Bridging the Gaps between Aspirin Guidelines and PregnancyOutcomes

IntroductionEarly pregnancy care involves the screening and identification of women with risk factors for adverse pregnancy outcomes, including stillbirth or preterm birth, to tailor pregnancy care and interventions accordingly. Most...

Pregnancies complicated by late-onset fetal growth restriction (FGR) are at increased risk of short- and long-term morbidities. Despite this, identification of cases at higher risk of adverse perinatal outcome, at the time of FGR diagnosis, is challenging. The aims of this study were to elucidate the strength of association between fetoplacental Doppler indices at the time of diagnosis of late-onset FGR and adverse perinatal outcome, and to determine their predictive accuracy. This was a prospective study of consecutive singleton pregnancies complicated by late-onset FGR. Late-onset FGR was defined as estimated fetal weight (EFW) or abdominal circumference (AC) < 3rd centile, or EFW or AC < 10th centile and umbilical artery (UA) pulsatility index (PI) > 95th centile or cerebroplacental ratio (CPR) < 5th centile, diagnosed after 32 weeks. EFW, uterine artery PI, UA-PI, fetal middle cerebral artery (MCA) PI, CPR and umbilical vein blood flow normalized for fetal abdominal circumference (UVBF/AC) were recorded at the time of the diagnosis of FGR. Doppler variables were expressed as Z-scores for gestational age. Composite adverse perinatal outcome was defined as the occurrence of at least one of emergency Cesarean section for fetal distress, 5-min Apgar score < 7, umbilical artery pH < 7.10 and neonatal admission to the special care unit. Logistic regression analysis was used to elucidate the strength of association between different ultrasound parameters and composite adverse perinatal outcome, and receiver-operating-characteristics (ROC)-curve analysis was used to determine their predictive accuracy. In total, 243 consecutive singleton pregnancies complicated by late-onset FGR were included. Composite adverse perinatal outcome occurred in 32.5% (95% CI, 26.7-38.8%) of cases. In pregnancies with composite adverse perinatal outcome, compared with those without, mean uterine artery PI Z-score (2.23 ± 1.34 vs 1.88 ± 0.89, P = 0.02) was higher, while Z-scores of UVBF/AC (-1.93 ± 0.88 vs -0.89 ± 0.94, P ≤ 0.0001), MCA-PI (-1.56 ± 0.93 vs -1.22 ± 0.84, P = 0.004) and CPR (-1.89 ± 1.12 vs -1.44 ± 1.02, P = 0.002) were lower. On multivariable logistic regression analysis, Z-scores of mean uterine artery PI (P = 0.04), CPR (P = 0.002) and UVBF/AC (P = 0.001) were associated independently with composite adverse perinatal outcome. UVBF/AC Z-score had an area under the ROC curve (AUC) of 0.723 (95% CI, 0.64-0.80) for composite adverse perinatal outcome, demonstrating better accuracy than that of mean uterine artery PI Z-score (AUC, 0.593; 95% CI, 0.50-0.69) and CPR Z-score (AUC, 0.615; 95% CI, 0.52-0.71). A multiparametric prediction model including Z-scores of MCA-PI, uterine artery PI and UVBF/AC had an AUC of 0.745 (95% CI, 0.66-0.83) for the prediction of composite adverse perinatal outcome. While CPR and uterine artery PI assessed at the time of diagnosis are associated independently with composite adverse perinatal outcome in pregnancies complicated by late-onset FGR, their diagnostic performance for composite adverse perinatal outcome is low. UVBF/AC showed better accuracy for prediction of composite adverse perinatal outcome, although its usefulness in clinical practice as a standalone predictor of adverse pregnancy outcome requires further research. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

In the United States, significant, intractable disparities exist in rates of major pregnancy outcomes between non-Hispanic black and non-Hispanic white women. A previously unexplored candidate influence on the black-white disparity in adverse birth outcomes is maternal vitamin D status. This review summarizes the evidence relating maternal vitamin D to preeclampsia, spontaneous preterm birth, gestational diabetes, and fetal growth restriction, and addresses gaps in our understanding of the contribution of vitamin D to the intractable black-white disparity in these conditions. The literature reviewed highlights strong biologic plausibility of role for vitamin D in the pathophysiology of these poor pregnancy outcomes. Data also suggest that maternal vitamin D deficiency may increase the risk of preeclampsia and fetal growth restriction. Less research has been done in support of relations with spontaneous preterm birth and gestational diabetes, and fetal and infant survival have rarely been studied. Few trials of vitamin D supplementation have been conducted in pregnant women with adequate power to test effects on birth outcomes. Importantly, black pregnant women have rarely been studied in vitamin D-birth outcomes research. Although vitamin D is a promising candidate influence on black-white disparities in preeclampsia, spontaneous preterm birth, fetal growth restriction, and gestational diabetes, these associations require further study in large samples of black US women. Because vitamin D deficiency is widespread and black-white disparities in pregnancy outcomes and infant survival have been resistant to previous interventions, research to test vitamin D as a causal factor is of major public health significance. Obstetricians & Gynecologist, Family Physicians. After completion of this educational activity, the reader will be able to appreciate risk factors for inadequate vitamin D status. Understand the basic aspects of vitamin D metabolism. Become aware of recent literature linking inadequate vitamin D status and adverse pregnancy outcomes such as preeclampsia and preterm birth.

Background: Decreased levels of pregnancy-associated plasma protein-A (PAPP-A) in maternal serum can be a marker not only for some chromosomal disorders and anomalies in the fetus but also specific for adverse pregnancy outcomes too, such as preeclampsia, spontaneous preterm birth, gestational diabetes, and fetal growth restriction (FGR) and to the extent of stillbirth. Hence, measurement of early pregnancy PAPP-A levels may help identify the areas of intervention for reducing the adverse outcome in later gestations. Materials and Methods: This was a prospective observational study. A total of 250 antenatal cases fulfilling the inclusion criteria were taken in the study. Early pregnancy serum levels of PAPP-A were measured for antenatal cases visiting outpatient department of tertiary level teaching hospital between 10 and 14 weeks period of gestation, and these cases were followed up for development of adverse pregnancy outcome. Results: Two hundred and thirty-five patients had normal outcomes, among which 24 patients had PAPP-A values ≤0.4 multiples of the median (MoM) and 211 patients had PAPP-A level >0.4 MoM. Twenty-nine patients out of 250 in our study group had PAPP-A level <0.4 MoM, 1 patient developed preeclampsia (P = 0.211) but underwent normal vaginal delivery at term, and 1 had FGR (P = 0.513). Three patients had preterm delivery and the PAPP-A values in preterm group were lower as compared to term group, and this result was statistically significant (P = 0.005). Conclusion: The study concludes that the patients with low early pregnancy PAPP-A levels may be deemed to develop preterm labor subsequently and effective measures may be taken to prevent the same. However, it would be prudent to replicate the study in a wider and more representative sample over multiple centers to see if the results hold true.

BackgroundTo compare the rates of adverse pregnancy outcomes between women with normal and abnormal inhibin-A levels.MethodsBased on a prospective database of Down syndrome screening program, the consecutive records were comprehensively reviewed. Pregnancies were classified into three groups: normal, high (> 2 MoM) and low (< 0.5 MoM) inhibin-A levels. The pregnancies with medical diseases, chromosome abnormalities and fetal anomalies were excluded. The primary outcomes were the rates of preterm birth, preeclampsia, and fetal growth restriction (FGR).ResultsOf 6679 recruited pregnancies, 5080 met the inclusion criteria, including 4600, 205 and 275 pregnancies in the group of normal, high, and low inhibin-A levels respectively. The rates of preterm birth, preeclampsia and FGR were significantly higher in the group of high levels; (RR, 1.51, 95%CI: 1.01–2.26; 3.47, 95% CI: 2.13–5.65; 3.04, 95% CI: 1.99–4.65 respectively), whereas the rates of other adverse outcomes were comparable. However, the rate of spontaneous preterm birth among women with high inhibin-A was not significantly increased. Based on multivariate analysis, the preterm birth rate was not significantly associated with inhibin-A levels, but it was rather a consequence of preeclampsia and FGR. Low levels of serum inhibin-A were not significantly associated with any adverse outcomes.ConclusionsHigh levels of maternal serum inhibin-A in the second trimester are significantly associated with abnormal placentation, which increases the risk of preeclampsia and FGR with a consequence of indicated preterm birth but not a risk of spontaneous preterm birth. In contrast, low inhibin-A levels were not associated with any common adverse pregnancy outcomes.

The leading causes of perinatal death are preterm birth, fetal abnormalities, and impaired placentation leading to preeclampsia and fetal growth restriction. Prophylactic use of low-dose aspirin beginning at 16 weeks’ gestation or less has been associated with significant reductions in the prevalence of these placenta-related complications. Improving deep placentation could reduce the incidence of several adverse pregnancy outcomes and rate of perinatal death. This systematic review and meta-analysis of recent randomized trials were done to compare the effect of early and late administration of aspirin on the risk of perinatal death and other adverse outcomes. EMBASE, PubMed, Cochrane Central Register of Controlled Trials, and Web of Science were searched for relevant citations from 1965 to October 2011. Only prospective, randomized controlled trials involving pregnant women treated with low-dose aspirin (≤150 mg), with or without dipyridamole (≤300 mg), were included. Control groups had to have received placebo or no treatment. All studies that involved women who initiated treatment at 16 weeks or less and at more than 16 weeks’ gestation were included. The main outcome was perinatal mortality (fetal death after 16 weeks’ gestation or neonatal death before 28 days). Secondary outcomes were preeclampsia, severe preeclampsia, fetal growth restriction, preterm birth, placental abruption, birth weight, and gestational age at delivery. Review Manager 5.0.25 and SAS 9.2 software were used for analysis. Relative risks (RRs) were calculated and pooled for global analysis with 95% confidence intervals (CIs) and stratified according to gestational age at entry (≤16 or >16 weeks). Forty-two of 66 studies meeting inclusion criteria were included (27,222 women randomized) in the final analysis. When compared with controls, treatment with low-dose aspirin started at 16 weeks’ gestation or less compared with low-dose aspirin started at more than 16 weeks’ gestation was associated with a greater reduction in perinatal death (RR = 0.41; 95% CI, 0.19–0.92 vs RR = 0.93; 95% CI, 0.73–1.19; P = 0.02), preeclampsia (RR = 0.47; 95% CI, 0.36–0.62 vs RR = 0.78; 95% CI, 0.61–0.99; P < 0.01), severe preeclampsia (RR = 0.18; 95% CI, 0.08–0.41 vs RR = 0.65; 95% CI, 0.40–1.07; P < 0.01), fetal growth restriction (RR = 0.46; 95% CI, 0.33–0.64 vs RR = 0.98; 95% CI, 0.88–1.08; P < 0.001), and preterm birth (RR = 0.35; 95% CI, 0.22–0.57 vs RR = 0.90; 95% CI, 0.83–0.97; P < 0.001). The difference in RR according to gestational age at entry remained statistically significant (P = 0.03) when comparing women recruited at 16 weeks or less with those recruited at 16 to 24 weeks (RR = 1.01; 95% CI, 0.49–2.08; P = 0.99). In 7 studies (22%) reporting the reasons for perinatal death, 17 (65%) of 26 perinatal deaths were related to preeclampsia, fetal growth restriction, or placental abruption. Similar effects of early aspirin prophylaxis were found in women who received 80 mg or less daily and those who received 100 mg or more daily and in women selected using abnormal uterine artery Doppler as an inclusion criterion as compared with those selected using anamnesis factors only. These results suggest that prophylaxis with low-dose aspirin can lead to significant reductions in perinatal death, preeclampsia, fetal growth restriction, and preterm birth provided treatment is started at 16 weeks’ gestation or less. The beneficial effect of aspirin likely results from an improvement in the transformation of uterine spiral arteries. Abnormal uterine artery blood flow is present as early as 12 weeks’ gestation in women who will later develop preeclampsia. Because low-dose aspirin improves uterine artery blood flow between the first and the second trimesters, such a regimen should probably be initiated at 8 to 12 weeks’ gestation in high-risk women.

Guideline No. 442: Fetal Growth Restriction: Screening, Diagnosis, and Management in Singleton Pregnancies

To compare immune cell subsets and interferon (IFN) expression in placentas from patients with systemic lupus erythematosus (SLE), primary Sjögren’s disease (pSjD), antiphospholipid syndrome (APS), healthy controls (HC) and of women with adverse pregnancy outcomes (APO) without these systemic rheumatic diseases (SRD). Placenta biopsies from HC, SLE, pSjD, APS, and patients with fetal growth restriction (FGR), spontaneous preterm birth (PTB), or FGR and preeclampsia (FGR/PE) attended between 2008 and 2022 were recovered from the pathology biobank of the University Medical Center Groningen. Clinical characteristics and APO were retrieved from medical records. Immunohistochemistry was performed for Myxovirus resistance protein 1 (MxA), CD3, CD20, CD56, CD68, CD123, and Foxp3. The proportion of positive cells was established using an automated detection classifier, while MxA expression was assessed semi/quantitatively discriminating between maternal (decidua) and fetal (villi) tissue. Finally, placental lesion classification was performed. Our study included placentas from 11 SLE, 4 pSjD, 8 APS, 4 PTB, 8 FGR, 8 FGR/PE patients and 11 HC. A high rate of APO (70%) was identified in SRD patients. Patients with SRD had a higher macrophage (CD68+) count in decidua and villi than HC, but no differences were observed in T (CD3+), B (CD20+), NK (CD56+) and T regulatory (Foxp3+) cell count. No plasmacytoid dendritic cells (CD123+) were identified. Furthermore, patients with these SRD had higher MxA values than HC in villi but not in decidua. SLE, pSjD and APS patients have an increased macrophage count and interferon upregulation in the placenta compared to HC. Therefore, a pro-inflammatory environment might be key inducing placental dysfunction, which may lead to subsequent APO development.

Beyond the unknown: Leveraging machine learning to predict adverse outcomes in pregnant women with aplastic anemia from a representative nationwide cohort

619: A history of prior preeclampsia is a major risk factor for preterm birth

P 23 Maternal vascular malperfusion in spontaneous preterm birth and outcome of subsequent pregnancy

Not discounting the important foetal or placental contribution, the endometrium is a key determinant of pregnancy outcomes. Given the inherently linked processes of menstruation, pregnancy and parturition with the endometrium, further understanding of menstruation will help to elucidate the maternal contribution to pregnancy. Endometrial health can be assessed via menstrual history and menstrual fluid, a cyclically shed, easily and non-invasively accessible biological sample that represents the distinct, heterogeneous composition of the endometrial environment. Menstrual fluid has been applied to the study of endometriosis, unexplained infertility and early pregnancy loss; however, it is yet to be examined regarding adverse pregnancy outcomes. These adverse outcomes, including preeclampsia, foetal growth restriction (FGR), spontaneous preterm birth and perinatal death (stillbirth and neonatal death), lay on a spectrum of severity and are often attributed to placental dysfunction. The source of this placental dysfunction is largely unknown and may be due to underlying endometrial abnormalities or endometrial interactions during placentation. We present existing evidence for the endometrial contribution to adverse pregnancy outcomes and propose that a more comprehensive understanding of menstruation can provide insight into the endometrial environment, offering great potential value as a diagnostic tool to assess pregnancy risk. As yet, this concept has hardly been explored.

Placental oxidative stress contributes to both normal and abnormal placentation during pregnancy. This review discusses the potential consequence of oxidative stress-induced placental dysfunction on pregnancies complicated by fetal death and pregnancies with a high risk of fetal death. The placenta is a source of reactive oxygen free radicals due to the oxidative metabolism required to meet the demands of the growing fetus. The placenta has an array of efficient antioxidant defense systems to deal with rising oxidative stress created by free radicals during pregnancy. Properly controlled physiological (low-level) free radical production is a necessary part of cellular signaling pathways and downstream activities during normal placental development; however, poorly controlled oxidative stress can cause aberrant placentation, immune disturbances and placental dysfunction. Abnormal placental function and immune disturbances are linked to many pregnancy-related disorders, including early and recurrent pregnancy loss, fetal death, spontaneous preterm birth, preeclampsia and fetal growth restriction. This review discusses the role of placental oxidative stress in both normal and pathological settings. Finally, based on previously published work, this review presents multiple lines of evidence for the strong association between oxidative stress and adverse pregnancy outcomes, including fetal death and pregnancies with a high risk of fetal death.

IntroductionCurrent research aimed at understanding and preventing stillbirth focuses almost exclusively on the role of the placenta. The underlying origins of poor placental function leading to stillbirth, however, remain poorly...

ObjectiveWe aimed to investigate the incidence of adverse pregnancy outcomes including preterm birth, preeclampsia (PE), and fetal growth restriction (FGR) in pregnant women with COVID‐19 according to the gestational age.MethodsThis retrospective study included 167 pregnant women who were hospitalized with confirmed COVID‐19. The patients were divided into three groups according to the time of diagnosis as follows: <12 weeks of gestation (first trimester, n = 10), 12–24 weeks of gestation (n = 28), and >24 weeks of gestation (n = 129). Medical records of the patients were reviewed retrospectively and adverse pregnancy outcomes were analyzed.ResultsA total of 49 (29.3%) patients had an active COVID‐19 infection at the time of delivery, while 118 (70.7%) gave birth after the infection was cleared. Twenty‐three patients had preterm birth and the gestational age was <34 weeks in only four of these patients. There was no significant difference in the preterm birth, PE, FGR, HELLP syndrome, and gestational diabetes mellitus among the three gestation groups (p = 0.271, 0.394, 0.403, 0.763, and 0.664, respectively). Four (2.39%) patients required intensive care unit stay. Maternal death was seen in only one (0.59%) patient.ConclusionOur study showed no significant correlation between the gestational age at the time of COVID‐19 infection and the frequency of adverse pregnancy outcomes such as preterm birth, PE, FGR, and gestational diabetes mellitus. However, further studies are needed to draw a firm conclusion on this topic.