Placenta accreta spectrum disorders clinical practice guidelines: A systematic review.

OBJECTIVES: To objectively assess the quality of the published clinical practice guidelines (CPGs) on the management of pregnancies complicated by placenta accreta spectrum (PAS)disorders. METHODS: MEDLINE, Embase, Scopus, and ISI Web of Science databases were searched. The following aspects related to the management of pregnancies with suspected PAS disorders were evaluated: risk factors for PAS, prenatal diagnosis, role of interventional radiology and ureteral stenting, and optimal surgical management. The assessment of risk of bias and quality assessment of the CPGs were performed using the (AGREE II) tool (Brouwers et al., 2010). To define a CPG as of good quality we adopted a cut-off score >60%. RESULTS: Nine CPGs were included. Specific risk factors for referral were assessed by 44.4% (4/9) of CPGs, mainly consisting in the presence of placenta previa and a prior cesarean delivery or uterine surgery. About 55.6% of CPGs (5/9) suggested ultrasound assessment of women with risk factors for PAS in the second and third trimester of pregnancy and 33.3% (3/9) recommended magnetic resonance imaging (MRI); 88.9% (8/9) of CPGs recommended cesarean delivery at 34-37 weeks of gestation. There was not generally consensus on the use of interventional radiology and ureteral stenting before surgery for PAS. Finally, hysterectomy was the recommend surgical approach by 77.8% (7/9) of the included CPGs. CONCLUSION: Most of the published CPGs on PAS are generally of good quality. There was general agreement among the different CPGs on PAS as a regard as risk stratification, timing at diagnosis and delivery but not on the indication for MRI, use of interventional radiology and ureteral stenting.

Role of lactoferrin in preventing preterm birth and pregnancy complications: a systematic review and meta-analysis.

INTRODUCTION: The aim of this systematic review was to report the role of lactoferrin supplementation for the prevention of preterm birth (PTB) in women at risk. EVIDENCE ACQUISITION: PubMed and Embase databases were searched. Inclusion criteria were studies exploring maternal and perinatal outcomes in women at high-risk for preterm birth receiving compared to those not receiving lactoferrin during pregnancy. The primary outcome was preterm PTB<37 weeks; the secondary outcomes were gestational age at birth, PTB<34 and 28 weeks, preterm premature rupture of the membranes (PPROM), chorioamnionitis and admission to Neonatal Intensive Care Unit. Random effect meta-analyses were used to analyze the data. EVIDENCE SYNTHESIS: Six studies (333 pregnancies) were included. Overall, women taking lactoferrin had a lower risk of PTB<37 weeks of gestation with an OR of 0.43 (95% CI: 0.2-0.9). Likewise, gestational age at delivery was higher in women-taking compared to those not-taking lactoferrin (MD=0.46 weeks, SD=0.17, P=0.006). The other included studies explored the role of lactoferrin in affecting the inflammatory profile in the amniotic fluid of women undergoing invasive test, without reporting its actual role in preventing PTB. CONCLUSIONS: Prophylactic administration of lactoferrin can reduce the risk of PTB in women at risk. Further large and adequately powered randomized trial are needed in order to elucidate the actual role of lactoferrin in reducing the risk of preterm birth and in affecting perinatal outcomes in women at risk.

Systematic review and meta-analysis on placenta accreta spectrum disorders in twin pregnancies: risk factors, detection rate and histopathology.

INTRODUCTION: The occurrence of PAS has been recently associated with the presence of twin pregnancy. Aim of this review is to report the risk factors, histopathological correlation, diagnostic accuracy of prenatal ultrasound and clinical outcome of twin pregnancies complicated by placenta accreta spectrum (PAS) disorders. EVIDENCE ACQUISITION: PubMed, Embase, Cinahl, Clinical Trial.Gov and Google Scholar databases were searched. Inclusion criteria were studies on twin pregnancies complicated by PAS. The outcomes explored were risk factors for PAS (including placenta previa, prior uterine surgery or assisted reproductive technology, ART), histopathology (placenta accreta and increta/percreta), detection rate of prenatal ultrasound and clinical outcome, including need for blood transfusion, hysterectomy, emergency or scheduled Cesarean delivery (CD), and maternal death. Random effect meta-analyses of proportions were sued to combine the data. EVIDENCE SYNTHESIS: Two studies considering 103 pregnancies were included in this systematic review: 41.86% (95% CI 27.0-57.9) of twin pregnancies complicated by PAS disorders had a prior CD, 28.22% (95% CI 13.4-46.0) presented placenta previa and 58.14% (95% CI 42.1-73.0) of twin pregnancies were conceived by ART. 74.49% (95% CI 41.6-96.5) of PAS in twin pregnancies were placenta accreta, while 25.51% (95% CI 3.5-58.4) were placenta increta or percreta. Prenatal diagnosis of PAS in twin pregnancies was accomplished only in 27.91% (95% CI 15.3-43.7) of cases. Finally, only one study consistently reported the clinical outcome of PAS in twins. 31.67% (95% CI 20.3-45.0) of women required blood transfusion, 26.67% (95% CI 16.1-39.7) had hysterectomy, while there was no case of maternal death. 44.19% of women had an emergency CD. CONCLUSIONS: There is still limited evidence on the clinical course of PAS disorders in twin pregnancies. Placenta previa, prior uterine surgery (mainly CD), and ART are the most commonly risk factors for PAS disorders in twins. Prenatal diagnosis of PAS in twins is lower compared to what reported in singleton. Finally, about 30% of women with a twin pregnancy complicated by PAS required blood transfusion and hysterectomy.

Neonatal Morbidity of Monoamniotic Twin Pregnancies: A Systematic Review and Meta-analysis.

OBJECTIVE: This study was aimed to report the incidence of neonatal morbidity in monochorionic monoamniotic (MCMA) twin pregnancies according to gestational age at birth and type of management adopted (inpatient or outpatient). STUDY DESIGN: Medline and Embase databases were searched. Inclusion criteria were nonanomalous MCMA twins. The primary outcome was a composite score of neonatal morbidity, defined as the occurrence of at least one of the following outcomes: respiratory morbidity, overall neurological morbidity, severe neurological morbidity, and infectious morbidity, necrotizing enterocolitis at different gestational age windows (24-30, 31-32, 33-34, and 35-36 weeks). Secondary outcomes were the individual components of the primary outcome and admission to neonatal intensive care unit (NICU). Subanalysis according to the type of surveillance strategy (inpatient compared with outpatient) was also performed. Random effect meta-analyses were used to analyze the data. RESULTS: A total of 14 studies including 685 MCMA twin pregnancies without fetal anomalies were included. At 24 to 30, 31 to 32, 33 to 34, and 35 to 36 weeks of gestation, the rate of composite morbidity was 75.4, 65.5, 37.6, and 18.5%, respectively, the rate of respiratory morbidity was 74.2, 59.1, 35.5, and 12.2%, respectively, while overall neurological morbidity occurred in 15.3, 10.2, 4.3, and 0% of the cases, respectively. Infectious morbidity complicated 13, 4.2, 3.1, and 0% of newborns while 92.1, 81.6, 58.7, and 0% of cases required admission to NICU. Morbidity in pregnancies delivered between 35 and 36 weeks of gestation was affected by the very small sample size of cases included. When comparing the occurrence of overall morbidity according to the type of management (inpatient or outpatient), there was no difference between the two surveillance strategies (p = 0.114). CONCLUSION: MCMA pregnancies are at high risk of composite neonatal morbidity, mainly respiratory morbidity that gradually decreases with increasing gestational age at delivery with a significant reduction for pregnancies delivered between 33 and 34 weeks. We found no difference in the occurrence of neonatal morbidity between pregnancies managed as inpatient or outpatient. KEY POINTS: · MCMA pregnancies are at high risk of composite neonatal morbidity, mainly respiratory morbidity.. · Neonatal morbidity gradually decreases with increasing GA at delivery, mostly between 33 and 34 weeks.. · There is no difference in the occurrence of neonatal morbidity between in- or outpatient management..

Diagnostic performance of cerebroplacental and umbilicocerebral ratio in appropriate for gestational age and late growth restricted fetuses attempting vaginal delivery: a multicenter, retrospective study.

BACKGROUND: Cerebroplacental Doppler studies have been advocated to predict the risk of adverse perinatal outcome (APO) irrespective of fetal weight. OBJECTIVE: To report the diagnostic performance of cerebroplacental (CPR) and umbilicocerebral (UCR) ratios in predicting APO in appropriate for gestational age (AGA) fetuses and in those affected by late fetal growth restriction (FGR) attempting vaginal delivery. STUDY DESIGN: Multicenter, retrospective, nested case-control study between 1 January 2017 and January 2020 involving five referral centers in Italy and Spain. Singleton gestations with a scan between 36 and 40 weeks and within two weeks of attempting vaginal delivery were included. Fetal arterial Doppler and biometry were collected. The AGA group was defined as fetuses with an estimated fetal weight and abdominal circumference >10th and <90th percentile, while the late FGR group was defined by Delphi consensus criteria. The primary outcome was the prediction of a composite of perinatal adverse outcomes including either intrauterine death, Apgar score at 5 min <7, abnormal acid-base status (umbilical artery pH < 7.1 or base excess of more than -11) and neonatal intensive care unit (NICU) admission. Area under the curve (AUC) analysis was performed. RESULTS: 646 pregnancies (317 in the AGA group and 329 in the late FGR group) were included. APO were present in 12.6% AGA and 24.3% late FGR pregnancies, with an odds ratio of 2.22 (95% CI 1.46-3.37). The performance of CPR and UCR for predicting APO was poor in both AGA [AUC: 0.44 (0.39-0.51)] and late FGR fetuses [AUC: 0.56 (0.49-0.61)]. CONCLUSIONS: CPR and UCR on their own are poor prognostic predictors of APO irrespective of fetal weight.

Outcome of fetal Vein Galen aneurysmal malformations: a systematic review and meta-analysis.

OBJECTIVES: To report the outcome of fetuses with a prenatal diagnosis of Vein of Galen (VOG) malformation. METHODS: PubMed and Embase databases were searched. Random effect meta-analysis of proportions was used to analyze the data. The outcomes explored were prenatal ultrasound findings, mortality, preterm birth (PTB), abnormal neurological outcome, associated findings detected at post-natal brain imaging, need for anticonvulsant therapy, and the rate of children free from neurological impairment. Random effect meta-analysis of proportions were used to analyze the data. RESULTS: Eleven studies (226 fetuses with a prenatal diagnosis of VOG malformation) were included. All cases were detected during the third trimester of pregnancy. Ventriculomegaly was detected in 31.8% (95% CI 27.6-47.7), cardiomegaly or other ultrasound signs of cardiac compromise in 23.1% (95% CI 14.9-32.5) and hydrops in 7.3% (95% CI 2.8-13.6) of cases. The incidence of IUD, NND, and PND was 1.5% (95% CI 0.2-4.3), 23.8% (95% CI 16.9-31.4), and 24.5% (95% CI 17.6-32.2), respectively, while 12.6% (95% CI 6.0-21.2) of pregnancies were complicated by PTB. Abnormal neurodevelopmental outcome was observed in 36.7% (95% CI 27.9-39.7) of cases, while 60.5% (95% CI 17.0-82.0) of children had abnormal findings on post-natal imaging and only 29.7% (95% CI 23.3-36.5) were free from neurological impairment after birth, although there was a wide heterogeneity in the time at follow-up between the included studies. CONCLUSION: VOG malformation diagnoses during fetal life is associated with a high incidence of brain damage, cardiac compromise, and abnormal neurodevelopmental outcome after birth.

Role of prenatal magnetic resonance imaging in fetuses with isolated severe ventriculomegaly at neurosonography: A multicenter study.

OBJECTIVE: The aim of this study was to report the rate of additional anomalies detected exclusively at prenatal magnetic resonance imaging (MRI) in fetuses with isolated severe ventriculomegaly undergoing neurosonography. METHOD: Multicenter, retrospective, cohort study involving 20 referral fetal medicine centers in Italy, United Kingdom, Spain and Denmark. Inclusion criteria were fetuses affected by isolated severe ventriculomegaly (≥15 mm), defined as ventriculomegaly with normal karyotype and no other additional central nervous system (CNS) and extra-CNS anomalies on ultrasound. In all cases, a multiplanar assessment of fetal brain as suggested by ISUOG guidelines on fetal neurosonography had been performed. The primary outcome was the rate of additional CNS anomalies detected exclusively at fetal MRI within two weeks from neurosonography. Subgroup analyses according to gestational age at MRI (

Comparison between Cerebroplacental Ratio and Umbilicocerebral Ratio in Predicting Adverse Perinatal Outcome in Pregnancies Complicated by Late Fetal Growth Restriction: A Multicenter, Retrospective Study.

INTRODUCTION: The role of cerebroplacental ratio (CPR) or umbilicocerebral ratio (UCR) to predict adverse intrapartum and perinatal outcomes in pregnancies complicated by late fetal growth restriction (FGR) remains controversial. METHODS: This was a multicenter, retrospective cohort study involving 5 referral centers in Italy and Spain, including singleton pregnancies complicated by late FGR, as defined by Delphi consensus criteria, with a scan 1 week prior to delivery. The primary objective was to compare the diagnostic accuracy of the CPR and UCR for the prediction of a composite adverse outcome, defined as the presence of either an adverse intrapartum outcome (need for operative delivery/cesarean section for suspected fetal distress) or an adverse perinatal outcome (intrauterine death, Apgar score <7 at 5 min, arterial pH <7.1, base excess of >-11 mEq/mL, or neonatal intensive care unit admission). RESULTS: Median CPR absolute values (1.11 vs. 1.22, p = 0.018) and centiles (3 vs. 4, p = 0.028) were lower in pregnancies with a composite adverse outcome than in those without it. Median UCR absolute values (0.89 vs. 0.82, p = 0.018) and centiles (97 vs. 96, p = 0.028) were higher. However, the area under the curve, 95% confidence interval for predicting the composite adverse outcome showed a poor predictive value: 0.580 (0.512-0.646) for the raw absolute values of CPR and UCR, and 0.575 (0.507-0.642) for CPR and UCR centiles adjusted for gestational age. The use of dichotomized values (CPR <1, UCR >1 or CPR <5th centile, UCR >95th centile) did not improve the diagnostic accuracy. CONCLUSION: The CPR and UCR measured in the week prior delivery are of low predictive value to assess adverse intrapartum and perinatal outcomes in pregnancies with late FGR.

Induction of labor in late FGR.

Late-onset FGR is a peculiar condition characterized by the inability for the fetus to reach its growth potential diagnosed from 32 weeks of gestation. Placental insufficiency is among the leading causes of late FGR and is commonly due to a primary maternal cardiovascular non-adaptation potentially leading to fetal decompensation during labor especially once exposed to uterine hyperstimulation. Abnormalities that usually characterize late FGR include reduced fetal growth, decreased Amniotic Fluid Index, and loss of fetal heart rate variability at CTG. Fetal hemodynamics study by Doppler ultrasound significantly improved management of pregnancies affected by fetal growth restriction. A major issue when dealing with pregnancies complicated by late FGR is how to induce these women. Induction of labor (IOL) can be essentially accomplished by pharmacological and non-pharmacological agents. Recent studies suggested that the pregnancies complicated by late FGR should undergo a tailored approach for IOL in view of the higher risk of fetal decompensation following uterine hyperstimulation. The present review aims to provide an up to date on the different types of IOL which can guide clinical management.

Outcome of cesarean scar pregnancy according to gestational age at diagnosis: A systematic review and meta-analysis.

OBJECTIVE: The association between the most severe types of placenta accreta spectrum disorders and caesarean scar pregnancy (CSP) poses the question of whether early diagnosis may impact the clinical outcome of these anomalies. The aim of this study is to report the outcome of cesarean scar pregnancy (CSP) diagnosed in the early (≤9 weeks) versus late (>9 weeks) first trimester of pregnancy. STUDY DESIGN: Medline, Embase and Clinicaltrail.gov databases were searched. Studies including cases of CSP with an early (≤9 weeks of gestation) compared to a late (>9 weeks) first trimester diagnosis of CSP, followed by immediate treatment, were included in this systematic review. The primary outcome was a composite measure of severe maternal morbidity including either severe first trimester bleeding, need for blood transfusion, uterine rupture or emergency hysterectomy. The secondary outcomes were the individual components of the primary outcome. Random-effect meta-analyses were used to combine data. RESULTS: Thirty-six studies (724 women with CSP) were included. Overall, composite adverse outcome complicated 5.9 % (95 % CI 3.5-9.0) of CSP diagnosed ≤9 weeks and 32.4 % (95 % CI 15.7-51.8) of those diagnosed >9 weeks. Massive hemorrhage occurred in 4.3 % (95 % CI 2.3-7.0) of women with early and in 28.0 % (95 % CI 14.1-44.5) of those with late first trimester diagnosis of CSP, while the corresponding figures for the need for blood transfusion were 1.5 % (95 % CI 0.6-2.8) and 15.8 % (95 % CI 5.5-30.2) respectively. Uterine rupture occurred in 2.5 % (95 % CI 1.2-4.1) of women with a prenatal diagnosis of CSP ≤ 9 weeks and in 7.5 % (95 % CI 2.5-14.9) of those with CSP > 9 weeks, while an emergency intervention involving hysterectomy was required in 3.7 % (95 % CI 2.2-5.4) and 16.3 % (95 % CI5.9-30.6) respectively. When computing the risk, early diagnosis of CSP was associated with a significantly lower risk of composite adverse outcome, (OR: 0.14; 95 % CI 0.1-0.4 p < 0.001). CONCLUSIONS: Early first trimester diagnosis of CSP is associated with a significantly lower risk of maternal complications, thus supporting a policy of universal screening for these anomalies in women with a prior cesarean delivery although the cost-effectiveness of such policy should be tested in future studies.

Role of prenatal magnetic resonance imaging in fetuses with isolated agenesis of corpus callosum in the era of fetal neurosonography: A systematic review and meta-analysis.

INTRODUCTION: Corpus callosum agenesis (ACC) is frequently diagnosed during fetal life; its prognosis depends also on additional anomalies. The additional value of fetal magnetic resonance imaging (MRI) in fetuses with "isolated" complete (cACC) and partial (pACC) agenesis of the corpus callosum on ultrasound is still debated. MATERIAL AND METHODS: We performed a systematic literature review and meta-analysis including fetuses with a prenatal diagnosis of cACC and pACC without associated structural anomalies on ultrasound, undergoing fetal MRI. The primary outcome was the rate of additional anomalies detected at fetal MRI. Further analyses assessed the effect of type of ultrasound assessment (neurosonography vs standard axial assessment), gestational age at fetal MRI and rate of postnatally detected brain anomalies. Random-effect meta-analyses of proportions were used to analyze the data. RESULTS: Fourteen studies (798 fetuses) were included. In cases with isolated cACC, 10.9% (95% CI 4.1-20.6) and 4.3% (95% CI 1.4-8.8) additional anomalies were detected by fetal MRI and postnatally, respectively. Stratifying according to the type of ultrasound assessment, the rate of associated anomalies detected only on fetal MRI was 5.7% (95% CI 0.5-16.0) with dedicated neurosonography and 18.5% (95% CI 7.8-32.4) with a standard axial assessment. In fetuses with isolated pACC, 13.4% (95% CI 4.0-27.0) and 16.2% (95% CI 5.9-30.3) additional anomalies were detected by fetal MRI or postnatally, respectively. Stratifying according to the type of ultrasound assessment, the rate of associated anomalies detected only on fetal MRI was 11.4% (95% CI 2.7-25.0) when dedicated neurosonography was performed. Cortical and posterior fossa anomalies represented the most common anomalies missed at ultrasound with both cACC and pACC. Due to the very small number of included cases, stratification according to early (<24 weeks of gestation) and late (>24 weeks) fetal MRI could not be done for either cACC or pACC. CONCLUSIONS: The rate of associated anomalies detected exclusively at fetal MRI in isolated ACC undergoing neurosonography is lower than previously reported. Cortical and posterior fossa anomalies are among the most common anomalies detected exclusively at MRI, thus confirming the crucial role of fetal MRI in determining the prognosis of these fetuses. However, some anomalies still go undetected prenatally and this should be stressed during parental counseling.

Outcome of fetal echogenic bowel: A systematic review and meta-analysis.

The main aim of this systematic review was to explore the outcome of fetuses with isolated echogenic bowel (EB) on antenatal ultrasound. Inclusion criteria were singleton pregnancies with isolated EB no associated major structural anomalies at the time of diagnosis. The outcomes observed were: chromosomal anomalies, cystic fibrosis (CF), associated structural anomalies detected only at follow-up scans and at birth, regression during pregnancy, congenital infections, intra-uterine (IUD), neonatal (NND) and perinatal (PND) death. Twenty-five studies (12 971 fetuses) were included. Chromosomal anomalies occurred in 3.3% of the fetuses, mainly Trisomy 21 and aneuploidies involving the sex chromosomes. Cystic fibrosis occurred in 2.2%. Congenital infections affected 2.2%, mainly congenital Cytomegalovirus (CMV) infection. The majority of fetuses with EB experienced regression or disappearance of the EB at follow-up scans. Associated anomalies were detected at a follow-up scan in 1.8%. Associated anomalies were detected at birth and missed at ultrasound in 2.1% of cases. IUD occurred in 3.2% of cases while the corresponding figures for NND and PND were 0.4% and 3.1%. Fetuses with EB are at increased risk of adverse perinatal outcome, highlighting the need for a thorough antenatal management and postnatal follow-up. Assessment during pregnancy and after birth should be performed in order to look for signs of fetal aneuploidy, congenital infections and associated structural anomalies.

Comparison between cerebroplacental ratio and umbilicocerebral ratio in predicting adverse perinatal outcome at term.

OBJECTIVE: Cerebroplacental ratio (CPR) has been associated with adverse perinatal outcome irrespective of fetal weight. More recently, it has been proposed that the ratio between umbilical and middle cerebral artery pulsatility index, the umbilicocerebral ratio (UCR) had a higher diagnostic accuracy compared to CPR in predicting adverse outcome. The aim of the study was to compare the diagnostic accuracy of CPR and UCR in predicting adverse perinatal outcome in the third trimester of pregnancy. STUDY DESIGN: Secondary analysis of prospective study carried out in a dedicated research ultrasound clinic in a single tertiary referral center over a one-year period. Inclusion criteria were consecutive singleton pregnancies between 36 + 0 and 37 + 6 weeks of gestation. Exclusion criteria were multiple gestations, pregnancies affected by structural or chromosomal anomalies, maternal medical complications or drugs intake and abnormal Doppler waveform in the UA, defined as PI>95th or absent/end diastolic flow. All women were pre-screened at 28-32 weeks of gestation in order to rule out signs of early fetal growth restriction. The primary outcome was to compare the diagnostic performance of CPR and UCR in detecting the presence of fetuses affected by a composite adverse outcome. RESULTS: Mean CPR (1.35 ± 0.39 vs 1.85 ± 0.58, p < 0.001) was significantly lower while mean UCR (0.78 ± 0.25 vs 0.58 ± 0.20, p = 0.001) was significantly higher in pregnancies experiencing compared to those not experiencing composite adverse outcome. There was no difference between CPR and UCR in predicting adverse perinatal outcome in the third trimester of pregnancy and both showed a very low diagnostic accuracy. CPR had an AUC of 0.51 (95 % CI 0.43-0.58) while UCR had an AUC of 0.51 (95 % CI 0.43-0.58) in predicting composite adverse outcome. Likewise, there was no difference in the diagnostic accuracy of CRP (AUC: 0.600, 95 % CI 0.36-0.83) and UCR (AUC: 0.589, 95 % CI 0.35-0.83) when considering only SGA fetuses. CONCLUSIONS: A low CPR and a high UCR are significantly associated with adverse perinatal outcome in singleton pregnancies at term. There was no difference between CPR and UCR in predicting perinatal outcome. Despite this, the diagnostic accuracy of both these parameters is too poor to advocate for their use as a screening tool of perinatal impairment at term, unless specific indications, such as SGA or FGR, have been identified.

Adverse intrapartum outcome in pregnancies complicated by small for gestational age and late fetal growth restriction undergoing induction of labor with Dinoprostone, Misoprostol or mechanical methods: A systematic review and meta-analysis.

OBJECTIVE: To investigate the outcome of pregnancies with small baby, including both small for gestational age (SGA) and late fetal growth restriction (FGR) fetuses, undergoing induction of labor (IOL) with Dinoprostone, Misoprostol or mechanical methods. STUDY DESIGN: Medline, Embase and Cochrane databases were searched. Inclusion criteria were non-anomalous singleton pregnancies complicated by the presence of a small fetus, defined as a fetus with estimated fetal weight (EFW) or abdominal circumference (AC) <10th centile undergoing IOL from 34 weeks of gestation with vaginal Dinoprostone, vaginal misoprostol, or mechanical methods (including either Foley or Cook balloon catheters). The primary outcome was a composite measure of adverse intrapartum outcome. Secondary outcomes were the individual components of the primary outcome, perinatal mortality and morbidity. All the explored outcomes were reported in three different sub-groups of pregnancies complicated by a small fetus including: all small fetuses (defined as those with an EFW and/or AC <10th centile irrespective of fetal Doppler status), late FGR fetuses (defined as those with EFW and/or AC <3rd centile or AC/EFW <10th centile associated with abnormal cerebroplacental Dopplers) and SGA fetuses (defined as those with EFW and/or AC <10th but >3rd centile with normal cerebroplacental Dopplers). Quality assessment of each included study was performed using the Risk of Bias in Non-randomized Studies-of Interventions tool (ROBINS-I), while the GRADE methodology was used to assess the quality of the body of retrieved evidence. Meta-analyses of proportions and individual data random-effect logistic regression were used to analyze the data. RESULTS: 12 studies (1711 pregnancies) were included. In the overall population of small fetuses, composite adverse intra-partum outcome occurred in 21.2 % (95 % CI 10.0-34.9) of pregnancies induced with Dinoprostone, 18.0 % (95 % CI 6.9-32.5) of those with Misoprostol and 11.6 % (95 % CI 5.5-19.3) of those undergoing IOL with mechanical methods. Cesarean section (CS) for non-reassuring fetal status (NRFS) was required in 18.1 % (95 % CI 9.9-28.3) of pregnancies induced with Dinoprostone, 9.4 % (95 % CI 1.4-22.0) of those with Misoprostol and 8.1 % (95 % CI 5.0-11.6) of those undergoing mechanical induction. Likewise, uterine tachysystole, was recorded on CTG in 13.8 % (95 % CI 6.9-22.3) of cases induced with Dinoprostone, 7.5 % (95 % CI 2.1-15.4) of those with Misoprostol and 3.8 % (95 % CI 0-4.4) of those induced with mechanical methods. Composite adverse perinatal outcome following delivery complicated 2.9 % (95 % CI 0.5-6.7) newborns after IOL with Dinoprostone, 0.6 % (95 % CI 0-2.5) with Misoprostol and 0.7 % (95 % CI 0-7.1) with mechanical methods. In pregnancies complicated by late FGR, adverse intrapartum outcome occurred in 25.3 % (95 % CI 18.8-32.5) of women undergoing IOL with Dinoprostone, compared to 7.4 % (95 % CI 3.9-11.7) of those with mechanical methods, while CS for NRFS was performed in 23.8 % (95 % CI 17.3-30.9) and 6.2 % (95 % CI 2.8-10.5) of the cases, respectively. Finally, in SGA fetuses, composite adverse intrapartum outcome complicated 8.4 % (95 % CI 4.6-13.0) of pregnancies induced with Dinoprostone, 18.6 % (95 % CI 13.1-25.2) of those with Misoprostol and 8.7 (95 % CI 2.5-17.5) of those undergoing mechanical IOL, while CS for NRF was performed in 8.4 % (95 % CI 4.6-13.0) of women induced with Dinoprostone, 18.6 % (95 % CI 13.1-25.2) of those with Misoprostol and 8.7 % (95 % CI 2.5-17.5) of those undergoing mechanical induction. Overall, the quality of the included studies was low and was downgraded due to considerable clinical and statistical heterogeneity. CONCLUSIONS: There is limited evidence on the optimal type of IOL in pregnancies with small fetuses. Mechanical methods seem to be associated with a lower occurrence of adverse intrapartum outcomes, but a direct comparison between different techniques could not be performed.

Reproductive outcome after cesarean scar pregnancy: A systematic review and meta-analysis.

INTRODUCTION: To evaluate subsequent reproductive among women with a prior cesarean scar pregnancy (CSP). MATERIAL AND METHODS: MEDLINE, Embase and ClinicalTrials.gov databases were searched. Inclusion criteria were women with a prior CSP, defined as the gestational sac or trophoblast within the dehiscence/niche of the previous cesarean section scar or implanted on top of it. The primary outcome was the recurrence of CSP; secondary outcomes were the chance of achieving a pregnancy after CSP, miscarriage, preterm birth, uterine rupture and the occurrence of placenta accreta spectrum disorders. Subgroup analysis according to the management of CSP (surgical vs non-surgical) was also performed. Random effect meta-analyses of proportions were used to analyze the data. RESULTS: Forty-four studies (3598 women with CSP) were included. CSP recurred in 17.6% of women. Miscarriage, preterm birth and placenta accreta spectrum disorders complicated 19.1% (65/341), 10.3% (25/243) and 4.0% of pregnancies, and 67.0% were uncomplicated. When stratifying the analysis according to the type of management, CSP recurred in 21% of women undergoing surgical and in 15.2% of those undergoing non-surgical management. Placenta accreta spectrum disorders complicated 4.0% and 12.0% of cases, respectively. CONCLUSIONS: Women with a prior CSP are at high risk of recurrence, miscarriage, preterm birth and placenta accreta spectrum. There is still insufficient evidence to elucidate whether the type of management adopted (surgical vs non-surgical) can impact reproductive outcome after CSP. Further large, prospective studies sharing an objective protocol of prenatal management and long-term follow up are needed to establish the optimal management of CSP and to elucidate whether it may affect its risk of recurrence and pregnancy outcome in subsequent gestations.

Extracellular Vesicles in Feto-Maternal Crosstalk and Pregnancy Disorders.

Extracellular vesicles (EVs) actively participate in inter-cellular crosstalk and have progressively emerged as key players of organized communities of cells within multicellular organisms in health and disease. For these reasons, EVs are attracting the attention of many investigators across different biomedical fields. In this scenario, the possibility to study specific placental-derived EVs in the maternal peripheral blood may open novel perspectives in the development of new early biomarkers for major obstetric pathological conditions. Here we reviewed the involvement of EVs in feto-maternal crosstalk mechanisms, both in physiological and pathological conditions (preeclampsia, fetal growth restriction, preterm labor, gestational diabetes mellitus), also underlining the usefulness of EV characterization in maternal-fetal medicine.