Long-term maternal morbidity and mortality associated with ischemic placental disease

Ischemic placental disease can have long-term maternal health implications. In this article, we discuss the three conditions of ischemic placental disease (preeclampsia, fetal growth restriction, and abruption placenta) and its associated long-term maternal morbidity. Retrospective observational studies comparing pregnancies complicated by ischemic placental disease to uncomplicated pregnancies suggest an increased long-term risk of hypertension, cardiovascular death, metabolic syndrome, and cerebrovascular disease. This association is much stronger in women who had an indicated-preterm delivery due to ischemic placental disease. It is important to adequately counsel women who are diagnosed with these conditions about their future health risks. Increased awareness of the potential health risks and multidisciplinary collaboration remains paramount to instituting the appropriate screening and preventative strategies (i.e., behavior modification) for affected women.     

Ischemic placental disease: epidemiology and risk factors

Objective

Preeclampsia, small for gestational age (SGA) and placental abruption - conditions that constitute the syndrome of “ischemic placental disease” (IPD) - may portend different clinical manifestations of a common underlying pathophysiology. We examined if (i) preeclampsia, SGA and abruption share similar risk profiles; and (ii) if there are any differences in these profiles between patients with IPD that delivered at term and preterm gestations.

Study design

We utilized data from the US Collaborative Perinatal Project, a multicenter, prospective cohort study (1959-1966), restricted to women that delivered singleton births at ≥20 weeks (n = 47,495.) We compared risk factors between women with and without IPD as well as preeclampsia, SGA and abruption.

Results

A strong overlap in risk factors for all 3 conditions was evident. Socio-economic class, income, age, parity, education, race, BMI, marital status, and history of preterm birth were different between preterm and term gestations in women with IPD. Although rates of preeclampsia only, SGA only and preeclampsia with SGA were similar between term and preterm birth, rates of other conditions were higher at preterm gestations, with abruption being the driving condition behind these associations.

Conclusions

The similar risk profiles for preeclampsia, SGA, and abruption provide compelling evidence to suggest that these conditions may share common pathophysiological mechanisms—ischemic placental disease. Greater homogeneity in risk profiles within preterm than term births suggests that IPD may be a syndrome that has strong underpinnings at preterm gestations.     

First trimester prediction of ischemic placental disease

Ischemic placental disease is characterized by one or more of the clinical manifestations of preeclampsia, fetal growth restriction, and/or placental abruption, resulting in indicated preterm delivery. Since over half of the indicated preterm deliveries are due to ischemic placental disease, accurate early prediction of the disease is of paramount importance in developing prevention strategies. This review article focuses on studies that have used the first trimester aneuploidy screening timing window to predict those patients who later develop ischemic placental disease. Emphasis was given to studies originating from the Fetal Medicine Foundation because of their uniformity in definitions and expertise of the personnel who performed the ultrasound screening exams.     

Neurodevelopmental outcomes of near-term small-for-gestational-age infants with and without signs of placental underperfusion

Objective

To evaluate 2-year neurodevelopmental outcomes of near-term, small-for-gestational-age (SGA) newborns segregated by presence or absence of histopathology reflecting placental underperfusion (PUP).

Patients and methods

A cohort of consecutive near-term (≥34.0 weeks) SGA newborns with normal prenatal umbilical artery Doppler studies was selected. All placentas were inspected for evidence of underperfusion and classified in accordance with established histologic criteria. Neurodevelopmental outcomes at 24 months (age-corrected) were then evaluated, applying the Bayley Scale for Infant and Toddler Development, Third Edition (Bayley-III) to assess cognitive, language, and motor competencies. The impact of PUP on each domain was measured via analysis of covariance, logistic and ordinal regression, with adjustment for smoking, socioeconomic status, gestational age at birth, gender, and breastfeeding.

Results

A total of 83 near-term SGA deliveries were studied, 46 (55.4%) of which showed signs of PUP. At 2 years, adjusted neurodevelopmental outcomes were significantly poorer in births involving PUP (relative to SGA infants without PUP) for all three domains of the Bayley scale: cognitive (105.5 vs 96.3, adjusted-p = 0.03), language (98.6 vs 87.8, adjusted-p<0.001), and motor (102.7 vs 94.5, adjusted-p = 0.007). Similarly, the adjusted likelihood of abnormal cognitive, language, and motor competencies in instances of underperfusion was 9.3-, 17.5-, and 1.44-fold higher, respectively, differing significantly for the former two domains.

Conclusions

In a substantial fraction of near-term SGA babies without Doppler evidence of placental insufficiency, histologic changes compatible with PUP are still identifiable. These infants are at greater risk of abnormal neurodevelopmental outcomes at 2 years.     

Risk factors for perinatal mortality in patients admitted to the hospital with the diagnosis of placental abruption

Objective: Placental abruption is a clinical term used when premature separation of the placenta from the uterine wall occurs prior to delivery of the fetus. Hypertension, substance abuse, smoking, intrauterine infection and recent trauma are risk factors for placental abruption. In this study, we sought for clinical factors that increase the risk for perinatal mortality in patients admitted to the hospital with the clinical diagnosis of placental abruption.

Materials and methods: We identified all placental abruption cases managed over the past 6 years at our Center. Those with singleton pregnancies and a diagnosis of abruption based on strict clinical criteria were selected. Eleven clinical variables that had potential for increasing the risk for perinatal mortality were selected, logistic regression analysis was used to identify variables associated with perinatal death.

Results: Sixty-one patients were included in the study with 16 ending in perinatal death (26.2%). Ethnicity, maternal age, gravidity, parity, use of tobacco, use of cocaine, hypertension, asthma, diabetes, hepatitis C, sickle cell disease and abnormalities of amniotic fluid volume were not the main factors for perinatal mortality. Gestational age at delivery, birthweight and history of recent trauma were significantly associated with perinatal mortality. The perinatal mortality rate was 42% in patients who delivered prior to 30 weeks of gestation compared to 15% in patients who delivered after 30 weeks of gestation (p?<?0.05). A three-fold increase in severe trauma was reported in the group of patients with perinatal mortality than in the group with perinatal survivors (25% versus 7%, respectively, p?<?0.05).

Conclusions: In patients admitted to hospital for placental abruption delivery prior to 30 weeks of gestation and a history of abdominal trauma are independent risk factors for perinatal death.     

Abnormal multiple marker screens are associated with adverse perinatal outcomes in cases of intrauterine growth restriction

OBJECTIVE: The purpose of this study was to determine if abnormal multiple marker screens (MMS) are associated with adverse perinatal outcomes in intrauterine growth restriction (IUGR) pregnancies. STUDY DESIGN: This was a case control study of IUGR pregnancies (birth weight <10th percentile for gestational age [GA]) delivered in our unit over 6 years. Cases were compared with controls for the association between abnormal MMS and adverse perinatal outcomes (APO). RESULTS: Of the 261 IUGR pregnancies, 39 (16%) had at least 1 APO. An elevated HCG was significantly associated with an APO (OR 2.6, 95% CI 1.1-6.4). A low uE3 was also associated with an APO (OR 5.5, 95% CI 2.2-14). The association between an elevated AFP and APO was not statistically significant (OR 1.6, 95% CI, 0.6-4.6). CONCLUSION: An elevated HCG and low uE3 were associated with APO in cases of IUGR. This information could be useful in identifying a subset of IUGR cases deserving closer surveillance.     

Association between placental pathology and neonatal outcome in preeclampsia: a large cohort study

Objective: To study associations between placental histopathology and neonatal outcome in preeclampsia (PE). Study design: The cohort consisted of 544 singleton pregnancies complicated by PE and managed at Karolinska University Hospital, Stockholm, Sweden during 2000–2009. Evaluation of placental histopathology was made by one senior perinatal pathologist, blinded to outcome. Clinical outcome was obtained from prospectively collected medical registry data and medical records. Main outcome measures were intrauterine fetal death, smallness for gestational age, admission to neonatal unit, major neonatal morbidity (defined as presence of intraventricular hemorrhage ≥grade 3, retinopathy of prematurity ≥grade 3, necrotizing enterocolitis, cystic periventricular leucomalacia and/or severe bronchopulmonary dysplasia) and neonatal mortality. Logistic regression analyses including gestational age were performed. Results: Abnormal placental weight, both low (adjusted odds ratio (OR) [95% confidence interval] 5.2 [1.1–24], p?=?0.03) and high (adjusted OR 1048 [21–51?663], p?p?=?0.02). Decidual arteriopathy increased the odds for admission to neonatal care (adjusted OR 2.7 [1.1–6.5], p?=?0.03). Infarction involving ≥5% of the placenta was associated with intrauterine fetal death and small for gestational age infants (adjusted OR’s 75 [5.5–1011], p?=?0.001 and 3.2 [1.7–5.9], p?Conclusion: Placental pathology in PE reflects adverse perinatal events and deviant placental weight predicts adverse neonatal outcome in preeclamptic women delivering preterm. Placental investigation without delay can contribute to neonatal risk assessment.     

Ischemic placental disease: Maternal versus fetal clinical presentations by gestational age

Objective.?Preeclampsia, small for gestational age (SGA), and abruption are considered ischemic placental diseases (IPD), and are major contributors to both maternal and fetal morbidity and mortality. Although the placenta is considered a fetal organ, these conditions can present clinically with either maternal or fetal manifestations, but their relationship to preterm births is largely unexplored.

Methods.?We designed a population-based study to assess the origins of IPD. IPD was classified as maternal (preeclampsia only), fetal (SGA only), or both (abruption only, preeclampsia with either SGA or abruption, or all 3). The study was based on 90,500 women that delivered singleton live births at 22–44 weeks gestation.

Results.?Among 77,275 term births with IPD, 23.2% presented as maternal disease only, 68.9% as fetal disease, and 7.9% as both. In contrast, among 12,906 preterm births with IPD, the proportions were roughly equal (maternal 32.9%, fetal 36.5%, and both 30.6%). Among spontaneous preterm births with IPD, a greater proportion had a fetal presentation (43.0%), whereas among indicated preterm births with IPD, a greater proportion (43.4%) had both maternal and fetal presentations.

Conclusions.?IPD at preterm gestations is more likely to involve both the mother and fetus than at term. The differing clinical presentations by gestational age suggest different pathways between term and preterm births. This may reflect heterogeneous processes for IPD at early vs. late gestations, regardless of the effects of differing gestational age thresholds for interventions.     

Prediction and prevention of ischemic placental disease

Preeclampsia, intrauterine growth restriction (IUGR), and placental abruption are obstetrical conditions that constitute the syndrome of ischemic placental disease or IPD, the leading cause of indicated preterm birth and an important cause of neonatal morbidity and mortality. While the phenotypic manifestations vary significantly for preeclampsia, IUGR, and abruption, these conditions may share a common underlying etiology as evidenced by: (1) shared clinical risk factors, (2) increased recurrence risk across pregnancies as well as increased co-occurrence of IPD conditions within a pregnancy, and (3) findings that suggest the underlying pathophysiologic processes may be similar. IPD is of major clinical importance and accounts for a large proportion of indicated preterm delivery ranging from the periviable to late preterm period. Successful prevention of IPD and resultant preterm delivery could substantially improve neonatal and maternal outcomes. This article will review the following topics: (1) The complicated research literature on aspirin and the prevention of preeclampsia and IUGR. (2) Research evidence on other medical interventions to prevent IPD. (3) New clinical interventions currently under investigations, including statins. (4) Current clinical recommendations for prevention of ischemic placental disease.     

Hemoglobin concentration in pregnancy and perinatal mortality: a London-based cohort study

OBJECTIVE: Failure of fetal growth during pregnancy, and preterm birth, are the major causes of stillbirth and early neonatal death. The objective of the study was to determine the association between maternal hemoglobin concentration during pregnancy and perinatal mortality. STUDY DESIGN: The design was prospective, using data on 222,614 first singleton pregnancies in the St Mary's Maternity Information System database in the Northwest Thames region of London. RESULTS: The association of perinatal mortality with maternal hemoglobin at first antenatal check was not statistically significant (P>.10), but a statistically significant (P<.001) U-shaped pattern was found with lowest recorded maternal hemoglobin concentration. Both early neonatal mortality and stillbirth rates were statistically significantly (P<.005) associated with lowest maternal hemoglobin concentration. The relationship of lowest hemoglobin with early neonatal mortality was largely mediated by the effect of preterm birth, and that between lowest hemoglobin and stillbirth by fetal growth restriction. The lowest perinatal mortality was associated with a lowest recorded maternal hemoglobin concentration of between 9-11 g/dL. CONCLUSION: There is an optimal range of lowest hemoglobin concentration in pregnancy, and on either side of this perinatal mortality is increased. The effect of lowest hemoglobin is largely mediated through associations with preterm birth and fetal growth restriction.     

Determinants of perinatal mortality in Nigeria

Objective

To determine risk factors for perinatal mortality among hospital-based deliveries in Nigeria.

Methods

The WHO Global Maternal and Perinatal Health Survey was implemented in Nigeria as a first step in establishing a global system for monitoring maternal and perinatal health. Twenty-one health facilities with more than 1000 deliveries annually were selected by a stratified multistage cluster sampling strategy. Information was recorded on all women who delivered and their neonates within a 3-month period.

Results

Overall, there were 9208 deliveries, comprising 8526 live births, 369 fresh stillbirths, 282 macerated stillbirths, 70 early neonatal deaths, and 721 perinatal deaths. The stillbirth and perinatal mortality rates were, respectively, 71 and 78 per 1000 deliveries; the early neonatal death rate was 8 per 1000 live births. Approximately 10% of all newborns weighed less than 2500 g, and 12.3% were born at less than 37 weeks of gestation. Predictors of perinatal mortality were mother's age, lack of prenatal care, unbooked status, prematurity, and birth asphyxia.

Conclusion

The perinatal mortality rate remains unacceptably high in Nigeria. Fresh stillbirth accounted for most perinatal deaths. Interventions to improve the utilization and quality of prenatal care, in addition to the quality of intrapartum care, would considerably reduce perinatal death.     

子痫前期及其高危因素对围产儿结局的不良影响

目的:探讨子痫前期(PE)及其高危因素对围产儿结局的影响.方法:根据国内外资料统计的PE高危因素,筛选2011年4月至2012年1月在上海交通大学医学院附属仁济医院妇产科产检和分娩的正常及存在高危因素的孕妇154例,最终发展为PE的孕妇50例,非PE孕妇104例.通过采集病史及实验室检查,追踪妊娠结局,分析PE及存在高危因素PE孕妇的围产儿结局.结果:(1)PE组的新生儿体重及分娩孕周显著小于非PE组(P＜0.05).(2)PE组的胎儿生长受限(FGR)、胎儿窘迫、早产、死胎、新生儿窒息发生率分别是非PE组的4.64倍、2.32倍、4.61倍、2.66倍、6.38倍.两组的FGR、胎儿窘迫、早产的发病率有显著差异(P＜0.05).(3)当MAP≥85 mmHg、蛋白尿、子宫/脐动脉血流异常、D-D＞0.246μg/ml、FDP＞4μg/ml、PAGT＞40％时,易发生围产儿不良结局(P均＜0.05).不同高危因素对围产儿结局的威胁程度不同,其中子宫/脐动脉血流异常时围产不良结局发生率均较高(P＜0.05).结论:PE对围产儿结局有不良影响.孕期可针对高危孕妇进行严格有效的筛查,严密监测围产儿生长发育,警惕PE及围产儿不良结局的发生.     

The effect of maternal thrombophilia on placental abruption: Histologic correlates

Objective.?To determine if the histology of placental abruption differs by maternal thrombophilia status.

Study design.?This was a multicentre, case–control study of women with abruption and delivering at ≥20 weeks' gestation, collected as part of the ongoing New Jersey-placental abruption study. Women were identified by clinical criteria of abruption. Maternal blood was collected postpartum and tested for anticardiolipin antibodies, and mutations in the Factor V Leiden and prothrombin genes. Cases were comprised of women with an abruption and a positive thrombophilia screen. Controls were comprised of women with an abruption and a negative thrombophilia screen. All placental histology was systematically reviewed by two perinatal pathologists, blinded to the abruption status.

Results.?A total of 135 women with placental abruption were identified, of which 63.0% (n = 85) had at least one diagnosed maternal thrombophilia. There were increases in the rates of meconium-stained membranes (7.9%vs. 2.1%, p = 0.015) and decidual necrosis (4.5%vs. 2.1%, p = 0.023) when a maternal thrombophilia was diagnosed. Although there was no difference in the overall presence of infarcts between the two groups (27.0%vs. 38.3%, p = 0.064), the presence of an old infarct was more common among women with a positive thrombophilia screen (83.3%vs. 44.4%, p = 0.003).

Conclusion.?Placental abruption with a positive maternal thrombophilia screen is associated with higher rates of old placental infarcts and decidual necrosis compared with abruption when thrombophilia is not diagnosed. These lesions suggest a chronic etiology of placental abruption in the presence of a maternal thrombophilia.     

A multilayered approach for the analysis of perinatal mortality using different classification systems

Many classification systems for perinatal mortality are available, all with their own strengths and weaknesses: none of them has been universally accepted. We present a systematic multilayered approach for the analysis of perinatal mortality based on information related to the moment of death, the conditions associated with death and the underlying cause of death, using a combination of representatives of existing classification systems. We compared the existing classification systems regarding their definition of the perinatal period, level of complexity, inclusion of maternal, foetal and/or placental factors and whether they focus at a clinical or pathological viewpoint. Furthermore, we allocated the classification systems to one of three categories: ‘when’, ‘what’ or ‘why’, dependent on whether the allocation of the individual cases of perinatal mortality is based on the moment of death (‘when’), the clinical conditions associated with death (‘what’), or the underlying cause of death (‘why’). A multilayered approach for the analysis and classification of perinatal mortality is possible by using combinations of existing systems; for example the Wigglesworth or Nordic Baltic (‘when’), ReCoDe (‘what’) and Tulip (‘why’) classification systems. This approach is useful not only for in depth analysis of perinatal mortality in the developed world but also for analysis of perinatal mortality in the developing countries, where resources to investigate death are often limited.     

Placental abruption: critical analysis of risk factors and perinatal outcomes

Objective.?To investigate risk factors and pregnancy outcome of patients with placental abruption.

Methods.?A population-based study comparing all pregnancies of women with and without placental abruption was conducted. Stratified analysis using multiple logistic regression models was performed to control for confounders.

Results.?During the study period there were 185,476 deliveries, of which 0.7% (1365) occurred in patients with placental abruption. The incidence of placental abruption increased between the years 1998 to 2006 from 0.6 to 0.8%. Placental abruption was more common at earlier gestational age. The following conditions were significantly associated with placental abruption, using a multivariable analysis with backward elimination: hypertensive disorders, prior cesarean section, maternal age, and gestational age. Placental abruption was significantly associated with adverse perinatal outcomes such as Apgar scores?<7 at 1 and 5?min and perinatal mortality. Patients with placental abruption were more likely to have cesarean deliveries, as well as cesarean hysterectomy.Using another multivariate analysis, with perinatal mortality as the outcome variable, controlling for gestational age, hypertensive disorders, etc., placental abruption was noted as an independent risk factor for perinatal mortality.

Conclusions.?Placental abruption is an independent risk factor for perinatal mortality. Since the incidence of placental abruption has increased during the last decade, risk factors should be carefully evaluated in an attempt to improve surveillance and outcome.     

影响胎盘早剥临床结局的相关因素及防范策略

目的探讨影响胎盘早剥临床结局的相关因素及临床防范策略,旨在提高临床识别和处理技能,降低危害程度。方法对1994年1月至2008年12月15年间北京大学第三医院收治的89例胎盘早剥患者的临床资料进行回顾性分析。其中子痫前期伴发胎盘早剥52例、原因不明胎盘早剥37例,采用单因素及多因素回归分析影响围产结局和产科结局的相关因素。结果首发临床征象分析显示子痫前期组以超声异常为首发征象显著多于原因不明胎盘早剥组(P=0.039),重度早剥以腹痛为首发征象者显著多于轻度早剥(P=0.010)。子痫前期(P=0.003)、首发临床征象至临床处理时限(P=0.008)是胎盘早剥轻重程度的独立影响因素。出现首发临床征象至临床处理时限是发生产后出血的独立影响因素(P=0.040)。子痫前期(P=0.016)、重度胎盘早剥(P=0.016)及临床首发征象至临床处理时限(P=0.003)是胎死宫内的独立影响因素。临床首发征象至临床处理时限(P=0.031)是新生儿窒息的独立影响因素。结论子痫前期是影响胎盘早剥病情程度的高风险因素。从临床发病到临床处理时限是影响胎盘早剥轻重程度的重要因素,也是影响产科和围产结局的重要因素。     

Epidemiology of ischemic placental disease: A focus on preterm gestations

Preeclampsia, placental abruption, and intrauterine growth restriction (IUGR) have collectively been termed ischemic placental disease (IPD) due to a suspected common biological pathway involving poor placentation in early pregnancy and subsequent placental insufficiency. Despite decades of research, the etiologies of these conditions remain largely unknown and preventive and therapeutic strategies are lacking. It has been suggested that the underpinnings of IPD lie primarily in preterm gestations and that classification of these conditions based on the gestational age at onset will facilitate etiologic research. The purpose of this review is to describe our current knowledge regarding the risk factors, co-occurrence, and recurrence of the conditions of IPD with a specific focus on the preterm gestational window.     

Optimal treatment of hypothyroidism associated with live birth in cases of previous recurrent placental abruption and stillbirth

Objective

To examine the clinical management of and placentas from pregnant women with hypothyroidism and obstetric history of recurrent stillbirth in order to identify possible etiologic mechanisms.

Methods

Two cases involving 26-year-old women with hypothyroidism and history of recurrent stillbirth are reported. Placentas from all of the women’s pregnancies were compared in order to identify histologic similarities.

Results

In both cases, multifocal hemorrhagic infarctions and abruptions were seen, indicating progressive uteroplacental ischemic damage leading to stillbirth. Thrombophilia, infection, and diabetes tests were all negative. With meticulous monitoring and normalization of thyroid function by end of first/early second trimester in subsequent pregnancies, there were live births and no evidence of infarction on placental histology.

Conclusion

The 2 reported cases raise the possibility of uteroplacental ischemia and placental abruption being mechanisms by which hypothyroidism can lead to stillbirth; they also highlight the potential of minimizing this risk via adequate levothyroxine treatment from early pregnancy.