Preterm birth in singleton pregnancies conceived by in vitro fertilization or intracytoplasmic sperm injection: an overview of systematic reviews.

BACKGROUND: The rate of preterm birth of singletons conceived through in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) is increased, being as high as 15% to 16% across Europe and the United States. However, the underlying etiology, phenotype, and mechanisms initiating preterm birth (PTB) are poorly understood. OBJECTIVE: To quantify the PTB risk and examine supposed etiology in IVF/ICSI singleton pregnancies compared to naturally conceived. STUDY DESIGN: Overview of reviews including all available systematic reviews with meta-analysis comparing PTB risk in IVF/ICSI and naturally conceived singletons. A comprehensive search of PubMed/MEDLINE, Embase, Scopus, and Cochrane Library databases was performed up to December 31, 2023. Information available on etiology, phenotype, initiation of PTB, and relevant moderators was retrieved and employed for subgroup analyses. Random-effects meta-analysis models were used for pooling effect measures. Estimates were presented as odds ratios (ORs) with 95% confidence intervals (CIs). The extent of overlap in the original studies was measured using the corrected covered area assessment. The quality of the included reviews was evaluated with the AMSTAR 2 tool. The Grading of Recommendations Assessment, Development and Evaluation approach was applied to rate evidence certainty. The protocol was registered on PROspective Register of Systematic Reviews (CRD42023411418). RESULTS: Twelve meta-analyses (16,522,917 pregnancies; ˃433,330 IVF/ICSI) were included. IVF/ICSI singletons showed a significantly higher PTB risk compared to natural conception (PTB ˂37 weeks: OR: 1.72, 95% CI: 1.57-1.89; PTB<32 weeks: OR: 2.19, 95% CI: 1.82-2.64). Influential analysis reinforced the strength of this association. Subgroup analyses investigating supposed etiology revealed a comparable risk magnitude for spontaneous PTB (OR: 1.79, 95% CI: 1.56-2.04) and a greater risk for iatrogenic PTB (OR: 2.28, 95% CI: 1.72-3.02). PTB risk was consistent in the subgroup of conventional IVF (OR: 1.95, 95% CI: 1.76-2.15) and higher in the subgroup of fresh only (OR: 1.79, 95% CI: 1.55-2.07) vs frozen-thawed embryo transfers (OR: 1.39, 95% CI: 1.34-1.43). There was minimal study overlap (13%). The certainty of the evidence was graded as low to very low. CONCLUSION: Singletons conceived through IVF/ICSI have a 2-fold increased risk of PTB compared to natural conception, despite the low certainty of the evidence. There is paucity of available data on PTB etiology, phenotype, or initiation. The greater risk increase is observed in fresh embryo transfers and involves iatrogenic PTB and PTB ˂32 weeks, likely attributable to placental etiology. Future studies should collect data on PTB etiology, phenotype, and initiation. IVF/ICSI pregnancies should undertake specialistic care with early screening for placental disorders, cervical length, and growth abnormalities, allowing appropriate timely follow-up, preventive measures, and therapeutic interventions strategies.

Maternal anxiety-driven modulation of fetal limbic connectivity designs a backbone linking neonatal brain functional topology to socio-emotional development in early childhood.

A link between maternal anxiety during pregnancy and adverse socio-emotional outcomes in childhood has been consistently sustained on the very early neurodevelopmental alteration of structural pathways between fetal limbic and cortical brain regions. In this study, we provide follow-up evidence for a feed-forward model linking (i) maternal anxiety, (ii) fetal functional neurodevelopment, (iii) neonatal functional network organization with (iv) socio-emotional neurobehavioral development in early childhood. Namely, we investigate a sample of 16 mother-fetus dyads and show how a maternal state-trait anxiety profile with pregnancy-specific worries can significantly influence functional synchronization patterns between regions of the fetal limbic system (i.e., hippocampus and amygdala) and the neocortex, as assessed through resting-state functional magnetic resonance imaging. Generalization of the findings was supported by leave-one-out cross-validation. We further show how this maternal-fetal cross-talk propagates to functional network topology in the neonate, specifically targeting connector hubs, and further maps onto socio-emotional profiles, assessed through Bayley-III socio-emotional scale in early childhood (i.e., in the 12-24 months range). Based on this evidence, we put forward the hypothesis of a "Maternal-Fetal-Neonatal Anxiety Backbone", through which neurobiological changes driven by maternal anxiety could trigger a divergence in the establishment of a cognitive-emotional development blueprint, in terms of the nascent functional homeostasis between bottom-up limbic and top-down higher-order neuronal circuitry.

Pregnancy outcome of confined placental mosaicism: meta-analysis of cohort studies.

OBJECTIVE: This study aimed to assess the rate of adverse obstetrical and neonatal outcomes in pregnancies diagnosed with confined placental mosaicism relative to that of unaffected controls. DATA SOURCES: Web-based databases were searched using relevant key words, and articles published from 1980 to February 2022 were retrieved. STUDY ELIGIBILITY CRITERIA: Observational studies in English language including ≥10 cases of singleton pregnancies with diagnosis of confined placental mosaicism were included. The diagnosis was established after detection of any chromosomal abnormality at chorionic villus sampling for any indication, followed by normal karyotype from amniotic fluid or neonatal leukocyte culture. METHODS: Two authors independently screened the references for eligibility, data extraction, and assessment of methodological quality using the Newcastle-Ottawa scale. All available obstetrical and neonatal outcomes were recorded. Random-effect meta-analysis was performed to estimate pooled odds ratios and 95% confidence intervals of available outcomes in pregnancies with and without confined placental mosaicism. Statistical heterogeneity was evaluated with I2 statistics (International Prospective Register of Systematic Reviews registration number: CRD42021260319). RESULTS: Of the 80 articles reviewed, 8 retrospective matched-cohort studies (708 cases of confined placental mosaicism and 11,599 unaffected controls) compared cases with and without confined placental mosaicism and were included in the meta-analysis. The risk of delivering small-for-gestational-age neonates was significantly increased in confined placental mosaicism pregnancies according to crude analysis (odds ratio, 2.45; 95% confidence interval, 1.23-4.89; I2=72%) and to sensitivity analysis of high-quality studies (odds ratio, 3.65; 95% confidence interval, 2.43-5.57; I2=0%). Similarly, confined placental mosaicism resulted in an increased risk of birthweight below the third centile (odds ratio, 5.33; 95% confidence interval, 1.19-24.19; I2= 83%). Subgroup analysis revealed that the risk of delivering small-for-gestational-age neonates was 3-fold higher for confined placental mosaicism excluding trisomy 16, and 11-fold higher for cases including trisomy 16 only vs unaffected controls, respectively. No difference was found in the risk of low birthweight and preterm birth (at <37 weeks' gestation). Other outcomes were insufficiently reported, therefore they were not analyzed. CONCLUSION: Pregnant women prenatally diagnosed with confined placental mosaicism have an increased risk of impaired fetal growth, suggesting the need for intensified antenatal surveillance.

The maternal-fetal neurodevelopmental groundings of preterm birth risk.

Background: Altered neurodevelopment is a major clinical sequela of Preterm Birth (PTB) being currently unexplored in-utero. Aims: To study the link between fetal brain functional (FbF) connectivity and preterm birth, using resting-state functional magnetic resonance imaging (rs-fMRI). Study design: Prospective single-centre cohort study. Subjects: A sample of 31 singleton pregnancies at 28-34 weeks assigned to a low PTB risk (LR) (n = 19) or high PTB risk (HR) (n = 12) group based on a) the Maternal Frailty Inventory (MaFra) for PTB risk; b) a case-specific PTB risk gradient. Methods: Fetal brain rs-fMRI was performed on 1.5T MRI scanner. First, directed causal relations representing fetal brain functional connectivity measurements were estimated using the Greedy Equivalence Search (GES) algorithm. HR vs. LR group differences were then tested with a novel ad-hoc developed Monte Carlo permutation test. Second, a MaFra-only random forest (RF) was compared against a MaFra-Neuro RF, trained by including also the most important fetal brain functional connections. Third, correlation and regression analyses were performed between MaFra-Neuro class probabilities and i) the GA at birth; ii) PTB risk gradient, iii) perinatal clinical conditions and iv) PTB below 37 weeks. Results: First, fewer fetal brain functional connections were evident in the HR group. Second, the MaFra-Neuro RF improved PTB risk prediction. Third, MaFra-Neuro class probabilities showed a significant association with: i) GA at birth; ii) PTB risk gradient, iii) perinatal clinical conditions and iv) PTB below 37 weeks. Conclusion: Fetal brain functional connectivity is a novel promising predictor of PTB, linked to maternal risk profiles, ahead of birth, and clinical markers of neurodevelopmental risk, at birth, thus potentially "connecting" different PTB phenotypes.

Obstetric, neonatal, and child health outcomes following embryo biopsy for preimplantation genetic testing.

BACKGROUND: Preimplantation genetic testing (PGT) of embryos developed in vitro requires a biopsy for obtaining cellular samples for the analysis. Signs of cell injury have been described in association with this procedure. Thus, the consequences of the biopsy on obstetric and neonatal outcomes have been the subject of some quantitative analyses, although the reliability of data pooling may be limited by important issues in the various reports. OBJECTIVE AND RATIONALE: The present review identifies evidence for whether pregnancies conceived after embryo biopsy are associated with a higher risk of adverse obstetric, neonatal, and long-term outcomes. Available evidence has been summarized considering manipulation at various stages of embryo development. SEARCH METHODS: We used the scoping review methodology. Searches of article databases were performed with keywords pertaining to the embryo biopsy technique and obstetric, neonatal, and postnatal outcomes. Studies in which embryos were biopsied at different stages (i.e. both at the cleavage and blastocyst stages) were excluded. We included data on fresh and frozen embryo transfers. The final sample of 31 documents was subjected to qualitative thematic analysis. OUTCOMES: Sound evidence is lacking to fully address the issues on the potential obstetric, neonatal or long-term consequences of embryo biopsy. For polar body biopsy, the literature is too scant to draw any conclusion. Some data, although limited and controversial, suggest a possible association of embryo biopsy at the cleavage stage with an increased risk of low birthweight and small for gestational age neonates compared to babies derived from non-biopsied embryos. An increase in preterm deliveries and birth defects in cases of trophectoderm biopsy was suggested. For both biopsy methods (at the cleavage and blastocyst stages), an increased risk for hypertensive disorders of pregnancy was found. However, these findings may be explained by confounders such as other embryo manipulation procedures or by intrinsic patient or population characteristics. WIDER IMPLICATIONS: Since there is inadequate evidence to assess obstetric, neonatal, and long-term health outcomes following embryo biopsy, an invasive PGT strategy should be developed with a cautious approach. A non-invasive approach, based on the analysis of embryo cell-free DNA, needs to be pursued to overcome the potential limitations of embryo biopsy.

Prenatal Diagnosis and Postnatal Outcomes of Left Brachiocephalic Vein Abnormalities: Systematic Review.

Abnormalities of the left brachiocephalic vein (LBCVA) are rare and poorly studied prenatally. An association with congenital heart defects (CHD), extracardiac and genetic abnormalities was described. The aim of our study was to estimate the rate and summarize the available evidence concerning prenatal diagnosis, associated anomalies, and outcomes of these anomalies. A systematic literature review was carried out selecting studies reporting on prenatal diagnosis of LBCVA, including unpublished cases from our experience. Frequencies were pooled from cohort studies to calculate prenatal incidence. Pooled proportions were obtained from all the studies including rates of associated CHD, extracardiac or genetic abnormalities and neonatal outcomes. The search resulted in the selection of 16 studies with 311 cases of LBCVA, with an incidence of 0.4% from six cohort studies. CHD occurred in 235/311 (75.6%) fetuses: 23 (7.4%) were major in cases of double, retroesophageal or subaortic course and 212 (68.2%) were minor in cases of absence (always associated with a persistent left superior vena cava) or intrathymic course. Data on other associated outcomes were scarce showing rare extracardiac anomalies (3.5%), rare genetic abnormalities (RASopathies and microdeletions associated with the retroesophageal course), and neonatal outcomes favorable in most cases, particularly in intrathymic forms.

Prevalence of Congenital Heart Defects in Pregnancies Conceived by Assisted Reproductive Technology: A Cohort Study.

BACKGROUND AND AIM OF THE STUDY: Pregnancies obtained by assisted reproductive technology (ART) are associated with an increased risk of complications and congenital anomalies, particularly congenital heart defects (CHDs). Therefore, our aim is to evaluate, retrospectively, the prevalence of CHD in ART pregnancies in our two centers and analyze their characteristics and outcomes. METHODS: Observational study including fetuses conceived by ART referred between June 2011 and September 2020 and undergoing a fetal cardiac ultrasound scan. Cases with genetic, chromosomal abnormalities or extracardiac malformations were excluded. Population included 1511 pregnancies, which consisted of 269 twins and 1242 singletons, 547 IVF (in vitro fertilization), 773 ICSI (intracytoplasmic sperm injection) and 191 oocyte donations (OD). RESULTS: CHDs were found in 29 fetuses, with an overall prevalence of 1.92% (29/1511), 1.85% (23/1242) in singletons and 2.23% in twins (6/269). Thirteen were IVF, eight ICSI and eight OD cases, with a greater risk of CHD after IVF and OD (IVF: 13/29 (44.8%)-one twin; ICSI: 8/29 (27.6%)-three twins); 22 had major and 7 minor defects. Two pregnancies with a hypoplastic left heart were terminated; the majority of live-born cases needed surgery. Three babies died (two post-surgery, one had a late death). CONCLUSIONS: Our data show an increased prevalence of CHD after ART with a heterogeneous spectrum of diagnoses, mainly major defects.

Mode of birth in women with low-lying placenta: protocol for a prospective multicentre 1:3 matched case-control study in Italy (the MODEL-PLACENTA study).

INTRODUCTION: The term placenta praevia defines a placenta that lies over the internal os, whereas the term low-lying placenta identifies a placenta that is partially implanted in the lower uterine segment with the inferior placental edge located at 1-20 mm from the internal cervical os (internal-os-distance). The most appropriate mode of birth in women with low-lying placenta is still controversial, with the majority of them undergoing caesarean section. The current project aims to evaluate the rate of vaginal birth and caesarean section in labour due to bleeding by offering a trial of labour to all women with an internal-os-distance >5 mm as assessed by transvaginal sonography in the late third trimester. METHODS AND ANALYSIS: The MODEL-PLACENTA is a prospective, multicentre, 1:3 matched case-control study involving 17 Maternity Units across Lombardy and Emilia-Romagna regions, Italy. The study includes women with a placenta located in the lower uterine segment at the second trimester scan. Women with a normally located placenta will be enrolled as controls. A sample size of 30 women with an internal-os-distance >5 mm at the late third trimester scan is needed at each participating Unit. Since the incidence of low-lying placenta decreases from 2% in the second trimester to 0.4% at the end of pregnancy, 150 women should be recruited at each centre at the second trimester scan. A vaginal birth rate ≥60% in women with an internal-os-distance >5 mm will be considered appropriate to start routinely admitting to labour these women. ETHICS AND DISSEMINATION: Ethical approval for the study was given by the Brianza Ethics Committee (No 3157, 2019). Written informed consent will be obtained from study participants. Results will be disseminated by publication in peer-reviewed journals and presentation in international conferences. TRIAL REGISTRATION NUMBER: NCT04827433 (pre-results stage).

Subcortico-Cortical Functional Connectivity in the Fetal Brain: A Cognitive Development Blueprint.

Recent evidence has shown that patterns of cortico-cortical functional synchronization are consistently traceable by the end of the third trimester of pregnancy. The involvement of subcortical structures in early functional and cognitive development has never been explicitly investigated, notwithstanding their pivotal role in different cognitive processes. We address this issue by exploring subcortico-cortical functional connectivity at rest in a group of normally developing fetuses between the 25th and 32nd weeks of gestation. Results show significant functional coupling between subcortical nuclei and cortical networks related to: (i) sensorimotor processing, (ii) decision making, and (iii) learning capabilities. This functional maturation framework unearths a Cognitive Development Blueprint, according to which grounding cognitive skills are planned to develop with higher ontogenetic priority. Specifically, our evidence suggests that a newborn already possesses the ability to: (i) perceive the world and interact with it, (ii) create salient representations for the selection of adaptive behaviors, and (iii) store, retrieve, and evaluate the outcomes of interactions, in order to gradually improve adaptation to the extrauterine environment.