Randomized Trial of Fetal Surgery for Severe Left Diaphragmatic Hernia.

BACKGROUND: Observational studies have shown that fetoscopic endoluminal tracheal occlusion (FETO) has been associated with increased survival among infants with severe pulmonary hypoplasia due to isolated congenital diaphragmatic hernia on the left side, but data from randomized trials are lacking. METHODS: In this open-label trial conducted at centers with experience in FETO and other types of prenatal surgery, we randomly assigned, in a 1:1 ratio, women carrying singleton fetuses with severe isolated congenital diaphragmatic hernia on the left side to FETO at 27 to 29 weeks of gestation or expectant care. Both treatments were followed by standardized postnatal care. The primary outcome was infant survival to discharge from the neonatal intensive care unit. We used a group-sequential design with five prespecified interim analyses for superiority, with a maximum sample size of 116 women. RESULTS: The trial was stopped early for efficacy after the third interim analysis. In an intention-to-treat analysis that included 80 women, 40% of infants (16 of 40) in the FETO group survived to discharge, as compared with 15% (6 of 40) in the expectant care group (relative risk, 2.67; 95% confidence interval [CI], 1.22 to 6.11; two-sided P = 0.009). Survival to 6 months of age was identical to the survival to discharge (relative risk, 2.67; 95% CI, 1.22 to 6.11). The incidence of preterm, prelabor rupture of membranes was higher among women in the FETO group than among those in the expectant care group (47% vs. 11%; relative risk, 4.51; 95% CI, 1.83 to 11.9), as was the incidence of preterm birth (75% vs. 29%; relative risk, 2.59; 95% CI, 1.59 to 4.52). One neonatal death occurred after emergency delivery for placental laceration from fetoscopic balloon removal, and one neonatal death occurred because of failed balloon removal. In an analysis that included 11 additional participants with data that were available after the trial was stopped, survival to discharge was 36% among infants in the FETO group and 14% among those in the expectant care group (relative risk, 2.65; 95% CI, 1.21 to 6.09). CONCLUSIONS: In fetuses with isolated severe congenital diaphragmatic hernia on the left side, FETO performed at 27 to 29 weeks of gestation resulted in a significant benefit over expectant care with respect to survival to discharge, and this benefit was sustained to 6 months of age. FETO increased the risks of preterm, prelabor rupture of membranes and preterm birth. (Funded by the European Commission and others; TOTAL ClinicalTrials.gov number, NCT01240057.).

Randomized Trial of Fetal Surgery for Moderate Left Diaphragmatic Hernia.

BACKGROUND: Fetoscopic endoluminal tracheal occlusion (FETO) has been associated with increased postnatal survival among infants with severe pulmonary hypoplasia due to isolated congenital diaphragmatic hernia on the left side, but data are lacking to inform its effects in infants with moderate disease. METHODS: In this open-label trial conducted at many centers with experience in FETO and other types of prenatal surgery, we randomly assigned, in a 1:1 ratio, women carrying singleton fetuses with a moderate isolated congenital diaphragmatic hernia on the left side to FETO at 30 to 32 weeks of gestation or expectant care. Both treatments were followed by standardized postnatal care. The primary outcomes were infant survival to discharge from a neonatal intensive care unit (NICU) and survival without oxygen supplementation at 6 months of age. RESULTS: In an intention-to-treat analysis involving 196 women, 62 of 98 infants in the FETO group (63%) and 49 of 98 infants in the expectant care group (50%) survived to discharge (relative risk , 1.27; 95% confidence interval [CI], 0.99 to 1.63; two-sided P = 0.06). At 6 months of age, 53 of 98 infants (54%) in the FETO group and 43 of 98 infants (44%) in the expectant care group were alive without oxygen supplementation (relative risk, 1.23; 95% CI, 0.93 to 1.65). The incidence of preterm, prelabor rupture of membranes was higher among women in the FETO group than among those in the expectant care group (44% vs. 12%; relative risk, 3.79; 95% CI, 2.13 to 6.91), as was the incidence of preterm birth (64% vs. 22%, respectively; relative risk, 2.86; 95% CI, 1.94 to 4.34), but FETO was not associated with any other serious maternal complications. There were two spontaneous fetal deaths (one in each group) without obvious cause and one neonatal death that was associated with balloon removal. CONCLUSIONS: This trial involving fetuses with moderate congenital diaphragmatic hernia on the left side did not show a significant benefit of FETO performed at 30 to 32 weeks of gestation over expectant care with respect to survival to discharge or the need for oxygen supplementation at 6 months. FETO increased the risks of preterm, prelabor rupture of membranes and preterm birth. (Funded by the European Commission and others; TOTAL ClinicalTrials.gov number, NCT00763737.).

Gestational diabetes mellitus and adverse maternal and perinatal outcomes in twin and singleton pregnancies: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to assess the risk of adverse maternal and perinatal complications between twin and singleton pregnancies affected by gestational diabetes mellitus and the respective group without gestational diabetes mellitus (controls). DATA SOURCES: A literature search was performed using MEDLINE, Embase, and Cochrane from January 1980 to May 2023. STUDY ELIGIBILITY CRITERIA: Observational studies reporting maternal and perinatal outcomes in singleton and/or twin pregnancies with gestational diabetes mellitus vs controls were included. METHODS: This was a systematic review and meta-analysis. Pooled estimate risk ratios with 95% confidence intervals were generated to determine the likelihood of adverse pregnancy outcomes between twin and singleton pregnancies with and without gestational diabetes mellitus. Heterogeneity among studies was evaluated in the model and expressed using the I2 statistic. A P value of <.05 was considered statistically significant. The meta-analyses were performed using Review Manager (RevMan Web). Version 5.4. The Cochrane Collaboration, 2020. Meta-regression was used to compare relative risks between singleton and twin pregnancies. The addition of multiple covariates into the models was used to address the lack of adjustments. RESULTS: Overall, 85 studies in singleton pregnancies and 27 in twin pregnancies were included. In singleton pregnancies with gestational diabetes mellitus, compared with controls, there were increased risks of hypertensive disorders of pregnancy (relative risk, 1.85; 95% confidence interval, 1.69-2.01), induction of labor (relative risk, 1.36; 95% confidence interval, 1.05-1.77), cesarean delivery (relative risk, 1.31; 95% confidence interval, 1.24-1.38), large-for-gestational-age neonate (relative risk, 1.61; 95% confidence interval, 1.46-1.77), preterm birth (relative risk, 1.36; 95% confidence interval, 1.27-1.46), and admission to the neonatal intensive care unit (relative risk, 1.43; 95% confidence interval, 1.38-1.49). In twin pregnancies with gestational diabetes mellitus, compared with controls, there were increased risks of hypertensive disorders of pregnancy (relative risk, 1.69; 95% confidence interval, 1.51-1.90), cesarean delivery (relative risk, 1.10; 95% confidence interval, 1.06-1.13), large-for-gestational-age neonate (relative risk, 1.29; 95% confidence interval, 1.03-1.60), preterm birth (relative risk, 1.19; 95% confidence interval, 1.07-1.32), and admission to the neonatal intensive care unit (relative risk, 1.20; 95% confidence interval, 1.09-1.32) and reduced risks of small-for-gestational-age neonate (relative risk, 0.89; 95% confidence interval, 0.81-0.97) and neonatal death (relative risk, 0.50; 95% confidence interval, 0.39-0.65). When comparing relative risks in singleton vs twin pregnancies, there was sufficient evidence to suggest that twin pregnancies have a lower relative risk of cesarean delivery (P=.003), have sufficient adjustment for confounders, and have lower relative risks of admission to the neonatal intensive care unit (P=.005), stillbirths (P=.002), and neonatal death (P=.001) than singleton pregnancies. CONCLUSION: In both singleton and twin pregnancies, gestational diabetes mellitus was associated with an increased risk of adverse maternal and perinatal outcomes. In twin pregnancies, gestational diabetes mellitus may have a milder effect on some adverse perinatal outcomes and may be associated with a lower risk of neonatal death.

Maternal vascular indices at 36 weeks' gestation in the prediction of preeclampsia.

BACKGROUND: Epidemiological studies have shown that women with preeclampsia (PE) are at increased long term cardiovascular risk. This risk might be associated with accelerated vascular ageing process but data on vascular abnormalities in women with PE are scarce. OBJECTIVE: This study aimed to identify the most discriminatory maternal vascular index in the prediction of PE at 35 to 37 weeks' gestation and to examine the performance of screening for PE by combinations of maternal risk factors and biophysical and biochemical markers at 35 to 37 weeks' gestation. STUDY DESIGN: This was a prospective observational nonintervention study in women attending a routine hospital visit at 35 0/7 to 36 6/7 weeks' gestation. The visit included recording of maternal demographic characteristics and medical history, vascular indices, and hemodynamic parameters obtained by a noninvasive operator-independent device (pulse wave velocity, augmentation index, cardiac output, stroke volume, central systolic and diastolic blood pressures, total peripheral resistance, and fetal heart rate), mean arterial pressure, uterine artery pulsatility index, and serum concentration of placental growth factor and soluble fms-like tyrosine kinase-1. The performance of screening for delivery with PE at any time and at <3 weeks from assessment using a combination of maternal risk factors and various combinations of biomarkers was determined. RESULTS: The study population consisted of 6746 women with singleton pregnancies, including 176 women (2.6%) who subsequently developed PE. There were 3 main findings. First, in women who developed PE, compared with those who did not, there were higher central systolic and diastolic blood pressures, pulse wave velocity, peripheral vascular resistance, and augmentation index. Second, the most discriminatory indices were systolic and diastolic blood pressures and pulse wave velocity, with poor prediction from the other indices. However, the performance of screening by a combination of maternal risk factors plus mean arterial pressure was at least as high as that of a combination of maternal risk factors plus central systolic and diastolic blood pressures; consequently, in screening for PE, pulse wave velocity, mean arterial pressure, uterine artery pulsatility index, placental growth factor, and soluble fms-like tyrosine kinase-1 were used. Third, in screening for both PE within 3 weeks and PE at any time from assessment, the detection rate at a false-positive rate of 10% of a biophysical test consisting of maternal risk factors plus mean arterial pressure, uterine artery pulsatility index, and pulse wave velocity (PE within 3 weeks: 85.2%; 95% confidence interval, 75.6%-92.1%; PE at any time: 69.9%; 95% confidence interval, 62.5%-76.6%) was not significantly different from a biochemical test using the competing risks model to combine maternal risk factors with placental growth factor and soluble fms-like tyrosine kinase-1 (PE within 3 weeks: 80.2%; 95% confidence interval, 69.9%-88.3%; PE at any time: 64.2%; 95% confidence interval, 56.6%-71.3%), and they were both superior to screening by low placental growth factor concentration (PE within 3 weeks: 53.1%; 95% confidence interval, 41.7%-64.3%; PE at any time: 44.3; 95% confidence interval, 36.8%-52.0%) or high soluble fms-like tyrosine kinase-1-to-placental growth factor concentration ratio (PE within 3 weeks: 65.4%; 95% confidence interval, 54.0%-75.7%; PE at any time: 53.4%; 95% confidence interval, 45.8%-60.9%). CONCLUSION: First, increased maternal arterial stiffness preceded the clinical onset of PE. Second, maternal pulse wave velocity at 35 to 37 weeks' gestation in combination with mean arterial pressure and uterine artery pulsatility index provided effective prediction of subsequent development of preeclampsia.

First trimester risk of preeclampsia and rate of spontaneous birth in patients without preeclampsia.

BACKGROUND: First-trimester screening for preeclampsia using a combination of maternal risk factors and mean arterial pressure, uterine artery pulsatility index, and placental growth factor, as proposed by the Fetal Medicine Foundation, provides effective prediction of preterm preeclampsia. Placental dysfunction is a potential precursor of spontaneous birth. OBJECTIVE: The objective of this study was to examine if the estimated risk of preeclampsia is associated with the gestational age at onset of spontaneous delivery in the absence of preeclampsia. STUDY DESIGN: This was a secondary analysis of the data from the Screening programme for pre-eclampsia trial in which there was a comparison of the performance of first-trimester screening for preterm preeclampsia using the Fetal Medicine Foundation model vs a traditional history-based risk scoring system. A subgroup of women from the trial with spontaneous onset of delivery (labor with intact membranes or preterm prelabor rupture of membranes) was included in this study and was arbitrarily divided into 3 groups according to the risk for preterm preeclampsia as determined by the Fetal Medicine Foundation model at 11 to 13 weeks' gestation as follows: group 1 low risk (˂1/100); group 2 intermediate risk (1/50 to 1/100); and group 3 high risk (˃1/50). A survival analysis was carried out using a Kaplan-Meier estimator and a Cox regression analysis with stratification by the 3 preeclampsia risk groups. Occurrence of spontaneous birth in the study groups was compared using log-rank tests and hazard ratios. RESULTS: The study population comprised 10,820 cases with delivery after spontaneous onset of labor among the 16,451 cases who participated in the Screening programme for pre-eclampsia trial. There were 9795 cases in group 1, 583 in group 2, and 442 in group 3. The gestational age at delivery was <28, <32, <35, <37, and <40 weeks in 0.29%, 0.64%, 1.68%, 4.52%, and 44.97% of cases, respectively, in group 1; 0.69%, 1.71%, 3.26%, 7.72%, and 55.23% of cases, respectively, in group 2; and 0.45%, 1.81%, 5.66%, 13.80%, and 63.12% of cases, respectively, in group 3. The curve profile of gestational age at spontaneous birth in the 3 study groups was significantly different overall and in pairwise comparisons (P values <.001). The Cox regression analysis showed that risks increased for spontaneous birth by 18% when the intermediate-risk group was compared with the low-risk group (P˂.001) and by 41% when the high-risk group was compared with the low-risk group (P˂.001). CONCLUSION: In this study that investigated birth after spontaneous onset of labor in women without preeclampsia, there were 2 major findings. First, the duration of pregnancy decreased with increasing first-trimester risk for preeclampsia. Second, in the high-risk group, when compared with the low-risk group, the risk for spontaneous birth was 4 times higher at a gestational age of 24 to 26 weeks, 3 times higher at 28 to 32 weeks, and 2 times higher at 34 to 39 weeks. These differences present major clinical implications for antepartum counselling, monitoring, and interventions in these pregnancies.

Blood pressure cutoffs at 11-13 weeks of gestation and risk of preeclampsia.

BACKGROUND: A parallel has been drawn between first-trimester placental vascular maturation and maternal cardiovascular adaptations, including blood pressure. Although 140/90 mm Hg is well-accepted as the threshold for chronic hypertension in the general obstetric population in early pregnancy, a different threshold could apply to stratify the risk of adverse outcomes, such as preeclampsia. This could have implications for interventions, such as the threshold for initiation of antihypertensive therapy and the target blood pressure level. OBJECTIVE: We evaluated the relationship between various blood pressure cutoffs at 11-13 weeks of gestation and the development of preeclampsia, overall and according to key maternal characteristics. STUDY DESIGN: This secondary analysis was of data from a prospective nonintervention cohort study of singleton pregnancies delivering at ≥24 weeks, without major anomalies, at 2 United Kingdom maternity hospitals, 2006-2020. Blood pressure at 11-13 weeks of gestation was classified according to American College of Cardiology/American Heart Association categories (mm Hg) as (1) normal blood pressure (systolic <120 and diastolic <80), (2) elevated blood pressure (systolic ≥120 and diastolic <80), stage 1 hypertension (systolic ≥130 or diastolic 80-89), and stage 2 hypertension (systolic ≥140 or diastolic ≥90). For blood pressure category thresholds and the outcome of preeclampsia, the following were calculated overall and across maternal age, body mass index, ethnicity, method of conception, and previous pregnancy history: detection rate, screen-positive rate, and positive and negative likelihood ratios, with 95% confidence intervals. A P value of <.05 was considered significant. RESULTS: There were 137,458 pregnancies screened at 11-13 weeks of gestation. The population was ethnically diverse, with 15.9% of Black ethnicity, 6.7% of South or East Asian ethnicity, and 2.7% of mixed ethnicity, with the remainder of White ethnicity. Compared with normal blood pressure, stage 2 hypertension was associated with both preterm preeclampsia (0.3% to 4.9%) and term preeclampsia (1.0% to 8.3%). A blood pressure threshold of 140/90 mm Hg was good at identifying women at increased risk of preeclampsia overall (positive likelihood ratio, 5.61 [95% confidence interval, 5.14-6.11]) and across maternal characteristics, compared with elevated blood pressure (positive likelihood ratio, 1.70 [95% confidence interval, 1.63-1.77]) and stage 1 hypertension (positive likelihood ratio, 2.68 [95% confidence interval, 2.58-2.77]). There were 2 exceptions: a blood pressure threshold of 130/80 mm Hg was better for the 2.1% of women with body mass index <18.5 kg/m2 (positive likelihood ratio, 5.13 [95% confidence interval, 3.22-8.16]), and a threshold of 135/85 mm Hg better for the 50.4% of parous women without a history of preeclampsia (positive likelihood ratio, 5.24, [95% confidence interval, 4.77-5.77]). There was no blood pressure threshold below which reassurance could be provided against the development of preeclampsia (all-negative likelihood ratios ≥0.20). CONCLUSION: The traditional blood pressure threshold of 140/90 mm Hg performs well to identify women at increased risk of preeclampsia. Women who are underweight or parous with no prior history of preeclampsia may be better identified by lower thresholds; however, a randomized trial would be necessary to determine any benefits of such an approach if antihypertensive therapy were also administered at this threshold. No blood pressure threshold is reassured against the development of preeclampsia, regardless of maternal characteristics.

Placental growth factor testing at 19-23 weeks of gestation as a guide to subsequent care in pregnancy: A prospective observational study.

OBJECTIVE: To determine whether serum placental growth factor (PlGF) at 19-23 weeks of gestation can improve the identification of risk for adverse outcomes. DESIGN: Prospective observational cohort study. SETTING: Two English maternity units. POPULATION: Unselected singleton pregnancies attending routine ultrasound at 19-23 weeks of gestation. METHODS: Outcomes ascertained by health record review. Diagnostic test properties evaluated clinical risk factors for pre-eclampsia (according to National Institute of Care Excellence) or fetal growth restriction (according to Royal College of Obstetricians and Gynaecologists), low PlGF at 19-23 weeks of gestation (<5th percentile) or both. MAIN OUTCOME MEASURES: Pre-eclampsia, gestational hypertension, stillbirth, birthweight below third percentile or neonatal intensive care unit (NICU) admission for ≥48 h. RESULTS: In 30 013 pregnancies, risk factors were present in 9941 (33.1%), low PlGF was present in 1501 (5.0%) and both ('two-stage' screening) were present in 547 (1.8%) pregnancies. Risk factors detected 41.7%-54.7% of adverse outcomes, and could not meaningfully revise the risk (all positive likelihood ratios, +LR, <5.0; all negative likelihood ratios, -LR, ≥0.2). Low PlGF detected 8.5%-17.4% of adverse outcomes, but meaningfully increased risks (other than NICU admission) associated with delivery <37 weeks of gestation (+LR = 5.03-15.55); all -LRs were ≥0.2. 'Two-stage' screening detected 4.2%-8.9% of adverse outcomes, with meaningful +LRs (6.28-18.61) at <37 weeks of gestation, except for NICU admission of ≥48 h, which had an +LR of 7.56 at <34 weeks of gestation; all -LRs were ≥0.2. No screening strategy meaningfully increased or decreased the detection of adverse outcome risk at term. CONCLUSIONS: Clinical risk factor screening has a high screen-positive rate and a poor detection of adverse outcomes. False positives cannot be reduced by PlGF testing at 19-23 weeks of gestation; therefore, this cannot be recommended as a useful strategy on its own.

Relation of antepartum stillbirth to birthweight and gestational age: Prospective cohort study.

OBJECTIVES: To investigate the incidence of antepartum stillbirth in relation to the distribution of neonatal/fetal weight for different gestational ages. DESIGN: Prospective observational cohort study. SETTING: Obstetric ultrasound departments in two UK maternity hospitals. POPULATION: 168 966 women with singleton pregnancies attending for routine antenatal care. METHODS: We examined the incidence of antepartum stillbirths, within different birthweight and fetal weight percentile subgroups, conditioning for gestational age. MAIN OUTCOME MEASURES: Incidence of antepartum stillbirth. RESULTS: The risk of stillbirth progressively increased for lower birthweight. Considering the 25-75th percentile as the reference category, the relative risks for stillbirth at <37 weeks' gestation were 7.6 (95% confidence interval [CI] 5.7-10.2) <1st percentile, 2.6 (95% CI 1.8-3.7) 1 to 10th percentile, 1.4 (95% CI 0.9-2.1) 10 to 25th percentile, 0.8 (95% CI 0.4-1.5) 75 to 90th percentile, 0.8 (95% CI 0.4-1.7) 90 to 99th percentile, 0.9 (95% CI 0.3-2.5) >99th percentile. The respective values for births at ≥37 weeks' gestation were 5.0 (95% CI 2.9-8.9), 2.1 (95% CI 1.4-3.3), 1.4 (95% CI 0.9-2.1), 1.2 (95% CI 0.7-1.8), 1.0 (95% CI 0.6-1.8) and 4.0 (95% CI 1.8-9.3). The incidence of stillbirth in ongoing low-risk singleton pregnancies gradually increases for smaller fetuses at any gestational point. The higher incidence (5.56%) was evident for fetal weight <1st percentile between 24 and 28 weeks' gestation. CONCLUSION: Fetal weight and the weight of the stillborn have a continuous association with the incidence of antepartum stillbirth which is affected by gestational age.

Calcium supplementation for the prevention of pre-eclampsia: Challenging the evidence from meta-analyses.

OBJECTIVE: To investigate the validity of the conclusion from Cochrane reviews and meta-analyses that treatment with calcium supplementation during pregnancy reduces the risk for pre-eclampsia by 55%, which has been influential in international guidelines and future research. DESIGN: Sensitivity analysis of data from Cochrane reviews of trials evaluating high-dose calcium supplementation (of at least 1 g/day) for reduction of pre-eclampsia risk. SETTING: Systematic review and meta-analysis. POPULATION: The Cochrane reviews and meta-analyses included 13 trials enrolling a total of 15 730 women. Random-effects meta-analysis of these studies resulted in a mean risk ratio (RR, calcium/placebo) of 0.45 (95% confidence interval [CI] 0.31-0.65; p < 0.0001). METHODS: We carried out a sensitivity analysis of evidence from the relevant Cochrane review, to examine the impact of study size. MAIN OUTCOME MEASURES: pre-eclampsia. RESULTS: In the three largest studies, accounting for 13 815 (88%) of total recruitment, mean RR was 0.92 (95% CI 0.80-1.06) and there was no evidence of heterogeneity between studies (I2 = 0). With inclusion of the smaller studies, mean RR decreased to 0.45 and I2 increased to 70%. CONCLUSIONS: In assessment of the effect of calcium supplementation on pre-eclampsia risk, the naive focus on the mean of the random-effects meta-analysis in the presence of substantial heterogeneity is highly misleading.

First-trimester prediction of preterm pre-eclampsia and prophylaxis by aspirin: Effect on spontaneous and iatrogenic preterm birth.

OBJECTIVE: To report the predictive performance for preterm birth (PTB) of the Fetal Medicine Foundation (FMF) triple test and National Institute for health and Care Excellence (NICE) guidelines used to screen for pre-eclampsia and examine the impact of aspirin in the prevention of PTB. DESIGN: Secondary analysis of data from the SPREE study and the ASPRE trial. SETTING: Multicentre studies. POPULATION: In SPREE, women with singleton pregnancies had screening for preterm pre-eclampsia at 11-13 weeks of gestation by the FMF method and NICE guidelines. There were 16 451 pregnancies that resulted in delivery at ≥24 weeks of gestation and these data were used to derive the predictive performance for PTB of the two methods of screening. The results from the ASPRE trial were used to examine the effect of aspirin in the prevention of PTB in the population from SPREE. METHODS: Comparison of performance of FMF method and NICE guidelines for pre-eclampsia in the prediction of PTB and use of aspirin in prevention of PTB. MAIN OUTCOME MEASURE: Spontaneous PTB (sPTB), iatrogenic PTB for pre-eclampsia (iPTB-PE) and iatrogenic PTB for reasons other than pre-eclampsia (iPTB-noPE). RESULTS: Estimated incidence rates of sPTB, iPTB-PE and iPTB-noPE were 3.4%, 0.8% and 1.6%, respectively. The corresponding detection rates were 17%, 82% and 25% for the triple test and 12%, 39% and 19% for NICE guidelines, using the same overall screen positive rate of 10.2%. The estimated proportions prevented by aspirin were 14%, 65% and 0%, respectively. CONCLUSION: Prediction of sPTB and iPTB-noPE by the triple test was poor and poorer by the NICE guidelines. Neither sPTB nor iPTB-noPE was reduced substantially by aspirin.

The Role of Regulatory T Cells and Their Therapeutic Potential in Hypertensive Disease of Pregnancy: A Literature Review.

Hypertensive disorders of pregnancy (HDP), including preeclampsia (PE) and gestational hypertension (GH), are major causes of maternal and foetal morbidity and mortality. This review elucidates the role of regulatory T cells (Tregs) in the immunological aspects of HDP and explores their therapeutic potential. Tregs, which play a critical role in maintaining immune homeostasis, are crucial in pregnancy to prevent immune-mediated rejection of the foetus. The review highlights that Tregs contribute to immunological adaptation in normal pregnancy, ensuring foetal acceptance. In contrast, HDP is associated with Treg dysfunction, which is marked by decreased numbers and impaired regulatory capacity, leading to inadequate immune tolerance and abnormal placental development. This dysfunction is particularly evident in PE, in which Tregs fail to adequately modulate the maternal immune response against foetal antigens, contributing to the pathophysiology of the disorder. Therapeutic interventions aiming to modulate Treg activity represent a promising avenue for HDP management. Studies in animal models and limited clinical trials suggest that enhancing Treg functionality could mitigate HDP symptoms and improve pregnancy outcomes. However, given the multifactorial nature of HDP and the intricate regulatory mechanisms of Tregs, the review explores the complexities of translating in vitro and animal model findings into effective clinical therapies. In conclusion, while the precise role of Tregs in HDP is still being unravelled, their central role in immune regulation during pregnancy is indisputable. Further research is needed to fully understand the mechanisms by which Tregs contribute to HDP and to develop targeted therapies that can safely and effectively harness their regulatory potential for treating hypertensive diseases of pregnancy.

Personalized stratification of pregnancy care for small for gestational age neonates from biophysical markers at midgestation.

BACKGROUND: Antenatal identification of pregnancies at high risk of delivering small for gestational age neonates may improve the management of the condition and reduce the associated adverse perinatal outcomes. In a series of publications, we have developed a new competing-risks model for small for gestational age prediction, and we demonstrated that the new approach has a superior performance to that of the traditional methods. The next step in shaping the appropriate management of small for gestational age is the timely assessment of these high-risk pregnancies according to an antenatal stratification plan. OBJECTIVE: This study aimed to demonstrate the stratification of pregnancy care based on individual patient risk derived from the application of the competing-risks model for small for gestational age that combines maternal factors with sonographic estimated fetal weight and uterine artery pulsatility index at midgestation. STUDY DESIGN: This was a prospective observational study of 96,678 singleton pregnancies undergoing routine ultrasound examination at 19 to 24 weeks of gestation, which included recording of estimated fetal weight and measurement of uterine artery pulsatility index. The competing-risks model for small for gestational age was used to create a patient-specific stratification curve capable to define a specific timing for a repeated ultrasound examination after 24 weeks. We examined different stratification plans with the intention of detecting approximately 80%, 85%, 90%, and 95% of small for gestational age neonates with birthweight <3rd and <10th percentiles at any gestational age at delivery until 36 weeks; all pregnancies would be offered a routine ultrasound examination at 36 weeks. RESULTS: The stratification of pregnancy care for small for gestational age can be based on a patient-specific stratification curve. Factors from maternal history, low estimated fetal weight, and increased uterine artery pulsatility index shift the personalized risk curve toward higher risks. The degree of shifting defines the timing for assessment for each pregnancy. If the objective of our antenatal plan was to detect 80%, 85%, 90%, and 95% of small for gestational age neonates at any gestational age at delivery until 36 weeks, the median (range) proportions (percentages) of population examined per week would be 3.15 (1.9-3.7), 3.85 (2.7-4.5), 4.75 (4.0-5.4), and 6.45 (3.7-8.0) for small for gestational age <3rd percentile and 3.8 (2.5-4.6), 4.6 (3.6-5.4), 5.7 (3.8-6.4), and 7.35 (3.3-9.8) for small for gestational age <10th percentile, respectively. CONCLUSION: The competing-risks model provides an effective personalized continuous stratification of pregnancy care for small for gestational age which is based on individual characteristics and biophysical marker levels recorded at the midgestation scan.

First-trimester preterm preeclampsia prediction with metabolite biomarkers: differential prediction according to maternal body mass index.

BACKGROUND: Prediction of preeclampsia risk is key to informing effective maternal care. Current screening for preeclampsia at 11 to 13 weeks of gestation using maternal demographic characteristics and medical history with measurements of mean arterial pressure, uterine artery pulsatility index, and serum placental growth factor can identify approximately 75% of women who develop preterm preeclampsia with delivery at <37 weeks of gestation. Further improvements to preeclampsia screening tests will likely require integrating additional biomarkers. Recent research suggests the existence of distinct maternal risk profiles. Therefore, biomarker evaluation should account for the possibility that a biomarker only predicts preeclampsia in a specific maternal phenotype. OBJECTIVE: This study aimed to verify metabolite biomarkers as preterm preeclampsia predictors early in pregnancy in all women and across body mass index groups. STUDY DESIGN: Observational case-control study drawn from a large prospective study on the early prediction of pregnancy complications in women attending their routine first hospital visit at King's College Hospital, London, United Kingdom, in 2010 to 2015. Pregnant women underwent a complete first-trimester assessment, including the collection of blood samples for biobanking. In 11- to 13-week plasma samples of 2501 singleton pregnancies, the levels of preselected metabolites implicated in the prediction of pregnancy complications were analyzed using a targeted liquid chromatography-mass spectrometry method, yielding high-quality quantification data on 50 metabolites. The ratios of amino acid levels involved in arginine biosynthesis and nitric oxide synthase pathways were added to the list of biomarkers. Placental growth factor and pregnancy-associated plasma protein A were also available for all study subjects, serving as comparator risk predictors. Data on 1635 control and 106 pregnancies complicated by preterm preeclampsia were considered for this analysis, normalized using multiples of medians. Prediction analyses were performed across the following patient strata: all subjects and the body mass index classes of <25, 25 to <30, and ≥30 kg/m2. Adjusted median levels were compared between cases and controls and between each body mass index class group. Odds ratios and 95% confidence intervals were calculated at the mean ±1 standard deviation to gauge clinical prediction merits. RESULTS: The levels of 13 metabolites were associated with preterm preeclampsia in the entire study population (P<.05) with particularly significant (P<.01) associations found for 6 of them, namely, 2-hydroxy-(2/3)-methylbutyric acid, 25-hydroxyvitamin D3, 2-hydroxybutyric acid, alanine, dodecanoylcarnitine, and 1-(1Z-octadecenyl)-2-oleoyl-sn-glycero-3-phosphocholine. Fold changes in 7 amino acid ratios, all involving glutamine or ornithine, were also significantly different between cases and controls (P<.01). The predictive performance of some metabolites and ratios differed according to body mass index classification; for example, ornithine (P<.001) and several ornithine-related ratios (P<.0001 to P<.01) were only strongly associated with preterm preeclampsia in the body mass index of <25 kg/m2 group, whereas dodecanoylcarnitine and 3 glutamine ratios were particularly predictive in the body mass index of ≥30 kg/m2 group (P<.01). CONCLUSION: Single metabolites and ratios of amino acids related to arginine bioavailability and nitric oxide synthase pathways were associated with preterm preeclampsia risk at 11 to 13 weeks of gestation. Differential prediction was observed according to body mass index classes, supporting the existence of distinct maternal risk profiles. Future studies in preeclampsia prediction should account for the possibility of different maternal risk profiles to improve etiologic and prognostic understanding and, ultimately, clinical utility of screening tests.

The implications of the Fetal Medicine Foundation 35- to 36-week preeclampsia prediction competing-risk model on timing of birth.

BACKGROUND: Preeclampsia is associated with increased risks of life-threatening, -altering, and -ending complications. Assessment of risk for preeclampsia at 35 to 36 weeks' gestation by the Fetal Medicine Foundation 36-week competing-risk model identifies approximately 75% of women who will develop term preeclampsia, at a 10% screen-positive rate. OBJECTIVE: This study aimed to assess whether the Fetal Medicine Foundation 36-week model can provide personalized guidance to women about the probable timing of their delivery, whether or not they develop pregnancy hypertension. STUDY DESIGN: In this prospective nonintervention screening study at 2 maternity hospitals in England, women who did not have preeclampsia (American College of Obstetricians and Gynecologists definition) and were attending a routine hospital visit at 35 0/7 to 36 6/7 weeks' gestation underwent assessment of risk for preeclampsia, including maternal demographic characteristics, medical history, mean arterial pressure, and serum placental growth factor and soluble fms-like tyrosine kinase-1. Fetal Medicine Foundation 36-week model risk categories for subsequent preeclampsia were defined as: A, ≥0.500; B, 0.20 to 0.499; C, 0.05 to 0.199; D, 0.020 to 0.049; and E, <0.020. Obstetrical records were examined for all women to identify their gestational age at delivery, and whether they experienced a spontaneous onset of labor (irrespective of mode of delivery) or had a medically indicated birth (either induction of labor or unlabored cesarean delivery). The cumulative incidence of delivery and risk ratios, for all deliveries and for spontaneous deliveries, was assessed. RESULTS: Among 29,035 women with singleton pregnancies, 1.0%, 2.9%, 3.3%, 5.0%, 9.9%, and 77.9% were in A, B, C, D, and E risk strata, respectively. In the A (vs E) stratum, 71.95% (vs 33.52%) of births were medically indicated. Compared with women in stratum E, women in higher risk strata were more likely to deliver, and to deliver following spontaneous labor, before their due date. For example, of the women in stratum A (vs E), 14.2% (vs 1.1%; risk ratio, 12.5 [95% confidence interval, 9.45-15.35]), 48.5% (vs 5.1%; risk ratio, 8.47 [7.48-9.35]), 69.6% (vs 15.5%; risk ratio, 3.86 [3.59-4.08]), and 90.1% (vs 44.8%; risk ratio, 6.72 [4.53-9.95]) gave birth before 37 0/7, 38 0/7, 39 0/7, and 40 0/7 weeks, respectively. For women in stratum A (vs E), when censored for medically indicated births, spontaneous labor occurred more commonly before 37 0/7 (risk ratio, 4.31 [1.99-6.57]), 38 0/7 (risk ratio, 3.71 [2.48-4.88]), 39 0/7 (risk ratio, 2.87 [2.22-3.46]), and 40 0/7 (risk ratio, 1.42 [1.14-1.77]) weeks. CONCLUSION: Women in higher-risk strata gave birth earlier, and more frequently following medically indicated delivery, compared with those in lower-risk strata. Importantly, the proportion of women who gave birth following spontaneous onset of labor before their due date was also greater in higher-risk than in lower-risk women. The Fetal Medicine Foundation 36-week competing-risk model incorporates biomarkers of placental aging, including angiogenic imbalance; these results imply that a fetoplacental response to placental aging may be an important trigger for the onset of labor at term.

Aspirin for evidence-based preeclampsia prevention trial: effects of aspirin on maternal serum pregnancy-associated plasma protein A and placental growth factor trajectories in pregnancy.

BACKGROUND: The exact mechanism by which aspirin prevents preeclampsia remains unclear. Its effects on serum placental biomarkers throughout pregnancy are also unknown. OBJECTIVE: To investigate the effects of aspirin on serum pregnancy-associated plasma protein A and placental growth factor trajectories using repeated measures from women at increased risk of preterm preeclampsia. STUDY DESIGN: This was a longitudinal secondary analysis of the Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-based Preeclampsia Prevention trial using repeated measures of pregnancy-associated plasma protein A and placental growth factor. In the trial, 1620 women at increased risk of preterm preeclampsia were identified using the Fetal Medicine Foundation algorithm at 11 to 13+6 weeks of gestation, of whom 798 were randomly assigned to receive aspirin 150 mg and 822 to receive placebo daily from before 14 weeks to 36 weeks of gestation. Serum biomarkers were measured at baseline and follow-up visits at 19 to 24, 32 to 34, and 36 weeks of gestation. Generalized additive mixed models with treatment by gestational age interaction terms were used to investigate the effect of aspirin on biomarker trajectories over time. RESULTS: Overall, there were 5507 pregnancy-associated plasma protein A and 5523 placental growth factor measurements. Raw pregnancy-associated plasma protein A values increased over time, and raw placental growth factor increased until 32 weeks of gestation followed by a decline. The multiple of the median mean values of the same biomarkers were consistently below 1.0 multiple of the median, reflecting the high-risk profile of the study population. Trajectories of mean pregnancy-associated plasma protein A and placental growth factor multiple of the median values did not differ significantly between the aspirin and placebo groups (aspirin treatment by gestational age interaction P values: .259 and .335, respectively). CONCLUSION: In women at increased risk of preterm preeclampsia, aspirin 150 mg daily had no significant effects on pregnancy-associated plasma protein A or placental growth factor trajectories when compared to placebo.

Vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in twin gestations: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the efficacy of vaginal progesterone for the prevention of preterm birth and adverse perinatal outcomes in twin gestations. DATA SOURCES: MEDLINE, Embase, LILACS, and CINAHL (from their inception to January 31, 2023), Cochrane databases, Google Scholar, bibliographies, and conference proceedings. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials that compared vaginal progesterone to placebo or no treatment in asymptomatic women with a twin gestation. METHODS: The systematic review was conducted according to the Cochrane Handbook for Systematic Reviews of Interventions. The primary outcome was preterm birth <34 weeks of gestation. Secondary outcomes included adverse perinatal outcomes. Pooled relative risks with 95% confidence intervals were calculated. We assessed the risk of bias in each included study, heterogeneity, publication bias, and quality of evidence, and performed subgroup and sensitivity analyses. RESULTS: Eleven studies (3401 women and 6802 fetuses/infants) fulfilled the inclusion criteria. Among all twin gestations, there were no significant differences between the vaginal progesterone and placebo or no treatment groups in the risk of preterm birth <34 weeks (relative risk, 0.99; 95% confidence interval, 0.84-1.17; high-quality evidence), <37 weeks (relative risk, 0.99; 95% confidence interval, 0.92-1.06; high-quality evidence), and <28 weeks (relative risk, 1.00; 95% confidence interval, 0.64-1.55; moderate-quality evidence), and spontaneous preterm birth <34 weeks of gestation (relative risk, 0.97; 95% confidence interval, 0.80-1.18; high-quality evidence). Vaginal progesterone had no significant effect on any of the perinatal outcomes evaluated. Subgroup analyses showed that there was no evidence of a different effect of vaginal progesterone on preterm birth <34 weeks of gestation related to chorionicity, type of conception, history of spontaneous preterm birth, daily dose of vaginal progesterone, and gestational age at initiation of treatment. The frequencies of preterm birth <37, <34, <32, <30, and <28 weeks of gestation and adverse perinatal outcomes did not significantly differ between the vaginal progesterone and placebo or no treatment groups in unselected twin gestations (8 studies; 3274 women and 6548 fetuses/infants). Among twin gestations with a transvaginal sonographic cervical length <30 mm (6 studies; 306 women and 612 fetuses/infants), vaginal progesterone was associated with a significant decrease in the risk of preterm birth occurring at <28 to <32 gestational weeks (relative risks, 0.48-0.65; moderate- to high-quality evidence), neonatal death (relative risk, 0.32; 95% confidence interval, 0.11-0.92; moderate-quality evidence), and birthweight <1500 g (relative risk, 0.60; 95% confidence interval, 0.39-0.88; high-quality evidence). Vaginal progesterone significantly reduced the risk of preterm birth occurring at <28 to <34 gestational weeks (relative risks, 0.41-0.68), composite neonatal morbidity and mortality (relative risk, 0.59; 95% confidence interval, 0.33-0.98), and birthweight <1500 g (relative risk, 0.55; 95% confidence interval, 0.33-0.94) in twin gestations with a transvaginal sonographic cervical length ≤25 mm (6 studies; 95 women and 190 fetuses/infants). The quality of evidence was moderate for all these outcomes. CONCLUSION: Vaginal progesterone does not prevent preterm birth, nor does it improve perinatal outcomes in unselected twin gestations, but it appears to reduce the risk of preterm birth occurring at early gestational ages and of neonatal morbidity and mortality in twin gestations with a sonographic short cervix. However, more evidence is needed before recommending this intervention to this subset of patients.

Preterm and term pre-eclampsia: Relative burdens of maternal and perinatal complications.

OBJECTIVE: To determine the relative burdens of maternal and perinatal complications for preterm and term pre-eclampsia. DESIGN: Prospective observational cohort study. SETTING: Two English maternity units. POPULATION: Unselected women with singleton pregnancies who developed pre-eclampsia (International Society for the Study of Hypertension in Pregnancy definition). METHODS: Outcomes were ascertained by health record review and compared between pregnancies with preterm (versus term) pre-eclampsia. MAIN OUTCOME MEASURES: Severe maternal hypertension, maternal mortality or major maternal morbidity, perinatal mortality or major neonatal morbidity, neonatal unit (NNU) admission ≥48 hours, and birthweight <3rd percentile. RESULTS: Among 40 241 singleton pregnancies, 298 (0.7%, 95% confidence interval [CI] 0.66-0.83) and 1194 (3.0%, 95% CI 2.8-3.1) developed preterm and term pre-eclampsia, respectively. Women with preterm (versus term) pre-eclampsia more commonly experienced adverse maternal or perinatal events: severe hypertension 18.5% (95% CI 14.5-23.3) versus 13.6% (95% CI 11.7-15.6); maternal mortality/major morbidity 7.4% (95% CI 4.9-10.9) versus 2.2% (95% CI 1.5-3.2); perinatal mortality/major neonatal morbidity 29.5% (95% CI 24.6-34.9) versus 2.2% (95% CI 1.5-3.2); and birthweight <3rd percentile 54.4% (95% CI 48.7-59.9) versus 14.2% (95% CI 12.4-16.3). However, in absolute terms, most maternal complications occurred in women with term pre-eclampsia, as did a large proportion of perinatal complications: severe hypertension 74.7% (95% CI 68.5-80.0); maternal mortality/major morbidity 54.2% (95% CI 40.3-67.4); perinatal mortality/major neonatal morbidity 22.8% (95% CI 16.1-31.3); NNU admission ≥48 hours 38.1% (95% CI 32.4-44.1); and birthweight <3rd percentile 51.2% (95% CI 45.8-56.5). CONCLUSIONS: Although adverse event risks are greater with preterm (versus term) pre-eclampsia, term disease is associated with at least equivalent total numbers of maternal, and a significant proportion of perinatal, adverse events. Increased efforts should be made to decrease the incidence of term pre-eclampsia.

Effect of race on the measurement of angiogenic factors for prediction and diagnosis of pre-eclampsia.

OBJECTIVE: To examine the effect of self-declared race on serum placental growth factor (PlGF) and sFlt-1/PlGF ratio and the impact on pre-eclampsia (PE) prediction. DESIGN: Prospective observational study. SETTING: Two UK maternity hospitals. POPULATION: 29 035 women with singleton pregnancies attending a routine 35+0 to 36+6 weeks' gestation hospital visit, including 654 (2.3%) who subsequently developed PE. METHODS: The predictive performance of PlGF and sFlt-1/PlGF for PE in minority racial groups (versus white) was examined. MAIN OUTCOME MEASURE: Delivery with PE. RESULTS: Compared with white women, mean PlGF was higher and sFlt-1/PlGF ratio lower in black, South Asian, East Asian and mixed race women. In white women at a PlGF concentration cut-off corresponding to a screen-positive rate (SPR) of 10%, detection rates (DRs) were 49.1% for PE at any time and 72.3% for PE within 2 weeks after screening. In black women, at the same PlGF concentration cut-off for white women, the SPR was 5.5%, and DRs 33.6% and 55.0%, respectively; the number of PE cases was too small to evaluate screening performance in other racial groups. Using a fixed cut-off in sFlt-1/PlGF ratio to identify women at risk of developing PE, similarly diagnostically disadvantaged black women. Bias was overcome by adjusting metabolite concentrations for maternal characteristics and use of the competing risks model to estimate patient-specific risks. CONCLUSION: Screening for PE with fixed cut-offs in PlGF or sFlt-1/PlGF diagnostically disadvantages black women. It is essential that measured levels of PlGF be adjusted for race as well as other maternal characteristics.

Maternal plasma diacylglycerols and triacylglycerols in the prediction of gestational diabetes mellitus.

OBJECTIVE: To define the lipidomic profile in plasma across pregnancy, and identify lipid biomarkers for gestational diabetes mellitus (GDM) prediction in early pregnancy. DESIGN: Case-control study. SETTING: Tertiary referral maternity unit. POPULATION OR SAMPLE: Plasma samples from 100 GDM and 100 normal glucose tolerance (NGT) women, divided into a training set (GDM first trimester = 50, GDM second trimester = 40, NGT first trimester = 50, NGT second trimester = 50) and a validation set (GDM first trimester = 45, GDM second trimester = 34, NGT first trimester = 44, NGT second trimester = 40). METHODS: Plasma samples were collected in the first (11+0 to 13+6 weeks), second (19+0 to 24+6 weeks), and third trimesters (30+0 to 34+6 weeks), and tested by ultra-high-performance liquid chromatography coupled with electrospray ionisation-quadrupole-time of flight-mass spectrometry; The GDM prediction model was established by the machine-learning method of random forest. MAIN OUTCOME MEASURES: Gestational diabetes mellitus. RESULTS: In both the GDM and NGT group, lyso-glycerophospholipids were down-regulated, whereas ceramides, sphingomyelins, cholesteryl ester, diacylglycerols (DGs) and triacylglycerols (TGs) and glucosylceramide were up-regulated across the three trimesters of pregnancy. In the training dataset, seven TGs and five DGs demonstrated good performance in the prediction of GDM in the first and second trimesters (area under the curve [AUC] = 0.96 with 95% confidence interval [CI] of 0.93-1 and AUC = 0.97 with 95% CI of 0.95-1, respectively), independent of maternal body mass index (BMI) and ethnicity. In the validation dataset, the predictive model achieved an AUC of 0.88 and 0.94 at the first and second trimesters, respectively. CONCLUSIONS: Our results have proposed new lipid biomarkers for the first trimester prediction of GDM, independent of ethnicity and BMI.

Fetal surgery using fetoscopic endoluminal tracheal occlusion for severe congenital diaphragmatic hernia: a single-center experience.

PURPOSE: To provide a comprehensive report of the experience gained in the prenatal treatment of congenital diaphragmatic hernia (CDH) using fetoscopic endoluminal tracheal occlusion (FETO) following its implementation at a newly established specialized fetal medicine center. METHODS: Mothers of fetuses with severe CDH were offered prenatal treatment by FETO. RESULTS: Between 2018 and 2021, 16 cases of severe CDH underwent FETO. The median gestational age (GA) at balloon insertion was 28.4 weeks (IQR 27.8-28.6). The median GA at delivery was 37 weeks (IQR 34.4-37.8). The survival rate was 8/16 cases (50%). None of the survivors required home oxygen therapy at 6 months of age. Comparison between the survivors and deceased showed that survivors had balloon insertion 1 week earlier (27.8 vs. 28.4 weeks, p = 0.007), a higher amniotic fluid level change between pre- to post-FETO (3.4 vs 1.3, p = 0.024), a higher O/E LHR change between pre- to post-FETO (50.8 vs. 37.5, p = 0.047), and a GA at delivery that was 2 weeks later (37.6 vs. 35.4 weeks, p = 0.032). CONCLUSIONS: The survival rate at 6 months of age in cases of severe CDH treated with FETO in our center was 50%. Our new fetal medicine center matches the performance of other leading international centers.