Universal Third Trimester Ultrasonic Screening Using Fetal Macrosomia in the Prediction of Adverse Perinatal Outcome, a Systematic Review and Meta-analysis of Diagnostic Test Accuracy.

Background: The effectiveness of screening for macrosomia is not well established. One of the critical elements of an effective screening program is the diagnostic accuracy of a test at predicting the condition. The objective of this study is to investigate the diagnostic effectiveness of universal ultrasonic fetal biometry in predicting the delivery of a macrosomic infant, shoulder dystocia, and associated neonatal morbidity in low- and mixed-risk populations. Methods and findings: We conducted a predefined literature search in Medline, Excerpta Medica database (EMBASE), the Cochrane library and ClinicalTrials.gov from inception to May 2020. No language restrictions were applied. We included studies where the ultrasound was performed as part of universal screening and those that included low- and mixed-risk pregnancies and excluded studies confined to high risk pregnancies. We used the estimated fetal weight (EFW) (multiple formulas and thresholds) and the abdominal circumference (AC) to define suspected large for gestational age (LGA). Adverse perinatal outcomes included macrosomia (multiple thresholds), shoulder dystocia, and other markers of neonatal morbidity. The risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Meta-analysis was carried out using the hierarchical summary receiver operating characteristic (ROC) and the bivariate logit-normal (Reitsma) models. We identified 41 studies that met our inclusion criteria involving 112,034 patients in total. These included 11 prospective cohort studies (N = 9986), one randomized controlled trial (RCT) (N = 367), and 29 retrospective cohort studies (N = 101,681). The quality of the studies was variable, and only three studies blinded the ultrasound findings to the clinicians. Both EFW >4,000 g (or 90th centile for the gestational age) and AC >36 cm (or 90th centile) had >50% sensitivity for predicting macrosomia (birthweight above 4,000 g or 90th centile) at birth with positive likelihood ratios (LRs) of 8.74 (95% confidence interval [CI] 6.84–11.17) and 7.56 (95% CI 5.85–9.77), respectively. There was significant heterogeneity at predicting macrosomia, which could reflect the different study designs, the characteristics of the included populations, and differences in the formulas used. An EFW >4,000 g (or 90th centile) had 22% sensitivity at predicting shoulder dystocia with a positive likelihood ratio of 2.12 (95% CI 1.34–3.35). There was insufficient data to analyze other markers of neonatal morbidity. Conclusions: In this study, we found that suspected LGA is strongly predictive of the risk of delivering a large infant in low- and mixed-risk populations. However, it is only weakly (albeit statistically significantly) predictive of the risk of shoulder dystocia. There was insufficient data to analyze other markers of neonatal morbidity

Universal third-trimester ultrasonic screening using fetal macrosomia in the prediction of adverse perinatal outcome: A systematic review and meta-analysis of diagnostic test accuracy

BackgroundThe effectiveness of screening for macrosomia is not well established. One of the critical elements of an effective screening program is the diagnostic accuracy of a test at predicting the condition. The objective of this study is to investigate the diagnostic effectiveness of universal ultrasonic fetal biometry in predicting the delivery of a macrosomic infant, shoulder dystocia, and associated neonatal morbidity in low- and mixed-risk populations.Methods and findingsWe conducted a predefined literature search in Medline, Excerpta Medica database (EMBASE), the Cochrane library and ClinicalTrials.gov from inception to May 2020. No language restrictions were applied. We included studies where the ultrasound was performed as part of universal screening and those that included low- and mixed-risk pregnancies and excluded studies confined to high risk pregnancies. We used the estimated fetal weight (EFW) (multiple formulas and thresholds) and the abdominal circumference (AC) to define suspected large for gestational age (LGA). Adverse perinatal outcomes included macrosomia (multiple thresholds), shoulder dystocia, and other markers of neonatal morbidity. The risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Meta-analysis was carried out using the hierarchical summary receiver operating characteristic (ROC) and the bivariate logit-normal (Reitsma) models. We identified 41 studies that met our inclusion criteria involving 112,034 patients in total. These included 11 prospective cohort studies (N = 9986), one randomized controlled trial (RCT) (N = 367), and 29 retrospective cohort studies (N = 101,681). The quality of the studies was variable, and only three studies blinded the ultrasound findings to the clinicians. Both EFW >4,000 g (or 90th centile for the gestational age) and AC >36 cm (or 90th centile) had >50% sensitivity for predicting macrosomia (birthweight above 4,000 g or 90th centile) at birth with positive likelihood ratios (LRs) of 8.74 (95% confidence interval [CI] 6.84–11.17) and 7.56 (95% CI 5.85–9.77), respectively. There was significant heterogeneity at predicting macrosomia, which could reflect the different study designs, the characteristics of the included populations, and differences in the formulas used. An EFW >4,000 g (or 90th centile) had 22% sensitivity at predicting shoulder dystocia with a positive likelihood ratio of 2.12 (95% CI 1.34–3.35). There was insufficient data to analyze other markers of neonatal morbidity.ConclusionsIn this study, we found that suspected LGA is strongly predictive of the risk of delivering a large infant in low- and mixed-risk populations. However, it is only weakly (albeit statistically significantly) predictive of the risk of shoulder dystocia. There was insufficient data to analyze other markers of neonatal morbidity

The role of uterine natural killer cell-inhibition in pregnancy

Education of natural killer (NK) cells is a genetically determined process that primes NK-cell activity upon the binding of their inhibitory receptors to self-ligands. Although NK-cell education is predictable and measurable in the laboratory, its biological significance is unknown. This thesis shows that the inhibitory NK cell receptor NKG2A protects against the hypertensive disorder of pregnancy pre-eclampsia in individuals genetically programmed to favour the engagement of NKG2A with its ligand HLA-E. Using NKG2A-deficient Klrc1-/- mice, this thesis demonstrates that NKG2A is required to educate uterine NK cells to regulate uterine vascular adaptation to pregnancy, placental function and transcriptome, as well as fetal growth. Immune checkpoint blockade of NKG2A during pregnancy in wild-type mice did not affect fetal growth, suggesting acute ablation of this pathway does not interfere with pregnancy outcome. In addition, generation of a humanised mouse model to test the notion that uterine NK cell inhibition driven by KIR: HLA interactions leads to poor pregnancy outcomes, was attempted

Local immune recognition of trophoblast in early human pregnancy: controversies and questions.

The role of the maternal immune system in reproductive success in humans remains controversial. Here we focus on the events that occur in the maternal decidua during the first few weeks of human pregnancy, because this is the site at which maternal leukocytes initially interact with and can recognize fetal trophoblast cells, potentially involving allorecognition by both T cells and natural killer (NK) cells. NK cells are the dominant leukocyte population in first-trimester decidua, and genetic studies point to a role of allorecognition by uterine NK cells in establishing a boundary between the mother and the fetus. By contrast, definitive evidence that allorecognition by decidual T cells occurs during the first trimester is lacking. Thus, our view is that during the crucial period when the placenta is established, damaging T cell-mediated adaptive immune responses towards placental trophoblast are minimized, whereas NK cell allorecognition contributes to successful implantation and healthy pregnancy

Long-term effects on the child of near-term glucocorticoids in the fetus.

The human fetal hypothalamic-pituitary axis (HPA) becomes activated as pregnancy advances towards term. This critical developmental trigger occurs in most mammalian species and results in a fetal adrenal glucocorticoid (GC) surge essential for lung maturation[1]. In addition, HPA activation also contributes to parturition and the maturation of other fetal organs. Precocious activation of GC receptors can be induced by endogenous cortisol release in response to fetal exposure to an adverse intrauterine environment, or when synthetic glucocorticoids are administered to the mother during pregnancy (antenatal maternal glucocorticoid, AMGC)

Ovarian surgery for symptom relief in women with polycystic ovary syndrome

This is the protocol for a review and there is no abstract. The objectives are as follows:To assess the effectiveness and harms of ovarian surgery as a treatment for symptomatic relief of hirsutism, acne and menstrual disturbances in women with PCOS

A genetically small fetus impairs placental adaptations near term

The placenta is a gatekeeper between the mother and fetus, adapting its structure and functions to support optimal fetal growth. Studies exploring adaptations of placentae that support the development of genetically small fetuses are lacking. Here, using a mouse model of impaired fetal growth, achieved by deleting Igf2 (insulin-like growth factor 2) in the epiblast, we assessed placental nutrient transfer and umbilical artery (UA) blood flow during late gestation. At embryonic day (E) 15.5, we observed a decline in the trans-placental flux of glucose (3H-MeG) a nd system A a mino acids (14 C-MeAIB), proportionate with the diminished fetal size, while UA blood flow was normal. However, at E18.5, the trans-placental flux of both tracers was disproportionately decreased and accompanied by blunted UA blood flow. Feto-placental growth and nutrient transfer were more impaired in female conceptuses. Thus, reducing the fetal genetic demand for growth impairs the adaptations in placental blood flow and nutrient transport that normally support the fast fetal growth in late gestation. These findings have important implications for our understanding of the pathophysiology of pregnancies afflicted by fetal growth restriction.This work was supported by the Biotechnology and Biological Sciences Research Council (grant BB/H003312/1 to M.C.), the Medical Research Council (MRC_MC_UU_12012/4 to M.C.; MRC_MC_UU_12012/5 to the MRC Metabolic Diseases Unit; MR/R022690/1 to A.N.S.-P.), the Wellcome Trust (Sir Henry Wellcome Postdoctoral Fellowship 220456/Z/20/Z to J.L.-T.), the Royal Society (Newton International Fellowship grant NF170988/RG90199 to J.L.-T.), Talent Attraction Grant from the Community of Madrid CESAR NOMBELA fellowship (grant No. 2023-T1/SAL-GL-28960); Dorothy Hodgkin Research Fellowship grant (DH130036 to A.N.S.-P.) and the Centre for Trophoblast Research