Role of gestational age at time of placental laser surgery in outcomes of twin-to-twin transfusion syndrome.

OBJECTIVE: There are conflicting data on whether fetoscopic laser photocoagulation of placental anastomoses (FLP) for treating twin-to-twin transfusion syndrome (TTTS) is associated with lower rates of overall survival. The objective of this study is to characterize survival and other associated morbidity after FLP across gestational ages of FLP. METHODS: This is a secondary analysis of prospectively collected data on patients with monochorionic-diamniotic twins that had FLP for TTTS at two centers between 2011 and 2022. Patients were divided into gestational age epochs for FLP before 18 wks, 18 0/7 - 19 6/7 wks, 20 0/7 - 21 6/7 wks, 22 0/7 - 23 6/7 wks, 24 0/7 - 25 6/7 wks and after 26 wks. Demographic characteristics, sonographic characteristics of TTTS and operative characteristics were compared across the gestational age epochs. Outcomes including overall survival, preterm delivery, preterm prelabor rupture of membranes (PPROM), intrauterine fetal demise (IUFD) and neonatal demise (NND) were also compared across gestational age epochs. Multivariate analysis was performed by fitting logistic regression models for these outcomes. Kaplan-Mejer curves were constructed to compare the interval from PPROM to delivery for each gestational age epoch. RESULTS: There were 768 patients that met inclusion criteria. The dual survival rate was 61.3% for FLP performed prior to 18 weeks compared to 78.0% - 86.7% across later gestational age epochs. This appears to be related to increased rates of donor IUFD following FLP performed before, versus after 18 weeks (28.0% vs. 9.3% - 14.1%). Rates of recipient IUFD/NND and donor NND were similar regardless of gestational age of FLP. Rates of PPROM were higher for earlier FLP, ranging from 45.6% for FLP before 18 weeks to 11.9% for FLP at 24 - 26 weeks gestational age. However, the gestational age of delivery was similar across gestational age epochs with a median of 31.7 weeks. In multivariate analysis, donor loss was independently associated with FLP before 18 weeks after adjusting for selective fetal growth restriction, Quintero stage and other covariates. PPROM and PTD were also associated with FLP before 18 weeks after adjusting for cervical length, placental location, trocar size, laser energy and amnioinfusion. CONCLUSION: FLP performed at earlier gestational ages is associated with lower overall survival, which is driven by higher risk of donor IUFD, as opposed to differences in PPROM or PTD. Counseling regarding survival should account for gestational age of presentation. This article is protected by copyright. All rights reserved.

Risk stratification for donor twin fetal death by evaluating middle cerebral artery in twin-to-twin transfusion syndrome in absence of twin anemia polycythemia sequence.

OBJECTIVE: To determine the association of high middle cerebral artery peak systolic velocity (MCA-PSV) with fetal demise in donor twins among pregnancies complicated by twin-to-twin transfusion syndrome (TTTS) in the absence of twin anemia polycythemia sequence (TAPS). METHODS: This prospective cohort study included TTTS cases that underwent laser surgery between 2011 and 2022 at a single center. TAPS cases were excluded from the study. The primary objective was to explore the association of high MCA-PSV (>1.5 multiples of the median) with fetal demise of the donor twin among pregnancies complicated by TTTS. Secondary objectives were: 1) to evaluate if donor or recipient MCA-PSV is associated with an increased risk for their corresponding fetal death using receiving operator characteristic curve analysis; and 2) to compare the proportion of fetuses with low MCA pulsatility index among donor twins with high MCA-PSV and in those with normal MCA-PSV to evaluate the contribution of blood flow redistribution to high MCA-PSV. Multivariable and Poisson regression analysis were performed to explore the association of isolated high donor MCA-PSV and fetal demise, adjusted for TTTS stage, selective fetal growth restriction (sFGR), and other confounders. p<0.05 was considered significant. RESULTS: Out of 660 TTTS cases, donor MCA-PSV was unavailable in 48 (7.3%) cases. Of the remaining 612 patients, 9 (1.5%) were lost to follow-up, and 96 TAPS cases were excluded. High donor MCA-PSV was seen in 6.5% (33/507) of the study population. High donor MCA-PSV was an independent risk factor for donor fetal demise (adjusted relative risk (aRR) of 4.52; 95% CI: 2.72-7.50), adjusted for confounders. Regression analysis restricted to each Quintero TTTS stage demonstrated that high donor MCA-PSV was an independent risk factor for donor fetal demise in Quintero stage II (aRR of 14.21; 95% CI: 1.09-186.2) and Quintero stage III (aRR of 3.41; 95% CI: 1.82-6.41). Donor MCA-PSV was associated with donor fetal demise (AUC: 0.69; p<0.001), but recipient MCA-PSV was not associated with its corresponding fetal demise (AUC: 0.54; p=0.44). A higher proportion of donor twins in the group with high MCA-PSV had a low MCA pulsatility index than in those with normal MCA-PSV (33.3% vs. 15.5%; p=0.016). CONCLUSIONS: Elevated donor MCA-PSV without TAPS prior to laser surgery is associated with a 4-fold increased risk for donor fetal demise, adjusted for sFGR, TTTS stage, and other confounders. Doppler evaluation of donor MCA-PSV prior to laser surgery can further stratify TTTS staging to evaluate the risk for donor fetal demise. This article is protected by copyright. All rights reserved.

Reduction in cervical length after vaginal progesterone in women with short cervix is significantly associated with preterm delivery at ≤ 34 weeks and < 37 weeks of gestation.

OBJECTIVE: To evaluate the association between changes in cervical length (CL) after vaginal progesterone treatment and preterm delivery (PTD). METHODS: This was a retrospective cohort study that included 197 singleton pregnancies without (n = 178) and with (n = 19) a history of PTD which were found to have a short cervix (≤ 25 mm) between 18 + 0 and 23 + 6 weeks' gestation with a follow-up transvaginal CL measurement taken at least 1 week after vaginal progesterone treatment started. Receiver-operating-characteristics (ROC)-curve analysis was performed and three CL shortening patterns were evaluated: (1) ≥ 10% reduction; (2) ≥ 20% reduction; and (3) ≥ 5 mm reduction relative to the first CL measurement. The predictive performance of each CL reduction cut-off and its association with PTD ≤ 34 weeks and PTD < 37 weeks were evaluated. RESULTS: Overall, the rate of PTD ≤ 34 weeks was 16.8% (33/197) and that of PTD < 37 weeks was 36.5% (72/197). The area under the ROC curve of cervical shortening expressed in % for predicting PTD ≤ 34 weeks and PTD < 37 weeks was 0.703 and 0.608, respectively. Cervical shortening was observed in 60/197 (30.5%) patients, with 49/60 (81.7%) women showing ≥ 10% reduction, 32/60 (53.3%) ≥ 20% reduction and 27/60 (45.0%) ≥ 5 mm reduction in CL. Sensitivity and specificity for PTD ≤ 34 weeks were, respectively, 48.5% and 79.9% for ≥ 10% reduction; 36.4% and 87.8% for ≥ 20% reduction; and 27.3% and 89.0% for ≥ 5 mm reduction in CL. For PTD < 37 weeks, sensitivity and specificity were, respectively, 36.1% and 81.6% for ≥ 10% reduction; 27.8% and 90.4% for ≥ 20% reduction; and 20.8% and 90.4% for ≥ 5 mm reduction in CL. The highest positive likelihood ratios for PTD ≤ 34 and < 37 weeks were for ≥ 20% CL reduction (2.98 (95% CI, 1.62-5.49) and 2.89 (95% CI, 1.52-5.57), respectively). Despite significant differences in sensitivity among the different cut-offs for cervical shortening, favoring the ≥ 10% reduction cut-off, a reduction of ≥ 20% in CL showed the strongest association with PTD ≤ 34 weeks (odds ratio (OR), 4.11 (95% CI, 1.75-9.62)) and < 37 weeks (OR, 3.62 (95% CI, 1.65-7.96)), as compared with a less pronounced reduction in CL. CONCLUSIONS: In women with a short cervix treated with vaginal progesterone, a reduction in CL on a subsequent ultrasound scan can predict PTD ≤ 34 and < 37 weeks. A ≥ 20% reduction in CL had the highest positive likelihood ratio and association with PTD ≤ 34 and < 37 weeks compared with ≥ 10% or ≥ 5 mm reduction. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Management of large placental chorioangioma: two-port laser approach for fetal intervention.

OBJECTIVES: There is a paucity of literature providing evidence-based guidelines for the management of large placental chorioangioma (≥ 4 cm in diameter). The objectives of this study were to compare outcomes between patients managed expectantly and those undergoing in-utero intervention and to describe the different in-utero techniques used for cessation of blood flow to the tumor and the associated outcome. METHODS: This was a retrospective cohort study of 34 patients referred for the management of large placental chorioangioma in a single center between January 2011 and December 2022, who were managed expectantly or underwent in-utero intervention. In-utero intervention was performed when the fetus developed any signs of impending compromise, including high combined cardiac output (CCO), worsening polyhydramnios or abnormal fetal Doppler velocimetry findings. Interventions included radiofrequency ablation (RFA), interstitial laser ablation (ILA) and single-port or two-port fetoscopic laser photocoagulation (FLP). Treatment selection was dependent on the proximity of the tumor to the umbilical cord insertion (UCI) and placental location. The two-port technique was performed in patients with a chorioangioma with large feeding vessels (≥ 3 mm) located in the posterior placenta, in which one port was used for occlusion using bipolar forceps and the other port was used for laser photocoagulation of the feeding vessels downstream. The single-port technique was used for chorioangioma with small feeding vessels (< 3 mm) located in the posterior placenta. ILA or RFA was performed in cases with an anterior placenta. Supportive treatments, including amnioreduction and intrauterine transfusion (IUT), were performed for worsening polyhydramnios and suspected fetal anemia based on middle cerebral artery Doppler flow studies, respectively. Comparative statistical analysis between cases undergoing expectant management vs in-utero intervention was performed. Descriptive details were provided for patients who underwent in-utero intervention. RESULTS: Thirty-four cases of large chorioangioma were evaluated, of which 25 (73.5%) were managed expectantly and nine (26.5%) underwent intervention. The frequency of polyhydramnios was significantly higher in the intervention group compared with the expectant-management group (66.7% vs 8.0%, P < 0.001). The live-birth rate among expectantly managed cases with large chorioangioma was significantly higher compared with that in cases that underwent in-utero intervention (96.0% vs 62.5%, P = 0.01). In the intervention group, preoperative CCO was elevated in all cases with available information and preoperative hydrops was present in 33.3% (3/9) of cases. One patient experienced fetal demise following IUT prior to planned FLP. Among the remaining eight patients, four underwent two-port FLP, two underwent single-port FLP, one underwent ILA and one underwent both ILA and RFA. All three cases in which hydrops was present at the time of intervention resulted in fetal demise. CONCLUSIONS: In-utero interventions aimed at cessation of blood flow in the feeding vessels are a therapeutic option for the management of cases with large chorioangioma. The two-port percutaneous technique appears to improve the efficiency of FLP when a large chorioangioma with large feeding vessels is located in the posterior placenta. We propose that in-utero interventions for large chorioangioma should be initiated prior to the development of fetal hydrops. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Primary vs patch-based skin closure for in-utero spina bifida repair.

OBJECTIVE: During in-utero spina bifida (SB) repair, closure of large defects is often challenging, requiring tissue graft for watertight skin closure. No prior studies have compared primary skin closure vs patch-based repair. Our objective was to compare neonatal and 1-year outcomes associated with these two types of skin closure for in-utero SB repair. METHODS: This was a prospective cohort study of 102 patients undergoing open prenatal SB repair from September 2011 to August 2021 at a single institution. All patients met the inclusion criteria of the Management of Myelomeningocele Study (MOMS), and the surgical procedure for in-utero SB repair was similar to that described in the MOMS trial. During the surgery, if primary skin approximation was not feasible due to the large size of the defect, the decision was at the discretion of the pediatric neurosurgeon to utilize a patch for closure. Neonatal outcomes at birth and 1-year outcomes were compared between the primary skin and patch-based closure groups. RESULTS: Of 102 patients included in the study, 70 (68.6%) underwent primary skin closure and 32 (31.4%) patch-based closure. The patch type included acellular bovine skin matrix (Durepair®; n = 31) and human acellular dermal matrix (Alloderm®; n = 1). Fetuses with myeloschisis were more likely to require patch-based repair than those with myelomeningocele. The median time of fetal repair was 4 min longer for patch-based compared with primary skin closure (37 vs 33 min; P = 0.001). Following patch-based repair, neonates had a longer length of stay in the neonatal intensive care unit (NICU) by 24 days (adjusted risk ratio, 2.40 (95% CI, 1.41-4.29)) compared to those that underwent primary skin closure. There was no difference between the two groups in the other neonatal outcomes, including the need for ventriculoperitoneal shunt placement and cerebrospinal fluid leakage. Outcome at 1 year of age was available for 90 infants. Need for wound revision within their first year after birth was more common in infants who underwent patch-based vs those with primary skin closure (19.4% vs 5.1%; P = 0.05). There was no difference between the two groups in other 1-year outcomes, including the need for ventriculoperitoneal shunt placement by 1 year of age and surgery for tethered cord. CONCLUSIONS: Patch-based closure during SB repair is often needed in fetuses with myeloschisis and is associated with prolonged fetal surgery time, long NICU stay and need for wound revision within the first year after birth. Further studies are required to identify optimal patches for SB repair or alternative methods to improve outcome. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Doppler evaluation of normal and abnormal placenta.

Doppler techniques are needed for the evaluation of the intraplacental circulation and can be of great value in the diagnosis of placental anomalies. Highly sensitive Doppler techniques can differentiate between the maternal (spiral arteries) and fetal (intraplacental branches of the umbilical artery) components of the placental circulation and assist in the evaluation of the placental functional units. A reduced number of placental functional units can be associated with obstetric complications, such as fetal growth restriction. Doppler techniques can also provide information on decidual vessels and blood movement. Abnormal decidual circulation increases the risk of placenta accreta. Doppler evaluation of the placenta greatly contributes to the diagnosis and clinical management of placenta accreta, vasa previa, placental infarcts, placental infarction hematoma, maternal floor infarction, massive perivillous fibrin deposition and placental tumors. However, it has a limited role in the diagnosis and clinical management of placental abruption, placental hematomas, placental mesenchymal dysplasia and mapping of placental anastomoses in monochorionic twin pregnancies. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Ultrasound and Doppler findings in pregnant women with SARS-CoV-2 infection.

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.

Reduced fetal growth velocity precedes antepartum fetal death.

OBJECTIVES: To determine whether decreased fetal growth velocity precedes antepartum fetal death and to evaluate whether fetal growth velocity is a better predictor of antepartum fetal death compared to a single fetal biometric measurement at the last available ultrasound scan prior to diagnosis of demise. METHODS: This was a retrospective, longitudinal study of 4285 singleton pregnancies in African-American women who underwent at least two fetal ultrasound examinations between 14 and 32 weeks of gestation and delivered a liveborn neonate (controls; n = 4262) or experienced antepartum fetal death (cases; n = 23). Fetal death was defined as death diagnosed at ≥ 20 weeks of gestation and confirmed by ultrasound examination. Exclusion criteria included congenital anomaly, birth at < 20 weeks of gestation, multiple gestation and intrapartum fetal death. The ultrasound examination performed at the time of fetal demise was not included in the analysis. Percentiles for estimated fetal weight (EFW) and individual biometric parameters were determined according to the Hadlock and Perinatology Research Branch/Eunice Kennedy Shriver National Institute of Child Health and Human Development (PRB/NICHD) fetal growth standards. Fetal growth velocity was defined as the slope of the regression line of the measurement percentiles as a function of gestational age based on two or more measurements in each pregnancy. RESULTS: Cases had significantly lower growth velocities of EFW (P < 0.001) and of fetal head circumference, biparietal diameter, abdominal circumference and femur length (all P < 0.05) compared to controls, according to the PRB/NICHD and Hadlock growth standards. Fetuses with EFW growth velocity < 10th percentile of the controls had a 9.4-fold and an 11.2-fold increased risk of antepartum death, based on the Hadlock and customized PRB/NICHD standards, respectively. At a 10% false-positive rate, the sensitivity of EFW growth velocity for predicting antepartum fetal death was 56.5%, compared to 26.1% for a single EFW percentile evaluation at the last available ultrasound examination, according to the customized PRB/NICHD standard. CONCLUSIONS: Given that 74% of antepartum fetal death cases were not diagnosed as small-for-gestational age (EFW < 10th percentile) at the last ultrasound examination when the fetuses were alive, alternative approaches are needed to improve detection of fetuses at risk of fetal death. Longitudinal sonographic evaluation to determine growth velocity doubles the sensitivity for prediction of antepartum fetal death compared to a single EFW measurement at the last available ultrasound examination, yet the performance is still suboptimal. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Doppler changes in umbilical artery, middle cerebral artery, cerebroplacental ratio and ductus venosus during open fetal microneurosurgery for intrauterine open spina bifida repair.

OBJECTIVE: To describe changes in fetal Doppler parameters during a novel technique for open fetal microneurosurgery for open spina bifida (OSB) repair. METHODS: This was a prospective study of 44 fetuses undergoing open fetal surgery for OSB repair using a novel microneurosurgery approach that is characterized by a mini-hysterotomy (diameter of 15 mm), minimal fetal manipulation and maintenance of a constant normal amniotic fluid volume throughout the procedure. Doppler velocimetry of the umbilical artery (UA), fetal middle cerebral artery (MCA) and ductus venosus (DV) was performed before the start of surgery and at prespecified timepoints during fetal surgery. UA pulsatility index (PI) > 95th percentile, DV-PI > 95th percentile, MCA-PI < 5th percentile and cerebroplacental ratio (CPR) < 5th percentile were considered abnormal. RESULTS: Median gestational age at fetal surgery was 25.2 weeks (range, 22.9-27.9 weeks). Doppler recordings were successfully obtained in all cases during all timepoints throughout the surgery. As compared with Doppler values before surgery, there was a significant increase in the proportion of fetuses with MCA-PI < 5th percentile (63.6% vs 13.6%; P < 0.001), CPR < 5th percentile (65.9% vs 15.9%; P < 0.001) and DV-PI > 95th percentile (22.7% vs 0%; P = 0.01) and a non-significant increase in the proportion of fetuses with UA-PI > 95th percentile (11.4% vs 0%; P = 0.12) during fetal surgery. None of the fetuses showed absent or reversed end-diastolic velocity in the UA or absent or reversed DV a-wave at any stage during OSB repair. All abnormal Doppler parameters returned to normal after surgery. CONCLUSIONS: During open fetal surgery for OSB repair, a small hysterotomy, reduced fetal manipulation and maintenance of a normal amniotic fluid volume seem to prevent severe fetal Doppler abnormalities. The mild Doppler changes observed during fetal surgery could be a manifestation of fetal adaptation to the stress of fetal surgery. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Quality assessment of fetal middle cerebral and umbilical artery Doppler images using an objective scale within an international randomized controlled trial.

OBJECTIVES: To determine the quality of Doppler images of the fetal middle cerebral artery (MCA) and umbilical artery (UA) using an objective scale, and to determine the reliability of this scale, within a multicenter randomized controlled trial (Revealed versus concealed criteria for placental insufficiency in unselected obstetric population in late pregnancy (Ratio37)). METHODS: The Ratio37 trial is an ongoing randomized, open-label, multicenter controlled study of women with a low-risk pregnancy recruited at 20 weeks. Doppler measurements of the fetal MCA and UA were performed at 37 weeks. Twenty patients from each of the six participating centers were selected randomly, with two images evaluated per patient (one each for the MCA and UA). The quality of a total of 240 images was evaluated by six experts, scored on an objective scale of six items. Inter- and intrarater reliability was assessed using the Fleiss-modified kappa statistic for ordinal scales. RESULTS: On average, 89.2% of MCA images and 85.0% of UA images were rated as being of perfect (score of 6) or almost perfect (score of 5) quality. Kappa values for intrarater reliability of quality assessment were 0.90 (95% CI, 0.88-0.92) and 0.90 (95% CI, 0.88-0.93) for the MCA and UA, respectively. The corresponding inter-rater reliability values were 0.85 (95% CI, 0.81-0.89) and 0.84 (95% CI, 0.80-0.89), respectively. CONCLUSION: The quality of MCA and UA Doppler ultrasound images can be evaluated reliably using an objective scale. Over 85% of images, which were obtained by operators from a broad range of clinical practices within a multicenter study, were rated as being of perfect or almost perfect quality. Intra- and inter-rater reliability of quality assessment was very good. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Prediction of adverse perinatal outcome by fetal biometry: comparison of customized and population-based standards.

OBJECTIVE: To compare the predictive performance of estimated fetal weight (EFW) percentiles, according to eight growth standards, to detect fetuses at risk for adverse perinatal outcome. METHODS: This was a retrospective cohort study of 3437 African-American women. Population-based (Hadlock, INTERGROWTH-21st , World Health Organization (WHO), Fetal Medicine Foundation (FMF)), ethnicity-specific (Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)), customized (Gestation-Related Optimal Weight (GROW)) and African-American customized (Perinatology Research Branch (PRB)/NICHD) growth standards were used to calculate EFW percentiles from the last available scan prior to delivery. Prediction performance indices and relative risk (RR) were calculated for EFW < 10th and > 90th percentiles, according to each standard, for individual and composite adverse perinatal outcomes. Sensitivity at a fixed (10%) false-positive rate (FPR) and partial (FPR < 10%) and full areas under the receiver-operating-characteristics curves (AUC) were compared between the standards. RESULTS: Ten percent (341/3437) of neonates were classified as small-for-gestational age (SGA) at birth, and of these 16.4% (56/341) had at least one adverse perinatal outcome. SGA neonates had a 1.5-fold increased risk of any adverse perinatal outcome (P < 0.05). The screen-positive rate of EFW < 10th percentile varied from 6.8% (NICHD) to 24.4% (FMF). EFW < 10th percentile, according to all standards, was associated with an increased risk for each of the adverse perinatal outcomes considered (P < 0.05 for all). The highest RRs associated with EFW < 10th percentile for each adverse outcome were 5.1 (95% CI, 2.1-12.3) for perinatal mortality (WHO); 5.0 (95% CI, 3.2-7.8) for perinatal hypoglycemia (NICHD); 3.4 (95% CI, 2.4-4.7) for mechanical ventilation (NICHD); 2.9 (95% CI, 1.8-4.6) for 5-min Apgar score < 7 (GROW); 2.7 (95% CI, 2.0-3.6) for neonatal intensive care unit (NICU) admission (NICHD); and 2.5 (95% CI, 1.9-3.1) for composite adverse perinatal outcome (NICHD). Although the RR CIs overlapped among all standards for each individual outcome, the RR of composite adverse perinatal outcome in pregnancies with EFW < 10th percentile was higher according to the NICHD (2.46; 95% CI, 1.9-3.1) than the FMF (1.47; 95% CI, 1.2-1.8) standard. The sensitivity for composite adverse perinatal outcome varied substantially between standards, ranging from 15% for NICHD to 32% for FMF, due mostly to differences in FPR; this variation subsided when the FPR was set to the same value (10%). Analysis of AUC revealed significantly better performance for the prediction of perinatal mortality by the PRB/NICHD standard (AUC = 0.70) compared with the Hadlock (AUC = 0.66) and FMF (AUC = 0.64) standards. Evaluation of partial AUC (FPR < 10%) demonstrated that the INTERGROWTH-21st standard performed better than the Hadlock standard for the prediction of NICU admission and mechanical ventilation (P < 0.05 for both). Although fetuses with EFW > 90th percentile were also at risk for any adverse perinatal outcome according to the INTERGROWTH-21st (RR = 1.4; 95% CI, 1.0-1.9) and Hadlock (RR = 1.7; 95% CI, 1.1-2.6) standards, many times fewer cases (2-5-fold lower sensitivity) were detected by using EFW > 90th percentile, rather than EFW < 10th percentile, in screening by these standards. CONCLUSIONS: Fetuses with EFW < 10th percentile or EFW > 90th percentile were at increased risk of adverse perinatal outcomes according to all or some of the eight growth standards, respectively. The RR of a composite adverse perinatal outcome in pregnancies with EFW < 10th percentile was higher for the most-stringent (NICHD) compared with the least-stringent (FMF) standard. The results of the complementary analysis of AUC suggest slightly improved detection of adverse perinatal outcome by more recent population-based (INTERGROWTH-21st ) and customized (PRB/NICHD) standards compared with the Hadlock and FMF standards. Published 2019. This article is a U.S. Government work and is in the public domain in the USA.

Sex differences in functional connectivity during fetal brain development.

Sex-related differences in brain and behavior are apparent across the life course, but the exact set of processes that guide their emergence in utero remains a topic of vigorous scientific inquiry. Here, we evaluate sex and gestational age (GA)-related change in functional connectivity (FC) within and between brain wide networks. Using resting-state functional magnetic resonance imaging we examined FC in 118 human fetuses between 25.9 and 39.6 weeks GA (70 male; 48 female). Infomap was applied to the functional connectome to identify discrete prenatal brain networks in utero. A consensus procedure produced an optimal model comprised of 16 distinct fetal neural networks distributed throughout the cortex and subcortical regions. We used enrichment analysis to assess network-level clustering of strong FC-GA correlations separately in each sex group, and to identify network pairs exhibiting distinct patterns of GA-related change in FC between males and females. We discovered both within and between network FC-GA associations that varied with sex. Specifically, associations between GA and posterior cingulate-temporal pole and fronto-cerebellar FC were observed in females only, whereas the association between GA and increased intracerebellar FC was stronger in males. These observations confirm that sexual dimorphism in functional brain systems emerges during human gestation.