Incidence and first trimester risk factors of stillbirth in Indonesia.

OBJECTIVES: To determine the incidence and the risk factors of stillbirth from maternal biophysical, ultrasound, and biochemical markers at 11-13 weeks of gestation in the Indonesian population. METHODS: This was a retrospective cohort study of pregnant women for first-trimester preeclampsia screening at 11-13 weeks of gestation in some clinics and hospital in Jakarta. Maternal characteristics and history, mean arterial pressure (MAP) measurement, uterine artery pulsatility index (UtA-PI) ultrasound, maternal ophthalmic peak ratio (Oph-PR) Doppler, and placental growth factor (PlGF) serum were collected during the visit. Stillbirth was classified into placental dysfunction-related when it occurred with preeclampsia or birth weight <10th percentile and non-placental dysfunction-related. Bivariate and multivariate logistic regression analyses were employed to determine the risk factors associated with stillbirth. RESULTS: Of 1,643 eligible participants, 13 (0.79 %) stillbirth cases were reported. More than half of the stillbirths (7) were placental dysfunction-related. After adjusted with maternal age, body mass index (BMI), and parity status, chronic hypertension (aOR (adjusted odds ratio)) 24.41, 95 % CI {confidence interval} 5.93-100.43), previous pregnancy with preeclampsia (aOR 15.79, 95 % CI 4.42-56.41), MAP >101.85 (aOR 26.67, 95 % CI 8.26-86.06), UtA-PI >1.90 (aOR 10.68, 95 % CI 2.34-48.58, and PlGF <28.77 pg/mL (aOR 18.60, 95 % CI 5.59-61.92) were associated with stillbirth. CONCLUSIONS: The incidence of stillbirth in the population is comparable to studies conducted in developed countries. Most routine variables assessed at the 11-13 weeks combined screening for preeclampsia are associated with the risk of stillbirth.

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 screening performance of first-trimester prediction models for preterm preeclampsia in an Asian population.

BACKGROUND: The administration of aspirin <16 weeks gestation to women who are at high risk for preeclampsia has been shown to reduce the rate of preterm preeclampsia by 65%. The traditional approach to identify such women who are at risk is based on risk factors from maternal characteristics, obstetrics, and medical history as recommended by the American College of Obstetricians and Gynecologists and the National Institute for Health and Care Excellence. An alternative approach to screening for preeclampsia has been developed by the Fetal Medicine Foundation. This approach allows the estimation of patient-specific risks of preeclampsia that requires delivery before a specified gestational age with the use of Bayes theorem-based model. OBJECTIVE: The purpose of this study was to examine the diagnostic accuracy of the Fetal Medicine Foundation Bayes theorem-based model, the American College of Obstetricians and Gynecologists, and the National Institute for Health and Care Excellence recommendations for the prediction of preterm preeclampsia at 11-13+6 weeks gestation in a large Asian population STUDY DESIGN: This was a prospective, nonintervention, multicenter study in 10,935 singleton pregnancies at 11-13+6 weeks gestation in 11 recruiting centers across 7 regions in Asia between December 2016 and June 2018. Maternal characteristics and medical, obstetric, and drug history were recorded. Mean arterial pressure and uterine artery pulsatility indices were measured according to standardized protocols. Maternal serum placental growth factor concentrations were measured by automated analyzers. The measured values of mean arterial pressure, uterine artery pulsatility index, and placental growth factor were converted into multiples of the median. The Fetal Medicine Foundation Bayes theorem-based model was used for the calculation of patient-specific risk of preeclampsia at <37 weeks gestation (preterm preeclampsia) and at any gestation (all preeclampsia) in each participant. The performance of screening for preterm preeclampsia and all preeclampsia by a combination of maternal factors, mean arterial pressure, uterine artery pulsatility index, and placental growth factor (triple test) was evaluated with the adjustment of aspirin use. We examined the predictive performance of the model by the use of receiver operating characteristic curve and calibration by measurements of calibration slope and calibration in the large. The detection rate of screening by the Fetal Medicine Foundation Bayes theorem-based model was compared with the model that was derived from the application of American College of Obstetricians and Gynecologists and National Institute for Health and Care Excellence recommendations. RESULTS: There were 224 women (2.05%) who experienced preeclampsia, which included 73 cases (0.67%) of preterm preeclampsia. In pregnancies with preterm preeclampsia, the mean multiples of the median values of mean arterial pressure and uterine artery pulsatility index were significantly higher (mean arterial pressure, 1.099 vs 1.008 [P<.001]; uterine artery pulsatility index, 1.188 vs 1.063[P=.006]), and the mean placental growth factor multiples of the median was significantly lower (0.760 vs 1.100 [P<.001]) than in women without preeclampsia. The Fetal Medicine Foundation triple test achieved detection rates of 48.2%, 64.0%, 71.8%, and 75.8% at 5%, 10%, 15%, and 20% fixed false-positive rates, respectively, for the prediction of preterm preeclampsia. These were comparable with those of previously published data from the Fetal Medicine Foundation study. Screening that used the American College of Obstetricians and Gynecologists recommendations achieved detection rate of 54.6% at 20.4% false-positive rate. The detection rate with the use of National Institute for Health and Care Excellence guideline was 26.3% at 5.5% false-positive rate. CONCLUSION: Based on a large number of women, this study has demonstrated that the Fetal Medicine Foundation Bayes theorem-based model is effective in the prediction of preterm preeclampsia in an Asian population and that this method of screening is superior to the approach recommended by American College of Obstetricians and Gynecologists and the National Institute for Health and Care Excellence. We have also shown that the Fetal Medicine Foundation prediction model can be implemented as part of routine prenatal care through the use of the existing infrastructure of routine prenatal care.

The prognostic role of various indices and ratios of Doppler velocimetry in patients with pre-eclampsia.

Doppler velocimetry is a non-invasive method to monitor pregnancies complicated by pre-eclampsia. We aimed to assess the predictive value of adverse perinatal or maternal outcome of three ratios, i.e. middle cerebral to umbilical arteries pulsatility indices (PI), middle cerebral to uterine arteries PI and uterine to umbilical arteries PI, compared with that of uterine and umbilical arteries PI in pre-eclamptic patients. This is a cohort study on 168 singleton pregnancies between January 2010 and June 2013. Doppler velocimetry was performed at the diagnosis of pre-eclampsia. Logistic regression analysis was performed and receiver-operating characteristics (ROC) curves were calculated to determine the predictive ability of each Doppler index. Multivariate analysis was run to adjust results for confounding parameters. Seventy-eight cases were complicated by adverse perinatal outcome, 79 by maternal one, 49 by both. Considering perinatal outcome, area under ROC curve was 0.730 for uterine arteries PI, 0.691 for umbilical artery PI and 0.834 for middle cerebral to uterine arteries PI ratio, while for maternal one 0.720 for uterine arteries PI, 0.686 for umbilical artery PI and 0.817 for middle cerebral to uterine arteries PI ratio. At multivariate analysis, only middle cerebral to uterine arteries PI ratio remain statistically significant for both outcomes (p = 0.001). The cited ratio appeared more accurate than all other considered indices in predicting perinatal and maternal outcomes in patients affected by pre-eclampsia.

The multiple reference range of mean uterine artery pulsatility index for natural and in vitro fertilization singletons during 11-14 gestational weeks.

Background: Ultrasonography of the uterine artery (UtA) in the first and second trimesters of pregnancy can assess uterine-placental blood perfusion and guide early clinical prevention. Establishing normal ranges of the UtA pulsatility index (UtA-PI) at 11-14 weeks of pregnancy is helpful for the early identification of high-risk pregnant women and improving the prognosis. This study aimed to establish a reference range of UtA-PI based on crown-rump length (CRL) for spontaneous and in vitro fertilization (IVF) singleton pregnancy during 11-14 weeks, respectively. Methods: A prospective study was performed at Peking Union Medical College Hospital. Healthy, low-risk women with a singleton pregnancy at 11-14 gestational weeks were consecutively recruited for this study from December 2017 to December 2020. All participants underwent routine prenatal ultrasound examination. The CRL of the fetus and the UtA-PI were measured in both uterine arteries, and average values were calculated. The LMS method was used to fit the percentile (P)5, P10, P25, P50, P75, P90, and P95 curves of the UtA-PI value of spontaneous and IVF singleton pregnancy with CRL changes, respectively. Results: A total of 1,962 pregnant women with normal fetuses were included in this study, including 1,792 pregnancies conceived naturally and 170 IVF fetuses. The UtA-PI reference range in the spontaneous pregnancy group was consistently higher than that in the IVF group during 11-14 weeks, and showed a statistically significant difference in UtA-PI for spontaneous and IVF pregnancies (P<0.001). According to the LMS method, each percentile curve of UtA-PI decreased with the increase of CRL in both the natural pregnancy group and the IVF group. The P95 range of UtA-PI for pregnant women with naturally conceived and IVF pregnancy was 2.74 to 2.11 and 2.50 to 1.94, respectively. The overall change of UtA-PI differentials of the two groups showed a downward trend and decreased slightly with the increase of CRL. Conclusions: This study provided a single-center, large sample of data and constructed a CRL-based reference value of UtA-PI for spontaneous and IVF singleton pregnancy, which provides a reliable basis for early UtA evaluation and early clinical decision-making during 11-14 gestational weeks.

Chinese traditional herbs enhanced the clinical efficacy of low-molecular-weight heparin in the treatment of recurrent spontaneous abortion complicated with thrombophilia.

Thrombophilia is an important cause of recurrent spontaneous abortion (RSA). The treatment of thrombophilia is beneficial to the prevention of RSA. Therefore, we explored the clinical effect of Chinese traditional herbs with the effects of invigorating the blood, tonifying the kidney and calming the fetus in the treatment of RSA complicated with thrombophilia. We retrospectively analyzed the clinical outcomes of 190 RSA patients combined with thrombophilia using different treatment methods. The traditional Chinese medicine group was treated with kidney-invigorating, blood-activating and fetus-soothing herbs and the western medicine group was treated with low molecular weight heparin (LMWH), and the traditional Chinese medicine combined with western medicine group was treated with LMWH plus Chinese traditional herbs with the effects of kidney tonifying, blood activating and fetus stabilizing. After treatments, platelet aggregation rate, plasma D-dimer and uterine artery blood flow resistance were significantly reduced in the LMWH plus herbs compared to the simple herbs and LMWH group (P < 0.0167). The LMWH plus herbs group significantly accelerated the growth of fetal bud compared with other groups (P < 0.0167). Moreover, the LMWH plus herbs group improved traditional Chinese medicine syndrome scores (P < 0.0167), showing a better clinical efficacy. Adverse reactions occurred in five patients in the LMWH group but not in the simple herbs and LMWH plus herbs group during the treatment period. Therefore, our study shows that for the treatment of RSA complicated with thrombophilia, Chinese traditional herbs plus LMWH can improve the blood supply of the uterus during pregnancy and contribute to a favorable environment for the growth of the fetus. Chinese traditional herbs exert a good curative effect with few adverse reactions.

Endometriosis and Impaired Placentation: A Prospective Cohort Study Comparing Uterine Arteries Doppler Pulsatility Index in Pregnancies of Patients with and without Moderate-Severe Disease.

The aim of this study was to evaluate if moderate-severe endometriosis impairs uterine arteries pulsatility index (UtA-PI) during pregnancy when compared to unaffected controls. In this prospective cohort study, pregnant women with stage III-IV endometriosis according to the revised American Fertility Society (r-AFS) classification were matched for body mass index and parity in a 1:2 ratio with unaffected controls. UtA-PIs were assessed at 11-14, 19-22 and 26-34 weeks of gestation following major reference guidelines. A General Linear Model (GLM) was implemented to evaluate the association between endometriosis and UtA-PI Z-scores. Significantly higher third trimester UtA-PI Z-scores were observed in patients with r-AFS stage III-IV endometriosis when compared to controls (p = 0.024). In the GLM, endometriosis (p = 0.026) and maternal age (p = 0.007) were associated with increased third trimester UtA-PI Z-scores, whereas conception by in-vitro fertilization with frozen-thawed embryo transfer significantly decreased UtA-PI measures (p = 0.011). According to these results, r-AFS stage III-IV endometriosis is associated with a clinically measurable impaired late placental perfusion. Closer follow-up may be recommended in pregnant patients affected by moderate-severe endometriosis in order to attempt prediction and prevention of adverse pregnancy and perinatal outcomes due to a defective late placental perfusion.

First trimester biomarkers for prediction of gestational diabetes mellitus.

PURPOSE: To develop a first trimester prediction model for gestational diabetes mellitus (GDM) using obesity, placental, and inflammatory biomarkers. METHODS: We used a first trimester dataset of the ASPRE study to evaluate clinical and biochemical biomarkers. All biomarkers levels (except insulin) were transformed to gestational week-specific medians (MoMs), adjusted for maternal body mass index (BMI), maternal age, and parity. The MoM values of each biomarker in the GDM and normal groups were compared and used for the development of a prediction model assessed by area under the curve (AUC). RESULTS: The study included 185 normal and 20 GDM cases. In the GDM group, compared to the normal group BMI and insulin (P = 0.003) were higher (both P < 0.003). The MoM values of uterine artery pulsatility index (UtA-PI) and soluble (s)CD163 were higher (both P < 0.01) while pregnancy associated plasma protein A (PAPP-A), placental protein 13 (PP13), and tumor-necrosis factor alpha (TNFα) were lower (all P < 0.005). There was no significant difference between the groups in placental growth factor, interleukin 6, leptin, peptide YY, or soluble mannose receptor (sMR/CD206). In screening for GDM in obese women the combination of high BMI, insulin, sCD163, and TNFα yielded an AUC of 0.95, with detection rate of 89% at 10% false positive rate (FPR). In non-obese women, the combination of sCD163, TNFα, PP13 and PAPP-A yielded an AUC of 0.94 with detection rate of 83% at 10% FPR. CONCLUSION: A new model for first trimester prediction of the risk to develop GDM was developed that warrants further validation.