Maternal-fetal comorbidities and obstetrical outcomes of fetal single ventricle cardiac defects: 10 years' experience with a multidisciplinary management protocol at a single center.

OBJECTIVES: To describe and compare maternal and fetal comorbidities and obstetrical outcomes in pregnancies with hypoplastic left and right heart (HLHS and HRH) single ventricle cardiac defects (SVCD) from a single center under a multidisciplinary protocol. METHOD: A single center retrospective review of fetal SVCD from 2013 to 2022. Maternal-fetal comorbidities, delivery, and postnatal outcomes were compared between HLHS and HRH using descriptive statistics and univariate and multivariate analyses. RESULTS: Of 181 SVCD pregnancies (131 HLHS; 50 HRH), 9% underwent termination, 4% elected comfort care, 5 died in utero and 147/152 liveborns survived to the first cardiac intervention. Cesarean delivery occurred in 57 cases (37%), planned in 36 and unplanned in 21. Comorbidities, which did not differ between HLHS and HRH, included fetal growth restriction (FGR, 17%), prematurity (14%), maternal hypertension (9%), maternal obesity (50%), fetal extracardiac anomalies and chromosome anomalies (12%, 13%). In multivariate analysis, only earlier gestational age at delivery and oligohydramnios predicted decreased odds of survival at one year. CONCLUSION: Maternal-fetal comorbidities are common in both HLHS and HRH. Earlier gestational age at delivery and oligohydramnios predict lower postnatal survival. FGR, even with severe early onset, did not significantly impact short- or long-term neonatal survival in single ventricle conditions.

Prenatal Diagnosis of Fetal Aqueductal Stenosis: A Multicenter Prospective Observational Study through the North American Fetal Therapy Network (NAFTNet).

INTRODUCTION: A critical component of an evidence-based reassessment of in-utero intervention for fetal aqueductal stenosis (fetal AS) is determining if the prenatal diagnosis can be accurately made at a gestational age amenable to in-utero intervention. METHODS: A multicenter, prospective, observational study was conducted through the North American Fetal Therapy Network (NAFTNet). Pregnancies complicated by severe CNS ventriculomegaly (lateral ventricle diameter >15 mm) not secondary to a primary diagnosis (myelomeningocele, encephalocele, etc.) were recruited at diagnosis. Imaging and laboratory findings were recorded in an online REDCap database. After evaluation, investigators were asked to render their degree of confidence in the diagnosis of fetal AS. The prenatal diagnosis was compared to the postnatal diagnosis obtained through neonatal neuroimaging. Performance characteristics of ultrasound and MRI were calculated, as was the mean gestational age at diagnosis. RESULTS: Between April 2015 and October 2022, eleven NAFTNet centers contributed 64 subjects with severe fetal CNS ventriculomegaly. Of these, 56 had both prenatal and postnatal diagnoses recorded. Ultrasound revealed 32 fetal AS true positives, 4 false positives, 7 false negatives, and 13 true negatives rendering a sensitivity of 0.82, a specificity of 0.76, a positive predictive value of 0.89, and a negative predictive value of 0.65. The mean gestational age at diagnosis by ultrasound was 25.5 weeks (std +/- 4.7w). The proportion of agreement (true positive + true negative/n) was highest at 24 weeks gestation. For fetal MRI (n=35), the sensitivity for fetal AS was 0.95, specificity was 0.69, positive predictive value was 0.84, and negative predictive value was 0.90. MRI was performed at 25 weeks on average. CONCLUSION: The prenatal diagnosis of fetal aqueductal stenosis can be made with accuracy at a gestational age potentially amenable to in-utero intervention. Only 7% of subjects were incorrectly diagnosed prenatally with fetal AS by ultrasound and 11% by MRI. Diagnostic accuracy of fetal AS will likely improve with increased experience.

Successful antenatal treatment of MAGED2-related Bartter syndrome and review of treatment options and efficacy.

A new form of transient antenatal Bartter syndrome (aBS) was recently identified that is associated with the X-linked MAGED2 variant. Case reports demonstrate that this variant leads to severe polyhydramnios that may result in preterm birth or pregnancy loss. There is limited but promising evidence that amnioreductions may improve fetal outcomes in this rare condition. We report a woman with two affected pregnancies. In the first pregnancy, the patient was diagnosed with mild-to-moderate polyhydramnios in the second trimester that ultimately resulted in preterm labor and delivery at 25 weeks with fetal demise. Whole exome sequencing of the amniotic fluid sample resulted after the pregnancy loss and revealed a c.1337G>A MAGED2 variant that was considered diagnostically. The subsequent pregnancy was confirmed by chorionic villi sampling to also be affected by this variant. The pregnancy was managed with frequent ultrasounds and three amnioreductions that resulted in spontaneous vaginal delivery at 37 weeks and 6 days of a viable newborn with no evidence of overt electrolyte abnormalities suggesting complete resolution. A detailed review of the published cases of MAGED2-related transient aBS is provided. Our review focuses on individuals who received antenatal treatment. A total of 31 unique cases of MAGED2-related transient aBS were compiled. Amnioreduction was performed in 23 cases and in 18 cases no amnioreduction was performed. The average gestational age at delivery was significantly lower in cases without serial amnioreduction (28.7 vs. 30.71 weeks, p = 0.03). Neonatal mortality was seen in 5/18 cases without serial amnioreduction, and no mortality was observed in the cases with serial amnioreduction. In cases of second trimester severe polyhydramnios without identifiable cause, whole exome sequencing should be considered. Intensive ultrasound surveillance and serial amnioreduction is recommended for the management of MAGED2-related transient aBS.

Successful Management of Fetal Torsades de Pointes and Long QT Syndrome by a Cardio-Obstetrical Team.

A 32-week fetus with tachycardia and bradycardia, diagnosed with torsades de pointes, atrioventricular block, and sinus bradycardia due to a de novo KCNH2 mutation was successfully managed by a cardio-obstetrical team. Maternal/fetal pharmacogenomic testing resulted in appropriate drug dosing without toxicity and delivery of a term infant in sinus rhythm.

Fetal lung volumes measured by MRI predict pulmonary morbidity among infants with giant omphaloceles.

OBJECTIVE: Giant omphaloceles (GO) have associated pulmonary hypoplasia and respiratory complications. Total lung volumes (TLV) on fetal MRI can prognosticate congenital diaphragmatic hernia outcomes; however, its applicability to GO is unknown. We hypothesize that late gestation TLV and observed-to-expected TLV (O/E TLV) on fetal MRI correlate with postnatal pulmonary morbidity in GO. METHOD: A single-institution retrospective review of GO evaluated between 2012 and 2022 was performed. Fetal MRI TLV between 32 and 36 weeks' gestation and O/E TLV throughout gestation were calculated and correlated with postnatal outcomes. RESULTS: 86 fetuses with omphaloceles were evaluated; however, only 26 met strict inclusion criteria. MRIs occurred between 18 and 36 weeks' gestation. Those requiring delivery room intubation had significantly lower late gestation TLV and O/E TLV. O/E TLV predicted tracheostomy placement and survival. Neither TLV nor O/E TLV predicted the length of hospitalization or supplemental oxygen after discharge. Three fetuses had a TLV less than 35 mL: one died of respiratory failure, and the other two required tracheostomy. CONCLUSIONS: Fetal MRI TLV measured between 32 and 36 weeks' gestation and O/E TLV predict the need for delivery room intubation and tracheostomy. O/E TLV correlated with survival. These data support fetal MRI as a prognostic tool to predict GO associated pulmonary morbidity.

Early outcomes of a myofascial repair technique for fetal myelomeningocele.

PURPOSE: Fetal repair of myelomeningocele (MMC) and myeloschisis leads to improved neurologic outcomes compared to postnatal repair, but the effects of modifications in closure techniques have not been extensively studied. Previous work has suggested that a watertight repair is requisite for improvement in hindbrain herniation (HBH) and to decrease postnatal hydrocephalus (HCP). Our institution adopted the myofascial closure technique for open fetal MMC repair in July 2019, which we hypothesized would result in decreased need for patch closure, improved HBH, and decreased rate of surgically-treated HCP. METHODS: A single-center retrospective study of patients who underwent fetal MMC or myeloschisis repair between March 2013 and February 2022 was performed. Outcomes were evaluated (n = 70 prior to July 2019, n = 34 after July 2019). Statistical significance was determined by Fisher's exact and Chi square tests (p < 0.05 significant). RESULTS: Patients who underwent myofascial closure were less likely to require a patch for skin closure (14.7% vs 58.6%, p < 0.0001). Myofascial closure was also associated with an increased rate of HBH improvement on two-week postoperative fetal MRI (93.9% vs 65.7%, p = 0.002). Surgically-treated HCP at one year was lower in the myofascial closure group (n = 21), however this did not reach statistical significance (23.8% vs 41.9%, p = 0.19). CONCLUSIONS: We conclude that the myofascial closure technique for repair of fetal MMC and myeloschisis is associated with significantly decreased need for patch closure and improvement in hindbrain herniation compared to our previous skin closure technique. These results support a surgical approach that employs a multilayer watertight closure.

Umbilical Venous Volume Flow in Late-Onset Fetal Growth Restriction.

OBJECTIVES: Umbilical vein flow (UVF) is reduced in fetal growth restriction (FGR). We compared absolute and size-adjusted UVF (estimated fetal weight [EFW] and abdominal circumference [AC]) and rates of abnormal UVF parameters (<10th percentile) among FGR fetuses meeting Delphi criteria (FGR-D) against small for gestational age (SGA) fetuses and appropriate for gestational age (AGA) controls. METHODS: Absolute UVF, UVF/EFW, and UVF/AC were compared between 73 FGR pregnancies (35 FGR-D, 38 SGA) and 108 AGA controls. Rates of abnormal UVF were compared to abnormal umbilical artery pulsatility index (UAPI). Independent samples t-tests, Mann-Whitney U, odds ratio (OR), chi-squared, and Fisher's exact tests were used as appropriate. RESULTS: Mean absolute UVF was significantly decreased in FGR-D compared to AGA (P = .0147), but not between SGA and AGA fetuses. The incidence of both abnormal absolute UVF and UVF/AC values (<10th centile) was higher among late-onset FGR fetuses versus AGA fetuses (UVF: OR 2.7, confidence interval [CI] 1.37-5.4; UVF/AC: OR 2.73, CI 1.37-5.4). UVF was more frequently abnormal than UAPI and in only two fetuses were both Doppler values abnormal. CONCLUSION: Absolute UVF is altered in late-onset FGR, and most pronounced among FGR-D. UVF may provide additional insight into fetal compromise in those affected by growth restriction.

Patterns of Brain Sparing in a Fetal Growth Restriction Cohort.

Objective: Our objective was to compare differences in Doppler blood flow in four fetal intracranial blood vessels in fetuses with late-onset fetal growth restriction (FGR) vs. those with small for gestational age (SGA). Methods: Fetuses with estimated fetal weight (EFW) <10th percentile were divided into SGA (n = 30) and FGR (n = 51) via Delphi criteria and had Doppler waveforms obtained from the middle cerebral artery (MCA), anterior cerebral artery (ACA), posterior cerebral artery (PCA), and vertebral artery (VA). A pulsatility index (PI) <5th centile was considered "abnormal". Outcomes included birth metrics and neonatal intensive care unit (NICU) admission. Results: There were more abnormal cerebral vessel PIs in the FGR group versus the SGA group (36 vs. 4; p = 0.055). In FGR, ACA + MCA vessel abnormalities outnumbered PCA + VA abnormalities. All 8 fetuses with abnormal VA PIs had at least one other abnormal vessel. Fetuses with abnormal VA PIs had lower BW (1712 vs. 2500 g; p < 0.0001), delivered earlier (35.22 vs. 37.89 wks; p = 0.0052), and had more admissions to the NICU (71.43% vs. 24.44%; p = 0.023). Conclusions: There were more anterior vessels showing vasodilation than posterior vessels, but when the VA was abnormal, the fetuses were more severely affected clinically than those showing normal VA PIs.

Improved survival for infants with severe congenital diaphragmatic hernia.

BACKGROUND: Survival for severe (observed to expected lung-head ratio (O:E LHR) < 25%) congenital diaphragmatic hernia (CDH) remains a challenge (15-25%). Management strategies have focused on fetal endoscopic tracheal occlusion (FETO) and/or extracorporeal membrane oxygenation therapy (ECMO) utilization. OBJECTIVE(S): Describe single center outcomes for infants with severe CDH. STUDY DESIGN: Observational study of 13 severe CDH infants managed with ECMO, a protocolized DR algorithm, and early repair on ECMO with an innovative perioperative anticoagulation strategy. RESULTS: 13/140 (9.3%) infants met criteria and were managed with ECMO. 77% survived ECMO and 69% survived to discharge. 22% underwent tracheostomy. Median days on mechanical ventilation was 39 days (IQR 22:107.5) and length of stay 135 days (IQR 62.5:211.5). All infants received a gastrostomy tube (GT) and were discharged home on oxygen and pulmonary hypertension (PH) meds. CONCLUSION: Survival for infants with severe CDH can be optimized with early aggressive intervention and protocolized algorithms (149).

The role of the fetal biophysical profile in the management of fetal growth restriction.

Growth-restricted fetuses are at risk of hypoxemia, acidemia, and stillbirth because of progressive placental dysfunction. Current fetal well-being, neonatal risks following delivery, and the anticipated rate of fetal deterioration are the major management considerations in fetal growth restriction. Surveillance has to quantify the fetal risks accurately to determine the delivery threshold and identify the testing frequency most likely to capture future deterioration and prevent stillbirth. From the second trimester onward, the biophysical profile score correlates over 90% with the current fetal pH, and a normal score predicts a pH >7.25 with a 100% positive predictive value; an abnormal score on the other hand predicts current fetal acidemia with similar certainty. Between 30% and 70% of growth-restricted fetuses with a nonreactive heart rate require biophysical profile scoring to verify fetal well-being, and an abnormal score in 8% to 27% identifies the need for delivery, which is not suspected by Doppler findings. Future fetal well-being is not predicted by the biophysical profile score, which emphasizes the importance of umbilical artery Doppler and amniotic fluid volume to determine surveillance frequency. Studies with integrated surveillance strategies that combine frequent heart rate monitoring with biophysical profile scoring and Doppler report better outcomes and stillbirth rates of between 0% and 4%, compared with those between 8% and 11% with empirically determined surveillance frequency. The variations in clinical behavior and management challenges across gestational age are better addressed when biophysical profile scoring is integrated into the surveillance of fetal growth restriction. This review aims to provide guidance on biophysical profile scoring in the in- and outpatient management of fetal growth restriction.

Differences in body composition and growth persist postnatally in fetuses diagnosed with severe compared to mild fetal growth restriction.

BACKGROUND: Fetal growth restriction (FGR) is most commonly diagnosed in pregnancy if the estimated fetal weight (EFW) is < 10th%. Those with abnormal Doppler velocimetry, indicating placental insufficiency and pathological FGR, demonstrate reduced fat and lean mass compared to both normally growing fetuses and FGR fetuses with normal Dopplers. The aim of this study was to determine how severity of FGR and abnormal Doppler velocimetry impacts neonatal body composition. Among a cohort of fetuses with an EFW < 10th%, we hypothesized that those with abnormal Dopplers and/or EFW < 3rd% would have persistent reductions in lean body mass and fat mass extending into the neonatal period compared to fetuses not meeting those criteria. METHODS: A prospective cohort of FGR fetuses with an estimated fetal weight (EFW) < 10th% was categorized as severe (EFW < 3rd% and/or abnormal Dopplers; FGR-S) versus mild (EFW 3-10th%; FGR-M). Air Displacement Plethysmography and anthropometrics were performed at birth and/or within the first 6-8 weeks of life. RESULTS: FGR-S versus FGR-M were born one week earlier (P = 0.0024), were shorter (P = 0.0033), lighter (P = 0.0001) with smaller weight-for-age Z-scores (P = 0.0004), had smaller head circumference (P = 0.0004) and lower fat mass (P = 0.01) at birth. At approximately 6-8 weeks postmenstrual age, weight, head circumference, and fat mass were similar but FGR-S neonates were shorter (P = 0.0049) with lower lean mass (P = 0.0258). CONCLUSION: Doppler velocimetry abnormalities in fetuses with an EFW < 10th% identified neonates who were smaller at birth and demonstrated catch-up growth by 6-8 weeks of life that favored fat mass accretion over lean mass and linear growth.

Doppler velocimetry discordance between paired umbilical artery vessels and clinical implications in fetal growth restriction.

BACKGROUND: Studies revealing a discrepancy in umbilical artery Dopplers between the two umbilical arteries in normally-grown fetuses necessitates further evaluation of the paired umbilical arteries in the setting of fetal growth restriction as this is a critical component in the surveillance of this population. OBJECTIVE: Umbilical artery Doppler sampling in fetal growth restriction is typically assessed in 1 umbilical artery in a free loop of cord. Although discrepancies of >20% between the 2 umbilical arteries occur in 1 of 3 normal pregnancies, this has not been assessed in fetal growth restriction. Our objectives were to determine the frequency of discordant Doppler pulsatility indices between paired umbilical arteries in a fetal growth restriction cohort and to determine if sampling of 1 or both arteries alters surveillance or timing of delivery. STUDY DESIGN: A cohort of 425 growth-restricted fetuses between 25 and 39 weeks of gestation had umbilical artery Doppler pulsatility indices determined from both umbilical arteries in a midsegment of the cord to determine: (1) the discrepancy percentage between paired umbilical artery pulsatility indices and (2) the frequency of both arteries being normal, abnormal, or discordant (pulsatility index < and >95th percentile). To determine what sampling method increased the detection of an abnormal Doppler index, 3 sampling methods were compared: (1) average pulsatility index from both umbilical arteries, (2) pulsatility index from 1 umbilical artery chosen randomly, and (3) highest pulsatility index of the 2 umbilical arteries. RESULTS: The mean percentage difference between umbilical artery pulsatility indices was 11.7%, and in 15.8% of cases, it exceeded 20%. Both umbilical artery pulsatility indices were normal in 71.1% (302/425), abnormal in 12.2% (52/425), and discordant in 16.7% (71/425) of cases (P<.0001). Of the 3 sampling methods, the pulsatility index was abnormal in: (1) 19.2% (82/425) of cases when averaged from both umbilical arteries, (2) 22.1% (94/425) of cases when choosing 1 umbilical artery at random, and (3) 28.9% (123/425) of cases when the highest umbilical artery pulsatility index was used (P=.003). CONCLUSION: In this large fetal growth restriction cohort, the overall discrepancy between the 2 umbilical artery pulsatility indices was 11.7%. Among fetuses with at least 1 abnormal umbilical artery pulsatility index, 71 of 123 (57.7%) had 1 normal pulsatility index and 1 abnormal. Thus, the number of arteries sampled and the sampling method used may alter clinical decision-making, including frequency of surveillance and timing of delivery.

Clinical Opinion: The diagnosis and management of suspected fetal growth restriction: an evidence-based approach.

This study reviewed the literature about the diagnosis, antepartum surveillance, and time of delivery of fetuses suspected to be small for gestational age or growth restricted. Several guidelines have been issued by major professional organizations, including the International Society of Ultrasound in Obstetrics and Gynecology and the Society for Maternal-Fetal Medicine. The differences in recommendations, in particular about Doppler velocimetry of the ductus venosus and middle cerebral artery, have created confusion among clinicians, and this review has intended to clarify and highlight the available evidence that is pertinent to clinical management. A fetus who is small for gestational age is frequently defined as one with an estimated fetal weight of <10th percentile. This condition has been considered syndromic and has been frequently attributed to fetal growth restriction, a constitutionally small fetus, congenital infections, chromosomal abnormalities, or genetic conditions. Small for gestational age is not synonymous with fetal growth restriction, which is defined by deceleration of fetal growth determined by a change in fetal growth velocity. An abnormal umbilical artery Doppler pulsatility index reflects an increased impedance to flow in the umbilical circulation and is considered to be an indicator of placental disease. The combined finding of an estimated fetal weight of <10th percentile and abnormal umbilical artery Doppler velocimetry has been widely accepted as indicative of fetal growth restriction. Clinical studies have shown that the gestational age at diagnosis can be used to subclassify suspected fetal growth restriction into early and late, depending on whether the condition is diagnosed before or after 32 weeks of gestation. The early type is associated with umbilical artery Doppler abnormalities, whereas the late type is often associated with a low pulsatility index in the middle cerebral artery. A large randomized clinical trial indicated that in the context of early suspected fetal growth restriction, the combination of computerized cardiotocography and fetal ductus venosus Doppler improves outcomes, such that 95% of surviving infants have a normal neurodevelopmental outcome at 2 years of age. A low middle cerebral artery pulsatility index is associated with an adverse perinatal outcome in late fetal growth restriction; however, there is no evidence supporting its use to determine the time of delivery. Nonetheless, an abnormality in middle cerebral artery Doppler could be valuable to increase the surveillance of the fetus at risk. We propose that fetal size, growth rate, uteroplacental Doppler indices, cardiotocography, and maternal conditions (ie, hypertension) according to gestational age are important factors in optimizing the outcome of suspected fetal growth restriction.

3D Fractional Limb Volume Identifies Reduced Subcutaneous and Lean Mass in Fetal Growth Restriction.

OBJECTIVES: Fetal 2D and 3D fractional limb volume (FLV) measurements by ultrasound can detect fetal lean and subcutaneous mass and possibly percent body fat. Our objectives were to 1) compare FLV measurements in fetuses with fetal growth restriction (FGR) versus small for gestational age (SGA) defined by the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG)-supported international Delphi consensus and 2) correlate FLV findings with birth metrics. We hypothesize that FLV measurements will be significantly smaller in FGR versus SGA fetuses and will correlate closer with Ponderal index (PIx) in the neonate than abdominal circumference (AC). METHODS: Patients were categorized as FGR or SGA as defined by ISUOG. Total thigh volume (TTV), volumes of lean mass (LMV), and fat mass volume (FMV) were calculated from 3D acquisitions. Measurements were compared between groups and correlated with birthweight (BW) and PIx (BW/crown-heal length). RESULTS: The FGR group (n = 37) delivered earlier (37/2 versus 38/0; P = .0847), were lighter (2.2 kg versus 2.6 kg; P = .0003) and had lower PIx (0.023 versus 0.025; P = .0013) than SGAs (n = 22). FGRs had reduced TTV (40.6 versus 48.4 cm3 ; P = .0164), FMV (20.8 versus 25.3 cm3 ; P = .0413), and LMV (19.8 versus 23.1 cm3 ; P = .0387). AC had the highest area under the curve (0.69) for FGR. FMV was more strongly associated with PIx than the AC (P = .0032). CONCLUSIONS: The AC and FLV measurements were significantly reduced in FGR fetuses compared to SGAs. While the AC outperformed FLV in predicting FGR, the FLV correlated best with PIx, which holds investigative promise.

Reduction of In Vivo Placental Amino Acid Transport Precedes the Development of Intrauterine Growth Restriction in the Non-Human Primate.

Intrauterine growth restriction (IUGR) is associated with reduced placental amino acid transport (AAT). However, it remains to be established if changes in AAT contribute to restricted fetal growth. We hypothesized that reduced in vivo placental AAT precedes the development of IUGR in baboons with maternal nutrient restriction (MNR). Baboons were fed either a control (ad libitum) or MNR diet (70% of control diet) from gestational day (GD) 30. At GD 140, in vivo transplacental AA transport was measured by infusing nine (13)C- or (2)H-labeled essential amino acids (EAAs) as a bolus into the maternal circulation at cesarean section. A fetal vein-to-maternal artery mole percent excess ratio for each EAA was measured. Microvillous plasma membrane (MVM) system A and system L transport activity were determined. Fetal and placental weights were not significantly different between MNR and control. In vivo, the fetal vein-to-maternal artery mole percent excess ratio was significantly decreased for tryptophan in MNR. MVM system A and system L activity was markedly reduced in MNR. Reduction of in vivo placental amino acid transport precedes fetal growth restriction in the non-human primate, suggesting that reduced placental amino acid transfer may contribute to IUGR.

Amniotic fluid microRNA profiles in twin-twin transfusion syndrome with and without severe recipient cardiomyopathy.

BACKGROUND: Twin-twin transfusion syndrome presents many challenges for clinicians, and the optimal means of identifying pregnancies that will benefit most from intervention is controversial. There is currently no clinically available biomarker to detect twin-twin transfusion syndrome or to stratify cases based on the risk factors. microRNAs are small RNAs that regulate gene expression and are biomarkers for various disease processes, including adult and pediatric heart failure. To date, no studies have investigated amniotic fluid microRNAs as biomarkers for disease severity, specifically for severe recipient cardiomyopathy in twin-twin transfusion syndrome cases. OBJECTIVE: This study aimed to assess whether amniotic fluid microRNAs could be useful as biomarkers to identify pregnancies at greatest risk for severe recipient cardiomyopathy associated with twin-twin transfusion syndrome. STUDY DESIGN: Amniotic fluid was collected at the time of amnioreduction or selective fetoscopic laser photocoagulation from monochorionic diamniotic twin pregnancies with twin-twin transfusion syndrome at any stage. Fetal echocardiography was performed on all twins before the procedure, and severe cardiomyopathy was defined as a right ventricular myocardial performance index of the recipient fetus of >4 Z-scores. microRNA was extracted from the amniotic fluid samples and analyzed using an array panel assessing 379 microRNAs (TaqMan Open Array, ThermoFisher). Student t tests were performed to determine significant differences in microRNA expression between pregnancies with severe recipient cardiomyopathy and those with preserved cardiac function. A stringent q value of <.0025 was used to determine differential microRNA expression. Random forest plots identified the top 3 microRNAs that separated the 2 groups, and hierarchical cluster analysis was used to determine if these microRNAs properly segregated the samples according to their clinical groups. RESULTS: A total of 14 amniotic fluid samples from pregnancies with twin-twin transfusion syndrome with severe cardiomyopathy were compared with samples from 12 twin-twin transfusion syndrome control cases with preserved cardiac function. A total of 110 microRNAs were identified in the amniotic fluid samples. Twenty microRNAs were differentially expressed, and the top 3 differentiating microRNAs were hsa-miR-200c-3p, hsa-miR-17-5p, and hsa-miR-539-5p. Hierarchical cluster analysis based on these top 3 microRNAs showed a strong ability to differentiate severe cardiomyopathy cases from controls. The top 3 microRNAs were used to investigate the sensitivity and specificity of these microRNAs to differentiate between the 2 groups with a receiver operating characteristic curve demonstrating sensitivity and specificity of 80.8%. All 20 differentially expressed microRNAs were down-regulated in the group with severe cardiomyopathy. CONCLUSION: Amniotic fluid microRNAs demonstrated differential expression between twin-twin transfusion syndrome recipient fetuses with severe cardiomyopathy and those without and have the potential to be important biomarkers of disease severity in this population.

Fetal Growth in Multiple Gestations: Evaluation and Management.

Multifetal gestation pregnancies present a clinical challenge due to unique complications including growth issues, prematurity, maternal risk, and pathologic processes, such as selective intrauterine growth restriction (sIUGR), twin-to-twin transfusion syndrome (TTTS), and twin anemia-polycythemia sequence. If sIUGR is found, then management may involve some combination of increased surveillance, fetal procedures, and/or delivery. The combination of sIUGR with TTTS or other comorbidities increases the risk of pregnancy complications. Multifetal pregnancy reduction is an option when a problem is confined to a single fetus or when weighing the risks and benefits of a multifetal gestation in comparison to a singleton pregnancy.