[Association between maternal plasma one-carbon biomarkers during pregnancy and fetal growth in twin pregnancies].

Objective: To characterize the relationship between the levels of plasma methyl donor and related metabolites (including choline, betaine, methionine, dimethylglycine and homocysteine) and fetal growth in twin pregnancies. Methods: A hospital-based cohort study was used to collect clinical data of 92 pregnant women with twin pregnancies and their fetuses who were admitted to Peking University Third Hospital from March 2017 to January 2018. Fasting blood was collected from the pregnant women with twin pregnancies (median gestational age: 18.9 weeks). The levels of methyl donors and related metabolites in plasma were quantitatively analyzed by high-performance liquid chromatography combined with mass spectrometry. The generalized estimation equation was used to analyze the relationship between maternal plasma methyl donors and related metabolites levels and neonatal outcomes of twins, and the generalized additive mixed model was used to analyze the relationship between maternal plasma methyl donors and related metabolites levels and fetal growth ultrasound indicators. Results: (1) General clinical data: of the 92 women with twin pregnancies, 66 cases (72%) were dichorionic diamniotic (DCDA) twin pregnancies, and 26 cases (28%) were monochorionic diamniotic (MCDA) twin pregnancies. The comparison of the levels of five plasma methyl donors and related metabolites in twin pregnancies with different basic characteristics showed that the median levels of plasma choline and betaine in pregnant women ≥35 years old were higher than those in pregnant women <35 years old, and the differences were statistically significant (all P<0.05). (2) Correlation between plasma methyl donor and related metabolites levels and neonatal growth indicators: after adjusting for confounding factors, plasma homocysteine level in pregnant women with twins was significantly negatively correlated with neonatal birth weight (ß=-47.9, 95%CI:-94.3- -1.6; P=0.043). Elevated methionine level was significantly associated with decreased risks of small for gestational age infants (SGA; OR=0.5, 95%CI: 0.3-0.9; P=0.021) and low birth weight infants (OR=0.6, 95%CI: 0.4-0.9; P=0.020). Increased homocysteine level was associated with increased risks of SGA (OR=1.5, 95%CI: 1.0-2.2; P=0.029) and inconsistent growth in twin fetuses (OR=1.9, 95%CI: 1.0-3.7; P=0.049). (3) Correlation between the levels of plasma methyl donors and related metabolites and intrauterine growth indicators of twins pregnancies: for every 1 standard deviation increase in plasma choline level in pregnant women with twin pregnancies, fetal head circumference, abdominal circumference, femoral length and estimated fetal weight in the second trimester increased by 1.9 mm, 2.6 mm, 0.5 mm and 20.1 g, respectively, and biparietal diameter, abdominal circumference and estimated fetal weight increased by 0.7 mm, 3.0 mm and 38.4 g in the third trimester, respectively, and the differences were statistically significant (all P<0.05). (4) Relationship between plasma methyl donor and related metabolites levels in pregnant women with different chorionicity and neonatal birth weight and length: the negative correlation between plasma homocysteine level and neonatal birth weight was mainly found in DCDA twin pregnancy (ß=-65.9, 95%CI:-110.6- -21.1; P=0.004). The levels of choline, betaine and dimethylglycine in plasma of MCDA twin pregnancy were significantly correlated with the birth weight and length of newborns (all P<0.05). Conclusion: Homocysteine level is associated with low birth weight in twins, methionine is associated with decreased risk of SGA, and choline is associated with fetal growth in the second and third trimesters of pregnancy.

Management of late-onset fetal growth restriction: pragmatic approach.

OBJECTIVES: There is limited prospective evidence to guide the management of late-onset fetal growth restriction (FGR) and its differentiation from small-for-gestational age. The aim of this study was to assess prospectively a novel protocol in which ultrasound criteria were used to classify women with suspected late FGR into two groups: those at low risk, who were managed expectantly until the anticipated date of delivery, and those at high risk, who were delivered soon after 37 weeks of gestation. We also compared the outcome of this prospective cohort with that of a historical cohort of women presenting similarly with suspected late FGR, in order to evaluate the impact of the new protocol. METHODS: This was a prospective study of women with a non-anomalous singleton pregnancy at ≥ 32 weeks' gestation attending a tertiary hospital in London, UK, between February 2018 and September 2019, with estimated fetal weight (EFW) ≤ 10th centile, or EFW > 10th centile in addition to a decrease in fetal abdominal circumference of ≥ 50 centiles compared with a previous scan, umbilical artery Doppler pulsatility index > 95th centile or cerebroplacental ratio < 5th centile. Women were classified as low or high risk based on ultrasound and Doppler criteria. Women in the low-risk group were delivered by 41 weeks of gestation, unless they subsequently met high-risk criteria, whereas women in the high-risk group (EFW < 3rd centile, umbilical artery Doppler pulsatility index > 95th centile or EFW between 3rd and 10th centiles (inclusive) with abdominal circumference drop or abnormal Dopplers) were delivered at or soon after 37 weeks. The primary outcome was adverse neonatal outcome and included hypothermia, hypoglycemia, neonatal unit admission, jaundice requiring treatment, suspected infection, feeding difficulties, 1-min Apgar score < 7, hospital readmission and any severe adverse neonatal outcome (perinatal death, resuscitation using inotropes or mechanical ventilation, 5-min Apgar score < 7, metabolic acidosis, sepsis, and cerebral, cardiac or respiratory morbidity). Secondary outcomes were adverse maternal outcome (operative delivery for abnormal fetal heart rate) and severe adverse neonatal outcome. Women managed according to the new protocol were compared with a historical cohort of 323 women delivered prior to the implementation of the new protocol, for whom management was guided by individual clinician expertise. RESULTS: Over 18 months, 321 women were recruited to the prospective cohort, of whom 156 were classified as low risk and 165 were high risk. Adverse neonatal outcome was significantly less common in the low-risk compared with the high-risk group (45% vs 58%; adjusted odds ratio (aOR), 0.6 (95% CI, 0.4-0.9); P = 0.022). There was no significant difference in the rate of adverse maternal outcome (18% vs 24%; aOR, 0.7 (95% CI, 0.4-1.2); P = 0.142) or severe adverse neonatal outcome (3.8% vs 8.5%; aOR, 0.5 (95% CI, 0.2-1.3); P = 0.153) between the low- and high-risk groups. Compared with women in the historical cohort classified retrospectively as low risk, low-risk women managed under the new protocol had a lower rate of adverse neonatal outcome (45% vs 58%; aOR, 0.6 (95% CI, 0.4-0.9); P = 0.026). CONCLUSIONS: Appropriate risk stratification to guide management of late FGR was associated with a reduced rate of adverse neonatal outcome in low-risk pregnancies. In clinical practice, a policy of expectantly managing women with a low-risk late-onset FGR pregnancy at term could improve neonatal and long-term development. Randomized controlled trials are needed to assess the effect of an evidence-based conservative management protocol for late FGR on perinatal morbidity and mortality and long-term neurodevelopment. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Which chart and which cut-point: deciding on the INTERGROWTH, World Health Organization, or Hadlock fetal growth chart.

OBJECTIVE: To determine how various centile cut points on the INTERGROWTH-21st (INTERGROWTH), World Health Organization (WHO), and Hadlock fetal growth charts predict perinatal morbidity/mortality, and how this relates to choosing a fetal growth chart for clinical use. METHODS: We linked antenatal ultrasound measurements for fetuses > 28 weeks' gestation from the British Columbia Women's hospital ultrasound unit with the provincial perinatal database. We estimated the risk of perinatal morbidity/mortality (decreased cord pH, neonatal seizures, hypoglycemia, and perinatal death) associated with select centiles on each fetal growth chart (the 3rd, 10th, the centile identifying 10% of the population, and the optimal cut-point by Youden's Index), and determined how well each centile predicted perinatal morbidity/mortality. RESULTS: Among 10,366 pregnancies, the 10th centile cut-point had a sensitivity of 11% (95% CI 8, 14), 13% (95% CI 10, 16), and 12% (95% CI 10, 16), to detect fetuses with perinatal morbidity/mortality on the INTERGROWTH, WHO, and Hadlock charts, respectively. All charts performed similarly in predicting perinatal morbidity/mortality (area under the curve [AUC] =0.54 for all three charts). The statistically optimal cut-points were the 39th, 31st, and 32nd centiles on the INTERGROWTH, WHO, and Hadlock charts respectively. CONCLUSION: The INTERGROWTH, WHO, and Hadlock fetal growth charts performed similarly in predicting perinatal morbidity/mortality, even when evaluating multiple cut points. Deciding which cut-point and chart to use may be guided by other considerations such as impact on workflow and how the chart was derived.

Associations of maternal blood pressure-raising polygenic risk scores with fetal weight.

Maternal blood pressure (BP) is associated with variations in fetal weight, an important determinant of neonatal and adult health. However, the association of BP-raising genetic risk with fetal weight is unknown. We tested the associations of maternal BP-raising polygenic risk scores (PRS) with estimated fetal weights (EFWs) at 13, 20, 27, and 40 weeks of gestation. This study included 622 White, 637 Black, 568 Hispanic, and 238 Asian pregnant women with genotype data from the NICHD Fetal Growth Studies. PRS of systolic (SBP) and diastolic BP (DBP) were calculated for each participant based on summary statistics from a recent genome-wide association study. Linear regression models were used to compare mean EFW differences between the highest versus lowest tertile of PRS, adjusting for maternal age, education, parity, genetic principal components and fetal sex. Hispanics in the highest DBP PRS tertile, compared to those in the lowest, had 8.1 g (95% CI: -15.1, -1.1), 32.4 g (-58.4, -6.4) and 119.4 g (-218.1, -20.7) lower EFW at 20, 27 and 40 weeks, respectively. Similarly, Asians in the highest DBP PRS tertile had 137.2 g (-263.5, -10.8) lower EFW at week 40, and those in the highest tertile of SBP PRS had 3.2 g (-5.8, -0.7), 12.9 g (-23.5, -2.4), and 39.8 g (-76.9, -2.7) lower EFWs at 13, 20, and 27 weeks. The findings showed that pregnant women's genetic susceptibility to high BP contributes to reduced fetal growth, suggesting a potential future clinical application in perinatal health.

Impact of Thyroid Autoimmunity on In Vitro Fertilization/Intracytoplasmic Sperm Injection Outcomes and Fetal Weight.

Several studies have reported the association between thyroid autoimmunity (TAI) and in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) outcomes. However, the findings remain controversial. We performed a large-scale retrospective cohort study to verify the effect of the presence of thyroid antibodies on IVF/ICSI outcomes and fetal growth and to evaluate the association between the types and titers of thyroid antibodies and adverse IVF/ICSI outcomes. A total of 16481 patients with infertility were referred to the Reproductive Center of Peking University Third Hospital for their first IVF/ICSI treatment between January 2018 and June 2019.Patients who sought IVF/ICSI treatment due to tubal or male factors infertility and who achieved fresh embryo transfer were included in our study. Finally, 778 patients with thyroid antibody positivity were selected as the TAI group, and 778 age-matched patients were included in the control group. The number of oocytes retrieved and high-graded embryos and the rates of clinical pregnancy, miscarriage, live birth, and preterm delivery were compared between the TAI and control groups. In addition, subgroup analysis was performed to demonstrate whether different types and titers of thyroid antibodies had different effects on IVF/ICSI outcomes. After adjusting for thyroid function, anti-Müllerian hormone levels, basal follicle stimulating hormone levels, basal estradiol levels and antral follicle count, the number of oocytes retrieved in the TAI group was significantly lower than that in the control group. No significant differences were observed between the two groups in the rates of clinical pregnancy, miscarriage, preterm delivery, live birth, and birth weight in singletons; however, the birth weight in twin pregnancy was significantly lower in the TAI group than in the control group. Subgroup analysis showed no association between the types or titers of thyroid antibodies and adverse IVF/ICSI outcomes. In conclusion, the presence of TAI in patients with infertility did not impair embryo quality or affect pregnancy outcomes, including clinical pregnancy, miscarriage, preterm delivery, and live birth. However, it decreased the number of oocytes retrieved and birth weight in twin pregnancy.

Placental Transcriptome Adaptations to Maternal Nutrient Restriction in Sheep.

Placental development is modified in response to maternal nutrient restriction (NR), resulting in a spectrum of fetal growth rates. Pregnant sheep carrying singleton fetuses and fed either 100% (n = 8) or 50% (NR; n = 28) of their National Research Council (NRC) recommended intake from days 35-135 of pregnancy were used to elucidate placentome transcriptome alterations at both day 70 and day 135. NR fetuses were further designated into upper (NR NonSGA; n = 7) and lower quartiles (NR SGA; n = 7) based on day 135 fetal weight. At day 70 of pregnancy, there were 22 genes dysregulated between NR SGA and 100% NRC placentomes, 27 genes between NR NonSGA and 100% NRC placentomes, and 22 genes between NR SGA and NR NonSGA placentomes. These genes mediated molecular functions such as MHC class II protein binding, signaling receptor binding, and cytokine activity. Gene set enrichment analysis (GSEA) revealed significant overrepresentation of genes for natural-killer-cell-mediated cytotoxicity in NR SGA compared to 100% NRC placentomes, and alterations in nutrient utilization pathways between NR SGA and NR NonSGA placentomes at day 70. Results identify novel factors associated with impaired function in SGA placentomes and potential for placentomes from NR NonSGA pregnancies to adapt to nutritional hardship.

Swedish intrauterine growth reference ranges for estimated fetal weight.

Fetal growth restriction is a strong risk factor for perinatal morbidity and mortality. Reliable standards are indispensable, both to assess fetal growth and to evaluate birthweight and early postnatal growth in infants born preterm. The aim of this study was to create updated Swedish reference ranges for estimated fetal weight (EFW) from gestational week 12-42. This prospective longitudinal multicentre study included 583 women without known conditions causing aberrant fetal growth. Each woman was assigned a randomly selected protocol of five ultrasound scans from gestational week 12 + 3 to 41 + 6. Hadlock's 3rd formula was used to estimate fetal weight. A two-level hierarchical regression model was employed to calculate the expected median and variance, expressed in standard deviations and percentiles, for EFW. EFW was higher for males than females. The reference ranges were compared with the presently used Swedish, and international reference ranges. Our reference ranges had higher EFW than the presently used Swedish reference ranges from gestational week 33, and higher median, 2.5th and 97.5th percentiles from gestational week 24 compared with INTERGROWTH-21st. The new reference ranges can be used both for assessment of intrauterine fetal weight and growth, and early postnatal growth in children born preterm.

Third-trimester growth diversity in small fetuses classified as appropriate-for-gestational age or small-for-gestational age at birth.

OBJECTIVE: We have shown previously that third-trimester growth in small fetuses (estimated fetal weight (EFW) < 10th percentile) with birth weight (BW) < 10th percentile is heterogeneous using individualized growth assessment (IGA). We aimed to test our hypothesis that individual growth patterns in small fetuses with BW > 10th percentile are also variable but in different ways. METHODS: This was a study of 191 cases with EFW < 10th percentile and BW > 10th percentile (appropriate-for-gestational-age (AGA) cohort), derived from the PORTO study. Composite size parameters were used to quantify growth pathology at individual third-trimester timepoints (individual composite prenatal growth assessment score (-icPGAS)). The fetal growth pathology score 1 (-FGPS1), calculated cumulatively from serial -icPGAS values, was used to characterize third-trimester growth patterns. Vascular-system evaluation included umbilical artery (UA) and middle cerebral artery (MCA) Doppler velocimetry. Outcome variables were birth age (preterm/term delivery) and BW (expressed as growth potential realization index for weight (GPRIWT ) and percentile). The findings from the AGA cohort were compared with those from small fetuses (EFW < 10th percentile) with BW < 10th percentile (small-for-gestational-age (SGA) cohort). RESULTS: The AGA cohort was found to have 134 fetuses (70%) with normal growth pattern and 57 (30%) with growth restriction based on IGA criteria. Seven growth-restriction -FGPS1 patterns were observed, including the previously defined progressive, late, adaptive and recovering types. The recovering type was the most common growth pattern in the AGA cohort (50.9%). About one-third of fetuses without any evidence of growth restriction had significant unexplained abnormalities in the UA (34%) and MCA (31%) and elevated mean GPRIWT values (113 ± 12.5%). Comparison of the AGA and SGA cohorts indicated a significant difference in the distribution of -FGPS1 growth patterns (P = 0.0001). Compared with the SGA cohort, the AGA cohort had more fetuses with a normal growth pattern (70% vs 38%) and fewer cases with growth restriction (30% vs 62%). While the recovering type was the most common growth-restriction pattern in the AGA cohort (51%), the progressive type was the primary growth-restriction pattern in the SGA cohort (44%). No difference in the incidence of MCA or UA abnormality was found between the SGA and AGA cohorts when comparing subgroups of more than 10 fetuses. CONCLUSIONS: Both normal-growth and growth-restriction patterns were observed in the AGA cohort using IGA, as seen previously in the SGA cohort. The seven types of growth restriction defined in the SGA cohort were also identified in AGA cases, but their distribution was significantly different. In one-third of cases without evidence of growth pathology in the AGA cohort, Doppler abnormalities in the UA and MCA were seen. This heterogeneity underscores the difficulty of accurate classification of fetal and neonatal growth status using conventional population-based methods. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Factors associated with small- and large-for-gestational-age in socioeconomically vulnerable individuals in the 100 Million Brazilian Cohort.

BACKGROUND: Evidence points to diverse risk factors associated with small- (SGA) and large-for-gestational-age (LGA) births. A more comprehensive understanding of these factors is imperative, especially in vulnerable populations. OBJECTIVES: To estimate the occurrence of and sociodemographic factors associated with SGA and LGA births in poor and extremely poor populations of Brazil. METHODS: The study population consisted of women of reproductive age (14-49 y), whose last child was born between 2012 and 2015. INTERGROWTH 21st consortium criteria were used to classify weight for gestational age according to sex. Multinomial logistic regression modeling was performed to investigate associations of interest. RESULTS: Of 5,521,517 live births analyzed, SGA and LGA corresponded to 7.8% and 17.1%, respectively. Multivariate analysis revealed greater odds of SGA in children born to women who self-reported as black (OR: 1.21; 95% CI: 1.19, 1.22), mixed-race (parda) (OR: 1.08; 95% CI: 1.07, 1.09), or indigenous (OR: 1.11; 95% CI: 1.06, 1.15), were unmarried (OR: 1.08; 95% CI: 1.07, 1.08), illiterate (OR: 1.47; 95% CI: 1.42, 1.52), did not receive prenatal care (OR: 1.57; 95% CI: 1.53, 1.60), or were aged 14-20 y (OR: 1.21; 95% CI: 1.20, 1.22) or 35-49 y (OR: 1.12; 95% CI: 1.10, 1.13). Considering LGA children, higher odds were found in infants born to women living in households with ≥3 inadequate housing conditions (OR: 1.11; 95% CI: 1.10, 1.12), in indigenous women (OR: 1.22; 95% CI: 1.19, 1.25), those who had 1-3 y of schooling (OR: 1.18; 95% CI: 1.17, 1.19), 1-3 prenatal visits (OR: 1.16; CI 95%: 1.14, 1.17), or were older (OR: 1.26; 95% CI: 1.25, 1.27). CONCLUSIONS: In poorer Brazilian populations, socioeconomic, racial, and maternal characteristics are consistently associated with the occurrence of SGA births, but remain less clearly linked to the occurrence of LGA births.

The impact of optimal dating on the assessment of fetal growth.

BACKGROUND: The impact of using the Intergrowth (IG) dating formulae in comparison to the commonly used Robinson dating on the evaluation of biometrics and estimated fetal weight (EFW) has not been evaluated. METHODS: Nationwide cross-sectional study of routine fetal ultrasound biometry in low-risk pregnant women whose gestational age (GA) had been previously assessed by a first trimester CRL measurement. We compared the CRL-based GA according to the Robinson formula and the IG formula. We evaluated the fetal biometric measurements as well as the EFW taken later in pregnancy depending on the dating formula used. Mean and standard deviation of the Z scores as well as the number and percentage of cases classified as <3rd, < 10th, >90th and > 97th percentile were compared. RESULTS: Three thousand five hundred twenty-two low-risk women with scans carried out after 18 weeks were included. There were differences of zero, one and 2 days in 642 (18.2%), 2700 (76.7%) and 180 (5%) when GA was estimated based on the Robinson or the IG formula, respectively. The biometry Z scores assessed later in pregnancy were all statistically significantly lower when the Intergrowth-based dating formula was used (p < 10- 4). Likewise, the number and percentage of foetuses classified as <3rd, < 10th, >90th and > 97th percentile demonstrated significant differences. As an example, the proportion of SGA foetuses varied from 3.46 to 4.57% (p = 0.02) and that of LGA foetuses from 17.86 to 13.4% (p < 10- 4). CONCLUSION: The dating formula used has a quite significant impact on the subsequent evaluation of biometry and EFW. We suggest that the combined and homogeneous use of a recent dating standard, together with prescriptive growth standards established on the same low-risk pregnancies, allows an optimal assessment of fetal growth.

Comparison of sonographic fetal weight estimation formulas in patients with preterm premature rupture of membranes.

BACKGROUND: Estimation of fetal weight (EFW) by ultrasound is useful in clinical decision-making. Numerous formulas for EFW have been published but have not been validated in pregnancies complicated by preterm premature rupture of membranes (PPROM). The purpose of this study is to compare the accuracy of EFW formulas in patients with PPROM, and to further evaluate the performance of the most commonly used formula - Hadlock IV. METHODS: A retrospective cohort study of women with singleton gestations and PPROM, admitted to a single tertiary center between 2005 and 2017 from 220/7-330/7 (n = 565). All women had an EFW within 14 days of delivery by standard biometry (biparietal diameter, head circumference, abdominal circumference and femur length). The accuracy of previously published 21 estimated EFW formulas was assessed by comparing the Pearson correlation with actual birth weight, and calculating the random error, systematic error, proportion of estimates within 10% of birth weight, and Euclidean distance. RESULTS: The mean gestational was 26.8 ± 2.4 weeks at admission, and 28.2 ± 2.6 weeks at delivery. Most formulas were strongly correlated with actual birth weight (r > 0.9 for 19/21 formulas). Mean systematic error was - 4.30% and mean random error was 14.5%. The highest performing formula, by the highest proportion of estimates and lowest Euclidean distance was Ott (1986), which uses abdominal and head circumferences, and femur length. However, there were minimal difference with all of the first 10 ranking formulas. The Pearson correlation coefficient for the Hadlock IV formula was strong at r = 0.935 (p < 0.001), with 319 (56.5%) of measurements falling within 10%, 408 (72.2%) within 15% and 455 (80.5%) within 20% of actual birth weight. This correlation was unaffected by gender (r = 0.936 for males, r = 0.932 for females, p < 0.001 for both) or by amniotic fluid level (r = 0.935 for mean vertical pocket < 2 cm, r = 0.943 for mean vertical pocket ≥2 cm, p < 0.001 for both). CONCLUSIONS: In women with singleton gestation and PPROM, the Ott (1986) formula for EFW was the most accurate, yet all of the top ten ranking formulas performed quite well. The commonly used Hadlock IV performed quite similarly to Ott's formula, and is acceptable to use in this specific setting.

Lipid metabolism is altered in maternal, placental, and fetal tissues of ewes with small for gestational age fetuses†.

Nutrient restriction (NR) has the potential to negatively impact birthweight, an indicator of neonatal survival and lifelong health. Those fetuses are termed as small for gestational age (SGA). Interestingly, there is a spectral phenotype of fetal growth rates in response to NR associated with changes in placental development, nutrient and waste transport, and lipid metabolism. A sheep model with a maternal diet, starting at Day 35, of 100% National Research Council (NRC) nutrient requirements (n = 8) or 50% NRC (n = 28) was used to assess alterations in fetuses designated NR SGA (n = 7) or NR NonSGA (n = 7) based on fetal weight at Day 135 of pregnancy. Allantoic fluid concentrations of triglycerides were greater in NR SGA fetuses than 100% NRC and NR NonSGA fetuses at Day 70 (P < 0.05). There was a negative correlation between allantoic fluid concentrations of triglycerides (R2 = 0.207) and bile acids (R2 = 0.179) on Day 70 and fetal weight at Day 135 for NR ewes (P < 0.05). Bile acids were more abundant in maternal and fetal blood for NR SGA compared to 100% NRC and NR NonSGA ewes (P < 0.05). Maternal blood concentrations of NEFAs increased in late pregnancy in NR NonSGA compared to NR SGA ewes (P < 0.05). Protein expression of fatty acid transporter SLC27A6 localized to placentomal maternal and fetal epithelia and decreased in Day 70 NR SGA compared to 100% NRC and NR NonSGA placentomes (P < 0.05). These results identify novel factors associated with an ability of placentae and fetuses in NR NonSGA ewes to adapt to, and overcome, nutritional hardship during pregnancy.

Ultrasound in the prediction of birthweight discordance in dichorionic twins.

INTRODUCTION: Large birthweight discrepancy has been identified as a risk factor for perinatal morbidity and mortality in twin pregnancies. However, it remains unclear whether such discordance can be predicted by various biological indices with specific cut-off values, and how these depend on the gestational age. We aimed to determine the most effective way to predict large birthweight discordance at various gestational ages. MATERIAL AND METHODS: A retrospective cohort study of dichorionic twins, live-born between 2008 and 2018, was conducted. Discordances in biparietal diameter, head circumference, humerus and femur length, abdominal circumference, and estimated fetal weight were calculated-([larger twin - smaller twin] / larger twin) × 100%-and compared between those with and without a large birthweight discordance (≥20%). Receiver operating characteristic curves were constructed to analyze the predictive characteristics of each parameter. RESULTS: Of 598 dichorionic twin pregnancies included, 83 (13.9%) had a birthweight discordance ≥20%. Group differences in biparietal diameter and head circumference discordance were the earliest to emerge (before 20 weeks of gestation), but became insignificant after 36 weeks, followed by humerus and femur length, estimated fetal weight discordance (after 20 weeks), and abdominal circumference discordance (after 28 weeks). The best predictors (with cut-off values) were discordance in biparietal diameter ≥7.8% at <20 weeks, head circumference ≥4.5% at 20-23+6  weeks, humerus length ≥4.5% at 24-27+6  weeks, and estimated fetal weight discordance (≥11.6% at 28-31+6  weeks, ≥10.5% at 32-35+6  weeks, and ≥15.0% ≥36 weeks), with sensitivity and specificity of 52%-77% and 69%-82%, respectively. CONCLUSIONS: Different predictors and cut-off values may be useful for predicting large inter-twin birthweight discordance in dichorionic twins at different gestational ages. It is more accurate to use biparietal diameter and head circumference discordance in the early second trimester, humerus length discordance in the late second trimester, and estimated fetal weight discordance in the third trimester.

Prenatal selection of cord blood donors according to the estimated fetal weight percentile and new approaches; results of a prospective cohort study.

BACKGROUND: Umbilical cord blood (UCB) donation is becoming inefficient and we recently proposed the estimated fetal weight percentile (EFWp) ≥60th as a predictor for a prenatal selection of donors. The aim of this study is to prospectively validate this and to identify new potential prenatal predictive parameters. STUDY DESIGN AND METHODS: Prospective cohort study of low-risk pregnancies undergoing third trimester ultrasound, whose UCB was collected at delivery (2016-2018) and compared with a historical cohort (2013-2016, N = 869). Several ultrasound parameters (EFWp, amniotic fluid, Doppler evaluation, placental thickness) were assessed ultrasound and perinatal data were collected. The association with standard of high quality of UCB was assessed by logistic regression analysis. RESULTS: Among 297 cases, 161 (54%) were selected according to the EFWp ≥60th for UCB units' collection. Cellular criteria for banking was achieved in 27 cases (16.8%), with an average increase of 1.7 times compared to the historical cohort (9.8%, P = .009). Selecting donors according to the 60th EFWp resulted in a higher probability of collecting clinical suitable UCB (P = .025). Among prenatal and perinatal parameters, EFWp, amniotic fluid, umbilical vein (UV) velocity, newborn weight and percentile and placental weight were significantly associated with a higher cellular content. At logistic regression analysis, significant contributors of UCB collection, were EFWp at 37-38 weeks ultrasound (OR 1.04; 95% CI: 1-1.08; P = .042) and UV velocity (OR 1.14; 95% CI: 1-1.29; P = .037). CONCLUSION: The evaluation of the EFWp equal or above 60 and the increased UV velocity can result in higher efficiency of public UCB donation programs.

Reduced growth velocity from the mid-trimester is associated with placental insufficiency in fetuses born at a normal birthweight.

BACKGROUND: Fetal growth restriction (FGR) due to placental insufficiency is a major risk factor for stillbirth. While small-for-gestational-age (SGA; weight < 10th centile) is a commonly used proxy for FGR, detection of FGR among appropriate-for-gestational-age (AGA; weight ≥ 10th centile) fetuses remains an unmet need in clinical care. We aimed to determine whether reduced antenatal growth velocity from the time of routine mid-trimester ultrasound is associated with antenatal, intrapartum and postnatal indicators of placental insufficiency among term AGA infants. METHODS: Three hundred and five women had biometry measurements recorded from their routine mid-trimester (20-week) ultrasound, at 28 and 36 weeks' gestation, and delivered an AGA infant. Mid-trimester, 28- and 36-week estimated fetal weight (EFW) and abdominal circumference (AC) centiles were calculated. The EFW and AC growth velocities between 20 and 28 weeks, and 20-36 weeks, were examined as predictors of four clinical indicators of placental insufficiency: (i) low 36-week cerebroplacental ratio (CPR; CPR < 5th centile reflects cerebral redistribution-a fetal adaptation to hypoxia), (ii) neonatal acidosis (umbilical artery pH < 7.15) after the hypoxic challenge of labour, (iii) low neonatal body fat percentage (BF%) reflecting reduced nutritional reserve and (iv) placental weight < 10th centile. RESULTS: Declining 20-36-week fetal growth velocity was associated with all indicators of placental insufficiency. Each one centile reduction in EFW between 20 and 36 weeks increased the odds of cerebral redistribution by 2.5% (odds ratio (OR) = 1.025, P = 0.001), the odds of neonatal acidosis by 2.7% (OR = 1.027, P = 0.002) and the odds of a < 10th centile placenta by 3.0% (OR = 1.030, P < 0.0001). Each one centile reduction in AC between 20 and 36 weeks increased the odds of neonatal acidosis by 3.1% (OR = 1.031, P = 0.0005), the odds of low neonatal BF% by 2.8% (OR = 1.028, P = 0.04) and the odds of placenta < 10th centile by 2.1% (OR = 1.021, P = 0.0004). Falls in EFW or AC of > 30 centiles between 20 and 36 weeks were associated with two-threefold increased relative risks of these indicators of placental insufficiency, while low 20-28-week growth velocities were not. CONCLUSIONS: Reduced growth velocity between 20 and 36 weeks among AGA fetuses is associated with antenatal, intrapartum and postnatal indicators of placental insufficiency. These fetuses potentially represent an important, under-recognised cohort at increased risk of stillbirth. Encouragingly, this novel fetal assessment would require only one additional ultrasound to current routine care, and adds to the potential benefits of routine 36-week ultrasound.

Pregnant alpha-1-microglobulin (A1M) knockout mice exhibit features of kidney and placental damage, hemodynamic changes and intrauterine growth restriction.

Alpha-1-microglobulin (A1M) is an antioxidant previously shown to be elevated in maternal blood during pregnancies complicated by preeclampsia and suggested to be important in the endogenous defense against oxidative stress. A knockout mouse model of A1M (A1Mko) was used in the present study to assess the importance of A1M during pregnancy in relation to the kidney, heart and placenta function. Systolic blood pressure (SBP) and heart rate (HR) were determined before and throughout gestation. The morphology of the organs was assessed by both light and electron microscopy. Gene expression profiles relating to vascular tone and oxidative stress were analyzed using RT-qPCR with validation of selected gene expression relating to vascular tone and oxidative stress response. Pregnant age-matched wild type mice were used as controls. In the A1Mko mice there was a significantly higher SBP before pregnancy that during pregnancy was significantly reduced compared to the control. In addition, the HR was higher both before and during pregnancy compared to the controls. Renal morphological abnormalities were more frequent in the A1Mko mice, and the gene expression profiles in the kidney and the heart showed downregulation of transcripts associated with vasodilation. Simultaneously, an upregulation of vasoconstrictors, blood pressure regulators, and genes for osmotic stress response, ion transport and reactive oxygen species (ROS) metabolism occurred. Fetal weight was lower in the A1Mko mice at E17.5. The vessels in the labyrinth zone of the placentas and the endoplasmic reticulum in the spongiotrophoblasts were collapsed. The gene profiles in the placenta showed downregulation of antioxidants, ROS metabolism and oxidative stress response genes. In conclusion, intact A1M expression is necessary for the maintenance of normal kidney, heart as well as placental structure and function for a normal pregnancy adaptation.

Controlled elevated temperatures during early-mid gestation cause placental insufficiency and implications for fetal growth in pregnant pigs.

It is known that pig offspring born from pregnant pigs exposed to elevated ambient temperatures during gestation have altered phenotypes, possibly due to placental insufficiency and impaired fetal growth. Therefore, the objective of this study was to quantify the effect of maternal heat exposure during early-mid gestation, when pig placentae grow heavily, on placental and fetal development. Fifteen pregnant pigs were allocated to thermoneutral (TN; 20 °C; n = 7) or cyclic elevated temperature conditions (ET; 28 to 33 °C; n = 8) from d40 to d60 of gestation. Following euthanasia of the pigs on d60, placental and fetal morphometry and biochemistry were measured. Compared to TN fetuses, ET fetuses had increased (P = 0.041) placental weights and a lower (P = 0.013) placental efficiency (fetal/placental weight), although fetal weights were not significantly different. Fetuses from ET pigs had reduced (P = 0.032) M. longissimus fibre number density and a thicker (P = 0.017) placental epithelial layer compared to their TN counterparts. Elevated temperatures decreased (P = 0.026) placental mRNA expression of a glucose transporter (GLUT-3) and increased (P = 0.037) placental IGF-2 mRNA expression. In conclusion, controlled elevated temperatures between d40 to d60 of gestation reduced pig placental efficiency, resulting in compensatory growth of the placentae to maintain fetal development. Placental insufficiency during early-mid gestation may have implications for fetal development, possibly causing a long-term phenotypic change of the progeny.

Identification of Pathways Associated with Placental Adaptation to Maternal Nutrient Restriction in Sheep.

Maternal nutrient restriction impairs placental growth and development, but available evidence suggests that adaptive mechanisms exist, in a subset of nutrient restricted (NR) ewes, that support normal fetal growth and do not result in intrauterine growth restriction (IUGR). This study utilized Affymetrix GeneChip Bovine and Ovine Genome 1.0 ST Arrays to identify novel placental genes associated with differential fetal growth rates within NR ewes. Singleton pregnancies were generated by embryo transfer and, beginning on Day 35 of pregnancy, ewes received either a 100% National Research Council (NRC) (control-fed group; n = 7) or 50% NRC (NR group; n = 24) diet until necropsy on Day 125. Fetuses from NR ewes were separated into NR non-IUGR (n = 6) and NR IUGR (n = 6) groups based on Day 125 fetal weight for microarray analysis. Of the 103 differentially expressed genes identified, 15 were upregulated and 88 were downregulated in NR non-IUGR compared to IUGR placentomes. Bioinformatics analysis revealed that upregulated gene clusters in NR non-IUGR placentomes associated with cell membranes, receptors, and signaling. Downregulated gene clusters associated with immune response, nutrient transport, and metabolism. Results illustrate that placentomal gene expression in late gestation is indicative of an altered placental immune response, which is associated with enhanced fetal growth, in a subpopulation of NR ewes.

Significant deviations in sonographic fetal weight estimation: causes and implications.

PURPOSE: To allocate parameters associated with significant deviations in sonographic estimated fetal weight (EFW) and evaluate labor outcomes in such circumstances. METHODS: Retrospective case-control study of women with a singleton gestation who underwent sonographic EFW within a week prior to delivery in a single tertiary university-affiliated medical center (2012-2018). The study group was comprised of 177 pregnancies in which sonographic EFW was at least ± 20% of actual birth weight, matched to 354 pregnancies with an accuracy of ± 1% of sonographic EFW to actual birth weight. Matching was based on age, gravidity, parity, and gestational age at delivery. Placental location, fetal presentation, spine position and amniotic fluid volumes during the ultrasound evaluation, as well as pregnancy outcomes, were compared between groups. RESULTS: Median gestational age at delivery (37.0 vs. 38.0 weeks, p < 0.001), median estimated fetal weight (2591 vs. 3198 g, p < 0.001) and median birth weight (2916 vs. 3158 g, p = 0.001) were all lower in the non-accurate compared to the accurate weight estimation group. Ultrasound parameters significantly differed between groups. Women in the non-accurate, compared to accurate weight estimations group, presented higher rates of breech presentation (20.34 vs. 9.89%, p = 0.001), lower rates of anterior placenta (44.6 vs. 53.67%, p = 0.002) and lateral spine position (80.23 vs. 88.42%, p < 0.021). Multivariate analysis was utilized to control potential confounders, non-lateral spine position was found to be an independent risk factor for inaccuracies in EFW [OR = 2.505, 95% CI 1.159-5.416, p = 0.0196]. Obstetric parameters did not differ between groups. Higher rates of neonatal intensive care unit admission (20.34 vs. 11.02%, p = 0.003) and neonatal respiratory complications (7.34 vs. 3.39%, p = 0.042) were observed in the non-accurate EFW subgroup. Multivariate analysis demonstrated that inaccuracy in sonographic EFW was an independent risk factor for NICU admission (OR = 2.4, 95% CI 1.034-5.577, p = 0.041). CONCLUSION: Accuracy in sonographic EFW depends on fetal presentation, spine position and placental location. Non-accuracy is associated with adverse neonatal outcomes.

Stillbirth at term: Does size really matter?

Placental dysfunction has a deleterious influence on fetal size and is associated with higher rates of perinatal morbidity and mortality. This association underpins the strategy of fetal size evaluation as a mechanism to identify placental dysfunction and prevent stillbirth. The optimal method of routine detection of small for gestational age (SGA) remains to be clarified with choices between estimation of symphyseal-fundal height versus routine third-trimester ultrasound, various formulae for fetal weight estimation by ultrasound, and the variable use of national, customized, or international fetal growth references. In addition to these controversies, the strategy for detecting SGA is further undermined by data demonstrating that the relationship between fetal size and adverse outcome weakens significantly with advancing gestation such that near term, the majority of stillbirths and adverse perinatal outcomes occur in normally sized fetuses. The use of maternal serum biochemical and Doppler parameters near term appears to be superior to fetal size in the identification of fetuses compromised by placental dysfunction and at increased risk of damage or demise. Multiparameter models and predictive algorithms using maternal risk factors, and biochemical and Doppler parameters have been developed, but need to be prospectively validated to demonstrate their effectiveness.