BACKGROUND: To longitudinally and cross-sectionally study the differences in the uterine artery pulsatility index (UTPI), umbilical artery pulsatility index (UAPI) and placental vascularization indices (PVIs, derived from 3-dimensional power Doppler) between normal and placental insufficiency pregnancies throughout gestation.
METHODS: UTPI, UAPI and PVI were measured 6 times at 4- to 5- week intervals from 11 to 13+6 weeks-36 weeks. Preeclampsia (PE) and fetal growth restriction (FGR) were defined as placental insufficiency. Comparisons of UTPI, UAPI and PVI between normal and insufficiency groups were performed by one-way repeated measures analysis of variance.
RESULTS: A total of 125 women were included: monitored regularly from the first trimester to 36 weeks of gestation: 109 with normal pregnancies and 16 with placental insufficiency. Longitudinal study of the normal pregnancy group showed that UTPI and UAPI decreased significantly every 4 weeks, while PVIs increased significantly every 8 weeks until term. In the placental insufficiency group however, this decrease occurred slower at 8 weeks intervals and UTPI stabilized after 24 weeks. No significant difference was noted in PVIs throughout pregnancy. Cross-sectional study from different stages of gestation showed that UTPI was higher in the insufficiency group from 15 weeks onward and PVIs were lower after 32 weeks.
CONCLUSIONS: Compared to high-risk pregnancies with normal outcome, UTPI and UAPI needed a longer time to reach a significant change in those with clinical confirmation of placental insufficiency pregnancies and no significant change was found in PVI throughout gestation. UTPI was the earliest factor in detecting adverse outcome pregnancies.

OBJECTIVE: To investigate the effect of low-molecular-weight heparin (LMWH) on placenta-mediated fetal growth restriction (FGR).
METHODS: A cohort of 570 pregnant women diagnosed with placenta-mediated FGR were enrolled from January 1, 2015 through to December 31, 2021. A birth database, including demographic data, antenatal complications, and detailed delivery and newborn data, was created to collect variables from the Hospital Information System (HIS) Database. The unique personal registration number, assigned to each patient on first registration with HIS in the West China Second University Hospital, was used to link these patients. LMWH use was defined as at least 1-week prescription from diagnosis of placenta-mediated FGR. Pregnant women received LMWH (Enoxaparin 4000 IU/day) by self-administered subcutaneous injection only when they agreed and signed informed consent. Primary outcome was intrauterine fetal death after 20 weeks of pregnancy. Secondary outcomes included preterm birth (PB), Apgar score less than 7 at 1 min, admission to neonatal intensive care unit (NICU), and birth weight. Logistic regression analysis was conducted to compute adjusted odds ratio (aOR) with 95% confidence intervals (CI) for outcomes.
RESULTS: After controlling for confounders, LMWH use was associated with a decreased risk of intrauterine fetal death (aOR 2.49, 95% CI 1.35-4.57, P = 0.003), PB before 37 weeks of pregnancy (aOR 3.35, 95% CI 2.14-5.23, P < 0.001), PB before 34 weeks of pregnancy (aOR 2.25, 95% CI 1.36-3.74, P = 0.002), Apgar score less than 7 at 1 min (aOR 2.25, 95% CI 1.36-3.74, P = 0.002), NICU admission (aOR 2.29, 95% CI 1.48-3.55, P < 0.001). Using LMWH increased the mean birth weight in PB before 32 weeks of pregnancy (mean ± standard deviation [SD] 1126.4 ± 520.0 g, P = 0.020), PB before 37 weeks of pregnancy (mean ± SD 1563.9 ± 502.7 g, P = 0.019), early-onset FGR (mean ± SD 2125.2 ± 665.7 g, P < 0.001), late-onset FGR (mean ± SD 2343.4 ± 507.9, P < 0.001), and non-severe FGR (mean ± SD 2231.1 ± 607.2 g, P < 0.001).
CONCLUSIONS: Use of LMWH can significantly improve the fetal and neonatal outcomes among pregnant women with placenta-mediated FGR, particularly reducing the risk of intrauterine fetal death.

Epidemiological and animal experimental studies suggest an association between gestational cholestasis and intrauterine growth restriction (IUGR). Here, we explored the mechanism through which gestational cholestasis induced IUGR. To establish gestational cholestasis model, pregnant mice were subcutaneously injected with 17α-Ethynylestradiol (E2) on gestational day 13 (GD13)-GD17. Some pregnant mice were intraperitoneally injected with 4μ8C on GD13-GD17. The results found that the apoptosis of trophoblast cells was elevated in placentas of mice with gestational cholestasis and in deoxycholic acid (DCA)-treated human trophoblast cell lines and primary mouse trophoblast cells. Correspondingly, the levels of placental cleaved caspase-3 and Bax were increased, while placental Bcl2 level was decreased in mice with gestational cholestasis and in DCA-treated trophoblast cells. Further analysis found that placental IRE1α pathway was activated in mice with gestational cholestasis and in DCA-treated trophoblast cells. Interestingly, 4μ8C, an IRE1α RNase inhibitor, significantly inhibited caspase-3 activity and apoptosis of trophoblast cells in vivo and in vitro. Importantly, 4μ8C rescued gestational cholestasis-induced placental insufficiency and IUGR. Furthermore, a case-control study demonstrated that placental IRE1α and caspase-3 pathways were activated in cholestasis cases. Our results provide evidence that gestational cholestasis induces placental insufficiency and IUGR may be via triggering IRE1α-mediated apoptosis of placental trophoblast cells.

BACKGROUND: Intrauterine growth restriction (IUGR) is defined as a fetus that fails to achieve its genetically determined growth potential. The exact molecular mechanisms of placental insufficiency IUGR pathogenesis are a little known. Our goal was to identify key genes and gene co-expression modules related to placental insufficiency IUGR.
METHODS: We used weighted gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) network analysis to examine the IUGR dataset GSE114691 from NCBI Gene Expression Omnibus. Core modules and hub nodes of the protein-protein interaction network were identified. A gene network was constructed and genes were classified by WGCNA into different modules. The validation of potential key genes was carried out using additional datasets (GSE12216 and GSE24129).
RESULTS: We identified in GSE114691 539 down regulated genes and 751 up regulated genes in placental tissues characteristic of placental insufficiency IUGR compared with non-IUGR, and defined 76 genes as hub nodes in the protein-protein interaction network. Genes in the key modules of the WGCNA network were most closely associated with placental insufficiency IUGR and significantly enriched in biological process such as cellular metabolic process and macromolecule metabolic process. We identified as key genes TGFB1, LEP, ENG, ITGA5, STAT5A, LYN, GATA3, FPR1, TGFB2, CEBPB, KLF4, FLT1, and PNPLA2. The RNA expression levels of ENG and LEP, as biomarkers, were validated.
CONCLUSIONS: A holistic gene expression profile of placental insufficiency IUGR has been generated and the key genes ENG and LEP has potential to serve as circulating diagnosis biomarkers and therapeutic targets for placental insufficiency IUGR.

BACKGROUND: The effect and extent of abnormal placental perfusion (APP) on the risk of male hypospadias are poorly understood. We compared the prevalence of male hypospadias in the offspring of women with APP and quantify the extent of the APP effect on the anomaly.
METHODS: A hospital-based retrospective analysis of births from 2012 to 2016 was conducted in 2018. Women of singleton pregnancy and male infants born to them were included (N = 21,447). A multivariate analysis was performed to compare the prevalence of male hypospadias in infants exposed to APP with those that were not exposed to APP.
RESULTS: Compared with the infants of women without APP, infants of women with APP showed an increased risk of male hypospadias (odds ratio, 2.40; 95% confidence interval, 1.09-5.29). The male hypospadias cumulative risk increased with the severity of APP. Infants exposed to severe APP had a significantly higher risk of male hypospadias than those without APP exposure (9.2 versus 1.7 per 1000 infants, P < 0.001). A path analysis indicated that 28.18-46.61% of the risk of hypospadias may be attributed to the effect of APP.
CONCLUSIONS: Male hypospadias risk was associated with APP and increased with APP severity, as measured in the second trimester. APP had an important role in the development of the anomaly.

Preeclampsia is defined as hypertension arising after 20 weeks of gestational age with proteinuria or other signs of end-organ damage and is an important cause of maternal and perinatal morbidity and mortality, particularly when of early onset. Although a significant amount of research has been dedicated in identifying preventive measures for preeclampsia, the incidence of the condition has been relatively unchanged in the last decades. This could be attributed to the fact that the underlying pathophysiology of preeclampsia is not entirely understood. There is increasing evidence suggesting that suboptimal trophoblastic invasion leads to an imbalance of angiogenic and antiangiogenic proteins, ultimately causing widespread inflammation and endothelial damage, increased platelet aggregation, and thrombotic events with placental infarcts. Aspirin at doses below 300 mg selectively and irreversibly inactivates the cyclooxygenase-1 enzyme, suppressing the production of prostaglandins and thromboxane and inhibiting inflammation and platelet aggregation. Such an effect has led to the hypothesis that aspirin could be useful for preventing preeclampsia. The first possible link between the use of aspirin and the prevention of preeclampsia was suggested by a case report published in 1978, followed by the first randomized controlled trial published in 1985. Since then, numerous randomized trials have been published, reporting the safety of the use of aspirin in pregnancy and the inconsistent effects of aspirin on the rates of preeclampsia. These inconsistencies, however, can be largely explained by a high degree of heterogeneity regarding the selection of trial participants, baseline risk of the included women, dosage of aspirin, gestational age of prophylaxis initiation, and preeclampsia definition. An individual patient data meta-analysis has indicated a modest 10% reduction in preeclampsia rates with the use of aspirin, but later meta-analyses of aggregate data have revealed a dose-response effect of aspirin on preeclampsia rates, which is maximized when the medication is initiated before 16 weeks of gestational age. Recently, the Aspirin for Evidence-Based Preeclampsia Prevention trial has revealed that aspirin at a daily dosage of 150 mg, initiated before 16 weeks of gestational age, and given at night to a high-risk population, identified by a combined first trimester screening test, reduces the incidence of preterm preeclampsia by 62%. A secondary analysis of the Aspirin for Evidence-Based Preeclampsia Prevention trial data also indicated a reduction in the length of stay in the neonatal intensive care unit by 68% compared with placebo, mainly because of a reduction in births before 32 weeks of gestational age with preeclampsia. The beneficial effect of aspirin has been found to be similar in subgroups according to different maternal characteristics, except for the presence of chronic hypertension, where no beneficial effect is evident. In addition, the effect size of aspirin has been found to be more pronounced in women with good compliance to treatment. In general, randomized trials are underpowered to investigate the treatment effect of aspirin on the rates of other placental-associated adverse outcomes such as fetal growth restriction and stillbirth. This article summarizes the evidence around aspirin for the prevention of preeclampsia and its complications.

Several epidemiological studies suggest an association between vitamin D deficiency (VDD) and fetal intrauterine growth restriction (IUGR). Here, we explored the mechanism through which VDD induced fetal IUGR. Pregnant mice were fed with VDD diet to establish VDD model. Cyp27b1+/- mice were generated to develop a model of active vitamin D3 deficiency. Cyp27b1+/- mice were injected with either 1α,25(OH)2D3 or vehicle once a day throughout pregnancy. As expected, fetal weight and crown-rump length were reduced in VDD diet-fed mice. Correspondingly, fetal weight and crown-rump length were lower in cyp27b1+/- mice. 1α,25(OH)2D3 elevated fetal weight and crown-rump length, and protected cyp27b1+/- mice from fetal IUGR. Further analysis found that placental proliferation was inhibited and placental weight was decreased in VDD diet-fed mice. Several growth factors and nutrient transfer pumps were downregulated in the placentas of VDD diet-fed mice. Mechanistically, several inflammatory cytokines were upregulated and placental NF-κB was activated not only in VDD diet-fed mice but also in VDD pregnant women. Interestingly, 1α,25(OH)2D3 inhibited the downregulated of placental nutrient transfer pumps and the upregulated of placental inflammatory cytokines in Cyp27b1+/- mice. These results provide experimental evidence that gestational VDD causes placental insufficiency and fetal IUGR may be through inducing placental inflammation.

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.

Parous women have a lower risk for pregnancy complications, such as preeclampsia or delivery of small-for-gestational-age neonates. However, parous women are a heterogeneous group of patients because they contain a low-risk cohort with previously uncomplicated pregnancies and a high-risk cohort with previous pregnancies complicated by preeclampsia and/or small for gestational age. Previous studies examining the effect of parity on maternal hemodynamics, including cardiac output and peripheral vascular resistance, did not distinguish between parous women with and without a history of preeclampsia or small for gestational age and reported contradictory results.
The objective of the study was to compare maternal hemodynamics in nulliparous women and in parous women with and without previous preeclampsia and/or small for gestational age.
This was a prospective, longitudinal study of maternal hemodynamics, assessed by a bioreactance method, measured at 11+0 to 13+6, 19+0 to 24+0, 30+0 to 34+0, and 35+0 to 37+0 weeks\' gestation in 3 groups of women. Group 1 was composed of parous women without a history of preeclampsia and/or small for gestational age (n = 632), group 2 was composed of nulliparous women (n = 829), and group 3 was composed of parous women with a history of preeclampsia and/or small for gestational age (n = 113). A multilevel linear mixed-effects model was performed to compare the repeated measures of hemodynamic variables controlling for maternal characteristics, medical history, and development of preeclampsia or small for gestational age in the current pregnancy.
In groups 1 and 2, cardiac output increased with gestational age to a peak at 32 weeks and peripheral vascular resistance showed a reversed pattern with its nadir at 32 weeks; in group 1, compared with group 2, there was better cardiac adaptation, reflected in higher cardiac output and lower peripheral vascular resistance. In group 3 there was a hyperdynamic profile of higher cardiac output and lower peripheral vascular resistance at the first trimester followed by an earlier sharp decline of cardiac output and increase of peripheral vascular resistance from midgestation. The incidence of preeclampsia and small for gestational age was highest in group 3 and lowest in group 1.
There are parity-specific differences in maternal cardiac adaptation in pregnancy.

OBJECTIVE: Aspirin has been shown to prevent preeclampsia. But the mechanisms remain unclear despite that improved placental circulation is considered as an underlying contributor. Our aim was to examine the hypoxia-related morphological and histopathological placental measures in relation to aspirin use during pregnancy.
METHODS: We used the Collaborative Perinatal Project (CPP) data, which is a cohort study conducted in the U.S. from 1959 to 1976. A total of 23, 604 women who had information on placental pathology and aspirin intake during pregnancy were included in the analysis. Among them, 1474 women had a history of hypertension or preeclampsia/eclampsia and were classified as a high-risk population; the rest were considered as a low-risk population. 47 placenta measures considered to be relevant to hypoxia were selected to build a composite hypoxia- related placenta index. The generalized linear mixed model was used to fit the relationship between aspirin and placental pathology.
METHODS: Hypoxia-related placental pathology.
RESULTS: Aspirin use during pregnancy was associated with a reduced risk of hypoxia-related placental pathology in the high-risk population [the adjusted odds ratio and 95% confidence interval in the 1st, 2nd, and 3rd trimesters: 0.55 (0.31, 1.00), 0.76 (0.49, 1.17), and 0.53 (0.29, 0.94), respectively]. Longer duration of aspirin use in pregnancy tended to have a lower risk of hypoxia-related placental pathologies in the high-risk population.
CONCLUSIONS: Aspirin use during pregnancy reduced risks of hypoxia-related placental pathologies in the high-risk women for preeclampsia. The duration of aspirin use determined its effects.