Cardiac adaptation and malformation in twin-twin transfusion syndrome and selective fetal growth restriction: A systematic review.

OBJECTIVES: This systematic review explores cardiac adaptation in monochorionic (MC) twins with twin-twin transfusion syndrome (TTTS) or selective fetal growth restriction (sFGR) and assesses the risk of congenital heart defects (CHDs). METHODS: Adhering to PRISMA guidelines, 63 studies were reviewed (49 on cardiac adaptation, 13 on CHD, one on both). A narrative synthesis of cardiac adaptation patterns was performed. Additionally, a meta-analysis compared the livebirth prevalence of CHD in TTTS and sFGR against uncomplicated MC twins. RESULTS: In TTTS recipients, cardiac function may be impaired for diastolic, systolic, as well as global functions, while in donors, cardiac function is generally preserved. In sFGR, large twins may show hypertrophic cardiomyopathy, and small twins may show impaired systolic function. Co-occurrence of TTTS and sFGR magnifies cardiac impact but is often underreported. Meta-analysis for CHD prevalence revealed a relative risk ratio of 3.5 (95% CI: 2.5-4.9) for TTTS and 2.2 (95%CI: 1.3-3.5) for sFGR compared with uncomplicated MC twins. CONCLUSIONS: This study highlights the well-documented cardiac adaptation in TTTS, contrasting with limited understanding in sFGR. Elevated CHD risks were observed in both conditions. Enhanced cardiovascular surveillance is warranted in complicated MC twin pregnancies. Future research should explore cardiac adaptation in sFGR and its long-term consequences.

Cardiac time intervals and myocardial performance index for prediction of twin-twin transfusion syndrome.

OBJECTIVES: To explore whether intertwin discordance in myocardial performance index (MPI) or cardiac time intervals enables the prediction of twin-twin transfusion syndrome (TTTS) in monochorionic diamniotic (MCDA) pregnancies with amniotic fluid discordance. METHODS: Prospective cohort study of MCDA pregnancies with amniotic fluid discordance ≥4 cm. Serial ultrasound examinations consisted of evaluation of amniotic fluid, fetal Dopplers and fetal cardiac function. RESULTS: We included 21 "future-TTTS" (group I), 18 selective fetal growth restriction (sFGR; group II) and 20 uncomplicated MCDA twin pairs (group III). Group I had a higher intertwin difference in left ventricle (LV) MPI and right ventricle (RV) MPI compared to group II and III. The intertwin difference in global heart relaxation time was significantly higher in group I compared to group III. Future recipient twins had significantly higher contraction times of the global heart and RV and lower relaxation times of the global heart and RV compared to the "expected recipients" in group II and III. CONCLUSION: Intertwin discordance in LV-MPI and RV-MPI differentiate between TTTS and MCDA pregnancies with transient discordant amniotic fluid volume. Cardiac time intervals identify future recipient twins. The clinical utility of cardiac time intervals and MPI should be investigated in large prospective studies.

Critical Coarctation of the Aorta in Selective Fetal Growth Restriction and the Role of Coronary Stent Implantation.

INTRODUCTION: Monochorionic twins are at increased risk of congenital heart defects (CHDs). Up to 26% have a birth weight <1,500 g, a CHD requiring neonatal surgery, therefore, poses particular challenges. OBJECTIVE: The aim of the study was to describe pregnancy characteristics, perinatal management, and outcome of monochorionic twins diagnosed with critical coarctation of the aorta (CoA). METHODS: We included monochorionic twins diagnosed with critical CoA (2010-2019) at 2 tertiary referral centers, and we systematically reviewed the literature regarding CoA in monochorionic twins. RESULTS: Seven neonates were included. All were the smaller twin of pregnancies complicated by selective fetal growth restriction. The median gestational age at birth was 32 weeks (28-34). Birth weight of affected twins ranged as 670-1,800 g. One neonate underwent coarctectomy at the age of 1 month (2,330 g). Six underwent stent implantation, performed between day 8 and 40, followed by definitive coarctectomy between 4 and 9 months in 4. All 7 developed normally, except for 1 child with neurodevelopmental delay. Three co-twins had pulmonary stenosis, of whom 1 required balloon valvuloplasty. The literature review revealed 10 cases of CoA, all in the smaller twin. Six cases detected in the first weeks after birth were treated with prostaglandins alone, by repeated transcatheter angioplasty or by surgical repair, with good outcome in 2 out of 6. CONCLUSIONS: CoA specifically affects the smaller twin of growth discordant monochorionic twin pairs. Stent implantation is a feasible bridging therapy to surgery in these low birth weight neonates.

Perioperative fetal hemodynamic changes in twin-twin transfusion syndrome and neurodevelopmental outcome at two years of age.

OBJECTIVE: To investigate whether perioperative fetal hemodynamic changes in twin-to-twin transfusion syndrome (TTTS) are associated with neurodevelopmental impairment (NDI) at two years. METHODS: Doppler parameters of three sonograms (day before, first day after and 1 week after laser surgery for TTTS) were assessed for correlation with neurodevelopmental outcome at two years (2008-2016). NDI was defined as: cerebral palsy, deafness, blindness, and/or a Bayley-III cognitive/motor developmental test-score > 2SD below the mean. RESULTS: Long-term outcome was assessed in 492 TTTS survivors. NDI was present in 5% (24/492). After adjustment for severe cerebral injury (present in 4%), associated with NDI were: middle cerebral artery peak systolic velocity (MCA-PSV) >1.5 multiples of the median (MoM) 1 day after surgery (odds ratio [OR] 4.96; 95% confidence interval [CI]: 1.17-21.05, P = .03), a change from normal umbilical artery pulsatility index (UA-PI) presurgery to UA-PI >p95 postsurgery (OR 4.19; 95% CI: 1.04-16.87, P = .04), a change from normal to MCA-PSV >1.5MoM (OR 4.75; 95% CI: 1.43-15.77, P = .01). CONCLUSION: Perioperative fetal hemodynamic changes in TTTS pregnancies treated with laser are associated with poor neurodevelopmental outcome. Prospective research on the cerebrovascular response to altered hemodynamic conditions is necessary to further understand the cerebral autoregulatory capacity of the fetus in relation to neurodevelopmental outcome.

Prevalence, risk factors, and outcome of postprocedural amniotic band disruption sequence after fetoscopic laser surgery in twin-twin transfusion syndrome: a large single-center case series.

BACKGROUND: Postprocedural amniotic band disruption sequence is a condition that is associated with intrauterine interventions, and it is characterized by a constriction of the limbs or umbilical cord by fibrous strands, leading to edema, amputation, and/or fetal demise. OBJECTIVE: To evaluate the prevalence of, risk factors for, and the outcome of postprocedural amniotic band disruption sequence after fetoscopic laser surgery in twin-twin transfusion syndrome cases. STUDY DESIGN: All consecutive cases of twin-twin transfusion syndrome treated with fetoscopic laser coagulation of the vascular anastomoses at our center between January 2002 and March 2019 were included in the study. The occurrence of postprocedural amniotic band disruption sequence in these cases was recorded, and the potential risk factors were analyzed. RESULTS: Postprocedural amniotic band disruption sequence was detected, at birth, in 2.2% (15/672) of twin-twin transfusion syndrome cases treated with fetoscopic laser surgery, in both the recipients (10/15, 67%) and the donors (5/15, 33%). Postprocedural amniotic band disruption sequence primarily affected the lower extremities (11/15, 73%) and, less frequently, the upper extremities (2/15, 13%), both the upper and lower extremities (1/15, 7%), or the umbilical cord (1/15, 7%). Postprocedural amniotic band disruption sequence led to the amputation of toes in 5 of 15 cases (33%) and resulted in fetal demise because of constriction of the umbilical cord in 1 case (7%). The independent risk factors identified for postprocedural amniotic band disruption sequence were lower gestational age at laser surgery (odds ratio per week, 1.43; 95% confidence interval, 1.12-1.79; P=.003) and the presence of postprocedural chorioamniotic membrane separation on antenatal ultrasound examination (odds ratio, 41.66; 95% confidence interval, 5.44-319.25; P<.001). CONCLUSION: The prevalence of postprocedural amniotic band disruption sequence is low, but, when present, it may lead to severe consequences, with amputation of extremities or fetal demise occurring in more than one-third of the cases. Lower gestational age at the time of laser therapy and chorioamniotic membrane separation are independent risk factors for the postprocedural amniotic band disruption sequence.

Early postnatal cardiac follow-up of survivors of twin-twin transfusion syndrome treated with fetoscopic laser coagulation.

OBJECTIVE: To assess the cardiac function and prevalence of congenital heart defects (CHD) in twin-twin transfusion syndrome (TTTS) survivors. STUDY DESIGN: Prospective follow-up of TTTS pregnancies treated with laser surgery (2015-2018). Echocardiography was performed 1 day and 1 month after birth (corrected for prematurity). Results were compared with a control group of age-matched uncomplicated monochorionic twin-pairs at 1 month. RESULT: Eighty-nine TTTS (168 neonates) and nine control pregnancies (18 neonates) were enrolled. CHD birth prevalence was 9.2% (8/87) in recipients and 13.6% (11/81) in donors (p = 0.37). Four of 19 (21%) were detected prenatally, all pulmonary stenosis. Donors had lower aortic peak velocities compared with recipients at day 1 (0.66 ± 0.15 m/s vs 0.71 ± 0.19 m/s, p = 0.04) and 1 month (1.04 ± 0.21 m/s vs 1.11 ± 0.18 m/s, p = 0.02), but not compared with controls. CONCLUSION: CHD prevalence in TTTS survivors is high, with a low prenatal detection of minor abnormalities. Follow-up fetal echocardiograms and a postnatal echocardiogram should be offered.

The value of echocardiography and Doppler in the prediction of fetal demise after laser coagulation for TTTS: A systematic review and meta-analysis.

This study aimed to investigate the value of echocardiography and Doppler before fetoscopic laser coagulation for twin-twin transfusion syndrome (TTTS) in the prediction of intrauterine fetal demise (IUFD). We performed a systematic review and meta-analysis to compare preoperative parameters between fetuses with and without demise after laser surgery. Eighteen studies were included. Recipient twins have an increased risk of demise in case of preoperative absent/reversed flow (A/REDF) in the umbilical artery (odds ratio [OR] 2.76, 95% confidence interval [CI], 1.78-4.28), absent or reversed a-wave in the ductus venosus (OR 2.32, 95% CI, 1.70-3.16), or a middle cerebral artery peak systolic velocity > 1.5 multiples of the median (MoM) (OR 7.59, 95% CI, 2.56-22.46). In donors, only A/REDF in the umbilical artery (OR 3.40, 95% CI, 2.68-4.32) and absent or reversed a-wave in the ductus venosus (OR 1.66, 95% CI, 1.12-2.47) were associated with IUFD. No association was found between donor-IUFD and preoperative myocardial performance index (MPI). Two studies found an association between abnormal MPI and recipient demise. With this study, we have identified a set of preoperative Doppler parameters predictive of fetal demise after laser surgery. More research is needed to assess the utility of preoperative echocardiographic parameters such as the MPI in predicting IUFD.

Congenital Heart Defects in Monochorionic Twins: A Systematic Review and Meta-Analysis.

Monochorionic (MC) twins are at an increased risk of developing congenital heart defects (CHDs) compared to singletons and dichorionic twins. The development of acquired CHDs in this specific group of twins is associated with twin-twin transfusion syndrome (TTTS). We performed a systematic review and meta-analysis to provide an overview of the reported birth prevalence of CHDs in liveborn MC twins with and without TTTS. Twelve studies were included in this review. Compared to the reference population, MC twins were 6.3 times more likely to be born with a CHD (59.3 per 1000 liveborn twins; relative risk (RR) 6.3; 95% confidence interval (CI): 4.4-9.1), and TTTS twins had a 12-fold increased risk of having a CHD at birth (87.3 per 1000 live births; RR 12.4, 95% CI: 8.6-17.8). The increased incidence of CHDs can mainly be attributed to the risk of right ventricular outflow tract obstruction (35/1000 TTTS twin live births vs. 0.5/1000 singleton live births). We recommend an expert fetal echocardiogram in all MC twins, follow-up scans in the event of TTTS, and a postnatal cardiac evaluation in all TTTS survivors.

Persistent pulmonary hypertension of the newborn after fetomaternal hemorrhage.

BACKGROUND: Newborns with anemia are at increased risk of persistent pulmonary hypertension of the newborn (PPHN), yet reports on the association between fetomaternal hemorrhage (FMH) and PPHN are rare. To optimize care for pregnancies complicated by FMH, clinicians should be aware of the risks of FMH and the possible diagnostic and therapeutic options. To increase the current knowledge, the incidence of PPHN and short-term neurologic injury in FMH cases were studied. STUDY DESIGN AND METHODS: We included all FMH cases (≥30 mL fetal blood transfused into the maternal circulation) admitted to our neonatal unit between 2006 and 2018. First, we evaluated the incidence of PPHN and short-term neurologic injury. Second, we studied the potential effect of intrauterine transfusion (IUT). RESULTS: PPHN occurred in 37.9% of newborns (11 of 29), respectively, 14.3% (one of seven) and 45.5% (10 of 22) in the IUT group and no-IUT group (p = 0.20). The mortality rate was 13.8% (4 of 29). Severe brain injury occurred in 34.5% (10 of 29), respectively, and 14.3% (one of seven) and 40.9% (nine of 22) in the IUT group and no-IUT group (p = 0.37). CONCLUSION: Awareness should be raised among perinatologists and neonatologists about the possible life-threatening consequences of FMH, as more than one-third of neonates with anemia due to FMH experience PPHN and suffer from severe brain injury. Antenatal treatment with IUT seems to reduce these risks. Specialists should therefore always consider fetal anemia in FMH cases and refer patients to a fetal therapy center. If anemia is present at birth, it should be corrected promptly and neonatologists should be aware of signs of PPHN.

Correction: Periconception Maternal Folate Status and Human Embryonic Cerebellum Growth Trajectories: The Rotterdam Predict Study.

[This corrects the article DOI: 10.1371/journal.pone.0141089.].

Persistent Pulmonary Hypertension of the Newborn in Twin-Twin Transfusion Syndrome: A Case-Control Study.

BACKGROUND: Persistent pulmonary hypertension of the newborn (PPHN) is associated with severe morbidity and mortality. Twin-twin transfusion syndrome (TTTS) is suggested to increase the risk of PPHN. OBJECTIVES: To describe the incidence of PPHN in TTTS twins and to identify risk factors in TTTS twins for the development of severe PPHN. METHODS: Cases with severe PPHN were extracted from our monochorionic twin database (2002-2016). Severe PPHN was defined as severe hypoxaemia requiring mechanical ventilation and inhaled nitric oxide (iNO) treatment, confirmed by strict echocardiographic criteria. A case-control comparison within TTTS survivors was conducted to identify risk factors for PPHN. RESULTS: The incidence of PPHN in TTTS twins was 4% (24/598, 95% confidence interval [CI] 2.7-5.9%) and 0.4% (2/493, 95% CI 0.1-1.5%) in uncomplicated monochorionic twins (odds ratio [OR] 10.3, 95% CI 2.4-43.9; p = 0.002). Two risk factors were independently associated with PPHN: severe prematurity (OR 3.3, 95% CI 1.0-11.4) and recipient status (OR 3.9, 95% CI 1.4-11.0). In TTTS recipients, another risk factor for PPHN is anaemia at birth (OR 7.2, 95% CI 1.8-29.6). CONCLUSION: Clinicians caring for neonates with TTTS should be aware of the 10-fold increased risk of PPHN compared to uncomplicated monochorionic twins. PPHN occurs more often in case of premature delivery and in recipient twins, particularly in the presence of anaemia at birth. As the development of severe PPHN is difficult to predict, we advise that all TTTS twins should be delivered in a tertiary care centre with iNO treatment options.

Periconception Maternal Folate Status and Human Embryonic Cerebellum Growth Trajectories: The Rotterdam Predict Study.

We aimed to investigate whether periconceptional maternal folate status affects human embryonic cerebellar size and growth trajectories. In a prospective periconceptional cohort participants filled out questionnaires and received weekly transvaginal 3D-ultrasounds between 7+0 and 12+6 weeks gestational age (GA). Viable non-malformed singleton pregnancies were selected for cerebellar measurements; transcerebellar diameter, (TCD), left and right cerebellar diameters (LCD, RCD). Linear mixed models were performed to estimate associations between questionnaire data on the timing of maternal folic acid supplement initiation and longitudinal cerebellar measurements as a function of crown-rump length (CRL) and GA. Maternal red blood cell folate concentrations were analysed before 8 weeks GA to validate the associations. A total of 263 serial high quality three-dimensional ultrasound scans of 135 pregnancies were studied. Preconceptional compared to postconceptional initiation of folic acid use was associated with slightly larger cerebellar diameters per millimetre increase of CRL (TCD: ß = 0.260mm, 95%CI = 0.023-0.491, p<0.05; LCD: ß = 0.171mm, 95%CI = 0.038-0.305, p<0.05; RCD: ß = 0.156mm, 95%CI = 0.032-0.280, p<0.05) and with proportional cerebellar growth (TCD/CRL:ß = 0.015mm/mm, 95%CI = 0.005-0.024, p<0.01; LCD/CRL:ß = 0.012mm/mm, 95%CI = 0.005-0.018, p<0.01; RCD/CRL:ß = 0.011mm/mm, 95%CI = 0.005-0.017, p<0.01). Cerebellar growth was significantly highest in the third quartile of maternal red blood cell folate levels (1538-1813 nmol/L). These first findings show that periconceptional maternal folate status is associated with human embryonic cerebellar development. Implications of these small but significant variations for fetal cerebellar growth trajectories and the child's neurodevelopmental outcome are yet unknown and warrant further investigation.