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Twin gestations are associated with increased risk of pregnancy complications. However, high-quality evidence regarding the management of twin pregnancies is limited, often resulting in inconsistencies in the recommendations of various national and international professional societies. In addition, some recommendations related to the management of twin gestations are often missing from the clinical guidelines dedicated to twin pregnancies and are instead included in the practice guidelines on specific pregnancy complications (eg, preterm birth) of the same professional society. This can make it challenging for care providers to easily identify and compare recommendations for the management of twin pregnancies. This study aimed to identify, summarize, and compare the recommendations of selected professional societies from high-income countries on the management of twin pregnancies, highlighting areas of both consensus and controversy. We reviewed clinical practice guidelines of selected major professional societies that were either specific to twin pregnancies or were focused on pregnancy complications or aspects of antenatal care that may be relevant for twin pregnancies. We decided a priori to include clinical guidelines from 7 high-income countries (United States, Canada, United Kingdom, France, Germany, and Australia and New Zealand grouped together) and from 2 international societies (International Society of Ultrasound in Obstetrics and Gynecology and the International Federation of Gynecology and Obstetrics). We identified recommendations regarding the following care areas: first-trimester care, antenatal surveillance, preterm birth and other pregnancy complications (preeclampsia, fetal growth restriction, and gestational diabetes mellitus), and timing and mode of delivery. We identified 28 guidelines published by 11 professional societies from the 7 countries and 2 international societies. Thirteen of these guidelines focus on twin pregnancies, whereas the other 16 focus on specific pregnancy complications predominantly in singletons but also include some recommendations for twin pregnancies. Most of the guidelines are recent, with 15 of the 29 guidelines published over the past 3 years. We identified considerable disagreement among guidelines, primarily in 4 key areas: screening and prevention of preterm birth, using aspirin to prevent preeclampsia, defining fetal growth restriction, and the timing of delivery. In addition, there is limited guidance on several important areas, including the implications of the "vanishing twin" phenomenon, technical aspects and risks of invasive procedures, nutrition and weight gain, physical and sexual activity, the optimal growth chart to be used in twin pregnancies, the diagnosis and management of gestational diabetes mellitus, and intrapartum care.This consolidation of key recommendations across several clinical practice guidelines can assist healthcare providers in accessing and comparing recommendations on the management of twin pregnancies and identifies high-priority areas for future research based on either continued disagreement among societies or limited current evidence to guide care. [ABSTRACT FROM AUTHOR]

Background: Two randomized controlled trials compared the neonatal and infant outcomes after fetoscopic endoluminal tracheal occlusion with expectant prenatal management in fetuses with severe and moderate isolated congenital diaphragmatic hernia, respectively. Fetoscopic endoluminal tracheal occlusion was carried out at 27+0 to 29+6 weeks' gestation (referred to as "early") for severe and at 30+0 to 31+6 weeks ("late") for moderate hypoplasia. The reported absolute increase in the survival to discharge was 13% (95% confidence interval, -1 to 28; P=.059) and 25% (95% confidence interval, 6-46; P=.0091) for moderate and severe hypoplasia.Objective: Data from the 2 trials were pooled to study the heterogeneity of the treatment effect by observed over expected lung-to-head ratio and explore the effect of gestational age at balloon insertion.Study Design: Individual participant data from the 2 trials were reanalyzed. Women were assessed between 2008 and 2020 at 14 experienced fetoscopic endoluminal tracheal occlusion centers and were randomized in a 1:1 ratio to either expectant management or fetoscopic endoluminal tracheal occlusion. All received standardized postnatal management. The combined data involved 287 patients (196 with moderate hypoplasia and 91 with severe hypoplasia). The primary endpoint was survival to discharge from the neonatal intensive care unit. The secondary endpoints were survival to 6 months of age, survival to 6 months without oxygen supplementation, and gestational age at live birth. Penalized regression was used with the following covariates: intervention (fetoscopic endoluminal tracheal occlusion vs expectant), early balloon insertion (yes vs no), observed over expected lung-to-head ratio, liver herniation (yes vs no), and trial (severe vs moderate). The interaction between intervention and the observed over expected lung-to-head ratio was evaluated to study treatment effect heterogeneity.Results: For survival to discharge, the adjusted odds ratio of fetoscopic endoluminal tracheal occlusion was 1.78 (95% confidence interval, 1.05-3.01; P=.031). The additional effect of early balloon insertion was highly uncertain (adjusted odds ratio, 1.53; 95% confidence interval, 0.60-3.91; P=.370). When combining these 2 effects, the adjusted odds ratio of fetoscopic endoluminal tracheal occlusion with early balloon insertion was 2.73 (95% confidence interval, 1.15-6.49). The results for survival to 6 months and survival to 6 months without oxygen dependence were comparable. The gestational age at delivery was on average 1.7 weeks earlier (95% confidence interval, 1.1-2.3) following fetoscopic endoluminal tracheal occlusion with late insertion and 3.2 weeks earlier (95% confidence interval, 2.3-4.1) following fetoscopic endoluminal tracheal occlusion with early insertion compared with expectant management. There was no evidence that the effect of fetoscopic endoluminal tracheal occlusion depended on the observed over expected lung-to-head ratio for any of the endpoints.Conclusion: This analysis suggests that fetoscopic endoluminal tracheal occlusion increases survival for both moderate and severe lung hypoplasia. The difference between the results for the Tracheal Occlusion To Accelerate Lung growth trials, when considered apart, may be because of the difference in the time point of balloon insertion. However, the effect of the time point of balloon insertion could not be robustly assessed because of a small sample size and the confounding effect of disease severity. Fetoscopic endoluminal tracheal occlusion with early balloon insertion in particular strongly increases the risk for preterm delivery. [ABSTRACT FROM AUTHOR]

Background: Sildenafil already is administered during gestation in patients with pulmonary hypertension and is under evaluation as a treatment for several pregnancy complications, such as preeclampsia and intrauterine growth restriction. Animal studies have shown a potential therapeutic effect of the drug in fetuses with congenital diaphragmatic hernia, rescuing peripheral pulmonary vasculature, and airway phenotype. When considering this drug for evaluation in a clinical trial, data on effective human placental drug passage are required.Objective: We quantified transplacental passage of sildenafil in the ex vivo dually perfused cotyledon model.Study Design: Six placentas that were collected after term delivery from healthy volunteers were cannulated and perfused dually. Sildenafil citrate was added to the maternal circulation at 2 different concentrations: 500 ng/mL, which represented the maximum tolerated concentration (n=3), and 50 ng/mL, which represented the therapeutic concentration (n=3). Samples were collected from both the fetal and the maternal reservoir at 0, 6, 30, 60, 90, 120, 150, and 180 minutes; the concentrations of sildenafil and its metabolite desmethyl-sildenafil were determined with the use of high performance liquid chromatography. The fetal/maternal concentration ratio was calculated for each timepoint. Transfer clearance was calculated as the rate of maternal to fetal passage/maternal concentration.Results: Sildenafil crossed the placenta at both maximal and therapeutic concentrations. Maternal and fetal levels reached a plateau at 90-120 minutes. Transfer clearance was the highest during the first hour of perfusion: 3.15 mL/min (range, 2.14-3.19 mL/min) for the maximum tolerated concentration and 3.07mL/min (range, 2.75-3.42 mL/min) for the therapeutic concentration (not significant). The fetomaternal concentration ratio significantly increased over time, up to 0.91±0.16 for the maximal concentration and 0.95±0.22 for the therapeutic concentration at the end of the perfusion (not significant). Desmethyl-sildenafil was not detected in any sample.Conclusion: Sildenafil crosses the term placenta at a relatively high rate ex vivo, which suggests that there is sufficient placental transfer to reach clinically active fetal drug levels at the currently used maternal doses. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to compare perinatal outcomes of pregnancies that undergo “early” (<17 weeks'' gestation) or “late” (>26 weeks'' gestation) fetoscopic laser ablation of placental vascular anastomoses for twin-twin transfusion syndrome (TTTS) with “conventional” cases that were treated at 17-26 weeks'' gestation. Study Design: We conducted a single center, retrospective analysis of 325 consecutive pregnancies that underwent fetoscopic laser therapy for severe TTTS. Results: Twenty-four “early,” 18 “late,” and 283 “conventional” pregnancies with severe TTTS underwent laser therapy. Fetoscopy duration, gestation at delivery, survival rate, and complications were comparable among groups, except for preterm premature rupture of membranes at <7 days after laser therapy, which was more common in the “early” group than in either of the other 2 groups. Conclusion: Laser therapy for TTTS at <17 or >26 weeks'' gestation has similar outcomes to procedures done at 17-26 weeks'' gestation. We suggest that conventional gestational age guidelines of 16-26 weeks for laser therapy for TTTS should be reevaluated. [Copyright &y& Elsevier]

Objective: The objective of the study was to determine whether cardiac troponin T (cTnT) and natriuretic peptides can be isolated from the amniotic fluid (AF) of pregnancies complicated by twin-to-twin transfusion syndrome (TTTS) and whether they correlate with fetal echocardiographic findings and recipient survival. Study Design: AF samples from the recipient sac were obtained in 52 TTTS cases and 16 controls. Samples were assayed for cTnT and natriuretic peptides. Prior to fetoscopic laser therapy, 34 recipient twins underwent assessment of atrioventricular flow patterns, myocardial performance index (MPI), and precordial venous Dopplers. Fetal survival was assessed 48 hours postoperatively. Results: AF B-type natriuretic peptide and cTnT levels were elevated in TTTS and correlated with functional echocardiographic findings. Postoperative recipient survival was 72% when both AF-cTnT and left ventricular MPI were increased. If 1 of both markers was normal, survival was 100% (P = .046). Conclusion: Combining ultrasound and AF-cTnT measurements allows the identification of fetuses at risk of postoperative demise. [Copyright &y& Elsevier]

Objective: We sought to assess fetal cardiac function in monochorionic twins before and after therapy for twin-to-twin transfusion syndrome (TTTS) and compare it with control subjects. Study Design: We conducted prospective longitudinal assessment of fetal cardiac function in cases undergoing curative fetal therapy for TTTS (n = 39) until 4 weeks postoperatively and in uncomplicated monochorionic twins (n = 23). Fetal cardiac function was assessed by the left and right ventricular myocardial performance index, atrioventricular valve flow pattern, ductus venosus a-wave, and umbilical vein pulsations. Results: Nomograms for the myocardial performance index were constructed. Fetal cardiac function was grossly abnormal in recipient twins of TTTS when compared with control subjects (P < .001 for all indices) but normalized by 4 weeks postoperatively. The donor developed abnormal ductus venosus flow and tricuspid regurgitation postoperatively that regressed within 4 weeks. Conclusion: The cardiac dysfunction in the recipient twin of TTTS normalizes within 1 month after laser. The donor develops a transient impairment of cardiac function postoperatively. [Copyright &y& Elsevier]

Objective: To study cefazolin pharmacokinetics in maternal plasma and amniotic fluid during pregnancy. Study Design: Newly collected time-concentrations profiles and reported studies investigating cefazolin disposition (plasma, amniotic fluid) were pooled. Nonlinear mixed effect modeling was applied. A 2-compartment linear disposition model was used to fit cefazolin plasma observations. A third compartment was used to model amniotic fluid concentration. Results: One hundred eighty-seven plasma and 96 amniotic fluid samples were collected in 82 pregnancies (17-40 weeks gestational age). Cefazolin clearance and distribution estimates were 7.44 L/h and 12.04 L without gestational age-dependent trends in maternal plasma. The equilibration half-life (Teq) between plasma and amniotic fluid at term gestational age was 4.4 hours, increased with decreasing gestational age, and was 9.09 times longer in patients with polyhydramnios. Conclusion: Cefazolin clearance and distribution volume are increased during pregnancy. The cefazolin Teq depends on gestational age and polyhydramnios. On the basis of these observations, dosing regimes to attain higher amniotic fluid concentrations were formulated. [Copyright &y& Elsevier]

Objective: The purpose of this study was to document pregnancy and neonatal outcome of monochorionic diamniotic twin pregnancies. Study Design: This observational study describes a prospective series included in the first trimester in 2 centers of the Eurotwin2twin project. Results: Of the 202 included twin pairs, 172 (85%) resulted in 2 survivors, 15 (7.5%) in 1 survivor, and 15 (7.5%) in no survivors. The mortality was 45 of 404 (11%), and 36 of 45 (80%) were fetal losses of 24 weeks or less, 5 of 45 (11%) between 24 weeks and birth, and 4 of 45 (9%) were neonatal deaths. Twin-to-twin transfusion syndrome (TTTS) occurred in 18 of 202 (9%). The mortality of TTTS was 20 of 36 (55%), which accounted for 20 of 45 (44%) of all losses. Severe discordant growth without TTTS occurred in 29 of 202 (14%). Its mortality was 5 of 58 (9%), which accounted for 5 of 45 (11%) of all losses. Major discordant congenital anomalies occurred in 12 of 202 (6%). Of the 178 pairs that continued after 24 weeks, 10 (6%) had severe hemoglobin differences at birth. After 32 weeks, the prospective risk of intrauterine demise was 2 in 161 pregnancies (1.2%; 95% confidence interval, 0.3-4.6). Conclusion: Of the monochorionic twins recruited in the first trimester, 85% resulted in the survival of both twins, and 92.5% resulted in the survival of at least 1 twin. Most losses were at 24 weeks or less, and TTTS was the most important cause of death. After 32 weeks, the risk of intrauterine demise appears to be small. [Copyright &y& Elsevier]

Objective: The purpose of this study was to examine the clinical and placental characteristics of monochorionic diamniotic twin pregnancies with early-onset discordant growth diagnosed at 20 weeks, late-onset discordant growth diagnosed at 26 weeks or later, and concordant growth. Study Design: We studied a prospective cohort that underwent an ultrasound scan in the first trimester, at 16, 20, and 26 weeks. We excluded pregnancies complicated by twin-to-twin transfusion syndrome, miscarriage, fetal death less than 16 weeks, or severe congenital anomalies. Placental sharing and angioarchitecture were assessed by injection of each cord vessel with dyed barium sulphate. The 2 territories were delineated on an X-ray angiogram. The diameter of each intertwin anastomosis was measured on a digital photograph. Results: We included 178 twin pairs. Early onset discordant growth, late-onset discordant growth, and concordant growth occurred in 15, 13, and 150 pregnancies, respectively. Twin pairs with early-onset discordant growth had lower survival rates and were delivered at an earlier gestational age than pairs with late-onset discordant and concordant growth. The degree of birthweight discordance was similar in early- and late-onset discordant growth. Severe intertwin hemoglobin differences at the time of birth occurred in 0%, 38%, and 3% of pairs with early-onset discordant growth, late-onset discordant growth, and concordant growth, respectively. The placentas of pairs with early-onset discordant growth were more unequally shared and had larger arterioarterial anastomoses and a larger total anastomotic diameter as compared with placentas of pairs with late onset-discordant or concordant growth. Conclusion: Unequal placental sharing appears to be involved in the etiology of early-onset discordant growth, whereas a late intertwin transfusion imbalance may be involved in some cases with late-onset discordant growth. [Copyright &y& Elsevier]

Objective: The purpose of this study was to determine the value of ultrasound examination in the first trimester and at 16 weeks to predict fetal complications in monochorionic diamniotic (MCDA) twin pregnancies, defined as the occurrence of either twin-to-twin transfusion syndrome, severe discordant growth, or intrauterine death. Study Design: We identified risk factors to predict a complicated fetal outcome in the first trimester and at 16 weeks in a prospective cohort of 202 twin pregnancies recruited during the first trimester in 2 centers of the EuroTwin2Twin project. Results: Significant predictors in the first trimester were the difference in crown-rump length (odds ratio [OR], 11) and discordant amniotic fluid (OR, 10). At 16 weeks, significant predictors were the difference in abdominal circumference (OR, 29), discordant amniotic fluid (OR, 7), and discordant cord insertions (OR, 3). Risk assessment in the first trimester and at 16 weeks detected 29% and 48% of cases with a complicated fetal outcome, respectively, with a false-positive rate of 3% and 6%, respectively. Combined first-trimester and 16 week assessment identified 58% of fetal complications, with a false-positive rate of 8%. Conclusion: Of the MCDA twin pregnancies classified as high risk on the combined first trimester and 16 weeks assessment (n = 41), 73% had a complicated fetal outcome with a survival rate of only 69%. In contrast, of the pregnancies classified as low risk (n = 154), 86% had an uneventful fetal outcome with a survival rate of 95%. [Copyright &y& Elsevier]