the VC, indicating the presence of a frontotemporal-occipital functional connectivity. Neonates in group A had a higher weight at measurement compared to those in group B, and had the lowest baseline total hemoglobin concentration and hematocrit compared to group C. To the best of our knowledge, this is the first fNIRS study showing (1) that the HRs of preterm-born neonates need to be classified into subgroups, (2) that the subgroups differed in terms of weight at measurement, and (3) that HRs can be observed also at the FTL during visual stimulation. These findings add insights into how neurovascular coupling develops in preterm-born neonates.

Background The majority of epidemiological studies concerning possible adverse effects of paracetamol (acetaminophen) in pregnancy have been focussed on childhood asthma. Initial results of a robust association have been confirmed in several studies. Recently, a few cohort studies have looked at particular neurocognitive outcomes, and several have implicated hyperactivity. Objectives In order to confirm these findings, further information and results are required. Here, we assess whether paracetamol intake between 18 and 32 weeks gestation is associated with childhood behavioural and cognitive outcomes using a large population. Methods Data collected by the Avon Longitudinal Study of Parents and Children (ALSPAC) at 32 weeks gestation and referring to the period from 18 to 32 weeks, identified 43.9% of women having taken paracetamol. We used an exposome analysis first to determine the background factors associated with pregnant women taking the drug, and then allowed for those factors to assess associations with child outcomes (measured using regression analyses). Results We identified 15 variables independently associated with taking paracetamol in this time period, which were used as potential confounders. Of the 135 neurocognitive variables considered, adjusting for the likelihood of false discovery, we identified 56 outcomes for adjusted analyses. Adjustment identified 12 showing independent associations with paracetamol use at P

Identifying factors that influence fetal growth in a sex-specific manner can help unravel mechanisms that explain sex differences in adverse neonatal outcomes and in-utero origins of cardiovascular disease disparities. Premature aging of the placenta, a tissue that supports fetal growth and exhibits sex-specific epigenetic changes, is associated with pregnancy complications. Using DNA methylation-based age estimator, we investigated the sex-specific relationship of placental epigenetic aging with fetal growth across 13-40 weeks gestation, neonatal size, and risk of low birth weight. Placental epigenetic age acceleration (PAA), the difference between DNA methylation age and gestational age, was associated with reduced fetal weight among males but with increased fetal weight among females. PAA was inversely associated with fetal weight, abdominal circumference, and biparietal diameter at 32-40 weeks among males but was positively associated with all growth measures among females across 13-40 weeks. A 1-week increase in PAA was associated with 2-fold (95% CI 1.2, 3.2) increased odds for low birth weight and 1.5-fold (95% CI 1.1, 2.0) increased odds for small-for-gestational age among males. In all, fetal growth was significantly reduced in males but not females exposed to a rapidly aging placenta. Epigenetic aging of the placenta may underlie sex differences in neonatal outcomes.

Disruption of physiological ageing of the placenta is associated with obstetric complications. Altered lipid metabolism is a known trigger of tissue ageing, but the effect of maternal dyslipidemia on placental ageing is not clearly understood. We examined the relationship between maternal dyslipidemia and placental age acceleration (PAA), an epigenetic ageing measure derived from the difference between DNA methylation age and chronological gestational age. We also assessed whether the association varies by maternal pre-pregnancy obesity status and fetal sex. Placental data were obtained as part of the NICHD Fetal Growth Studies that involved participants from four race/ethnic groups. Placental DNA methylation age was estimated using 62 CpGs that have previously been found to have high placental age prediction accuracy. We used multivariable linear regression to test associations between maternal dyslipidemia during early gestation (i.e., high-density lipoprotein cholesterol (HDLc), low-density lipoprotein cholesterol (LDLc), total cholesterol (TChol), and triglycerides) and PAA adjusting for fetal sex and socio-demographic factors. Among normal-weight women, low HDLc, compared to high HDLc, was associated with 0.82 (95% CI: 0.00, 1.64) weeks higher PAA. Among women with female neonates, low HDLc, compared to high HDLc, was associated with 1.20 (95% CI: 0.17, 2.24) weeks higher PAA. High TChol was associated with 1.28 (95% CI: 0.12, 2.45) weeks higher PAA among Whites. In all, the study found that maternal dyslipidemia due to low HDLc was associated with accelerated epigenetic ageing of the placenta among mothers with normal pre-pregnancy weight and a female fetus.

Introduction Organ volumes at postmortem magnetic resonance imaging (PMMR) should reflect autopsy organ weights, and thus brain: liver volume ratios on imaging could be a surrogate for weight volume ratios at autopsy to indicate fetal growth restriction (FGR). This study aims to determine whether imaging-based organ volume ratios can replace autopsy organ weight ratios. Materials and Methods An unselected cohort of perinatal deaths underwent PMMR prior to autopsy. Semiautomated brain and liver volumes were compared to autopsy organ weights and ratios. Ratios were compared using Bland-Altman plots, and intra- and interobserver variability was assessed. Results A total 49 fetuses (25 male, 51%) at 17–42 weeks gestation were ­assessed. There was a reasonable correlation between autopsy-derived brain: liver weight ratios (AB: LwR) and imaging-derived brain: liver volume ratios (IB: LvR; r = 0.8). The mean difference between AB: LwR and IB: LvR was +0.7 (95% limits of agreement range −1.5 to +2.9). In a small subset where FGR was present, the optimal IB: LvR ≥5.5 gave 83.3% sensitivity and 86.0% specificity for diagnosis. There was acceptable agreement within readers (mean difference in IB: LvRs 0.77 ± 2.21) and between readers −0.36 ± 0.68. Conclusion IB: LvR provides a surrogate evaluation of AB: LwRs, and may be used as a marker of FGR where autopsy is declined.

Background Antenatal exposure to intra-uterine inflammation results in precocious Haptoglobin (Hp) expression (switch-on status). We investigated the relationships between foetal Hp expression at birth with newborn and childhood outcomes. Methods We evaluated cord blood samples from 921 newborns of women at imminent risk for preterm delivery randomised to either placebo (n = 471, birth gestational age (GA) median [min-max]: 31 [24–41] weeks) or magnesium sulphate (n = 450, GA 31 [24–42] weeks]). Primary outcome was infant death by 1 year and/or cerebral palsy (CP) ≥ 2 years of corrected age. Adjusted odd ratios (aOR) for neonatal and childhood outcomes were calculated controlling for GA, birth weight, sex, and magnesium exposure. Findings Primary outcome occurred in 2.8% of offspring. Newborns were classified in three pre-defined categorisation groups by cord blood Hp switch status and IL-6 levels: inflammation-nonexposed (Category 1, n = 432, 47%), inflammation-exposed haptoglobinemic (Category 2, n = 449, 49%), and inflammation-exposed anhaptoglobinemic or hypohaptoglobinemic (Category 3, n = 40, 4%). Newborns, found anhaptoglobinemic or hypohaptoglobinemic (Category 3) had increased OR for intraventricular haemorrhage (IVH) and/or death (aOR: 7.0; 95% CI: 1.4–34.6, p = 0.02) and for CP and/or death (aOR: 6.27; 95% CI: 1.7–23.5, p = 0.006) compared with Category 2. Foetal ability to respond to inflammation by haptoglobinemia resulted in aOR similar to inflammation-nonexposed newborns. Hp1-2 or Hp2-2 phenotypes protected against retinopathy of prematurity (aOR = 0.66; 95% CI 0.48–0.91, p = 0.01). Interpretation Foetal ability to switch-on Hp expression in response to inflammation was associated with reduction of IVH and/or death, and CP and/or death. Foetuses unable to mount such a response had an increased risk of adverse outcomes. Trial Registration: clinicaltrials.gov Identifier: NCT00014989

Objective: To demonstrate the differences in intrauterine fetal deaths and neonatal deaths between small for date (SFD) and Non-SFD neonates by applying a novel classification from both Z scores of placental weight (PW) and fetal/placental weight ratio (F/P) to small for gestational age (SGA) neonates. Methods: From 93,034 placentas/infants of mothers who vaginally delivered a singleton infant (Japan Perinatal Registry Network database 2013), SGA (n=7,780) was chosen according to the reference to Japanese neonatal growth chart. They were divided into two subgroups: SFD (body weight and height less than the 10th percentile, n=3,379) and Non-SFD (only body weight less than the 10th percentile, n=4,401). Z scores of PW and F/P based on the standard curves for sex-, parity-, and gestational-age-specific PW and F/P were calculated. The population was classified into 9 groups according to the combination of 'low vs. middle vs. high' i) PW Z score and ii) F/P Z score. In both i) and ii), ± 1.28 standard deviations in the Z scores were used for classifying low vs. middle vs. high, with 3×3 making 9 groups. From top-left to bottom-right, we labeled the groups as Group A to Group I. Results: SFD and Non-SFD neonates distributed in the same 6 groups (A, D, E, G, H, I). In group E, which was considered to be balanced placental and infant growth, the incidence of intrauterine fetal death was significantly higher in Non-SFD neonates than in SFD neonates. In group D, which was considered to be small placenta and balanced infant growth, the incidence of neonatal death was significantly higher in SFD neonates than in Non-SFD neonates. Conclusion: Assessment of SGA neonates by dividing them into SFD and Non-SFD neonates and application of a 9-group classification by PW and F/P Z scores were informative to understand the pathophysiological involvement of an imbalance between placental and fetal sizes.

Introduction: There are limited data available regarding the fraction of inspired oxygen (FiO2) predictive of the failure of continuous positive airway pressure (CPAP) in preterm infants with respiratory distress syndrome (RDS). Therefore, we investigated factors predictive of CPAP failure in the first 72 h of life, with special attention to the prognostic role of FiO2. Methods: This multicenter, prospective study enrolled infants 2 threshold was determined with ROC curve analysis. Results: Of 389 recruited newborns, CPAP failure occurred in 108 infants (27.8%). In the univariate model, each gestational week reduced the odds of CPAP failure by 19%, and each 100 g of birth weight reduced the odds by 16% (both p < 0.05). The risk was increased by 4.2 and 7.5% for each 0.01 increase in FiO2in the first and second hours of life, respectively. In the final multivariate model, birth weight and FiO2 in the second hour of life were the predictive measures. The prognostic threshold was FiO2 = 0.29 in the second hour of life (AUC 0.7; p < 0.0001), with a sensitivity of 73% and a specificity of 57%. CPAP failure implied a more than 20-fold higher risk of death and pneumothorax and a 2- to 5-fold higher risk of typical complications of prematurity, including bronchopulmonary dysplasia and severe intraventricular hemorrhage. Conclusion: FiO2 in the second hour of life is a significantpredictor of CPAP failure. The threshold of 0.29 best discriminates the CPAP outcome. Nonresponders to CPAP have a remarkably higher incidence of complications and a higher mortality rate.

Intraventricular hemorrhage (IVH) is usually associated with premature infants; however, it has been estimated to occur in up to 5% of infants born at term and may be associated with different prenatal, perinatal and postnatal risk factors. The present retrospective study included toddlers aged 13-24 months, born at term (≥36 weeks), referred to the Department of Rheumatology, Physical Medicine and Rehabilitation in Zagreb, Croatia, because they had at least two risk factors for neurodevelopmental delay. A total of 63 patients without hemorrhage were control subjects, while 103 case patients were children with IVH. The ordinal logistic regression revealed that neurodevelopmental outcome in term infants was associated with IVH grade (p0.05)., Intraventrikulsko krvarenje (IVK) obično se povezuje s prerano rođenom djecom, međutim, procjenjuje se kako se pojavljuje i do 5% djece rođene u terminu te se može povezati s različitim prenatalnim, perinatalnim i postnatalnim rizičnim čimbenicima. Ova retrospektivna studija obuhvatila je djecu u dobi od 13 do 24 mjeseca koja su rođena u terminu (≥36 tjedana), a koja su upućena na Kliniku za reumatologiju, fizikalnu medicinu i rehabilitaciju u Zagrebu zato što su imala barem dva rizična čimbenika za neuromotoričko odstupanje. Kontrolnu skupinu činilo je 63 djece bez intraventrikulskog krvarenja, dok je 103 djece imalo IVK. Ordinalna logistička regresija pokazala je kako je neuromotoričko odstupanje u djece rođene u terminu povezano sa stupnjem IVK-a (p0,05).

Introduction: The aim of this study was to investigate the development of midgut herniation in vivo using three-dimensional (3D) ultrasonographic volume and distance measurements and to create reference data for physiological midgut herniation in ongoing pregnancies in a tertiary hospital population. Materials and Methods: The transvaginal 3D ultrasound volumes of 112 women, seen weekly during the first trimester of pregnancy, were obtained and subsequently analysed in a virtual reality environment. The width of the umbilical cord insertion, the maximum diameter of the umbilical cord, and the volume of midgut herniation were measured from 6 until 13 weeks gestational age (GA). Results: All parameters had a positive relation with GA, crown-rump length, and abdominal circumference. In approximately 1 of 10 volumes no midgut herniation could be observed at 9 and 10 weeks GA. In 5.0% of the fetuses the presence of midgut herniation could still be visualised at 12 weeks GA. Conclusion: Reference charts for several dimensions of physiological midgut herniation were created. In the future, our data might be used as a reference in the first trimester for comparison in case of a suspected pathological omphalocele.

Objectives: To evaluate the efficacy of a single injection of 0.3 mg intravitreal ranibizumab for the treatment of retinopathy of prematurity (ROP). Methods:We conducted this retrospective case series study at King Abdul Aziz Medical City, Riyadh, Saudi Arabia. Seventy-four eyes of 37 preterm infants with ROP stage III with plus disease in zone I, posterior zone II, and aggressive posterior ROP received a single injection of 0.3 mg intravitreal ranibizumab. The favorable outcome measure was complete regression of the disease with normal vascularization of the retina of those infants. Results: The gestational age of the 37 included cases was in the range of 23–28 weeks and their body weight at birth was between 510 and 1,235 g except for one case with 2,550 g under oxygen therapy Conclusion: One injection of 0.3 mg intravitreal ranibizumab is effective in treating ROP stage III mainly in zones I and II.

Background and Objectives: The aim of this study was to evaluate the value of adding fetal growth velocity and first trimester maternal biomarkers to baseline screening, for the prediction of small-for-gestational age (SGA) and adverse neonatal outcomes. Method: A retrospective cohort study was conducted of singleton pregnancies in the Maastricht University Medical Centre between 2012 and 2016. The biomarkers PAPP-A, β-hCG, PlGF, and sFlt-1 were measured at 11–13 weeks of gestational age (GA) and two fetal growth scans were performed (18–22 and 30–34 weeks of GA). Differences in biomarkers and growth velocities were compared between appropriate-for-gestational age (AGA; birth weight percentile 10–90) and SGA (birth weight percentile Results: We included 296 singleton pregnancies. Compared to AGA (n = 251), SGA neonates (n = 45) had significantly lower growth velocities in the abdominal circumference (mm/week): 10.1 ± 0.98 versus 10.8 ± 0.98, p = 0.001. Compared with AGA, the SGA neonates had higher sFlt-1 multiples of the median (MoM): 0.89 (0.55) versus 0.76 (0.44), p = 0.023, and a higher sFlt-1/PlGF MoM ratio: 1.09 (1.03) versus 0.90 (0.64), p = 0.027. For a 15% false-positive rate, the prediction of SGA neonates increased from 44.8% for the baseline screening model to 56.5% after the addition of fetal growth velocities, and to 73.9% after the further addition of maternal biomarkers (PPV 9.6%, NPV 82.4%). The corresponding AUC for the three models were 0.722, 0.804, and 0.839, respectively. In addition, AGA neonates with reduced fetal growth velocity had more adverse neonatal outcomes compared to the AGA reference group (12.4 vs. 3.9%, p = 0.013). Conclusions: Combining fetal growth velocity with first trimester biomarkers resulted in a better prediction of SGA compared to baseline screening parameters alone. This approach could possibly result in reduced adverse neonatal outcomes in neonates, who are at a potential risk due to late mild placental dysfunction.

Introduction Respiratory distress syndrome (RDS) is defined as acute respiratory distress caused by surfactant deficiency that disturbs gas exchange in preterm infants. It is one of the most common neonatal problems and has been considered to be the most common cause of mortality and morbidity in preterm babies. Aim In this study, different variables were studied to predict factors for INSURE failure that might help in choosing infants for this procedure early. Methods Sixty three (63) patients were enrolled in this study as they met the inclusion criteria. All neonates were intubated briefly less than 2 hours, given natural surfactant in the dose of 3 ml/kg. As soon as it was appropriate and the neonate was stable in the form of normal heart rate and oxygenation, extubation was done and the baby connected to NCPAP at a pressure of 6 cmH2O. INSURE failure was considered if the patient needed mechanical ventilation for more than 72 hours while INSURE success was considered if we were able to wean the patient from CPAP or if the patient didn't need mechanical ventilation in the first 72 hours after surfactant administration. The indications for mechanical ventilation after INSURE procedure were respiratory distress with desaturation (02 sat less than 90%), recurrent apnea, Pco2 more than 60 mmHg. Results Since INSURE procedure is being largely applied in the neonatal intensive care units, it is important to determine the candidate neonate for this procedure with the minimum failure rate. Although the sample of our study is small, but we can suggest that neonate with gestational age less than 28, birth weight less than 1000 gm, umbilical PH of less than 7, low Apgar score and anemic patients are at high risk for INSURE failure. Conclusion Early diagnosis of PDA and IVH is essential to avoid INSURE method in these patients.

Introduction The labor pain is probably the most severe pain a mother experiences in her lifetime and is usually severe and prolonged in women with pregnancy. Aim To evaluate the effects of labor epidural and spinal analgesia on the incidence of cesarean section in painless delivery. Methods This randomized clinical trial was conducted on pregnant women aged 37-42 weeks of pregnancy. Female candidates for painless labor were divided into two groups: Epidural Analgesia (EA) and Spinal Analgesia (SA). Patients in the labor epidural group underwent analgesia using marcaine and fentanyl and after fully assuring the normal hemodynamic status of the mother and fetal hearth rate (FHR), labor spinal analgesia was used for other group. Results The average age of mothers was 27.5 years, their mean gestational age was 39 weeks and their mean weight was determined to be 72 kg. Frequency of cesarean delivery in mothers was found as 12.9%. Significantly, the incidence of cesarean section in the labor epidural analgesia group was higher than the labor spinal analgesia group (P = 0.02). In addition, the mean second phase of delivery in the labor epidural analgesia group was significantly higher than the labor spinal analgesia group (P = 0.03). There was no significant in 1st and 5th min Apgar scores between groups in infants (8.6 and 9.6, respectively). Conclusion Labor epidural analgesia and labor spinal analgesia result in a significant reduction in pain due to normal delivery. Due to the similarity of Apgar and arterial blood gas (ABG) in neonates, labor epidural analgesia may serve as an alternative in childbirth delivery.

Objective: To investigate the origin and outcome in a cohort of male and female fetuses with intra-abdominal cysts, in order to provide recommendations on management and to improve prenatal counselling. Methods: From 2002 to 2016, intra-abdominal cysts were detected by ultrasound in 158 fetuses. Cases with an umbilical vein varix were excluded. Fetal, neonatal, and maternal characteristics were retrieved from electronic patient files. Results: In female fetuses (n = 114), intra-abdominal cysts were diagnosed at a later gestational age compared with male fetuses (n = 44) (median 32.0 vs. 21.5 weeks, p < 0.001). The maximum prenatal cyst diameter was larger in female fetuses (median 35 vs. 17 mm, p < 0.001). Associated anomalies were less frequent in females (n = 15, 13.2%) compared with males (n = 15, 34.1%). In females (n = 114), most cysts were of ovarian origin (n = 81, 71.1%). Surgery was performed in 30 (26.3%) female and 15 (34.1%) male neonates (p = 0.33). Anorectal malformations were present in 6 cases and often not recognized prenatally. Conclusions: The differences in the origin of intra-abdominal cysts between male and female fetuses, resulting in differences in prenatal presentation and postnatal outcome should be taken into account in prenatal counseling within a multidisciplinary team. Evaluation of the fetal perianal muscular complex is indicated.

Aims: The aim of the study was to evaluate the effect of a Mediterranean diet (MedDiet), enhanced with extra virgin olive oil (EVOO) and nuts, on a composite of adverse maternofoetal outcomes of women with normoglycemia during pregnancy. Methods: This was a sub-analysis of the St Carlos gestational diabetes mellitus Prevention Study. Only normoglycemic women were analysed (697). They were randomized (at 8–12th gestational weeks) to: standard-care control group (337), where fat consumption was limited to 30% of total caloric intake; or intervention group (360), where a MedDiet, enhanced with EVOO and pistachios (40–42% fats of total caloric intake) was recommended. The primary outcome was a composite of maternofoetal outcomes (CMFOs): at least having 1 event of emergency C-section, perineal trauma, pregnancy-induced hypertension and preeclampsia, prematurity, large-for-gestational-age and small-for gestational-age. Results: Crude relative risk showed that the intervention was associated with a significant reduction in the risk of CMFOs (0.48 [0.37–0.63]; p = 0.0001), with a number-needed-to-treat = 5. Risk of urinary tract infections, emergency C-sections, perineal trauma, large-for-gestational-age and small-for gestational age new-borns were also significantly reduced. Conclusion: A MedDiet, enhanced with EVOO and nuts, was associated with a risk reduction of CMFOs in over 50% in normoglycemic pregnant women. Therefore, it might be a potentially adequate diet for pregnant women. Trial registration: Identifier ISRCTN84389045. The study was registered on September 27, 2013. Last edited on September 26, 2018

Background The optimal management of neonatal post-hemorrhagic hydrocephalus (PHH) is still debated, though several treatment options have been proposed. In the last years, ventriculosubgaleal shunt (VSgS) and neuroendosdcopic lavage (NEL) have been proposed to overcome the drawbacks of more traditional options, such as external ventricular drainage and ventricular access device. Methods We retrospectively reviewed neonates affected by PHH treated at our institution since September 2012 to September 2020. Until 2017 patients received VSgS as initial treatment. After the introduction of NEL, this treatment option was offered to patients with large intraventricular clots. After NEL, VSgS was always placed. Primary VSgS was reserved to patients without significant intraventricular clots and critically ill patients that could not be transferred to the operating room and undergo a longer surgery. Results We collected 63 babies (38 males and 25 females) with mean gestational age of 27.8 ± 3.8SD weeks (range 23–38.5 weeks) and mean birthweight of 1199.7 ± 690.6 SD grams (range 500–3320 g). In 6 patients, hemorrhage occurred in the third trimester of gestation, while in the remaining cases hemorrhage complicated prematurity. This group included 37 inborn and 26 outborn babies. Intraventricular hemorrhage was classified as low grade (I–II according to modified Papile grading scale) in 7 cases, while in the remaining cases the grade of hemorrhage was III to IV. Mean age at first neurosurgical procedure was 32.2 ± 3.6SD weeks (range 25.4–40 weeks). Death due to prematurity occurred in 5 patients. First-line treatment was VSgS in 49 patients and NEL in the remaining 14 cases. Mean longevity of VSgS was 30.3 days (range 10–97 days) in patients finally requiring an additional treatment of hydrocephalus. Thirty-two patients required one to three redo VSgS. Interval from initial treatment to permanent shunt ranged from 14 to 312 days (mean 70.9 days). CSF infection was observed in 5 patients (7.9%). Shunt dependency was observed in 51 out of 58 surviving patients, while 7 cases remained shunt-free at the last follow-up. Multiloculated hydrocephalus was observed in 14 cases. Among these, only one patient initially received NEL and was complicated by isolated trapped temporal horn. Conclusions VSgS and NEL are two effective treatment options in the management of PHH. Both procedures should be part of the neurosurgical armamentarium to deal with PHH, since they offer specific advantages in selected patients. A treatment algorithm combining these two options may reduce the infectious risk and the risk of multiloculated hydrocephalus.

Available evidence shows conflicting results regarding the association between hypertensive disorders of pregnancy (HDPs)/preeclampsia (PE) and small for gestational age (SGA) and birthweight discordance (BWD). This retrospective study of 2131 twin pregnancies aimed to evaluate the association of HDPs/PE with the presence of SGA and BWD. The eligible pregnancies were categorized into four study groups: concordant pairs without SGA fetuses, discordant pairs without SGA fetuses, concordant pairs with SGA fetuses, and discordant pairs with SGA fetuses. We applied binary logistic regression models to compare the incidence of HDPs/PE and multinomial logit regression models to evaluate the severity of PE between the study groups. The models were adjusted for potential confounders. Increases in HDPs were observed in concordant (aOR, 2.33; 95% CI: 1.46–3.73) and discordant (aOR, 3.50; 95% CI: 2.26–5.43) pregnancies with SGA fetuses but not in discordant pregnancies without SGA fetuses (aOR, 1.42; 95% CI: 0.81–2.49); increases in PE were also found in concordant (aOR, 1.87; 95% CI: 1.08–3.23) and discordant (aOR, 3.75; 95% CI: 2.36–5.96) pregnancies with SGA fetuses but not in discordant pregnancies without SGA fetuses (aOR, 1.34; 95% CI: 0.71–2.52). Discordant pregnancies with SGA fetuses were associated with severe PE (aRRR, 3.48; 95% CI: 1.79–6.77), whereas concordant pregnancies with SGA fetuses were associated with only mild PE (aRRR, 2.54; 95% CI: 1.33–4.88). Our results suggest that SGA is associated with the development of HDP/PE, while discordant growth is associated with the severity of PE. These associations need to be further investigated using estimated fetal weight (EFW).

Background Fetal growth restriction (FGR) is thought to negatively affect lung development resulting in increased respiratory morbidity. However, research performed in singletons is often limited by a certain level of bias caused by individual differences in genetic constitution, obstetrical and maternal factors. Methods Respiratory morbidity was compared between the smaller and the larger twin in monochorionic twins with selective fetal growth restriction (sFGR), defined as a birth weight discordance ≥ 20%, born in our center between 2010 and 2019 in this retrospective study. Respiratory distress syndrome (RDS) was diagnosed based on the clinical picture of a neonate with respiratory failure requiring mechanical ventilation and/or surfactant, confirmed by a chest X-ray. Bronchopulmonary dysplasia (BPD) was diagnosed when the neonate required treatment with >21% oxygen for at least 28 days. Findings Median gestational age at birth for the 94 included pregnancies was 32.4 (IQR 30.4-34.3) weeks. Within-pair analyses showed that the prevalence of RDS was lower in the smaller twin compared to the larger twin, 19.1% (18/94) vs 34.0% (32/94), respectively (p = 0.004). The odds of RDS for the larger twin was doubled (OR 2.1 (CI95% 1.3-3.5). In contrast, the rate of BPD in the smaller twin was higher as opposed to the larger twin, 16.7% (15/90) vs 6.7% (6/89), respectively (p = 0.008), with a more than doubled odds (OR 2.5 (CI95% 1.3-4.9)). Interpretation Despite being genetically identical, sFGR twins have different respiratory outcomes. Adverse growth condition in utero in the smaller twin is associated with a reduced odds of RDS at birth but a more than doubled odds of BPD, reflecting the pathophysiologic adverse effect of growth restriction on lung development. Funding The Dutch Heart Foundation (2017T075).

Background: Structural racism leads to adverse health outcomes, as highlighted by inequities in COVID-19 infections. We characterized Black/White disparities among pregnant women with SARS-CoV-2 in Cuyahoga County which has some of the most extreme health disparities in the U.S., such as a rate of Black infant mortality that is three times that of White counterparts. Methods: This was a retrospective cohort study using data collected as part of public health surveillance between March 16, 2020 until October 1, 2020. This study aimed to compare Black and Non-Black pregnant women infected with SARS-CoV-2 to understand how the distribution of risk factors may differ by race. Outcomes included age, gestational age at infection, medical co-morbidities, exposure history, socio-economic status, occupation, symptom severity and pregnancy complications. Findings: One hundred and sixty-two women were included. 81 (50%) were Black, 67 (41%) White, 9 (0·05%) Hispanic, 2 (0·01%) Asian; and three did not self-identify with any particular race. More than half who supplied occupational information (n = 132) were essential workers as classified by the CDC definition (55%, n = 73). Black women were younger (p = 0·0062) and more likely to identify an occupational contact as exposing them to SARS-CoV-2 (p = 0·020). Non-Black women were more likely to work from home (p = 0·018) and indicate a personal or household contact as their exposure (p = 0·020). Occupation was a risk factor for severe symptoms (aOR 4·487, p = 0·037). Most Black women lived in areas with median income