The value of angiogenetic biomarkers in the detection of early onset fetal growth restriction.

OBJECTIVE: The identification of fetal growth restriction (FGR) due to uteroplacental insufficiency is important to improve perinatal outcomes. To distinguish FGR from small for gestational age (SGA), FGR consensus definition is currently based on biometry and/or additional biophysical parameters. This study aims to verify if this definition might be modified by including circulating angiogenic factors. STUDY DESIGN: This historical cohort study included singleton pregnancies with SGA fetuses after 20 weeks. All patients underwent detailed ultrasound and measurements of soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) at first assessment. ISUOG criteria for FGR were applied. Total PlGF was calculated using free PlGF, sFlt-1 and a receptor pharmacology model, and multiple of the median (MoM) values for sFlt-1, free PlGF, total PlGF and sFlt-1/PlGF ratio were calculated to adjust for gestational age. RESULTS: 72 pregnancies with SGA were first evaluated at median (IQR) of 28+5 (26+2 -31+3) weeks' gestation, and 51 fetuses (70.8 %) satisfied the FGR consensus definition. Pregnancies with FGR showed significantly lower levels of free and total PlGF MoM (0.12, 95 % IQR: 0.07-0.36 vs 0.32, 95 % IQR: 0.20-0.53, p = 0.008) and 0.26, 95 % CI: 0.16-0.55 vs 0.43, 95 % IQR: 0.23-0.53, p = 0.028) respectively; and higher sFlt-1 MoM (4.62, 95 % IQR: 1.80-7.30 vs 1.74, 95 % IQR:1.11-3.61, p = 0.014) than pregnancies not classified as FGR. Free and total PlGF MoM correlated significantly with gestational age at delivery (r = 0.776, p < 0.001 and r = 0.707, p < 0.001, respectively). sFlt-1 MoM and sFlt-1/PlGF ratio MoM also correlated with gestational age at delivery (r = -0.681, p < 0.001 and r = -0.823, p < 0.001). Six cases identified as FGR at first ultrasound were not confirmed at birth showing significantly higher levels of free PlGF MoM (0.77, 95 % IQR: 0.27-3.07 vs 0.17, 95 % IQR: 0.08-0.43, p = 0.022). CONCLUSION: These findings show that total as well as free PlGF levels are lower in pregnancies affected with placental growth restriction. Angiogenic biomarkers might improve the differentiation between placental growth restriction and constitutional smallness. Further studies are needed to determine how to integrate them into the current definitions of FGR.

Left Atrial Mechanics Following Preeclamptic Pregnancy.

BACKGROUND: Preterm preeclampsia is a pregnancy complication associated with myocardial dysfunction and premature cardiovascular disease morbidity and mortality. Left atrial (LA) strain is a noninvasive index of left ventricular end diastolic pressure and an early marker of heart failure risk. This study aimed to evaluate LA strain during the postpartum period in participants with and without preterm preeclampsia and to assess whether this varied in the presence of hypertension, cardiac dysfunction or both. METHODS: In this longitudinal cohort study, 321 women from 28 hospitals with preterm preeclampsia (cases) underwent cardiovascular assessment 6 months postpartum. This is a secondary analysis of the PHOEBE study (ISRCTN01879376). An uncomplicated pregnancy control group (n=30) was recruited from a single center for comparison. A full cross-sectional transthoracic echocardiogram was performed, and from these images, the myocardial strain of the left atrium, including reservoir, conduit, and contractile strain, as well as LA stiffness, were calculated. RESULTS: At 6 months postpartum, compared with controls, prior preeclampsia was associated with a significantly attenuated LA reservoir, conduit, and contractile strain, as well as increased LA stiffness (all P<0.001). LA strain was further reduced in preeclamptic women who had and had not developed hypertension, systolic, or diastolic dysfunction at 6 months postpartum (all P<0.05). CONCLUSIONS: LA mechanics were significantly attenuated at 6 months postpartum in participants with preterm preeclampsia, whether or not they remained hypertensive or had evidence of ventricular dysfunction. Further studies are needed to determine whether postnatal LA strain may identify women at greater risk for future cardiovascular disease.

Pre-eclampsia and Cardiovascular Disease: From Pregnancy to Postpartum.

Hypertensive disorders of pregnancy (HDP) complicate approximately 10% of pregnancies. In addition to multiorgan manifestations related to endothelial dysfunction, HDP confers an increased risk of cardiovascular disease during delivery hospitalisation, such as heart failure, pulmonary oedema, acute MI and cerebrovascular events. However, the cardiovascular legacy of HDP extends beyond birth since these women are significantly more likely to develop cardiovascular risk factors in the immediate postnatal period and major cardiovascular disease in the long term. The main mediator of cardiovascular disease in women with a history of HDP is chronic hypertension, followed by obesity, hypercholesterolaemia and diabetes. Therefore, optimising blood pressure levels from the immediate postpartum period until the first months postnatally could have beneficial effects on the development of hypertension and improve long-term cardiovascular health. Peripartum screening based on maternal demographic, and clinical and echocardiographic data could help clinicians identify women with HDP at highest risk of developing postpartum hypertension who would benefit from targeted primary cardiovascular prevention.

Myocardial Function in Fetuses with Congenital Cytomegalovirus Infection.

INTRODUCTION: The objective of this study was to investigate myocardial deformation of left (LV) and right ventricle (RV) using 2-dimensional speckle-tracking echocardiography (2D-STE) in fetuses with and without congenital cytomegalovirus (CMV) infection. METHODS: This was a prospective single-center study. Vertical transmission was defined by a positive CMV polymerase chain reaction (PCR) test on the amniotic fluid or on the neonate's urine. Fetuses were divided into group 1 and group 2 if CMV-PCR was positive or negative, respectively. LV and RV global longitudinal strain (GLS) values were obtained and adjusted for gestational age by calculating Z-scores. Univariate analysis was carried out to compare cardiac indices between group 1 and group 2. RESULTS: Fetuses from group 1 (n = 11) had a significantly lower LV myocardial shortening than those from group 2 (n = 32). GLS was -20.7 ± 5.2% and -26.3 ± 4.1%, respectively (p = 0.001). Similarly, GLS Z-score was lower (0.02 ± 0.72) in group 1 than in group 2 (-0.80 ± 0.59) (p = 0.001). Similarly, RV GLS Z-score was significantly impaired in group 1 compared to group 2 (-0.44 ± 1.03 vs. -1.04 ± 0.71, p = 0.041). CONCLUSION: Fetuses with congenital CMV showed subclinical biventricular myocardial dysfunction. Further studies are needed to confirm the potential role of 2D-STE in identifying fetuses with congenital CMV at risk of postnatal cardiovascular morbidities.

Transthoracic Echocardiographic Assessment of the Heart in Pregnancy-a position statement on behalf of the British Society of Echocardiography and the United Kingdom Maternal Cardiology Society.

Pregnancy is a dynamic process associated with profound hormonally mediated haemodynamic changes which result in structural and functional adaptations in the cardiovascular system. An understanding of the myocardial adaptations is important for echocardiographers and clinicians undertaking or interpreting echocardiograms on pregnant and post-partum women. This guideline, on behalf of the British Society of Echocardiography and United Kingdom Maternal Cardiology Society, reviews the expected echocardiographic findings in normal pregnancy and in different cardiac disease states, as well as echocardiographic signs of decompensation. It aims to lay out a structure for echocardiographic scanning and surveillance during and after pregnancy as well as suggesting practical advice on scanning pregnant women.

Postpartum cardiovascular function in patients with hypertensive disorders of pregnancy: a longitudinal study.

BACKGROUND: Women with a history of hypertensive disorders of pregnancy are at increased risk of cardiovascular diseases, which are usually mediated by the development of cardiovascular risk factors, such as chronic hypertension, metabolic syndrome, or subclinical myocardial dysfunction. Increasing evidence has been showing that little time elapses between the end of pregnancy and the development of these cardiovascular risk factors. OBJECTIVE: This study aimed to assess the persistence of hypertension and myocardial dysfunction at 4 months postpartum in a cohort of women with hypertensive disorders of pregnancy, and to compare the echocardiographic parameters between the peripartum and the postpartum period. STUDY DESIGN: In a longitudinal prospective study, a cohort of women with preterm or term hypertensive disorders of pregnancy and an unmatched group of women with term normotensive pregnancy were recruited. Women with preexisting chronic hypertension (n=29) were included in the hypertensive disorders of pregnancy cohort. All participants underwent 2 cardiovascular assessments: the first was conducted either before or within 1 week of delivery (V1: peripartum assessment), and the second between 3 and 12 months following delivery (V2: postpartum assessment). The cardiovascular evaluation included blood pressure profile, maternal transthoracic echocardiography (left ventricular mass index, relative wall thickness, left atrial volume index, E/A, E/e', peak velocity of tricuspid regurgitation, ejection fraction, and left ventricular global longitudinal strain and twist), and metabolic assessment (fasting glycemia, insulin, lipid profile, and waist measurement). Echocardiographic data were compared between V1 and V2 using paired t test or McNemar test in hypertensive disorders of pregnancy and in the control groups. RESULTS: Among 260 patients with pregnancies complicated by hypertensive disorders of pregnancy and 33 patients with normotensive pregnancies, 219 (84.2%) and 30 (90.9%) attended postpartum follow-up, respectively. Patients were evaluated at a median of 124 days (interquartile range, 103-145) after delivery. Paired comparisons of echocardiographic findings demonstrated significant improvements in cardiac remodeling rates (left ventricular mass index [g/m2], 63.4±14.4 vs 78.9±16.2; P<.001; relative wall thickness, 0.35±0.1 vs 0.42±0.1; P<.001), most diastolic indices (E/e', 6.3±1.6 vs 7.4±1.9; P<.001), ejection fraction (ejection fraction <55%, 9 [4.1%] vs 28 [13.0%]; P<.001), and global longitudinal strain (-17.3±2.6% vs -16.2±2.4%; P<.001) in the postpartum period compared with the peripartum. The same improvements in cardiac indices were observed in the normotensive group. However, at the postnatal assessment, 153 of 219 (69.9%) had either hypertension (76/219; 34.7%) or an abnormal global longitudinal strain (125/219; 57.1%), 13 of 67 (19.4%) had metabolic syndrome, and 18 of 67 (26.9%) exhibited insulin resistance. CONCLUSION: Although persistent postpartum cardiovascular impairment was evident in a substantial proportion of patients given that more than two-thirds had either hypertension or myocardial dysfunction postpartum, cardiac modifications because of pregnancy-related overload and hypertension were more pronounced in the peripartum than in the postpartum period.

Pan-Genomic Regulation of Gene Expression in Normal and Pathological Human Placentas.

In this study, we attempted to find genetic variants affecting gene expression (eQTL = expression Quantitative Trait Loci) in the human placenta in normal and pathological situations. The analysis of gene expression in placental diseases (Pre-eclampsia and Intra-Uterine Growth Restriction) is hindered by the fact that diseased placental tissue samples are generally taken at earlier gestations compared to control samples. The difference in gestational age is considered a major confounding factor in the transcriptome regulation of the placenta. To alleviate this significant problem, we propose here a novel approach to pinpoint disease-specific cis-eQTLs. By statistical correction for gestational age at sampling as well as other confounding/surrogate variables systematically searched and identified, we found 43 e-genes for which proximal SNPs influence expression level. Then, we performed the analysis again, removing the disease status from the covariates, and we identified 54 e-genes, 16 of which are identified de novo and, thus, possibly related to placental disease. We found a highly significant overlap with previous studies for the list of 43 e-genes, validating our methodology and findings. Among the 16 disease-specific e-genes, several are intrinsic to trophoblast biology and, therefore, constitute novel targets of interest to better characterize placental pathology and its varied clinical consequences. The approach that we used may also be applied to the study of other human diseases where confounding factors have hampered a better understanding of the pathology.

Low-dose aspirin for the prevention of superimposed preeclampsia in women with chronic hypertension: a systematic review and meta-analysis.

OBJECTIVE: This systematic review and meta-analysis investigated whether the use of low-dose aspirin during pregnancy by women with chronic hypertension reduces the odds of superimposed preeclampsia and poor perinatal outcomes. DATA SOURCES: In September 2021, the following sources were searched: Embase, MEDLINE, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform, and EU Clinical Trials Register. Only human studies were included, with no time or language restrictions. STUDY ELIGIBILITY CRITERIA: Cohort, case-control, and randomized controlled studies reporting women with chronic hypertension pregnant with a singleton were included. Eligible studies compared low-dose aspirin use during pregnancy with a control arm. METHODS: Risk of bias was assessed using the RoB 2 and ROBINS-I tools. A meta-analysis was performed using a random-effects model, estimating odds ratios and 95% confidence and prediction intervals, and the quality of data was assessed with the GRADE approach. Heterogeneity was investigated in regard to study methodology, timing of commencement of aspirin, and the outcome of preterm preeclampsia. RESULTS: Nine studies (3 retrospective cohort studies and 6 randomized trials) including 2150 women with chronic hypertension were included. Low-dose aspirin prophylaxis did not significantly reduce the odds of superimposed preeclampsia in the randomized controlled trials (odds ratio, 0.83; 95% confidence interval, 0.55-1.25; prediction interval, 0.27-2.56; low-quality evidence) or observational studies (odds ratio, 1.21; 95% confidence interval, 0.78-1.87; prediction interval, 0.07-20.80; very low-quality evidence). Low-dose aspirin also did not reduce the odds of preterm preeclampsia (odds ratio, 1.17; 95% confidence interval, 0.74-1.86), and early aspirin initiation had no significant impact. There was no significant effect on small-for-gestational-age neonates or perinatal mortality; however, there was a significant reduction in preterm birth (odds ratio, 0.63; 95% confidence interval, 0.45-0.89; moderate-quality evidence). The quality of the evidence is limited by heterogeneity and risk of bias. CONCLUSION: This meta-analysis was unable to demonstrate a significant change in the odds of superimposed preeclampsia, small-for-gestational-age infants, or perinatal mortality with the use of low-dose aspirin in women with chronic hypertension. However, significant reduction in preterm birth justifies the continued use of aspirin prophylaxis. This work was prospectively registered on the International Prospective Register of Systematic Reviews (registration number CRD42021285921).

Peripartum and Long-Term Maternal Cardiovascular Health After Preeclampsia.

There is widespread acceptance of the increased prevalence of cardiovascular diseases occurring within 1 to 2 decades in women following a preeclamptic pregnancy. More recent evidence suggests that the deranged biochemical and echocardiographic findings in women do not resolve in the majority of preeclamptic women following giving birth. Many women continue to be hypertensive in the immediate postnatal period with some exhibiting occult signs of cardiac dysfunction. There is now promising evidence that with close monitoring and effective control of blood pressure control in the immediate postnatal period, women may have persistently lower blood pressures many years after stopping their medication. This review highlights the evidence that delivering effective medical care in the fourth trimester of pregnancy can improve the long-term cardiovascular health after a preeclamptic birth.

Fetal cerebral ventriculomegaly: What do we tell the prospective parents?

Fetal cerebral ventriculomegaly is a relatively common finding, observed during approximately 1% of obstetric ultrasounds. In the second and third trimester, mild (≥10 mm) and severe ventriculomegaly (≥15 mm) are defined according to the measurement of distal lateral ventricles that is included in the routine sonographic examination of central nervous system. A detailed neurosonography and anatomy ultrasound should be performed to detect other associated anomalies in the central nervous system and in other systems, respectively. Fetal MRI might be useful when neurosonography is unavailable or suboptimal. The risk of chromosomal and non-chromosomal genetic disorders associated with ventriculomegaly is high, therefore invasive genetic testing, including microarray, is recommended. Screening for prenatal infections, in particular cytomegalovirus and toxoplasmosis, should also be carried out at diagnosis. The prognosis is determined by the severity of ventriculomegaly and/or by the presence of co-existing abnormalities. Fetal ventriculoamniotic shunting in progressive isolated severe ventriculomegaly is an experimental procedure. After delivery, ventricular-peritoneal shunting or ventriculostomy are the two available options to treat hydrocephalus in specific conditions with similar long-term outcomes. A multidisciplinary fetal neurology team, including perinatologists, geneticists, pediatric neurologists, neuroradiologists and neurosurgeons, can provide parents with the most thorough prenatal counseling. This review outlines the latest evidence on diagnosis and management of pregnancies complicated by fetal cerebral ventriculomegaly.

Peripartum Screening for Postpartum Hypertension in Women With Hypertensive Disorders of Pregnancy.

BACKGROUND: Chronic hypertension (CHT) is the main risk factor for cardiovascular diseases in women with a history of hypertensive disorders of pregnancy (HDP). OBJECTIVES: This study sought to assess the effectiveness of peripartum screening in predicting CHT after HDP. METHODS: In this longitudinal prospective study, women with HDP underwent peripartum transthoracic echocardiography and were evaluated for CHT (blood pressure ≥140/90 mm Hg or on antihypertensive medication) at least 3 months postpartum. Univariable and multivariable analyses assessed the association between clinical and transthoracic echocardiography data and a postpartum diagnosis of CHT. RESULTS: At a median postpartum follow-up of 124 days (IQR: 103-145 days), 70 (33.2%) of 211 women remained hypertensive. Compared with normotensive women, women with CHT were older (35.5 ± 5.0 years vs 32.9 ± 5.6 years; P = 0.001), were more likely to be Afro-Caribbean (27.1% vs 7.8%; P < 0.0001), had higher body mass index (33.4 ± 5.9 kg/m2 vs 31.2 ± 5.4 kg/m2; P = 0.006), and had higher mean arterial pressure (106.5 ± 8.4 mm Hg vs 103.3 ± 7.0 mm Hg; P = 0.004). Moreover, they showed significantly higher left ventricular mass index (84.0 ± 17.9 g/m2 vs 76.3 ± 14.8 g/m2; P = 0.001), higher relative wall thickness (0.46 ± 0.10 vs 0.40 ± 0.10; P < 0.0001), and lower global longitudinal strain (-15.6% ± 2.7% vs -16.6% ± 2.2%; P = 0.006) than normotensive women. A prediction model combining clinical (maternal age and first trimester mean arterial pressure) and echocardiographic features (left ventricular mass index >75 g/m2, relative wall thickness >0.42, and E/e' ratio >7) showed excellent accuracy in identifying women with persistent hypertension after HDP (area under the curve: 0.85; 95% CI: 0.79-0.90). CONCLUSIONS: This peripartum screening approach might be used to identify women at risk of CHT who would benefit from intensive blood pressure monitoring and pharmacological strategies from the early postpartum period to prevent cardiovascular disease.

Antioxidants in Pregnancy: Do We Really Need More Trials?

Human pregnancy can be affected by numerous pathologies, from those which are mild and reversible to others which are life-threatening. Among these, gestational diabetes mellitus and hypertensive disorders of pregnancy with subsequent consequences stand out. Health problems experienced by women during pregnancy and postpartum are associated with significant costs to health systems worldwide and contribute largely to maternal mortality and morbidity. Major risk factors for mothers include obesity, advanced maternal age, cardiovascular dysfunction, and endothelial damage; in these scenarios, oxidative stress plays a major role. Markers of oxidative stress can be measured in patients with preeclampsia, foetal growth restriction, and gestational diabetes mellitus, even before their clinical onset. In consequence, antioxidant supplements have been proposed as a possible therapy; however, results derived from large scale randomised clinical trials have been disappointing as no positive effects were demonstrated. This review focuses on the latest evidence on oxidative stress in pregnancy complications, their early diagnosis, and possible therapies to prevent or treat these pathologies.

Single extracellular vesicle analysis in human amniotic fluid shows evidence of phenotype alterations in preeclampsia.

Amniotic fluid surrounding the developing fetus is a complex biological fluid rich in metabolically active bio-factors. The presence of extracellular vesicles (EVs) in amniotic fluid has been mainly related to foetal urine. We here characterized EVs from term amniotic fluid in terms of surface marker expression using different orthogonal techniques. EVs appeared to be a heterogeneous population expressing markers of renal, placental, epithelial and stem cells. Moreover, we compared amniotic fluid EVs from normal pregnancies with those of preeclampsia, a hypertensive disorder affecting up to 8% of pregnancies worldwide. An increase of CD105 (endoglin) expressing EVs was observed in preeclamptic amniotic fluid by bead-based cytofluorimetric analysis, and further confirmed using a chip-based analysis. HLA-G, a typical placental marker, was not co-expressed by the majority of CD105+ EVs, in analogy with amniotic fluid stromal cell derived-EVs. At a functional level, preeclampsia-derived EVs, but not normal pregnancy EVs, showed an antiangiogenic effect, possibly due to the decoy effect of endoglin. Our results provide a characterization of term amniotic fluid-EVs, supporting their origin from foetal and placental cells. In preeclampsia, the observed antiangiogenic characteristics of amniotic fluid-EVs may reflect the hypoxic and antiangiogenic microenvironment and could possibly impact on the developing fetus or on the surrounding foetal membranes.

The Role of the Multidisciplinary Health Care Team in the Management of Patients with Systemic Sclerosis.

Systemic sclerosis (SSc) is a rare connective tissue disease characterised by immune dysfunction, vascular damage and fibrosis affecting the skin and multiple internal organs. The clinical spectrum of SSc is wide and its manifestations may lead to severe morbidity and mortality, in addition to a great impact on patients' quality of life. Due to the multifaceted clinical manifestations of SSc, its management requires a combined expertise of different medical specialists to guarantee an adequate disease control and prevent organ complications. Multi-disciplinary teams (MDT), which are composed by physicians and other specialized health professionals, represent therefore a key element for the comprehensive management of SSc patients. Moreover, MTD can improve communication and patients' empowerment while the presence of dedicated nurses can help patients to ask questions about their condition. The scope of this narrative review is to analyse the available evidences regarding the role of MDT in the management of SSc patients, and how this holistic approach may improve different disease domains and the overall prognosis. MDT regarding the cardiovascular and lung complication are the more represented in literature, given the great impact in prognosis. Nonetheless, MDT have been shown to be fundamental also in other disease domains as they can intercept early manifestations, thus stratifying patients based on the individual risks in order to personalize patients' follow-up. MDTs may also minimize the treatment delay, enabling fast-track specialist referral. On the other hand, there are few trials specifically studying MDT in SSc and several authors have highlight the lack of standardization.

Myocardial Mechanics in Hypertensive Disorders of Pregnancy: a Systematic Review and Meta-Analysis.

Global longitudinal strain (GLS) is becoming routinely used to direct the medical management of various cardiac diseases, but its application in pregnancy is unclear. Our objective was to perform a meta-analysis and pool multiple study data to consolidate the evidence base for the role of GLS in the assessment of women with hypertensive disorders of pregnancy (HDP). Electronic database searches were performed in PubMed/Medline and EMBASE for research articles reporting GLS in pregnancies complicated by HDP and normotensive pregnancies that have been published up to September 2021. The meta-analysis included 17 studies with a pooled sample size of 1723 participants, which included 951 women with HDP, of which 680 were preeclamptic, and 772 controls. The primary random-effects pooled analysis demonstrated a statistically significant weighted mean difference in GLS between the HDP and control group (mean difference: 3.08% [CI, 2.33-3.82], P<0.001). When analyzed including only preeclamptic studies, there was also a statistically significant mean difference (mean difference: 2.98% [95% CI, 1.97-3.99], P<0.001). This meta-analysis demonstrates that HDP is associated with greater cardiac maladaptation, evidenced by a significantly reduced GLS compared with normal pregnancy. Echocardiography should be considered as a screening tool in women with HDP to enable early cardiovascular risk prevention through national initiatives.

IVF/ICSI treatment and the risk of iatrogenic preterm birth in singleton pregnancies: systematic review and meta-analysis of cohort studies.

OBJECTIVES: Preterm birth (PTB) is more frequent among in vitro fertilization (IVF) as compared to natural conception and recent research in this group describes an increase of its spontaneous etiology. However, clear description and quantification of iatrogenic preterm birth (IPTB) was not determined in IVF/ICSI (intra-cytoplasmic sperm injection) conceptions. This study quantifies the risk of IPTB in singleton pregnancies resulting from IVF/ICSI as compared to spontaneous conceptions (SCs). METHODS: Web-based databases search (PubMed/Medline, Scopus, Web of Science) from inception up to January 2019 looking for cohort studies comparing the risk of IPTB in singleton pregnancies obtained with IVF/ICSI (intervention group) or SC (control group). Only studies with clear distinction of spontaneous and indicated PTB were included. Primary outcome was IPTB before 37 weeks of gestation, defined as indicated delivery for any medical recommendation. All pertinent secondary outcomes were also included: IPTB <34/32/28 weeks, abnormal cardiotocography (CTG), abruptio, placenta previa, pre-eclampsia, fetal growth restriction, any other available indication to IPTB. A meta-analysis calculated the pooled odds ratio (OR) for IPTB in IVF/ICSI and SC, using random effects model. Sensitivity analysis for study quality, methodology of case counting, use of cryotransfer, and secondary analyses for available indications of IPTB were also performed. Prospero RN: CRD42019117672. RESULTS: Pooled crude analysis showed a sample size of 9590 births with significant increase in IPTB <37 weeks in IVF/ICSI pregnancies (nine studies, pooled proportion IPTB IVF/ICSI 4.73% vs. SC 1.81%; OR = 2.47; 95% CI: 1.46-4.18; I2 = 67%). Pooled analysis was impossible for most secondary outcomes due to lack of available data and failed to show statistical significance for abnormal CTG. The risk for IPTB due to abruptio placentae or placenta previa was significantly increased in IVF/ICSI pregnancies (two studies, 561 pregnancies; pooled proportion IPTB IVF/ICSI 2.12% vs. SC 1.06%; OR = 5.41; 95% CI: 1.26-23.25; I2: 0%). CONCLUSION: The risk of IPTB <37 weeks in singleton pregnancies achieved after IVF/ICSI is significantly greater than that occurring in SC. This is likely due to a multifactorial etiology, in which placental diseases are included. Full etiologic understanding of this association needs further clarification. SUMMARY: The risk of IPTB below 37 weeks in singleton pregnancies achieved after IVF/ICSI is more than double than that occurring in natural conception.