Antenatal suspicion of ischemic placental disease. coexisting maternal and fetal placental

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1 Research BASIC SCIENCE: OBSTETRICS Antenatal suspicion of ischemic placental disease and coexistence of maternal and fetal placental disease: analysis of over 500 cases Sharon M. Cooley, MD; Fiona R. Reidy, MB BCh BAO; Eoghan E. Mooney, FRCPath; Fionnuala M. McAuliffe, MD OBJECTIVE: To investigate the antenatal suspicion of placental disease and the coexistence of maternal and fetal placental ischemic disease. STUDY DESIGN: A prospective cohort study on normally formed singleton infants from 2000 to 2008 inclusive with placental ischemic disease. RESULTS: Uteroplacental ischemia or fetoplacental thrombotic vasculopathy was identified in 511 of 74,857 births (7/1000 births). Four hundred fifty-nine cases met the inclusion criteria. Maternal and fetal placental vascular disease coexisted in 9.2% (n 42) of cases. Placental ischemic disease was suspected antenatally in 70% (324/459). Maternal placental disease occurred in 40% (184/459) and 30% (140/ 459) had fetal pathology. The perinatal mortality rate was 12.7/1000. Antenatal suspicion of placental disease led to increased obstetric intervention and delivery of small-for-gestational age infants. CONCLUSION: Maternal and fetoplacental vascular disease coexisted in 9.2%. Placental disease was suspected antenatally in 70% of cases and was associated with increased rates of obstetric intervention. Key words: antenatal disease, outcome, placental ischemia Cite this article as: Cooley SM, Reidy FR, Mooney EE, et al. Antenatal suspicion of ischemic placental disease and coexistence of maternal and fetal placental disease: analysis of over 500 cases. Am J Obstet Gynecol 2011;205:576.e1-6. The placenta has 2 circulations and either or both may show vascular disease. Placental vascular disease may be maternal as manifest by uteroplacental ischemia (UPI), or fetal with fetoplacental thrombotic vasculopathy (FTV). Either may be associated with increased perinatal morbidity and mortality. 1-3 Placental disease is usually a diagnosis that is achieved after delivery of the infant. However, there is little in the literature about the accuracy of the antenatal From the Fetal Medicine Center (Dr Cooley), UCD Obstetrics and Gynaecology, School of Medicine and Medical Science, University College Dublin (Dr McAuliffe and Ms Reidy), and the Department of Pathology (Dr Mooney), National Maternity Hospital, Dublin, Ireland. Received Jan. 12, 2011; revised May 10, 2011; accepted June 15, The authors report no conflict of interest. Reprints: Fionnuala M. McAuliffe, MD, UCD Obstetrics and Gynaecology, School of Medicine and Medical Science, University College Dublin, National Maternity Hospital, Dublin 2, Ireland. Fionnuala.mcauliffe@ucd.ie /$ Mosby, Inc. All rights reserved. doi: /j.ajog clinical suspicion of placental disease. We hypothesized that placental ischemic disease could be suspected antenatally secondary to maternal or fetal clinical complications, and that the obstetric outcome would differ when compared with pregnancies where placental disease is not suspected antenatally. In addition few authors have examined the coexistence of maternal and fetal placental disease and its associated clinical outcome. 3 The secondary hypothesis was that maternal and fetal placental ischemic disease may coexist. Such coexistence could suggest a common cause such as inherited thrombophilia. 4 We aimed to record incidence of coexisting maternal and fetal placental disease and to compare obstetric outcome in these cases with cases with maternal placental ischemic disease only. The purpose of this study therefore was to examine the obstetric outcomes of cases with antenatal suspicion of placental ischemic disease and to record the incidence of coexisting maternal and fetal placental disease. MATERIALS AND METHODS A prospective cohort study was conducted on normally formed infants from Jan. 1, 2000, to Dec. 31, 2008, inclusive. All cases had a routine single ultrasound at weeks to confirm gestation and review anatomy. All cases with anomaly, multiple pregnancies and incomplete data were excluded from the study. All cases were identified following a triage system in our laboratory where all cases with antenatal maternal or fetal disease, abnormal gross placental pathology, or adverse obstetric outcome undergo placental analysis. This highlights one-third of all placentae for examination. These cases form the basis of the denominator. Cases are further triaged for gross examination only or histologic examination. This study examines a subset in which maternal or fetal placental ischemic disease was identified on histologic examination. All cases were prospectively coded in a laboratory database by one of the authors (E.M.). At delivery, the umbilical cord was clamped (ie, both on the infant and placental side when cut). The placenta was measured in its longest dimension and in the dimension perpendicular to that. The umbilical cord length was measured from cord insertion to the cord clamp. In our hospital a segment of the umbilical DECEMBER 2011 American Journal of Obstetrics & Gynecology 576.e1

2 Research Basic Science: Obstetrics TABLE 1 Ultrasound requirement and the incidence of maternal and fetal disease in the cohort (n 459) Groups No. (%) Antenatal suspicion of placental disease 324 (70.6) a Placental disease not suspected antenatally 125 (29.4) a Ultrasound for maternal reasons 230 Ultrasound for fetal reasons 135 Maternal disease 184 (40.1) Preeclampsia 133 (28.9) Eclampsia 5 (1.1) Hypertension 6 (1.3) Placenta praevia 8 (1.7) Antepartum hemorrhage 16 (3.5) Abruption 5 (1.1) Obstetric cholestasis 2 (0.4) Diabetes 9 (2.1) Fetal complications 140 (30.5) Fetal growth restriction 86 (18.7) Abnormal biophysical profile 10 (2.2) Nonreassuring CTG 42 (9.2) Intrauterine fetal demise 2 (0.4) CTG, cardiotocograph. a P.05. cord is not removed for fetal cord blood gas assessment. Placentas were weighed fresh. The placenta was weighed trimmed of cord and membranes and the weight was recorded to the nearest 5 g. Cord length diameter and insertion were recorded. Circumvallate placentation was considered to constitute placental disease, whereas circummargination was not. Two portions from the central two thirds of the placenta and samples from all central gross lesions were placed in 10% buffered formalin and standard hematoxylin and eosin (H&E) sections prepared. One section of cord and membranes and 5 sections of placental parenchyma were reviewed. This included at least 2 sections of grossly normal placenta. Maternal placental ischemic disease was defined as UPI, which is the presence of accelerated villous maturation (AVM) or infarction. Fetal placental ischemic disease was defined as the presence of FTV. Coexistent disease was defined as the presence of both maternal and fetal placental ischemic disease. AVM was defined as the presence of villous features at a more advanced stage than expected for gestational age. Features included an increase in syncytial knots and distal villous hypoplasia. Syncytial knots were not evaluated separately from distal villous hypoplasia. Placental infarction was defined as the presence of necrotic villi and included recent, aging, and old infarcts. The percentage of placenta infarcted was recorded ( 5% or 5%). 1,5 Placental disease secondary to maternal vascular underperfusion was graded with reference to previously published parameters. 6 Severe maternal placental ischemic disease was any placental infarction pre-34 weeks gestation, placental infarction greater than 5% or central placental infarction between 34 and 37 weeks gestation, or placental infarction greater than 20% at term (37-42 weeks gestation). Placental infarction of less than 5% at term was considered normal. Mild-to-moderate maternal placental ischemic disease comprised lesser degrees of placental infarction, with variable distal villous hypoplasia and increased syncytial knots. 6 Normal placentas did not show these features and were of normal weight for gestation. FTV was defined as any one of the following: extensive avascular villi, hemorrhagic endovasculitis, obliterated stem arteries, or occlusive thrombi. 1,7 Severe FTV was defined as 2 or more sections with over 15 villi per section showing hyalinization or stromal-vascular karyorrhexis. Cases with lesser degrees of fetal vascular obstruction were classified as mild-to-moderate disease whereas cases without any fetal vascular lesions were called normal. 8 The diagnosis of mural thrombi was made when nonocclusive fibrin aggregates were identified adherent to the luminal aspect of fetal vessels. The diagnosis of occlusive thrombi was made when at least 80% of the vessel lumen crosssectional area was occupied by a thrombus. The presence of fresh blood or clot behind the placenta (retroplacental hemorrhage [RPH] or thrombosis) was recorded. Chorioamnionitis was classified as acute and was staged as minimal/mild (stage I/II), moderate (stage III), or severe (stage IV). 9 Delayed villous maturation was defined as reduced vascularization of the chorionic villi with decreased vasculosyncytial membranes. 10 Villitis was graded from 1 to For the purposes of this study, grade 1 and grade 2 villitis were grouped as low grade, whereas grade 3 and grade 4 were grouped as high-grade disease. The criteria for suspicion of fetal placental ischemic disease included: fetal growth restriction (FGR), 1 abnormal biophysical profile, a nonreassuring cardiotocograph or in utero fetal demise. The biophysical profile was considered abnormal if oligohydramnios ( 2 cm vertical pocket of amniotic fluid), decreased fetal breathing movements (absent or no episode of fetal breathing e2 American Journal of Obstetrics & Gynecology DECEMBER 2011

3 Basic Science: Obstetrics Research seconds), decreased fetal movements (absent or 2 discrete movements), or abnormal fetal tone were present. A nonreassuring cardiotocograph was reduced baseline variability of less than 5 beats per minute over 40 minutes, persistent early decelerations (of 15 beats per minute lasting for 15 seconds), or the presence of variable or late decelerations. The maternal and fetal outcome were reviewed. Maternal age, parity, ethnicity, alcohol use, cigarette smoking, and previous operative delivery were obtained from the hospital database. Maternal alcohol and cigarette smoking are recorded after direct questioning by a midwife at the maternal booking visit. Maternal outcome parameters included maternal disease, the requirement for fetal growth assessment by ultrasound, fetal growth parameters on ultrasound, gestation at delivery, onset of labor, indication for induction, and mode of delivery. Our hospital operates under the Mastership system where 1 clinician (a medical Chief Executive Officer) is responsible for clinical management. Hospital management guidelines for maternal disease are based on best practice guidelines produced by the Royal College of Obstetricians and Gynaecologists. 12 Fetal outcome parameters include birthweight, cord ph (where available), Apgar score, Neonatal Intensive Care Unit (NICU) admission, duration of NICU stay, and perinatal outcome. Fetal growth restriction (FGR) was defined as delivery of an infant less than the 10th percentile for gestational age and sex. 13 Severe FGR was defined as fetal birthweight less than the 3rd percentile. Data analysis was undertaken using the Statistical Package for the Social Sciences (version 15.0; SPSS Inc, Chicago, IL). Normality was assessed with the Kolmogoroff-Smirnoff test. Frequencies, ranges, means, and medians were used to describe the findings. The 2 analysis was used to compare proportions. Odds ratios are presented to compare the odds of an event happening between 2 groups in bivariate analysis. The comparison of means between groups was carried out using t tests and f tests as appropriate. The Mann-Whitney and Kruskall-Wallis tests were used in place TABLE 2 Maternal demographics of the study cohort (n 459) Maternal demographics Antenatal suspicion of placental disease (n 324), n (%) of the t test and f test, respectively, for nonparametric variables. RESULTS In total, 511 cases of either UPI or FTV were identified giving a rate of 7/1000 births. Fifty-two cases were excluded because of multiple births or incomplete data and a further 13 cases were excluded because of fetal anomaly. The remaining 459 cases comprised the study group. Of the study group, 305 women were primiparous and 154 were multiparous. The study group was further subdivided into those where placental disease was suspected antenatally based on the maternal or fetal condition (n 324, 70.6%) and those where placental disease was diagnosed after delivery in the absence of either maternal or fetal clinical indicators (n 135, 29.4%). The group in which placental disease was suspected antenatally was subdivided into cases where the predominant concern was maternal disease or fetal disease. In 10 cases (2.2%) more than 1 indication for intervention existed, therefore in these cases the primary medical concern was taken. The incidence of maternal and fetal disease in the study and the indication for ultrasound in which warranted is outlined in Table 1. Table 2 outlines the maternal characteristics of both groups. Placental disease not suspected antenatally (n 135), n (%) P value Mean maternal age y (SD) 31.2 (6.0) 30.6 (6.0).37 Primip 223 (71.9) 82 (60.7).01 Ethnicity White 276 (85.2) 114 (84.4).47 African 12 (3.7) 6 (4.4).44 Asian 17 (5.2) 6 (4.4).46 Current smokers 112 (34.6) 48 (35.6) per day 23 (7.1) 15 (11.1) per day 17 (5.2) 9 (6.7) per day 3 (2.7) 4 (8.3).12 Alcohol consumption 21 (6.5) 9 (6.7).54 Primipara accounted for 44.2% of our delivery population over the study period. In total 69.2% (n 310) of our study population were primiparous. There was also a statistically higher incidence of primiparous women in the group in which placental disease was suspected antenatally (71.9% vs 60.7%; P.013). In the group in which placental disease was suspected antenatally a higher incidence of induction of labor was observed as shown in Table 4. A statistically higher incidence of preterm birth (delivery 37 weeks gestation) and delivery less than 32 weeks gestation was also recorded. Over 86% of preterm births in the group where placental disease was suspected antenatally were iatrogenic secondary to a prelabor cesarean section or induction of labor. These measures were undertaken in which there were significant concerns about maternal or fetal wellbeing that outweighed the perceived risks of prematurity. These included severe preeclampsia (for example, a patient with visual disturbance at 29 weeks gestation with a diastolic blood pressure in excess of 110 mm Hg despite methyldopa and labetalol treatment) and FGR (31 weeks gestation with oligohydramnios, reduced fetal movements, and a fall off in fetal growth). Umbilical cord blood gases were performed for clinical DECEMBER 2011 American Journal of Obstetrics & Gynecology 576.e3

4 Research Basic Science: Obstetrics TABLE 3 Placental findings of the cohort (n 459) Placental findings Antenatal suspicion of placental disease (n 324), n (%) indications and were available in 45.5% (n 204) of cases. The management of each case was individualized and the decision for delivery was made by a consultant obstetrician. Review of the fetal outcome parameters reveals a 3-fold increase in the incidence of infants born less than the 10th and less than the 3rd percentile for gestational age in the group in which placental disease was suspected antenatally. This was statistically significant. The overall corrected perinatal mortality rate (PNMR) for the study cohort was 12.7/ This compares with a corrected PNMR for the hospital over the study period of 7.9/1000. Similar rates of fetal acidosis (cord ph 7.2) and Apgar scores less than 7 at 5 minutes of age were seen between the 2 groups; however, the NICU admission rate was statistically higher in the antenatally suspected group. Although there was no difference Placental disease not suspected antenatally (n 135), n (%) P values Placental weight, Kgs (SD) (0.102) (0.117).00 Accelerated villous maturation 309 (95.4) 125 (92.6).17 Mild AVM 148 (45.7) 98 (72.6).00 Moderate AVM 95 (29.3) 24 (17.8).01 Severe AVM 68 (21.0) 5 (3.7).00 Placental infarction 133 (41.0) 25 (18.5).00 5% 70 (21.6) 12 (8.9).00 5% 67 (20.7) 14 (10.4).00 Fetothrombotic vasculopathy 39 (12.0) 5 (3.7).00 FTV with AVM 37 (11.4) 5 (3.7).00 Delayed villous maturation 8 (100.0) 7 (87.5).50 Decidual necrosis 48 (14.8) 22 (16.3).39 Cord diameter, cm (SD) 1.2 (0.4) 1.3 (0.4).26 Central cord insertion 179 (55.2) 78 (57.8).35 Circummargination 35 (10.8) 8 (5.9).07 Circumvallation 4 (1.2) 0.25 Villitis 34 (10.5) 11 (8.1).28 Low grade 27 (8.3) 10 (7.4).25 High grade 7 (2.2) 1 (0.7).26 AVM, accelerated villous maturation; FTV, fetoplacental thrombotic vasculopathy. in Apgar scores or fetal acidosis there was a 2 week difference in gestation at delivery (33.4 weeks vs 35.5 weeks) and a 4-fold increase in delivery of an infant weighing less than the fifth percentile for gestation (19.15 vs 5.2%) in the antenatally suspected group accounting for the higher rate of admission to NICU. There were no statistically significant differences in the duration of NICU stay or perinatal death rates between the 2 groups. The placental characteristics of both groups are shown in Table 3. The placental weight and cord lengths are statistically smaller in the group where placental disease was suspected antenatally (0.279 Kgs vs Kgs; P.0001 and 42.4 cms vs 46.9 cms; P.002). The mean placental z score for the study population was 0.93 (0.96). The z score for cases where placental disease was not suspected antenatally was 0.69 (1.15), whereas the z score for cases where placental disease was suspected antenatally was 1.02 (0.86). The z scores for the 2 groups are significantly different (P.003). The difference in umbilical cord length may be contributed to by the higher incidence of preterm deliveries in the antenatally suspected group. The incidence of placental infarction is higher in the group where placental disease is suspected antenatally (41.0% vs 18.5%; P.0001). The rates of delayed villous maturation and decidual necrosis were not statistically significantly different between the groups. The incidence of mild acute chorioamnionitis is higher in the group in which placental disease was not suspected antenatally (11.9% vs 3.7%; P.001). There were 59 cases of RPH or thromboses. This included the 5 cases of clinical abruption in our cohort. In 33 cases (56%) with RPH more than 5% of the placenta was infarcted. Gross placental morphology was abnormal or there was an eccentric cord insertion in 25 cases (42.4%) with RPH. There were 10 cases (16.9%) of FTV in the subgroup with RPH and all of these cases had coexistent maternal disease. The overall incidence of FTV in the study group with UPI was 9.6% (n 44). This is 3-fold higher than the expected reported incidence for FTV in singleton pregnancies. 1,11 A higher incidence of FTV is also present in the group in which placental disease was suspected antenatally (12.0% vs 3.7%; P.003). In 9.2% (n 42) there was coexistent maternal and fetal disease. There was no correlation between the severity of maternal and fetal vascular disease (Table 5). Those cases with coexistent maternal and fetal placental disease (n 42) were more likely to deliver preterm when compared with those with maternal placental disease only (12.4% vs 4.0%; P.002). The mean gestation at delivery was also less in the presence of coexistent disease (32.6 weeks vs 34.1 weeks; P.040). These deliveries were more likely to involve a prelabor cesarean section in the maternal or fetal interest (16.0% vs 3.6%; P.001) and delivery of an infant 576.e4 American Journal of Obstetrics & Gynecology DECEMBER 2011

5 Basic Science: Obstetrics Research with a birthweight less than the 3rd percentile for gestation (16.9% vs 7.8%; P.020) requiring Neonatal Intensive Care admission (11.2% vs 2.0%; P.002). There was no difference in the mean duration of NICU stay in cases with coexistent disease when compared with cases with UPI in isolation (23.3 days vs 22.1 days; P.420). There were no stillbirths in the group with coexistent disease. There was 1 neonatal death at 5 days of age after delivery of a growth restricted infant weighing kg at 27 weeks and 1 day gestation to a preeclamptic mother. The neonatal death was secondary to complications of prematurity. COMMENT This study has 2 principal findings. First, placental ischemic disease was suspected antenatally and led to increased obstetric intervention and increased rates of preterm birth. There were 511 cases of UPI or FTV identified in the 74,857 births in the hospital in the study period giving an overall incidence of placental ischemic disease of 0.7%. Second, maternal and fetal placental ischemic disease coexisted in 9.2% of cases. The overall incidence of FTV in our study group was 9.6%. This is 3-fold higher than the expected incidence of FTV in a singleton population. 1,14 The incidence of FTV is also statistically higher in cohort with clinical disease. FTV is associated with an adverse neurologic outcome and the gestation at onset of placental dysfunction has significant impact on neonatal outcome. 1,15,16 FTV in the context of maternal uteroplacental disease is poorly documented. The coexistence has been noted in the context of preeclampsia in which it did not show an association with gestational age. 17 An overlap between maternal and fetal vascular disease was seen in smallfor-gestational age infants with multiple placental pathologies in 12%, but specific figures for overlap of vascular disease were not presented. 18 This study has shown significantly smaller placentas in cases in which placental disease is suspected antenatally. This is contributed to by the high rate of iatrogenic preterm birth in the group in TABLE 4 Pregnancy outcome for the study cohort (n 459) Pregnancy outcome which placental disease is suspected antenatally. However, even when gestation is controlled for, the placental weight is statistically smaller in those infants born less than 37 weeks and less than 32 weeks gestation. This is substantiated by other studies in which chronic maternal placental vascular underperfusion resulted in small placentas for gestation. 19 The overall corrected PNMR in our study was 12.7/1000. This is 1.5-fold higher than the overall PNMR for the hospital over the study period. Death of a growth-restricted fetus has been shown to be the second most common cause of stillbirth. 20 The estimated risk of an FGR infant dying in utero is approximately 5-fold higher than its appropriately grown counterpart. 21 The majority of these deaths occur when the fetus is preterm and a natural reluctance exists to deliver a fetus that may be subject to additional complications. 22 Moreover, the risk of FGR and fetal demise associated with placental disease do not end with delivery of the affected fetus, but exist for subsequent pregnancies. 21 In this study, Antenatal suspicion of placental disease (n 324), n (%) Placental disease not suspected antenatally (n 135), n (%) P values Induction of labor 75 (23.1) 17 (12.6).01 Maternal disease evident 32 (9.9) 5 (3.7).02 Fetal disease evident 43 (13.3) 12 (8.9).12 Mean gestation at delivery, wks (SD) 33.4 (4.2) 35.5 (4.7).00 Preterm delivery 28 wks 28 (8.6) 10 (7.4).41 Preterm delivery 32 wks 96 (29.6) 23 (17.0).00 Preterm delivery 37 wks 219 (67.6) 61 (45.2).00 Prelabor cesarean section 190 (58.6) 13 (9.6).00 Intrapartum cesarean section 35 (10.8) 11 (8.1).25 Birthweight 10th percentile 125 (38.6) 18 (13.3).00 Birthweight 3rd percentile 62 (19.1) 7 (5.2).00 Apgar 7 at 5 min 16 (4.9) 8 (5.9).25 Cord ph (12.6) 15 (11.1).48 NICU admission 260 (80.2) 88 (65.1).00 NICU admission duration, d Perinatal deaths 5 (1.5) 1 (0.7).44 NICU, neonatal intensive care unit. although antenatal suspicion of placental disease was associated with a statistically significantly higher incidence of operative delivery, preterm birth, delivery of a growth-restricted infant, and NICU admission the overall perinatal mortality was not statistically significantly different from the group in which placental disease was not suspected antenatally. However, in centers in which neonatal services are limited, identification of a subset of the population that may re- TABLE 5 Cases with coexistence of maternal and fetal placental ischemic disease Variable Mild-mod UPI Severe UPI Mild-moderate FTV Severe FTV Severity of disease overlap (n 42). FTV, fetoplacental thrombotic vasculopathy; UPI, uteroplacental insufficiency. Cooley. Antenatal suspicion of placental ischemic disease. Am J Obstet Gynecol DECEMBER 2011 American Journal of Obstetrics & Gynecology 576.e5

6 Research Basic Science: Obstetrics quire increased surveillance and increased intervention either antenatally or postnatally may be of benefit. A link between inherited and acquired thrombophilia and placental disease has been suggested. 23,24 The possibility of an underlying thrombophilia cannot be excluded in our study cohort, particularly in view of the high incidence of maternal and fetal disease. An increase in thrombophilia has been reported in a minority of cases with FTV, though does not satisfactorily explain coexistent placental disease. 4 This study has shown that placental disease can be suspected antenatally in 70% of cases, and is more likely to be suspected on the basis of maternal disease than the presence of fetal disease. FTV is associated with adverse neurologic outcome. 1,6,15 The coexistence of fetal with maternal disease should be considered in reviewing the outcomes of intervention, as preexisting fetal disease may ultimately limit the success of operative intervention in preventing adverse fetal outcomes. f ACKNOWLEDGMENT We would like to thank Paul Dingle, Senior Anatomic Pathology Technician, for his assistance in the retrieval and processing of all placentas in this study. REFERENCES 1. McDonald DG, Kelehan P, McMenamin JB, et al. Placental fetal thrombotic vasculopathy is associated with neonatal encephalopathy. Hum Pathol 2004;35: Redline RW. Placental pathology: a systematic approach with clinical correlations. Placenta 2008;29 Suppl A:S Kraus FT, Acheen VI. Fetal thrombotic vasculopathy in the placenta: cerebral thrombi and infarcts, coagulopathies, and cerebral palsy. Hum Pathol 1999;30: Gogia N, Machin GA. Maternal thrombophilias are associated with specific placental lesions. 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Acta Obstet Gynecol Scand 2004;83: Said JM, Higgins JR, Moses EK, et al. Inherited thrombophilia polymorphisms and pregnancy outcomes in nulliparous women. Obstet Gynecol 2010;115: Alonso A, Soto I, Urgellés MF, Corte JR, Rodríguez MJ, Pinto CR. Acquired and inherited thrombophilia in women with unexplained fetal losses. Am J Obstet Gynecol 2002;187: e6 American Journal of Obstetrics & Gynecology DECEMBER 2011