The impact of intrahepatic cholestasis on pregnancy outcomes: a retrospective cohort study.

BACKGROUND: This study analyzed the pregnancy outcomes of patients with intrahepatic cholestasis of pregnancy (ICP) in Hangzhou, China. METHODS: Cases of pregnant women monitored by antepartum testing at Hangzhou Women's Hospital from January 2018 to December 2020 were reviewed. Subjects were classified into two groups according to whether they had ICP: 688 cases of ICP were assigned to an exposure group while 38,556 cases of non-ICP were assigned to a non-exposed group. Univariate analysis was performed on qualitative or quantitative data using the Chi-Squared test or Mann-Whitney U test, and the adjusted odds ratio (aOR) and 95% confidence interval (CI) of the two groups of related variables were calculated by multivariate binary logistic regression analysis. RESULTS: The incidence rate of ICP was 1.75%. Pregnant women with hepatitis B virus were correlated with ICP. Hepatitis B carriers (aOR = 3.873), preeclampsia (PE, aOR = 3.712), thrombocytopenia (aOR = 1.992), gestational hypertension (GH, aOR = 1.627), hyperlipidemia (aOR = 1.602) and gestational diabetes mellitus (GDM, aOR = 1.265) were all risk factors for ICP. In contrast, Body Mass Index (BMI) ≥ 30 kg/m2 (aOR = 0.446), 25 m2 < maternal BMI < 29.9 kg/m2 (aOR = 0.699) and parity ≥ 1 (aOR = 0.722) were protective factors for ICP. Pregnant women in the ICP group had an increased risk of gestation days < 259 days (aOR = 4.574) and cesarean delivery (aOR = 1.930) after ICP, and a decreased risk of longer gestational days (aOR = 0.105), premature rupture of membranes (aOR = 0.384) and fetal macrosomia (aOR = 0.551). CONCLUSIONS: By analyzing a Chinese population with ICP, we identified that pregnant women who are hepatitis B carriers or with PE, thrombocytopenia, GH, hyperlipidemia, and GDM are at higher risk of ICP. Moreover, ICP is associated with adverse pregnancy outcomes; in particular, ICP may increase the incidence of shorter gestational days and non-vaginal delivery methods such as cesarean section but reduce the incidence of premature rupture of membranes and fetal macrosomia.

Correlation between elevated maternal serum alpha-fetoprotein and ischemic placental disease: a retrospective cohort study.

BACKGROUND: To evaluate the correlation between elevated maternal serum alpha-fetoprotein (AFP) in the second trimester and ischemic placental disease (IPD). METHODS: A retrospective cohort study was conducted to analyze the data of 22,574 pregnant women who delivered in the Department of Obstetrics at Hangzhou Women's Hospital from 2018 to 2020, and were screened for maternal serum AFP and free beta-human chorionic gonadotropin (free ß-hCG) in the second trimester. The pregnant women were divided into two groups: elevated maternal serum AFP group (n = 334, 1.48%); and normal group (n = 22,240, 98.52%). Mann-Whitney U-test or Chi-square test was used for continuous or categorical data. Modified Poisson regression analysis was used to calculate the relative risk (RR) and 95% confidence interval (CI) of the two groups. RESULTS: The AFP MoM and free ß-hCG MoM in the elevated maternal serum AFP group were higher than the normal group (2.25 vs. 0.98, 1.38 vs. 1.04) and the differences were all statistically significant (all P < .001). Placenta previa, hepatitis B virus carrying status of pregnant women, premature rupture of membranes (PROM), advanced maternal age (≥35 years), increased free ß-hCG MoM, female infants, and low birth weight (RR: 2.722, 2.247, 1.769, 1.766, 1.272, 0.624, 2.554 respectively) were the risk factors for adverse maternal pregnancy outcomes in the elevated maternal serum AFP group. CONCLUSIONS: Maternal serum AFP levels during the second trimester can monitor IPD, such as IUGR, PROM, and placenta previa. Maternal women with high serum AFP levels are more likely to deliver male fetuses and low birth weight infants. Finally, the maternal age (≥35 years) and hepatitis B carriers also increased maternal serum AFP significantly.

External Quality Assessment of Maternal Serum Levels of Alpha-Fetoprotein, Free Beta-Human Chorionic Gonadotropin, and Unconjugated Estriol in Detecting Down Syndrome and Neural Tube Defects in the Second Trimester of 87 Maternal Serum Samples, Based on 105-139 Days.

BACKGROUND We aimed to insure the accuracy and reproducibility of alpha-fetoprotein (AFP), free beta-human chorionic gonadotropin (free ß-hCG), and unconjugated estriol (uE3) concentrations for the screening for trisomy 21 (T21) and neural tube defects (NTD) in the second trimester. We conducted an external quality assessment of 6 laboratories, using maternal serum specimens. MATERIAL AND METHODS Serum specimens collected from 87 women of singleton pregnancies (4 with T21, 5 with NTD, and 78 with normal fetuses) were divided into 6 equivalent-volume fractions and transported to 6 laboratories (A, B, C, D, E, and F). All laboratories used the time-resolved fluorescence analyzer and supporting reagents to measure concentrations of AFP, free ß-hCG, and uE3. The screening efficacies of T21 and NTD were compared with the certified or accredited status of the participants' quality systems. RESULTS Concentrations of AFP measured by laboratory F were low compared with those determined by the other 5 laboratories, and the differences were significant (P<0.01). There was no statistically significant difference in the free ß-hCG and uE3 concentrations measured by the 6 laboratories (P>0.05). The correlation coefficients for the 3 multiples of the median values were all >0.900. The McNemar paired chi-squared test showed the differences in the positivity and detection rates were not statistically significant (P=1.000). CONCLUSIONS AFP, free ß-hCG, and uE3 values measured by the other 5 laboratories were comparable with those of laboratory A, with good linear correlation. When used in the maternal prenatal screening of T21 and NTD, the test results met the clinical requirements.

A retrospective cohort study on the effects of Down's screening markers and maternal characteristics on pregnancy outcomes in preeclampsia.

BACKGROUND: To investigate the effects of down's screening markers and maternal characteristics on preeclampsia (PE) pregnancy outcome during early and middle pregnancy. METHODS: A retrospective study of a cohort of 246 PE and 18,709 No-PE pregnant women who participated in Down's screening during early and middle pregnancy was performed. Clinical data of pregnancy-related were collected. Multivariate binary logistic regression was used to analyze the adjusted odds ratio (aOR) and 95% confidence interval (CI) of Down's screening markers, maternal characteristics, pregnancy outcome, and other related variables, and to evaluate the influencing factors of each indicator on PE. P < .05 was considered to be statistically significant. RESULTS: Compared with the non-PE group, the concentration and median multiple (MoM) of pregnancy-associated plasma protein-A (PAPP-A) and free beta subunit of human chorionic gonadotropin (free ß-hCG) in PE group were both lower (P < .001). Multivariate binary logistic regression analysis showed that low birth weight, hydronephrosis, premature delivery, fetal growth retardation, cesarean section, live birth, hyperlipemia, infection, decreased free ß-hCG and first trimester maternal weight were risk factors for PE (aOR were: 7.552, 6.684, 4.154, 3.762, 3.612, 2.454, 1.757, 1.562, 1.270, and 1.077, respectively), while uterine scar, premature rupture of membranes and elevated PAPP-A were protective factors of PE (aOR were: 0.222, 0.328 and 0.612, respectively). CONCLUSION: Decreased maternal serum PAPP-A level, increased free ß-hCG, hyperlipemia, premature delivery, cesarean section, live birth, hydronephrosis, fetal growth retardation, low birth weight, and infection are risk factors for PE, while uterine scar and premature rupture of membrane are protective factors for PE.

Correlations between maternal hepatitis B virus carrier status and Down's syndrome prenatal screening indicators and their effects on the screening results.

The aim of this study was to determine the correlation between maternal hepatitis B virus (HBV) carrier status and pregnancy-associated serum screening indicators, as well as their implications on the prenatal screening results of Down's syndrome (DS). This retrospective cohort study included two groups, namely the healthy gravidas group (n = 19804) and the maternal HBV carrier group (n = 792). Serum pregnancy-associated plasma protein A (PAPP-A), alpha-fetoprotein (AFP), and free beta subunit of human chorionic gonadotropin (free ß-hCG) levels, as well as the foetal nuchal translucency (NT) thickness, were measured. Multivariatebinary logistic regression analysis was used to evaluate the association between the HBV carrier status and prenatal screening biomarkers. The PAPP-A multiple of the medium (MoM) and free ß-hCG MoM in the first trimester were significantly higher in the HBV carrier group than in the control group (both P < .05). Multivariate binary logistic regression analysis showed that HBV carrier status was identified as a risk factor for PAPP-A and the intrahepatic cholestasis of pregnancy (ICP), with adjusted odds ratios (aOR) of 1.363 (1.216-1.527) and 3.255 (2.356-4.499), respectively. Pregnant women with HBV carrier status had higher influence on serum PAPP-A level and ICP, and the risk calculation algorithm for DS in HBV carriers should be corrected in the first trimester of pregnancy. IMPACT STATEMENTWhat is already known on this subject? The maternal serum levels of pregnancy-associated plasma protein A (PAPP-A), alpha-fetoprotein (AFP), and free beta subunit of human chorionic gonadotropin (free ß-hCG), as well as the foetal nuchal translucency (NT) thickness, have been collectively used in the prenatal screening of Down's syndrome (DS), Edward's syndrome (ES), and open neural tube defects (ONTD). However, many factors, including the maternal age; maternal weight; gestational age; race; history of smoking and so on can affect those serum biomarker levels. Our aim is to know whether there is a difference for HBV status to pregnancy-associated serum screening indicators hoes.What the results of this study add? The PAPP-A multiple of the medium (MoM) and free ß-hCG MoM in the first trimester were significantly higher in the HBV carrier group than in the control group (both p < .05). Multivariate binary logistic regression analysis showed that the PAPP-A and intrahepatic cholestasis of pregnancy (ICP) were risk factors for HBV carriers, with aORs of 1.363 (1.216-1.527) and 3.255 (2.356-4.499), respectively.What the implications are of these findings for clinical practice and/or further research? The PAPP-A MoM in maternal HBV carriers was significantly higher than that in healthy gravidas, and the risk calculation algorithm for DS in maternal HBV carriers should be corrected in the first trimester of pregnancy.

Correlation and predictive value of serum miR-146b-5p expression during the first trimester of pregnancy with pre-eclampsia.

The aim of this study was to investigate the correlation and predictive value of serum miR-146b-5p expression during the first trimester of pregnancy with pre-eclampsia (PE). In total, 32 normal pregnant women (the control group) and 58 subjects with PE were randomly selected from eligible case data. The serum levels of miR-146b-5p, pregnancy associated plasma protein A (PAPP-A) and free beta subunit of human chorionic gonadotropin (free ß-hCG) were then detected. Next, we established predictive models of single or multiple markers for PE. The levels of miR-146b-5p in the mild pre-eclampsia (mPE) and severe pre-eclampsia (sPE) groups were higher than the control group and there were significant differences between the three groups (F = 3.424, P = 0.037). The statistical results of the model before and after 200 times 10-fold cross-validation were as follows: miR-146b-5p (AUC = 0.723 vs AUC = 0.710); miR-146b-5p + BMI + MAP + free ß-hCG MoM + PAPP-A MoM (AUC = 0.929 vs AUC = 0.851). We found that expression levels of miR-146b-5p in the first trimester were significantly higher in the serum of pregnant women with PE than in the normal pregnancy group. A prediction model in combination with miR-146b-5p and other markers improved the early predictive value for PE.IMPACT STATEMENTWhat is already known on this subject? Pre-eclampsia is a complex systemic disease with hypertension as the main clinical manifestation and causes extensive damage to the body. Some existing maternal biochemical markers have limited value in predicting PE, and new biomarkers with high sensitivity and specificity are urgently needed in clinical practice. There are a variety of abnormal expression miRNAs in PE, however, the relationship between miR-146b-5p and PE has yet to be fully elucidated.What do the results of this study add? We first found that expression levels of serum miR-146b-5p in the first trimester were significantly higher in PE than in a normal pregnancy group. A prediction model a combination of miR-146b-5p and other maternal characteristics and biochemical markers can improve the early predictive value for PE.What are the implications of these findings for clinical practice and/or further research? PE progresses rapidly and has become a severe target organ complication when discovered. Therefore, the early prediction of a high risk of PE, along with early intervention and prevention measures, are of great significance. Compared to maternal biochemical markers, combination of miR-146b-5p and maternal characteristics and biochemical markers can improve the early predictive value for PE.

Second trimester maternal serum D-dimer combined with alpha-fetoprotein and free ß-subunit of human chorionic gonadotropin predict hypertensive disorders of pregnancy: a systematic review and retrospective case-control study.

BACKGROUND: This study investigated whether maternal serum D-dimer (DD) alone or DD combined with alpha-fetoprotein (AFP) and free ß-subunit of human chorionic gonadotropin (free ß-hCG) in the second trimester could be used to predict hypertensive disorders of pregnancy (HDP). MATERIALS AND METHODS: In this retrospective case-control study, the data of gravidas patients who delivered at hospital were divided into the following groups: control (n = 136), gestational hypertension (GH, n = 126), preeclampsia (PE, n = 53), and severe preeclampsia (SPE, n = 41). Receiver operator characteristic (ROC) curves were used to evaluate the diagnostic value of maternal serum DD, AFP, and free ß-hCG levels for HDP. RESULTS: DD levels of the GH, PE, and SPE groups were significantly higher than that of the control group (P < 0.001). The order of effectiveness for models predicting HDP was as follows: DD + AFP + free ß-hCG > DD > DD + AFP > DD + free ß-hCG > AFP + free ß-hCG > AFP > free ß-hCG. For predicting different types of HDP, DD alone had the best diagnostic value for SPE, followed by PE and GH. DD alone had a sensitivity of 100% with a 0% false negative rate and had the highest positive likelihood ratio (+ LR) for SPE. DD alone in combination with AFP alone, free ß-hCG alone and AFP + free ß-hCG could reduce false positive rate and improve + LR. CONCLUSION: DD is possible the best individual predictive marker for predicting HDP. Levels of DD alone in the second trimester were positively correlated with the progression of elevated blood pressure in the third trimester, demonstrating the predicting the occurrence of HDP. The risk calculation model constructed with DD + free ß-hCG + AFP had the greatest diagnostic value for SPE.

Perinatal factors and early neonatal outcomes of abnormal birthweight infants in Hangzhou, China, 2015-2021: a retrospective cohort study.

BACKGROUND: This study aimed to investigate the perinatal factors and early neonatal outcomes of abnormal birth weight (ABW) in Hangzhou, China from 2015 to 2021. METHODS: A retrospective cohort study was designed to analyse the data of 76 847 newborns, in which the case groups included 3042 cases of low birth weight (LBW) and 2941 cases of fetal macrosomia (MAC), and 70 864 cases of normal weight were as the reference group. RESULTS: The incidence of LBW and MAC was 3.96% and 3.83% in Hangzhou, China from 2015 to 2021. Prematurity (<37 weeks), multiple births, hospitalisation >7 days, fetal anomalies, caesarean section, pregnancy complications, maternal coinfection with pathogens and summer births would be correlated with the incidence of LBW (ORs=43.50, 7.60, 2.09, 1.89, 1.57, 1.28, 1.19 and 1.18, all p<0.05). Factors such as post-term pregnancy (>41 weeks), scarred uterus, anterior vaginal incision and gravidity ≥2 were correlated with decreased incidence of LBW, with ORs of 0.05, 0.54, 0.65 and 0.80. Moreover, caesarean delivery, post-term pregnancy (> 41 weeks), parity ≥1, lateral vaginal incision, gravidity ≥2, hospitalisation >7 days, winter births and pregnancy complications also have association with the incidence of MAC (ORs=3.92, 2.73, 2.19, 1.87, 1.22, 1.20, 1.17 and 1.13, all p<0.05) while prematurity (<37 weeks), scarred uterus and anterior vaginal incision have close association with decreased incidence of MAC, with ORs of 0.07, 0.21 and 0.74 (all p<0.05). CONCLUSION: There was a trend of yearly increase in ABW in Hangzhou, China from 2015 to 2021. Several neonatal and maternal-related variables such as caesarean section, pregnancy complications and hospitalisation >7 days are associated with the odds of LBW and MAC, however, factors such as pregnancy with scarred uterus relate to the decrease of ABW. Close monitoring and intervention during pregnancy are essential to reduce the occurrence of ABW.

The prevalence of hypospadias in newborn males in Hangzhou, China from 2011 to 2020: A cross-sectional population-based study.

BACKGROUND: Hypospadias is one of the most common anomalies of the human genitourinary system. The prevalence of hypospadias varies considerably by region, ethnicity, and clinical practice. OBJECTIVE: This research was designed to investigate the prevalence and related influencing factors of neonatal hypospadias in Hangzhou from 2011 to 2020 in order to provide a scientific basis for the clinical prevention and treatment of hypospadias. STUDY DESIGN: This study retrospectively analyzed the Hangzhou Maternal Child Information System and Birth Defect Monitoring System and included data from a total of 1,008,754 pregnant women between October 2010 and September 2020. The chi-square test was adopted to compare the prevalence of hypospadias at different maternal ages and different years. RESULTS: The prevalence of neonatal hypospadias in Hangzhou, China, was 2.89 per 10,000, with a total of 292 newborns diagnosed with hypospadias from 2011 to 2020. The prevalence of hypospadias in Hangzhou showed temporal, regional, and age distribution characteristics: from 1.08/10,000 in 2011 to 7.03/10,000 in 2020; the prevalence was higher in suburban areas than that in the urban area and the counties, with statistically significant differences (P < 0.001); the prevalence of hypospadias was lowest in maternal age < 25 years (1.20/10,000) and highest in maternal age ≥ 40 years old (14.59/10,000). The difference was statistically significant (P < 0.001). The risk factor for hypospadias in the offspring of advanced pregnant women was 3.86 times higher than that of younger pregnant women. CONCLUSIONS: The overall prevalence of neonatal hypospadias in Hangzhou from 2011 to 2020 was 2.89/10,000 and showed temporal, regional, and age distribution characteristics.

Role of microRNAs regulating trophoblast cell function in the pathogenesis of pre­eclampsia (Review).

Pre-eclampsia (PE) is a complicated pregnancy-specific disease and is considered the primary reason for maternal and foetal mortality and morbidity. PE has a multifactorial pathogenesis but the causes of PE remain unclear. The functions of trophoblasts, including differentiation, proliferation, migration, invasion and apoptosis, are essential for successful pregnancy. During the early stages of placental development, trophoblasts are strictly regulated by several molecular pathways; however, an imbalance of these molecular pathways can lead to severe placental lesions and pregnancy complications. Certain microRNAs (miRs) are abnormally expressed in PE, with several miRs involved in the regulation of pregnancy-associated genes. The present review discusses the miRs regulating trophoblast function, how they affect the pathogenesis of PE and evaluating the possibility of miRs in screening, diagnosis and treatment of PE.

The importance of the trisomy 21 local cutoff value evaluation for prenatal screening in the second trimester of pregnancy.

OBJECTIVE: The aim of this work was to compare different local cutoff values (LCV) and inline cutoff values (ICV) in pregnant women in the second trimester at high risk for carrying fetuses with trisomy 21. METHODS: This retrospective cohort study analyzed prenatal screening outcomes in pregnant women (n = 311,561). The receiver operating characteristic curve was used to evaluate the diagnostic significance of the trisomy 21 risk value, alpha-fetoprotein, and free beta human chorionic gonadotropin multiple of the median for predicting trisomy 21 risk. The cutoff value corresponding to the maximal Youden index was taken as the LCV. The screening efficiency of both cutoff values was compared. RESULTS: The LCV cutoff value was lower than the ICV cutoff value (1/643 vs 1/270). The sensitivity increased by 19.80%, the positive predictive value decreased by 0.20%, and the false-positive rate increased by 6.50%. CONCLUSION: The LCV should be used to determine trisomy 21 risk, which can increase the detection rate of trisomy 21 in the second trimester.

Maternal prenatal screening programs that predict trisomy 21, trisomy 18, and neural tube defects in offspring.

OBJECTIVE: To determine the efficacy of three different maternal screening programs (first-trimester screening [FTS], individual second-trimester screening [ISTS], and first- and second-trimester combined screening [FSTCS]) in predicting offspring with trisomy 21, trisomy 18, and neural tube defects (NTDs). METHODS: A retrospective cohort involving 108,118 pregnant women who received prenatal screening tests during the first (9-13+6 weeks) and second trimester (15-20+6 weeks) in Hangzhou, China from January-December 2019, as follows: FTS, 72,096; ISTS, 36,022; and FSTCS, 67,631 gravidas. RESULT: The high and intermediate risk positivity rates for trisomy 21 screening with FSTCS (2.40% and 5.57%) were lower than ISTS (9.02% and 16.14%) and FTS (2.71% and 7.19%); there were statistically significant differences in the positivity rates among the screening programs (all P < 0.05). Detection of trisomy 21 was as follows: ISTS, 68.75%; FSTCS, 63.64%; and FTS, 48.57%. Detection of trisomy 18 was as follows; FTS and FSTCS, 66.67%; and ISTS, 60.00%. There were no statistical differences in the detection rates for trisomy 21 and 18 among the 3 screening programs (all P > 0.05). The positive predictive values (PPVs) for trisomy 21 and 18 were highest with FTS, while the false positive rate (FPR) was lowest with FSTCS. CONCLUSION: FSTCS was superior to FTS and ISTS screening and substantially reduced the number of high risk pregnancies for trisomy 21 and 18; however, FSTCS was not significantly different in detecting fetal trisomy 21 and 18 and other confirmed cases with chromosomal abnormalities.

A Risk Model for Predicting Fetuses with Trisomy 21 Using Alpha-Fetoprotein Variants L2 Combined with Maternal Serum Biomarkers in Early Pregnancy.

To establish a risk prediction model and the clinical value of trisomy 21 using alpha-fetoprotein variants L2 (AFP-L2) combined with maternal serum biomarkers and nuchal translucency (NT) thickness in early pregnancy. A retrospective case-control study was conducted. The subjects were divided into the case group (n = 40) or the control group (n = 40). An enzyme-linked immunosorbent assay was used to measure the maternal serum AFP-L2 level in both groups. The AFP-L2 single-index or multi-index combined risk model was used to predict the efficiency of trisomy 21. The best cut-off value and area under the curve (AUC) were determined to evaluate the predictive efficacy of different risk models constructed by AFP-L2. The maternal serum AFP-L2 level in the case group was 1.59 (0.61-3.61) Multiple of medium (MoM), which was higher than 1.00 (0.39-2.12) MoM in the control group (P < 0.001). The free beta-human chorionic gonadotropin (free ß-hCG) level and NT in the case group were significantly higher than those in the control group (P < 0.001). The pregnancy-associated plasma protein A (PAPP-A) level in the case group was lower than that in the control group (P < 0.001). The AUC of AFP-L2 in predicting trisomy 21 was 0.797. After considering the maternal serum AFP-L2 level, the AUC, detection rate (DR), positive predictive value (PPV), negative predictive value (NPV), falsepositive rate (FPR), false negative rate (FNR), positive likelihood ratio (+LR), and negative likelihood ratio (-LR) were significantly improved. In this study, PAPP-A + free ß-hCG + NT + AFP-L2 and PAPP-A + free ß-hCG + AFP-L2 increased the integrated discrimination improvement (IDI) and net classification improvement (NRI) of predicting fetuses with trisomy 21 (1.10% and 5.27%; 11.07% and 2.78%)  (1.10% and 5.27%; 11.07% and 2.78%), respectively, after considering the maternal serum AFP-L2 level. The maternal serum AFP-L2 level in early pregnancy had high sensitivity and specificity, and it was a good biomarker to predict fetuses with trisomy 21.

Diagnostic value of maternal alpha-fetoprotein variants in second-trimester biochemical screening for trisomy 21 and 18.

To evaluate the clinical predictive value of serum alpha-fetoprotein variants (AFP-L2, AFP-L3) in combination with maternal serum prenatal screening biomarkers in predicting fetal trisomy 21 and trisomy 18. We analyze the data of singleton pregnant women at 15-20+6 weeks of 731,922 gravidas from October 2007 to September 2019. The research objects were separated into the following groups: control (n = 569), trisomy 21 (n = 116), and trisomy 18 (n = 52). The cases were diagnosed by chromosomal karyotypic analysis of amniotic fluid cells. Level of AFP-L2 and AFP-L3 were detected in maternal serum among control women and patients. Receiver operator characteristic analysis, detection rate, false positive rate, false negative rate, positive predictive value, negative predictive value, positive likelihood ratio and negative likelihood ratio, comprehensive discriminant improvement, net weight classification improvement, decision curve analysis and Hosmer-lemeshow (H-L) test were used to investigate the predictive value of free ß-hCG, AFP, AFP-L2 and AFP-L3 on the risk models of trisomy 21, 18. There was a statistically significant difference in maternal serum AFP-L2 and AFP-L3 multiple of the median (MoM) among the trisomy 21, trisomy 18, and control groups. The AUCs of AFP-L2 and AFP-L3 for the screening trisomy 21 and trisomy 18 fetus were 0.785, 0.758 and 0.775, 0.754. According to ROC, the optimal cut-off values of AFP-L2 and AFP-L3 for predicting trisomy 21 and trisomy 18 fetuses all were 1.09 MoM and 1.30 MoM, respectively. The risk-calculation model constructed by AFP-L2 + AFP-L3 MoM manifested better efficiency than the original single-value truncation method using AFP MoM alone. Compared with different modeling methods, the AUC of trisomy 21 fetuses predicted by AFP-L2 + AFP-L3 + free ß-hCG achieved an optimal value (0.938), while the AUC of trisomy 18 fetus predicted by AFP-L2 + free ß-hCG was the best (0.991). Compared with AFP, the IDI of AFP-L2 or AFP-L3 alone increased 9.56% and 12.34%; the NRI increased 26.50% and 26.70 in predicting trisomy 21. For trisomy 18, the IDI of AFP-L2 or AFP-L3 alone declined with 8.12% and 1.52%; the NRI declined with 13.84% and 8.54%. In the combined model, the model with best detection rate, false positive rate and positive likelihood ratio was AFP-L2 + AFP-L3 + free ß-hCG, followed by AFP-L2 + free ß-hCG and AFP-L3 + free ß-hCG, and finally AFP + free ß-hCG. Maternal serum AFP-L2 and AFP-L3 in the second trimester is a good marker for screening trisomy 21 and trisomy18 with high sensitivity and specificity. The combined screening results are better than the single marker, and the efficiency of AFP-L2 + AFP-L3 + free ß-hCG is the best.

Effectiveness of alpha-fetoprotein variants L2 and L3 as substitutes of alpha-fetoprotein in screening for fetal Trisomy 18.

OBJECTIVE: To evaluate the effectiveness of alpha-fetoprotein variants (AFP-L2, AFP-L3) in fetal screening for Trisomy 18 in place of alpha fetoprotein (AFP). METHODS: A retrospective case-control study was conducted. Collectively, 39 pregnant women bearing Trisomy 18 fetuses and 48 pregnant women with clinically normal and healthy fetuses were included. The serum AFP-L2 and AFP-L3 concentrations were detected by enzyme-linked immunosorbent assays. The likelihood ratio method and Python software were used to construct the risk model with AFP, free ß-hCG, AFP-L2, and AFP-L3 to predict Trisomy 18. Receiver operating characteristic (ROC) curves were used to determine the optimal cutoff value, while the area under the curve (AUC) was used to assess the screening performance of AFP-L2 and AFP-L3 for fetal Trisomy 18. RESULTS: Compared to values observed for the control group, AFP-L2 and AFP-L3 concentrations which were significantly higher (both p< .001) in pregnant women with Trisomy 18 fetuses were 7.95 ± 3.57 ng/mL and 2.53 ± 1.80 ng/mL, respectively. Comparisons across multiple modeling methods showed that the highest AUC of screened Trisomy 18 fetuses (0.992, 0.986, and 0.976) was yielded by AFP-L2 + AFP-L3 + free ß-hCG, AFP-L2 + free ß-hCG, and AFP-L3 + free ß-hCG, with a sensitivity of 1.000 indicated in both instances. In different modeling methods, the order of AUC values was AFP-L2 + AFP-L3 + free ß-hCG > AFP-L2 + free ß-hCG > AFP-L3 + free ß-hCG > AFP + free ß-hCG. CONCLUSIONS: AFP-L2 and AFP-L3 showed higher sensitivity and specificity as substitutes for AFP in screening Trisomy 18. These two markers indeed improved the screening efficiency and reduced the false positive rate, when compared with AFP only.

Predicting Hypertensive Disease in the First Trimester of Pregnancy: Risk Models and Analysis of Serum D-dimer Levels Combined with Plasma Pregnancy-Associated Protein A, Free ß-Subunit of Human Chorionic Gonadotropin, and Fetal Nuchal Translucency.

We aimed to investigate the predictive ability of serum levels of D-dimer (DD) in the first trimester for the occurrence of hypertensive disorders of pregnancy (HDP). In this retrospective, case-cohort study, we measured the levels of DD, plasma pregnancy-associated protein A (PAPP-A), and free ß-subunit of human chorionic gonadotropin (free ß-hCG) and analyzed fetal nuchal translucency (NT) in 150 healthy gravidas, 126 cases of gestational hypertension (GH), 53 cases of preeclampsia (PE), and 41 cases with severe preeclampsia (SPE). Likelihood ratio models and risk models were built using single markers (DD, PAPP-A, free ß-hCG, and NT) and combinations of those markers. Analyses showed that the levels of DD multiple of the median (MoM) in the GH, PE, and SPE groups were all significantly higher than those in the control group, with significant differences between groups (χ 2 = 70.325, P < 0.001). The area under curve (AUCs) for DD in the GH, PE, and SPE groups was 0.699, 0.784, and 0.893, respectively; the positive likelihood ratio (+LR) was 1.534, 1.804, and 2.941, respectively; and the negative likelihood ratio (-LR) was 0.022, 0.081, and 0, respectively. When the cut-off values of DD for the GH, PE, and SPE groups were 0.725, 0.815, and 0.945 MoM, respectively, the corresponding sensitivities were 0.992, 0.962, and 1.000, respectively. As gestational hypertension progressed, the levels of DD tended to increase gradually. The maternal serum level of DD in the first trimester had correlative and diagnostic value for HDP. The sensitivity and specificity of maternal serum levels of DD level in the first trimester for different types of HDP were significantly different; the best sensitivity and specificity were detected in the SPE group. First trimester DD level, combined with other biochemical markers, may improve our ability to diagnose HDP.

A risk model that combines MAP, PlGF, and PAPP-A in the first trimester of pregnancy to predict hypertensive disorders of pregnancy.

Whether the first trimester maternal mean arterial pressure (MAP), placental growth factor (PlGF), and pregnancy-associated plasma protein A (PAPP-A) can predict hypertensive disorders of pregnancy (HDP) is unclear. We conducted a retrospective case-control study with the total population of 539 gravidas, of these 447 had normal pregnancy, 27 had gestational hypertension (GH), 36 had preeclampsia (PE), and 29 had preeclampsia with severe features (SPE). Prediction for HDP was determined by the area under curve (AUC). Compared to the healthy group, the multiple of the median (MoM) for MAP was increased in the study groups, while PlGF and PAPP-A were decreased. When the cutoff values for MAP, PlGF, and PAPP-A were 1.069, 0.769, and 0.673 MoM, respectively, the sensitivities for predicting HDP were 0.517, 0.446, and 0.500 and the specificities were 0.744, 0.826, and 0.769, respectively. To predict GH, the highest AUC was 0.755 (95% CI: 0.655-0.856, p < 0.001) based on MAP, PlGF, and PAPP-A. The combined PlGF and PAPP-A had the highest AUC (0.683 [95% CI: 0.584-0.782, p < 0.001] and 0.755 [95% CI: 0.682-0.829, p < 0.001]) for prediction of PE and SPE. We found that MAP, serum levels of PlGF, and PAPP-A in the first trimester pregnancy are markers that predict HDP in the third trimester. The combination of markers is far superior to single markers alone. To improve the diagnostic value, specific cutoff values should be applied to GH, PE, SPE in each condition.

Construction and predictive value of risk models of maternal serum alpha-fetoprotein variants and fetal open neural tube defects.

The correlation of maternal serum alpha-fetoprotein (AFP) variants (AFP-L2, AFP-L3), free beta-human chorionic gonadotropin (free ß-hCG), and open neural tube defects (ONTDs) during the second trimester, and the screening efficiency of different risk models remain indistinct. We conducted a retrospective case-control study, and studied 57 pregnant women with ONTD fetuses and 569 pregnant women with normal fetuses. The receiver operating characteristic curve method indicated the best cutoff value and area under the curve (AUC). The predictive value of ONTD risk models by free ß-hCG, AFP, AFP-L2, and AFP-L3 was investigated via integrated discrimination improvement (IDI), net reclassification improvement (NRI), and decision curve analysis (DCA). Compared to the control group, AFP, AFP-L2, and AFP-L3 levels were significantly higher, while free ß-hCG level was significantly lower in the study group. The triple-index model of free ß-hCG + AFP-L2 + AFP-L3 and the dual-index model of AFP-L2 + AFP-L3 showed the best predictive values, respectively (AUC = 0.905; AUC = 0.885). The order of the single-index model AUCs was AFP-L3 > AFP-L2 > AFP > free ß-hCG. The negative predictive value, false positive rate, and negative likelihood ratio of AFP-L2, AFP-L3 alone, or combined with free ß- hCG were better than those of AFP alone; however, the positive likelihood ratio was the opposite. The replacement of AFP by AFP-L2 or AFP-L3 combined with free ß-hCG increased the IDI and NRI for predicting ONTD. The top five DCAs were AFP-L2 + free ß-hCG, free ß-hCG, AFP-L3, AFP + free ß-hCG, and AFP. Indicators of maternal serum free ß-hCG, AFP-L2, and AFP-L3 in the second trimester exhibited high sensitivity and specificity screening for ONTD fetuses. Risk models constructed using AFP-L2 + AFP-L3 and AFP-L2 + AFP-L3 + free ß-hCG demonstrated better screening efficiency.