Validation of the first-trimester machine learning model for predicting pre-eclampsia in an Asian population.

OBJECTIVES: To evaluate the performance of an artificial intelligence (AI) and machine learning (ML) model for first-trimester screening for pre-eclampsia in a large Asian population. METHODS: This was a secondary analysis of a multicenter prospective cohort study in 10 935 participants with singleton pregnancies attending for routine pregnancy care at 11-13+6 weeks of gestation in seven regions in Asia between December 2016 and June 2018. We applied the AI+ML model for the first-trimester prediction of preterm pre-eclampsia (<37 weeks), term pre-eclampsia (≥37 weeks), and any pre-eclampsia, which was derived and tested in a cohort of pregnant participants in the UK (Model 1). This model comprises maternal factors with measurements of mean arterial pressure, uterine artery pulsatility index, and serum placental growth factor (PlGF). The model was further retrained with adjustments for analyzers used for biochemical testing (Model 2). Discrimination was assessed by area under the receiver operating characteristic curve (AUC). The Delong test was used to compare the AUC of Model 1, Model 2, and the Fetal Medicine Foundation (FMF) competing risk model. RESULTS: The predictive performance of Model 1 was significantly lower than that of the FMF competing risk model in the prediction of preterm pre-eclampsia (0.82, 95% confidence interval [CI] 0.77-0.87 vs. 0.86, 95% CI 0.811-0.91, P = 0.019), term pre-eclampsia (0.75, 95% CI 0.71-0.80 vs. 0.79, 95% CI 0.75-0.83, P = 0.006), and any pre-eclampsia (0.78, 95% CI 0.74-0.81 vs. 0.82, 95% CI 0.79-0.84, P < 0.001). Following the retraining of the data with adjustments for the PlGF analyzers, the performance of Model 2 for predicting preterm pre-eclampsia, term pre-eclampsia, and any pre-eclampsia was improved with the AUC values increased to 0.84 (95% CI 0.80-0.89), 0.77 (95% CI 0.73-0.81), and 0.80 (95% CI 0.76-0.83), respectively. There were no differences in AUCs between Model 2 and the FMF competing risk model in the prediction of preterm pre-eclampsia (P = 0.135) and term pre-eclampsia (P = 0.084). However, Model 2 was inferior to the FMF competing risk model in predicting any pre-eclampsia (P = 0.024). CONCLUSION: This study has demonstrated that following adjustment for the biochemical marker analyzers, the predictive performance of the AI+ML prediction model for pre-eclampsia in the first trimester was comparable to that of the FMF competing risk model in an Asian population.

Aspirin versus metformin in pregnancies at high risk of preterm pre-eclampsia in China (AVERT): protocol for a multicentre, double-blind, 3-arm randomised controlled trial.

INTRODUCTION: Pre-eclampsia (PE) affects about 5% of Chinese pregnant women and is a major cause of maternal and perinatal morbidity and mortality. The first trimester screening model developed by the Fetal Medicine Foundation, which uses the Bayes theorem to combine maternal characteristics and medical history together with measurements of biomarkers, has been proven to be effective and has superior screening performance to that of the traditional risk factor-based approach for the prediction of PE. Prophylactic use of low-dose aspirin in women at risk for PE has resulted in a lower incidence of preterm-PE. However, there is no consensus on the preferred aspirin dosage for the prevention of preterm-PE. Evidence has also suggested that metformin has the potential benefit in preventing PE in pregnant women who are at high risk of the disorder. METHOD AND ANALYSIS: We present a protocol (V.2.0, date 17 March 2022) for the AVERT trial, which is a multicentre, double-blinded, 3-arm randomised controlled trial (RCT) that uses an effective PE screening programme to explore the optimal dosage of aspirin and the role of metformin for the prevention of PE among high-risk pregnant women in China. We intend to recruit 66 000 singleton pregnancies without treatment of low-dose aspirin and metformin at 11-13 weeks' gestation and all eligible women attending for their first trimester routine scan will be invited to undergo screening for preterm-PE by the combination of maternal factors, mean arterial pressure and placental growth factor. Women found to be at high risk of developing preterm-PE will be invited to take part in the RCT. This study will compare the incidence of preterm-PE with delivery at <37 weeks' gestation, as the primary outcome, of three different interventional groups: (1) aspirin 75 mg daily, (2) aspirin 150 mg daily and (3) aspirin 75 mg with metformin 1.5 g daily. 957 participants per treatment group are required to detect a significant difference of 59% in the reduction of the incidence of preterm-PE with 80% power and type I error of 5%. Pregnancy and neonatal outcomes will be collected and analysed. ETHICS AND DISSEMINATION: Ethical approval for the study was obtained from the Joint Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee (CREC Ref. No. 2021.406) in Hong Kong and the Ethics Committee of each participating hospital in Mainland China. The study is registered at ClinicalTrials.gov. The results of the AVERT trial will be disseminated at international academic conferences and published in high-impact factor journals. TRIAL REGISTRATION NUMBER: NCT05580523.

Prediction of labour outcomes using prelabour computerised cardiotocogram and maternal and fetal Doppler indices: A prospective cohort study.

OBJECTIVES: To investigate the association and the potential value of prelabour fetal heart rate short-term variability (STV) determined by computerised cardiotocography (cCTG) and maternal and fetal Doppler in predicting labour outcomes. DESIGN: Prospective cohort study. SETTING: The Prince of Wales Hospital, a tertiary maternity unit, in Hong Kong SAR. POPULATION: Women with a term singleton pregnancy in latent phase of labour or before labour induction were recruited during May 2019-November 2021. METHODS: Prelabour ultrasonographic assessment of fetal growth, Doppler velocimetry and prelabour cCTG monitoring including Dawes-Redman CTG analysis were registered shortly before induction of labour or during the latent phase of spontaneous labour. MAIN OUTCOME MEASURES: Umbilical cord arterial pH, emergency delivery due to pathological CTG during labour and neonatal intensive care unit (NICU)/special care baby unit (SCBU) admission. RESULTS: Of the 470 pregnant women invited to participate in the study, 440 women provided informed consent and a total of 400 participants were included for further analysis. Thirty-four (8.5%) participants underwent emergency delivery for pathological CTG during labour. A total of 6 (1.50%) and 148 (37.00%) newborns required NICU and SCBU admission, respectively. Middle cerebral artery pulsatility index (MCA-PI) and MCA-PI z-score were significantly lower in pregnancies that required emergency delivery for pathological CTG during labour compared with those that did not (1.23 [1.07-1.40] versus 1.40 [1.22-1.64], p = 0.002; and 0.55 ± 1.07 vs. 0.12 ± 1.06), p = 0.049]. This study demonstrated a weakly positive correlation between umbilical cord arterial pH and prelabour log10 STV (r = 0.107, p = 0.035) and the regression analyses revealed that the contributing factors for umbilical cord arterial pH were smoking (p = 0.006) and prelabour log10 STV (p = 0.025). CONCLUSIONS: In pregnant women admitted in latent phase of labour or for induction of labour at term, prelabour cCTG STV had a weakly positive association with umbilical cord arterial pH but was not predictive of emergency delivery due to pathological CTG during labour.

Incidence of intrauterine adhesion after ultrasound-guided manual vacuum aspiration (USG-MVA) for first-trimester miscarriages: a prospective cohort study.

PURPOSE: Ultrasound-guided manual vacuum aspiration (USG-MVA) is a feasible and effective outpatient treatment to treat early pregnancy loss. METHODS: This was a prospective observational study at a university-affiliated hospital. All women undergoing either a USG-MVA or electric vacuum aspiration (EVA) were invited to return 3-6 months later for follow-up at which women completed a questionnaire to document their post-evacuation menstrual and reproductive history, and underwent a hysteroscopy if they were not pregnant. The severity of intrauterine adhesion (IUA), if present, was graded (Stage I-III) according to the American fertility society classification. RESULTS: A total of 292 women had a hysteroscopy after their initial surgical evacuation, USG-MVA 169(57.9%) versus EVA 123(42.1%). Women undergoing EVA as opposed to a USG-MVA had a 12.9% higher incidence of IUA (24.1% vs. 37.0%, p = 0.042) equivalent to 1.84 times higher risk (95% CI 1.01-3.34; p = 0.048). Women having EVA continued to show an increased but not statistically significant trend towards an increased risk of IUA after adjusting for the type of miscarriage (aOR = 1.3; 95% CI 0.66-2.50; p = 0.46). CONCLUSION: There were no significant differences in their reproductive outcomes and fewer women post-USG-MVA complained of hypomenorrhea. IUA may still occur in women undergoing USG-MVA but it is lower than the rate in women undergoing EVA. Clinical trials registry The trial was registered with the Centre for Clinical Research and Biostatistics - Clinical Trials Registry (CCRBCTR), a partner registry of the WHO Primary Registry-Chinese Clinical Trials Registry (ChiCTR) with a Unique Trial Number: CUHK_CCRB00541 on 22 Dec 2016.

Ultrasound-guided manual vacuum aspiration (USG-MVA) with cervical preparation for early pregnancy loss: A cost-effectiveness analysis.

BACKGROUND AND AIM: Approximately one in four women will experience a miscarriage in their lifetime. Ultrasound-guided manual vacuum aspiration (USG-MVA) is an ideal outpatient surgical treatment alternative to traditional surgical evacuation. We aimed to examine the cost-effectiveness of US-MVA with cervical preparation for treatment of early pregnancy loss from the perspective of public healthcare provider of Hong Kong. METHODS: A decision-analytic model was designed to simulate outcomes in a hypothetical cohort of patients with early pregnancy loss on four interventions: (1) US-MVA, (2) misoprostol, (3) surgical evacuation of uterus by dilation and curettage (surgical evacuation), and (4) expectant care. Model inputs were retrieved from published literature and public data. Model outcome measures were total direct medical cost and disutility-adjusted life-year (DALY). Base-case model results were examined by sensitivity analysis. RESULTS: The expected DALYs (0.00141) and total direct medical cost (USD736) of US-MVA were the lowest of all interventions in base-case analysis, and US-MVA was the preferred cost-effective option. One-way sensitivity analysis showed that the misoprostol group became less costly than the US-MVA group if the evacuation rate of misoprostol (base-case value 0.832) exceeded 0.920. In probabilistic sensitivity analysis, At the willingness-to-pay (WTP) threshold of 49630 USD/DALY averted (1x gross domestic product per capita of Hong Kong), the US-MVA was cost-effective in 72.9% of the time. CONCLUSIONS: US-MVA appeared to be cost-saving and effective for treatment of early pregnancy loss from the perspective of public healthcare provider of Hong Kong.

A point-of-care urine test to predict adverse maternal and neonatal outcomes in Asian women with suspected preeclampsia.

OBJECTIVES: To assess clinical utility of the urine Congo red dot test (CRDT) in predicting composite adverse maternal and neonatal outcomes in women with suspected preeclampsia (PE). METHODS: CRDT result and pregnancy outcomes were prospectively documented in women with new onset or pre-existing hypertension, new or pre-existing proteinuria, PE symptoms and suspected PE-related fetal growth restriction or abnormal Doppler presenting from 20 weeks' gestation between January 2020 and December 2022. Participants and clinicians were blinded to the CRDT result and managed according to internally agreed protocols. Composite maternal outcome was defined as PE, postpartum hemorrhage, intensive care unit admission, and maternal death. Composite neonatal outcome was defined as small for gestational age, preterm birth, 5-min Apgar score < 7, neonatal intensive care unit admission, and neonatal death. RESULTS: Two hundred and forty-four women out of two hundred and fifty-one (97.2%) had a negative CRDT. All seven women with positive CRDT had both adverse maternal and neonatal outcomes, giving positive predictive values (PPV) of 100%. Rates of composite adverse maternal and neonatal outcomes in CDRT negative women were 103/244 [42.2%, 95% confidence interval (CI) 36.2%-48.5%] and 170/244 (69.7%, 95% CI 63.6%-75.1%), respectively. CRDT negative predictive values (NPV) for adverse maternal and neonatal outcomes were, respectively, 141/244 (57.8%, 95% CI 48.6%-68.2%) and 74/244 (30.3%, 95% CI 23.8%-38.1%). CONCLUSION: CRDT had low NPV but high PPV for adverse maternal and neonatal outcomes in women with suspected PE. Its role in clinical management and triage of women with suspected PE is limited as it cannot identify those at low risk of developing adverse outcomes.

Evaluation of first trimester maternal serum inhibin-A for preeclampsia screening.

BACKGROUND: International professional organizations recommend aspirin prophylaxis to women screened high risk for preterm preeclampsia (PE) in the first trimester. The UK Fetal Medicine Foundation (FMF) screening test for preterm PE using mean arterial pressure (MAP), uterine artery pulsatility index (UTPI) and placental growth factor (PlGF) was demonstrated to have lower detection rate (DR) in Asian population studies. Additional biomarkers are therefore needed in Asian women to improve screening DRs as a significant proportion of women with preterm and term PE are currently not identified. OBJECTIVES: To evaluate maternal serum inhibin-A at 11-13 weeks as an alternative to PlGF or as an additional biomarker within the FMF screening test for preterm PE. STUDY DESIGN: This is a nested case-control study using pregnancies initially screened at 11-13 weeks for preterm PE using the FMF triple test in a non-intervention study conducted between December 2016 and June 2018. Inhibin-A levels were retrospectively measured in 1,792 singleton pregnancies, 112 (1.7%) with PE matched for time of initial screening with 1,680 unaffected pregnancies. Inhibin-A levels were transformed to multiple of the expected median (MoM). The distribution of log10 inhibin-A MoM in PE and unaffected pregnancies and the association between log10 inhibin-A MoM and gestational age (GA) at delivery in PE were assessed. The screening performance determined by area under receiver operating characteristic curves (AUC) and detection rates (DRs) at a 10% fixed false positive rate (FPR), for preterm and term PE was determined. All risks for preterm and term PE were based on the FMF competing risk model and Bayes theorem. Differences in AUC (ΔAUC) between different biomarker combinations were compared using the Delong test. McNemar's test was used to assess the off-diagonal change in screening performance at a fixed 10% FPR after adding inhibin-A or replacing PlGF in the preterm PE adjusted risk estimation model. RESULTS: Inhibin-A levels in unaffected pregnancies were significantly dependent on GA, maternal age and weight and were lower in parous women with no previous history of PE. Mean log10 inhibin-A MoM in any-onset PE (p<0.001), preterm (p<0.001) and term PE (p = 0.015) pregnancies were all significantly higher than that of unaffected pregnancies. Log10 inhibin-A MoM was inversely but not significantly correlated (p = 0.165) with GA at delivery in PE pregnancies. Replacing PlGF with inhibin-A in the FMF triple test reduced AUC and DR from 0.859 and 64.86% to 0.837 and 54.05%, the ΔAUC was not statistically significant. AUC and DR when adding inhibin-A to the FMF triple test were 0.814, 54.05% and the -0.045 reduction in AUC was statistically significant (p = 0.001). At a fixed 10% FPR, replacing PlGF with inhibin-A identified 1 (2.7%) additional pregnancy but missed 5 (13.5%) pregnancies which subsequently developed preterm PE identified by the FMF triple test. Adding inhibin-A missed 4 (10.8%) pregnancies and did not identify any additional pregnancies with preterm PE. CONCLUSION: Replacing PlGF by inhibin-A or adding inhibin-A as an additional biomarker in and to the FMF triple screening test for preterm PE does not improve screening performance and will fail to identify pregnancies that are currently identified by the FMF triple test.

Biomarkers at 6 weeks' gestation in the prediction of early miscarriage in pregnancy following assisted reproductive technology.

INTRODUCTION: Miscarriage is a major concern in early pregnancy among women having conceived with assisted reproductive treatments. This study aimed to examine potential miscarriage-related biophysical and biochemical markers at 6 weeks' gestation among women with confirmed clinical pregnancy following in vitro fertilization (IVF)/embryo transfer (ET) and evaluate the performance of a model combining maternal factors, biophysical and biochemical markers at 6 weeks' gestation in the prediction of first trimester miscarriage among singleton pregnancies following IVF/ET. MATERIAL AND METHODS: A prospective cohort study was conducted in a teaching hospital between December 2017 and January 2020 including women who conceived through IVF/ET. Maternal mean arterial pressure, ultrasound markers including mean gestational sac diameter, fetal heart activity, crown rump length and mean uterine artery pulsatility index (mUTPI) and biochemical biomarkers including maternal serum soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), kisspeptin and glycodelin-A were measured at 6 weeks' gestation. Logistic regression analysis was carried out to determine significant predictors of miscarriage prior to 13 weeks' gestation and performance of screening was estimated by receiver-operating characteristics curve analysis. RESULTS: Among 169 included pregnancies, 145 (85.8%) pregnancies progressed to beyond 13 weeks' gestation and had live births whereas 24 (14.2%) pregnancies resulted in a miscarriage during the first trimester. In the miscarriage group, compared to the live birth group, maternal age, body mass index, and mean arterial pressure were significantly increased; mean gestational sac diameter, crown rump length, mUTPI, serum sFlt-1, glycodelin-A, and the rate of positive fetal heart activity were significantly decreased, while no significant differences were detected in PlGF and kisspeptin. Significant prediction for miscarriage before 13 weeks' gestation was provided by maternal age, fetal heart activity, mUTPI, and serum glycodelin-A. The combination of maternal age, ultrasound (fetal heart activity and mUTPI), and biochemical (glycodelin-A) markers achieved the highest area under the curve (AUC: 0.918, 95% CI 0.866-0.955), with estimated detection rates of 54.2% and 70.8% for miscarriage before 13 weeks' gestation, at fixed false positive rates of 5% and 10%, respectively. CONCLUSIONS: A combination of maternal age, fetal heart activity, mUTPI, and serum glycodelin-A at 6 weeks' gestation could effectively identify IVF/ET pregnancies at risk of first trimester miscarriage.

A point-of care urine test to predict preeclampsia development in Asian women with suspected preeclampsia.

OBJECTIVES: To evaluate the diagnostic performance and clinical utility of the urine Congo red dot test (CRDT) in predicting preeclampsia (PE) within 7 days, 14 days and 28 days of assessment. STUDY DESIGN: A prospective single center double blind non-intervention study conducted from January 2020 to March 2022. Urine congophilia has been proposed as a point-of-care test for the prediction and rapid identification of PE. In our study, urine CRDT and pregnancy outcomes were assessed in women presenting with clinical features of suspected PE after 20 weeks of gestation. RESULTS: Among the 216 women analyzed, 78 (36.1 %) women developed PE, in which only 7 (9.0 %) of them had a positive urine CRDT test. The median (IQR) interval between the initial test and the diagnosis of PE was significantly shorter for women with a positive urine CRDT compared with women with a negative urine CRDT (1 day (0-5 days) vs 8 days (1-19 days), P = 0.027). The negative predictive value of a negative urine CRDT test for PE within 7 days, 14 days and 28 days of assessment were 83.73 % (95 %CI 81.75 %- 85.54 %), 78.92 % (95 % confidence interval [CI] 77.07 %- 80.71 %) and 71.77 % (95 %CI 70.06 %- 73.42 %) respectively. The sensitivity of the urine CRDT in ruling in PE within 7 days, 14 days and 28 days of assessment were 17.07 % (95 %CI 7.15 %- 32.06 %), 13.73 % (95 %CI 5.70 %- 26.26 %) and 10.61 % (95 %CI 4.37 %- 20.64 %), respectively. CONCLUSIONS: Urine CRDT alone has high specificity yet low sensitivity in the short-term prediction of PE in women with suspected PE. Further studies are required to evaluate its clinical utility.

Effectiveness of Interactive Digital Decision Aids in Prenatal Screening Decision-making: Systematic Review and Meta-analysis.

BACKGROUND: Increasing prenatal screening options and limited consultation time have made it difficult for pregnant women to participate in shared decision-making. Interactive digital decision aids (IDDAs) could integrate interactive technology into health care to a facilitate higher-quality decision-making process. OBJECTIVE: The objective of this study was to assess the effectiveness of IDDAs on pregnant women's decision-making regarding prenatal screening. METHODS: We searched Cochrane Central Register of Controlled Trials, MEDLINE, Embase, PsycINFO, World Health Organization International Clinical Trials Registry Platform, Google Scholar, and reference lists of included studies until August 2021. We included the randomized controlled trials (RCTs) that compared the use of IDDAs (fulfilling basic criteria of International Patient Decision Aid Standards Collaboration and these were interactive and digital) as an adjunct to standard care with standard care alone and involved pregnant women themselves in prenatal screening decision-making. Data on primary outcomes, that is, knowledge and decisional conflict, and secondary outcomes were extracted, and meta-analyses were conducted based on standardized mean differences (SMDs). Subgroup analysis based on knowledge was performed. The Cochrane risk-of-bias tool was used for risk-of-bias assessment. RESULTS: Eight RCTs were identified from 10,283 references, of which 7 were included in quantitative synthesis. Analyses showed that IDDAs increased knowledge (SMD 0.58, 95% CI 0.26-0.90) and decreased decisional conflict (SMD -0.15, 95% CI -0.25 to -0.05). Substantial heterogeneity in knowledge was identified, which could not be completely resolved through subgroup analysis. CONCLUSIONS: IDDAs can improve certain aspects of decision-making in prenatal screening among pregnant women, but the results require cautious interpretation.

Genome-Wide Cell-Free DNA Test for Fetal Chromosomal Abnormalities and Variants: Unrestricted Versus Restricted Reporting.

This study aimed to compare the screening performance of genome-wide cfDNA testing for chromosomal abnormalities between two periods where additional findings were reported and not reported. Data were obtained from consecutive pregnant women with a singleton pregnancy at ≥10 weeks who requested cfDNA testing during 2015-2019. The performance of screening of the cfDNA test was determined by calculating the concordance rate, detection rate, and false-positive rate. Data from 3981 women were included. The no-result rates were similar between the two reporting periods (2.04% vs. 2.08%). Concordance rates for trisomy 21 and 18 were 100% and 100%, respectively. There were two cases tested high risk for trisomy 13, with a concordance rate of 0%. In total, 12 cases were high risk for any sex chromosome aneuploidy with an overall concordance of 75%, and 15 cases tested high risk for any rare autosomal trisomy, with a 13.3% concordance rate. The detection rates for trisomy 21 and 18 were 100% and 100%, respectively. For any SCA, the detection rate was 90%. For the two reporting periods, the combined false-positive rates were 0.93% and 0.17%, which were significantly different (p = 0.002). Restricting the reporting of additional findings from genome-wide cfDNA analysis has reduced the false-positive rate but without a reduction in the no-result rate.

First Trimester Screening for Gestational Diabetes Mellitus with Maternal Factors and Biomarkers.

INTRODUCTION: This study aimed to identify risk factors among maternal characteristics, obstetric history, and first trimester preeclampsia-specific biomarkers that were associated with subsequent development of gestational diabetes mellitus (GDM) and evaluate the performance of the prediction models. METHODS: This study was a secondary analysis of a prospective cohort study. The performance of the prediction models was assessed by area under the receiver operating characteristic curve (AUROC). RESULTS: A total of 837 (8.9%) cases of GDM and 8,535 (91.1%) unaffected cases were included. The AUROC of the prediction model combining maternal characteristics and obstetric history (0.735) was better than that of the model utilizing maternal characteristics (AUROC 0.708) and preeclampsia-specific biomarkers (AUROC 0.566). Among the preeclampsia-specific biomarkers, the mean arterial pressure (MAP) contributed to the increasing risk of GDM; however, its addition did not improve the AUROC of the model combining maternal characteristics and obstetric history (0.738). CONCLUSION: The first trimester prediction model for GDM with maternal characteristics and obstetric history achieves moderate predictability. The inclusion of MAP in the model combining maternal characteristics and obstetric history does not improve the screening performance for GDM. Future studies are needed to explore the effect of blood pressure control from early pregnancy on preventing GDM.

Iron deficiency anaemia associated with increased placenta praevia and placental abruption: a retrospective case-control study.

BACKGROUND/OBJECTIVES: A few studies reported association between placenta praevia (PP) and placental abruption (PA) with maternal iron deficiency anaemia (IDA), which is not an established risk factor for these conditions. This retrospective case-control study was performed to determine the relationship between IDA with PP and PA. METHODS: Maternal characteristics, risk factors for and incidence of antepartum haemorrhage overall, and PP and PA, were compared between women with IDA only and controls without IDA or haemoglobinopathies matched for exact age and parity (four controls to each index case), who carried singleton pregnancy to ≥22 weeks and managed under our care from 1997 to 2019. RESULTS: There were 1,176 women (0.8% of eligible women in the database) with IDA only, who exhibited slightly but significantly different maternal characteristics, and increased antepartum haemorrhage overall (3.4% versus 2.2%, p = 0.031, OR 1.522, 95% CI 1.037-2.234) and PP (1.8% versus 0.9%, p = 0.010, OR 1.953, 95% CI 1.164-3.279), but not PA (1.2% versus 1.1%, p = 0.804, OR 1.077, 95% CI 0.599-1.936). When stratified by parity status, increased PP was found in nulliparous women only. On multivariate analysis adjusting for parity, previous abortion history, overweight and obesity, short stature, other antenatal complications as a composite factor, preterm (<37) delivery, previous caesarean delivery, and infant gender, IDA was associated with PP (aOR 3.485, 95% CI 1.959-6.200) and PA (aOR 2.181, 95% CI 1.145-4.155). CONCLUSIONS: Both PP and PA are increased in women with IDA, the prevention of which could be a means to reduce the occurrence of both PP and PA.

Parity status and the relationship between antenatal rubella serology with obstetric outcome.

Routine antenatal rubella serological testing is adopted in many countries. In a population covered by universal childhood rubella immunization for four decades, we have observed an association between pre-eclampsia with maternal rubella seronegativity among multiparous gravidae. This retrospective cohort study was further performed to elucidate the interaction between parity status and rubella seronegativity on obstetric outcome in singleton pregnancies carried to ≥ 24 weeks gestation managed from 1997 to 2019, with the data retrieved from a computerized database used for annual statistics and auditing. Of the 133,926 singleton pregnancies eligible for the study, the 13,320 (9.9%) rubella seronegative gravidae had higher mean booking weight and body mass index (BMI), but shorter height, and higher incidence of advanced age (≥ 35 years), high BMI, short stature, and lower incidence of nulliparas. Univariate analysis showed that adverse obstetric outcomes were more frequently found among the multiparas. On multivariate analysis, there was increased postdated (> 41 weeks) pregnancy irrespective of parity status, while nulliparas had reduced gestational hypertension (aRR 0.714, 95% CI 0.567-0.899) and gestational diabetes (aRR 0.850, 95% CI 0.762-0.950), and multiparas had increased pre-eclampsia (aRR 1.261, 95% CI 1.005-1.582), neonatal death (aRR 2.796, 95% CI 1.243-6.291), and perinatal death (aRR 2.123, 95% CI 1.257-3.587). In conclusion, in a population covered by universal childhood rubella immunization, antenatal rubella seronegativity is associated with increased pre-eclampsia and perinatal loss only in multiparas, suggesting that the rubella seronegativity in these women served as proxy for some form of altered immune response which increases adverse pregnancy outcome.

Iron Deficiency Anaemia and Atonic Postpartum Haemorrhage Following Labour.

The purpose of this retrospective cohort study is to determine if iron deficiency anaemia (IDA) is associated with increased atonic postpartum haemorrhage (PPH) following labour. Women with singleton pregnancy carried to 24 or more weeks gestation, who were delivered under our care from 1997 to 2019, constituted the study population. A diagnosis of IDA was based on the finding of haemoglobin <10 g/dL and serum ferritin <15 µg/L in the absence of haemoglobinopathies. Women with elective caesarean section were excluded. Maternal characteristics, use of oxytocin, labour outcome and occurrence of PPH were compared between women with and without a diagnosis of IDA. The 1032 women (0.86%) with IDA exhibited slightly but significantly different maternal characteristics and had significantly higher incidence of total (4.5% versus 3.2%, p = 0.024) and atonic PPH (3.1% versus 2.0%, p = 0.011) despite similar incidences of labour induction, augmentation, and instrumental and intrapartum caesarean delivery. Multivariate analysis with adjustment for the effects of age, body mass index, height, parity, abortion history, labour induction and augmentation, instrumental delivery and infant macrosomia demonstrated that IDA was independently associated with total PPH (adjusted relative risk, aRR: 1.455, 95% confidence ratio, CI: 1.040-2.034) and atonic PPH (aRR: 1.588, 95% CI: 1.067-2.364). Our results indicate that despite the low prevalence in our population, IDA was independently associated with atonic PPH, probably consequent to placental adaptive changes in the presence of IDA. The correction and prevention of IDA could be the most important measure in countering the rising global prevalence of atonic PPH.

Prelabor short-term variability in fetal heart rate by computerized cardiotocogram and maternal fetal doppler indices for the prediction of labor outcomes.

OBJECTIVES: To investigate (i) the association between pre-labor maternal-fetal Dopplers and fetal heart rate short-term variability (FHR STV) with arterial cord blood pH and (ii) the potential value of pre-labor maternal-fetal Dopplers, FHR STV and Dawes-Redman criteria in predicting composite neonatal morbidity at term in a cohort of unselected women. METHOD: A prospective study in 218 women with term singleton pregnancy in latent phase of labor or due to undergo induction of labor. Data on maternal characteristics, maternal-fetal Dopplers indices and computerized cardiotocography (CTG) findings of FHR STV and Dawes-Redman criteria were collected. Pearson correlation analysis was used to determine the relationship between maternal-fetal Dopplers and FHR STV and arterial cord blood pH. Logistic regression analysis was used to determine which factors amongst maternal characteristics, labor onset, indication of labor induction, estimated fetal weight (EFW), maternal-fetal Dopplers, FHR STV and Dawes-Redman criteria were significant predictors of composite neonatal morbidity and arterial cord blood pH less than 7.2. RESULT: Of the 218 cases, 12 (5.5%) women were delivered by emergency operative delivery for pathological CTG, and 42 babies (19.3%) had composite neonatal morbidities. Arterial cord blood pH was not associated with maternal-fetal Doppler indices and FHR STV, but rather it was associated with maternal age and body mass index. The composite neonatal morbidity and arterial cord blood pH less than 7.2 were not significantly associated with maternal characteristics, labor onset, indication of labor induction, pre-labor assessment of EFW, maternal-fetal Doppler indices, FHR STV and Dawes-Redman criteria by computerized CTG. CONCLUSION: In unselected women in latent phase of labor or undergoing induction of labor at term, admission maternal-fetal Doppler indices, FHR STV and Dawes-Redman criteria are not predictive of composite neonatal morbidity.

First trimester preeclampsia screening and prediction.

Preeclampsia is a major cause of maternal and perinatal morbidity and mortality. Early-onset disease requiring preterm delivery is associated with a higher risk of complications in both mothers and babies. Evidence suggests that the administration of low-dose aspirin initiated before 16 weeks' gestation significantly reduces the rate of preterm preeclampsia. Therefore, it is important to identify pregnant women at risk of developing preeclampsia during the first trimester of pregnancy, thus allowing timely therapeutic intervention. Several professional organizations such as the American College of Obstetricians and Gynecologists (ACOG) and National Institute for Health and Care Excellence (NICE) have proposed screening for preeclampsia based on maternal risk factors. The approach recommended by ACOG and NICE essentially treats each risk factor as a separate screening test with additive detection rate and screen-positive rate. Evidence has shown that preeclampsia screening based on the NICE and ACOG approach has suboptimal performance, as the NICE recommendation only achieves detection rates of 41% and 34%, with a 10% false-positive rate, for preterm and term preeclampsia, respectively. Screening based on the 2013 ACOG recommendation can only achieve detection rates of 5% and 2% for preterm and term preeclampsia, respectively, with a 0.2% false-positive rate. Various first trimester prediction models have been developed. Most of them have not undergone or failed external validation. However, it is worthy of note that the Fetal Medicine Foundation (FMF) first trimester prediction model (namely the triple test), which consists of a combination of maternal factors and measurements of mean arterial pressure, uterine artery pulsatility index, and serum placental growth factor, has undergone successful internal and external validation. The FMF triple test has detection rates of 90% and 75% for the prediction of early and preterm preeclampsia, respectively, with a 10% false-positive rate. Such performance of screening is superior to that of the traditional method by maternal risk factors alone. The use of the FMF prediction model, followed by the administration of low-dose aspirin, has been shown to reduce the rate of preterm preeclampsia by 62%. The number needed to screen to prevent 1 case of preterm preeclampsia by the FMF triple test is 250. The key to maintaining optimal screening performance is to establish standardized protocols for biomarker measurements and regular biomarker quality assessment, as inaccurate measurement can affect screening performance. Tools frequently used to assess quality control include the cumulative sum and target plot. Cumulative sum is a sensitive method to detect small shifts over time, and point of shift can be easily identified. Target plot is a tool to evaluate deviation from the expected multiple of median and the expected median of standard deviation. Target plot is easy to interpret and visualize. However, it is insensitive to detecting small deviations. Adherence to well-defined protocols for the measurements of mean arterial pressure, uterine artery pulsatility index, and placental growth factor is required. This article summarizes the existing literature on the different methods, recommendations by professional organizations, quality assessment of different components of risk assessment, and clinical implementation of the first trimester screening for preeclampsia.

Prospective Evaluation of International Prediction of Pregnancy Complications Collaborative Network Models for Prediction of Preeclampsia: Role of Serum sFlt-1 at 11-13 Weeks' Gestation.

The study aimed to investigate whether serum sFlt-1 (soluble fms-like tyrosine kinase-1) at 11-13 weeks' gestation in pregnancies that subsequently developed preeclampsia was different from those without preeclampsia and compare screening performance of the International Prediction of Pregnancy Complications (IPPIC) reported models, which include various combinations of maternal factors, systolic blood pressure, diastolic blood pressure, PlGF (placental growth factor) and sFlt-1 and the competing risk (CR) models, which include various combinations of maternal factors, mean arterial pressure (MAP) and PlGF for predicting any-onset, early-onset, and late-onset preeclampsia. This was a prospective multicenter study in 7877 singleton pregnancies. The differences of the predictive performance between the IPPIC and CR models were compared. There were 141 women (1.79%) who developed preeclampsia, including 13 cases (0.17%) of early-onset preeclampsia and 128 cases (1.62%) of late-onset preeclampsia. In pregnancies that developed preeclampsia compared to unaffected pregnancies, median serum sFlt-1 levels and its MoMs were not significantly different (p>0.05). There was no significant association between gestational age at delivery and log10 sFlt-1 and log10 sFlt-1 MoM (p>0.05). The areas under the curve of CR models were significantly higher than the IPPIC models for the prediction of any-onset and late-onset preeclampsia but not for early-onset preeclampsia. In conclusion, there are no significant differences in the maternal serum sFlt-1 levels at 11-13 weeks' gestation between women who subsequently develop preeclampsia and those who do not. Moreover, the CR models for the prediction of any-onset and late-onset preeclampsia perform better than the IPPIC reported model.

Assessment of embryo morphology following perinatal exposure to aspirin, ibuprofen and paracetamol using whole embryo culture system.

BACKGROUND: Recent evidence from a meta-analysis indicates that maternal prenatal exposure, single or repeated, to non-steroidal anti-inflammatory drugs (NSAIDs) or non-opioid painkillers, is associated with increased risk of cerebral palsy and cognitive-behavioral disorders in offspring. One potential route of action is interference with the neurulation process and hence early brain development. OBJECTIVE: To examine the effect of prenatal exposure to common NSAIDs and non-opioid drugs on neurulation using an in vitro whole embryo culture system. METHODS: Mouse embryos from in-bred Institute of Cancer Research albino strain mice were exteriorized on embryonic day 7.5 and cultured for 48 h in either 1 mL heat-inactivated rat serum + 0.1% dimethyl sulfoxide ("Control") or 1 mL of rat serum supplemented with six increasing concentrations of laboratory-grade aspirin, paracetamol, and ibuprofen ("Experimental"). After culture, embryo morphological and developmental parameters were documented using standardized scoring systems at each dosage concentration. The assessed concentration in rat serum culture ranged from 1.23 to 13.57 mg/mL for aspirin and 0.06-4.93 mg/mL for paracetamol and ibuprofen. The equivalent respective human dosages were 600-6600 mg and 30-2400 mg. RESULTS: Between-group comparisons ("Control" vs "Experimental") and post-hoc pair-wise tests, adjusted for multiple comparisons, indicating no statistically significant effect on crown-rump length (p > .21), head length (p > .28), somite number (p > .25), incidence of absent hindlimb buds (p > .18), yolk sac circulation score (p > .07) and posterior neuropore closure (p > .35) in the aspirin, paracetamol and ibuprofen experiments. All embryos had forelimb buds, closed anterior neuropores and none had neural tube defects. CONCLUSION: This study has demonstrated that there are no safety concerns regarding high-dose aspirin, ibuprofen, and paracetamol on mice's embryonic development.

Hyoscine butylbromide in pain reduction associated with ultrasound-guided manual vacuum aspiration: a randomized placebo-controlled trial.

RESEARCH QUESTION: What is the effect of adding an anti-spasmodic drug to an existing ultrasound-guided manual vacuum aspiration (USG-MVA) protocol to alleviate immediate post-procedure abdominal cramping pain in women treated for early pregnancy loss? DESIGN: Double-blind, placebo-controlled, randomized controlled trial conducted between February 2018 and January 2020. Participants were assigned to receive a 1-ml intravenous injection containing 20-mg hyoscine butylbromide (HBB) (n=55) or saline (n =56) as a control immediately before USG-MVA. Primary outcome was reduced abdominal pain after adding a 20-mg dose of HBB to the current pain control regimen. Secondary outcomes were vaginal pain, complications and side-effects, women's pre- and post-procedure psychological state, physiological stress (saliva alpha-amylase) and procedure pain control satisfaction. Two-way mixed ANOVA was used to evaluate the main effects and interactions. RESULTS: VAS abdominal pain scores in the HBB group were 16% lower immediately after and 21% lower 2 h after surgery (not statistically significant). Two-way ANOVA indicated that time (F[1108] = 83.41, P < 0.001) was the only significant main effect for reduced abdominal pain after the procedure and vaginal pain score (F[1108] = 180.1, P < 0.0001) but not drug received. No adverse events were reported. No significant difference was found for psychological state, physiological stress and procedure pain control satisfaction between the two groups. CONCLUSIONS: Anti-spasmodic drugs can help to reduce abdominal cramping pain associated with USG-MVA; HBB produced an insignificant decrease in abdominal pain score. Further studies with longer acting or larger doses of anti-spasmodic drugs are warranted.