UOG Journal Club: February 2019 systematic review and meta-analysis Perinatal mortality, timing of delivery and prenatal management of monoamniotic twin pregnancy: systematic review and meta-analysis F. D’ANTONIO , A. ODIBO, V. BERGHELLA, A. KHALIL, K. HACK, G. SACCONE, F. PREFUMO, D. BUCA, M. LIBERATI, G. PAGANI and G. ACHARYA Volume 53, Issue 2, Pages 166–174 Journal Club slides prepared by Dr Yael Raz (UOG Editor for Trainees)

systematic review and meta-analysis Perinatal mortality, timing of delivery and prenatal management of monoamniotic twin pregnancy: systematic review and meta-analysis D’Antonio et al., UOG 2019 Introduction Monochorionic (MC) twin pregnancies are at higher risk of perinatal mortality and morbidity compared with dichorionic (DC) pregnancies. Certain complications are unique to MC placentas, such as twin – twin transfusion syndrome (TTTS), twin reversed arterial perfusion (TRAP) sequence and selective intrauterine growth restriction. Monoamnionicity carries a further increased risk of adverse pregnancy outcome compared with MC diamniotic pregnancies thus prenatal identification of monochorionic monoamniotic (MCMA) twins is fundamental.

systematic review and meta-analysis Perinatal mortality, timing of delivery and prenatal management of monoamniotic twin pregnancy: systematic review and meta-analysis D’Antonio et al., UOG 2019 Introduction There is no randomized controlled trial addressing the type and frequency of follow-up in MCMA pregnancy. Some studies advocate inpatient follow-up of these pregnancies with serial ultrasound and cardiotocographic (CTG) assessment, while others report no difference in the perinatal outcome between cases managed as inpatients and those managed as outpatients. No specific recommendation on how to manage MCMA twins is provided by the different national bodies. MCMA pregnancies are usually delivered between 32 and 34 weeks of gestation in view of the reported high risk of unexpected fetal loss with advancing gestation.

systematic review and meta-analysis Perinatal mortality, timing of delivery and prenatal management of monoamniotic twin pregnancy: systematic review and meta-analysis D’Antonio et al., UOG 2019 Birth-weight discordance and neonatal morbidity in twin pregnancy: analysis of STORK multiple pregnancy cohort D’Antonio et al., UOG 2018 Aims of the study Primary Quantify the incidence of perinatal mortality in MCMA twin pregnancies, according to gestational age. Secondary Ascertain the risk of mortality in pregnancies managed as inpatients compared with those managed as outpatients.

systematic review and meta-analysis Methods – Primary outcomes Birth-weight discordance and neonatal morbidity in twin pregnancy: analysis of STORK multiple pregnancy cohort D’Antonio et al., UOG 2018 Perinatal mortality, timing of delivery and prenatal management of monoamniotic twin pregnancy: systematic review and meta-analysis D’Antonio et al., UOG 2019 Methods – Primary outcomes Incidence of intrauterine death (IUD), neonatal death (NND) and perinatal death (PND) in MCMA twins in the following gestational age windows: 24–30 weeks, 31–32 weeks, 33–34 weeks, 35–36 weeks and ≥ 37 weeks. IUD = Fetal demise from 24 weeks’ gestation, divided into: single (sIUD) and double (dIUD) according to the death of one or both twins. Sudden or unexpected - IUD occurring in a MCMA twin without a prior recognizable chronic condition such as transfusion events or growth abnormalities. NND = Death of at least one of the newborns up to 28 days postpartum. PND = IUD plus NND.

systematic review and meta-analysis Methods – Secondary outcomes Birth-weight discordance and neonatal morbidity in twin pregnancy: analysis of STORK multiple pregnancy cohort D’Antonio et al., UOG 2018 Perinatal mortality, timing of delivery and prenatal management of monoamniotic twin pregnancy: systematic review and meta-analysis D’Antonio et al., UOG 2019 Methods – Secondary outcomes Incidence of IUD, NND and PND in twins according to the type of fetal monitoring. Twin pregnancies were divided into those admitted electively to the hospital for fetal monitoring (inpatients) and those followed up as outpatients. Incidence of delivery ahead of schedule in MCMA twin pregnancies scheduled for elective delivery at 32 weeks and those scheduled for delivery between 32 and 34 weeks of gestation.

systematic review and meta-analysis Birth-weight discordance and neonatal morbidity in twin pregnancy: analysis of STORK multiple pregnancy cohort D’Antonio et al., UOG 2018 Perinatal mortality, timing of delivery and prenatal management of monoamniotic twin pregnancy: systematic review and meta-analysis D’Antonio et al., UOG 2019 Methods Inclusion Studies reporting the number of MCMA twin pregnancies in each gestational-age window and the relative number of deaths. Exclusion Studies including cases with fetal anomaly. Case reports, abstracts and case series with fewer than three cases. Studies published before 2000.

systematic review and meta-analysis Results – Included studies Birth-weight discordance and neonatal morbidity in twin pregnancy: analysis of STORK multiple pregnancy cohort D’Antonio et al., UOG 2018 Perinatal mortality, timing of delivery and prenatal management of monoamniotic twin pregnancy: systematic review and meta-analysis D’Antonio et al., UOG 2019 Results – Included studies

Results - General characteristics of included studies Birth-weight discordance and neonatal morbidity in twin pregnancy: analysis of STORK multiple pregnancy cohort D’Antonio et al., UOG 2018 Perinatal mortality, timing of delivery and prenatal management of monoamniotic twin pregnancy: systematic review and meta-analysis D’Antonio et al., UOG 2019 Results - General characteristics of included studies Included in studies: 1068 MCMA pregnancies (2136 twins). Included in systematic review: 814 pregnancies (1628 twins) with data available on perinatal mortality according to gestational age at loss.

Results - Mortality according to gestational age Birth-weight discordance and neonatal morbidity in twin pregnancy: analysis of STORK multiple pregnancy cohort D’Antonio et al., UOG 2018 Perinatal mortality, timing of delivery and prenatal management of monoamniotic twin pregnancy: systematic review and meta-analysis D’Antonio et al., UOG 2019 Results - Mortality according to gestational age The incidence of mortality varied according to gestational age window. There was no IUD, either single or double, from 35 weeks of gestation, although the sample size was small.

systematic review and meta-analysis Results – The etiology of IUD Perinatal mortality, timing of delivery and prenatal management of monoamniotic twin pregnancy: systematic review and meta-analysis D’Antonio et al., UOG 2019 Birth-weight discordance and neonatal morbidity in twin pregnancy: analysis of STORK multiple pregnancy cohort D’Antonio et al., UOG 2018 Results – The etiology of IUD 29.5% (95% CI, 13.5–48.8%; I2 =55.2%) of the overall losses were due to TTTS or growth restriction, while 54.0% (95% CI, 37.1–71.3%; I2 = 42.8%) were unexpected IUD. From 31 weeks of gestation, all IUDs included in the systematic review were reported to be unexpected.

systematic review and meta-analysis Results – Patient Management Perinatal mortality, timing of delivery and prenatal management of monoamniotic twin pregnancy: systematic review and meta-analysis D’Antonio et al., UOG 2019 Birth-weight discordance and neonatal morbidity in twin pregnancy: analysis of STORK multiple pregnancy cohort D’Antonio et al., UOG 2018 Results – Patient Management

Results – Delivery ahead of schedule Birth-weight discordance and neonatal morbidity in twin pregnancy: analysis of STORK multiple pregnancy cohort D’Antonio et al., UOG 2018 Perinatal mortality, timing of delivery and prenatal management of monoamniotic twin pregnancy: systematic review and meta-analysis D’Antonio et al., UOG 2019 Results – Delivery ahead of schedule Risk of unexpected delivery: Inpatients: 44.9% (95% CI, 28.7–61.6%); 22.7% (95% CI, 10.3–38.2%) due to PTB and 44.9% (95% CI, 28.7–61.6%) due to CTG abnormality. Outpatients: 42.3% (95% CI, 26.4–59.4%); 16.4% (95% CI, 10.4–23.4%) due to PTB and 16.7% (95% CI, 5.9–31.4%) due to CTG abnormality.

systematic review and meta-analysis Discussion – Main findings Perinatal mortality, timing of delivery and prenatal management of monoamniotic twin pregnancy: systematic review and meta-analysis D’Antonio et al., UOG 2019 Birth-weight discordance and neonatal morbidity in twin pregnancy: analysis of STORK multiple pregnancy cohort D’Antonio et al., UOG 2018 Discussion – Main findings The overall incidence of fetal loss in MCMA pregnancies is approximately 6%. Most IUDs were unexpected, thus questioning the optimal type of assessment in these pregnancies. The incidence of fetal loss in twins of pregnancies managed mainly as inpatients was 3% as compared with 7% in those followed up as outpatients. The heterogeneity in the type of prenatal assessment among the included studies highlights the need for developing an adequate protocol for prenatal management of MCMA twin pregnancies, focusing on the type and frequency of follow-up rather than admission to the hospital.

systematic review and meta-analysis Perinatal mortality, timing of delivery and prenatal management of monoamniotic twin pregnancy: systematic review and meta-analysis D’Antonio et al., UOG 2019 Birth-weight discordance and neonatal morbidity in twin pregnancy: analysis of STORK multiple pregnancy cohort D’Antonio et al., UOG 2018 Discussion Strengths Limitations The most comprehensive published estimate of the investigated outcomes in MCMA twin pregnancies. Small number of cases in some of the included studies. Retrospective non-randomized design in some of the included studies. Dissimilarity of the populations (due to varied inclusion criteria). Lack of standardized criteria for the antenatal management of MCMA twin pregnancies. Assessment of potential publication bias was problematic.

systematic review and meta-analysis Implications for practice Perinatal mortality, timing of delivery and prenatal management of monoamniotic twin pregnancy: systematic review and meta-analysis D’Antonio et al., UOG 2019 Birth-weight discordance and neonatal morbidity in twin pregnancy: analysis of STORK multiple pregnancy cohort D’Antonio et al., UOG 2018 Implications for practice Prenatal identification of MCMA pregnancies is fundamental in their risk stratification and tailoring their antenatal care. In this systematic review, only 30% of IUDs were due to recognizable conditions such as TTTS. However, prenatal diagnosis of TTTS in MCMA twin pregnancy is challenging and it is possible that some of the fetal losses labeled as unexpected were the result of undiagnosed TTTS. Thorough regular examination of MCMA twins in order to look for signs of TTTS is needed (serial assessment of amniotic fluid, fetal urinary bladders and Doppler studies). A policy of elective delivery at 32 weeks of gestation may look appropriate in view of the apparently higher risk of fetal demise occurring later on in gestation, but should be balanced against the potentially higher risk of neonatal morbidity.

systematic review and meta-analysis Implications for practice Perinatal mortality, timing of delivery and prenatal management of monoamniotic twin pregnancy: systematic review and meta-analysis D’Antonio et al., UOG 2019 Birth-weight discordance and neonatal morbidity in twin pregnancy: analysis of STORK multiple pregnancy cohort D’Antonio et al., UOG 2018 Implications for practice It is unclear whether systematic evaluation of umbilical cords to diagnose entanglement may reduce the risk of fetal loss, as many of them are acute events that may not be easily predicted. A twice-weekly fetal monitoring starting from 24 – 26 weeks of gestation has been proposed in view of the high rate of perinatal loss occurring at 24 – 30 weeks of gestation. Despite this, parental counseling should stress the fact that a normal scan cannot completely rule out adverse events, as they may occur acutely.

systematic review and meta-analysis Birth-weight discordance and neonatal morbidity in twin pregnancy: analysis of STORK multiple pregnancy cohort D’Antonio et al., UOG 2018 Perinatal mortality, timing of delivery and prenatal management of monoamniotic twin pregnancy: systematic review and meta-analysis D’Antonio et al., UOG 2019 Future perspectives Large studies are needed in order to develop objective protocols for antenatal surveillance of MCMA twins, aiming at reducing the risk of perinatal mortality and morbidity in these pregnancies. Points for discussion In light of the improvement in the supportive treatment of premature infants, should MCMA twins be delivered between 30-32 weeks in selected centers? Can serial Doppler examinations starting as early as the second trimester minimize unexpected IUD due to entanglement?