Objective
Pregnancy-induced hypertension/preeclampsia (PIH) and fetal growth restriction (FGR) share a common placental origin. The pathologic classification that divides placental lesions to maternal or fetal origin was compared between these disorders.
Study Design
Placentas from pregnancies that were complicated by PIH, normotensive FGR, or by both (combined) were analyzed, and lesions were classified as those consistent with maternal under-perfusion and with fetal thromboocclusive disease.
Results
Maternal vascular lesions were more common in the PIH group and combined group (61% and 59%, respectively), compared with the FGR group (16.2%; P < .001), and villous lesions were more common in the combined group, compared with the FGR and PIH groups (79.5%, 53.5%, and 46.9%, respectively; P = .004). Fetal villous changes were observed in 16.2% in the FGR group, compared with 3.1% in the PIH group ( P = .03), and chronic villitis was 15.2% in the FGR group vs 1.6% in the PIH group ( P = .004).
Conclusion
Placental lesions correspond with different clinical presentations.
The entities of pregnancy-induced hypertension (PIH)/preeclampsia and normotensive fetal growth restriction (FGR) with obvious placental insufficiency , defined as decreased blood flow to the placenta and decreased oxygen delivery to fetal blood, share a common placental origin and pathophysiologic condition. There is a growing body of evidence that supports that normal vascular remodeling and placental development are altered in such pregnancies and responsible for inadequate trophoblast invasion, impaired perfusion through the fetal-placental unit, and ultimate placental hypoxia and insufficiency. Indeed, there are different thresholds for the development of preeclampsia because of genetic factors, obesity, and concomitant diseases that may explain the reason that the same degree of abnormal placental development and placental ischemia causes PIH/preeclampsia in some hosts but not in others. Currently, no clear explanation exists to elucidate the reason that poor placentation in early stages of pregnancy that leads to placental ischemia develops into 2 different clinical presentations: maternal (PIH/preeclampsia), fetal (FGR), or into both.
Placental pathologic condition is a valuable link that explains how underlying pregnancy pathologic condition results in adverse pregnancy outcomes. The maternal and fetal vascular trees are dynamic structures that can be altered significantly by abnormal development. There is a range of placental reaction patterns that can develop in the attempt to supplement the developing fetus. Characterization of placental lesions has been proposed that would separate the noninfection placental pattern of injury into 2 different categories of lesions; lesions that are consistent with maternal vascular circulation (maternal under-perfusion) and lesions that are consistent with fetal vascular supply (thromboocclusive disease). Although recent studies on placental lesions and pregnancy complications attempted to establish a relationship between morphologic lesions and clinical severity of the various pregnancy complications, there is a lack of studies on the association between microscopic features of placental morphologic condition and the etiopathogenesis of the different disorders. Although the association between abnormality of the maternal side of the placental circulation, which is often a result of arteriopathy, and PIH or FGR is established, fetal-side pathologic changes of the placenta circulation is less understood. Therefore, we studied different placental lesions by dividing them into maternal or fetal origin in pregnancies that were complicated by PIH/preeclampsia, FGR, or both in the search for a possible placental fetal origin component for these disorders.
Materials and Methods
Study design
The medical records of all patients who had PIH/preeclampsia (PIH group) or normotensive FGR (FGR group) or whose condition was complicated by both (combined group) and their placentas underwent histopathologic examination and were included in the study, which was conducted in the Department of Obstetrics and Gynecology, Edith Wolfson Medical Center in Holon, Israel, from January 2006 to December 2008. The information that was collected included maternal characteristics such as age, gravidity, parity, cigarettes smoked (per day), known chronic disease as pregestational diabetes mellitus (DM; type 1 and 2), thrombophilia, epilepsy, asthma, and chronic pharmacotherapy , which was defined as medical treatment received by the patient during whole pregnancy, except vitamin or iron supplements. In addition, data concerning pregnancy follow-up evaluation, complications that developed during pregnancy (such as gestational DM [GDM] A1 and A2) and mode of delivery, were also recorded. At birth, all neonates were examined by pediatricians. Birthweights and the specific percentiles for weight were assigned with the updated Israeli growth charts. Exclusion criteria included multiple pregnancies and pregnancies that were complicated with neonatal chromosomal or structural anomalies or by intrauterine infection. Approval for the study was obtained from the Local Ethics Committee.
Hypertensive syndromes in pregnancy were classified according to well-established characteristics such as laboratory and clinical criteria into gestational hypertension (PIH), chronic hypertension, and preeclampsia. FGR was defined when the actual birthweight was below the 10th percentile for gestational age. The gestational age estimation was based on the last menstrual period and validated by fetal ultrasound scanning that was performed in >90% of the women before week 13 of gestation in the study groups.
Collection and preparation of tissue
Placental pathologic examinations were performed according to a standard protocol. Placental weight was recorded, and its percentile was assigned based on specific placental weight charts. The fetoplacental weight ratio was calculated as the ratio between fetal birthweight to placental weight. Placentas were formalin fixed. From each placenta, 6 tissue samples were embedded in paraffin blocks for microscopic assessment: 1 role of the free membranes (chorion and amnion with attached deciduas capsularis) and a section of umbilical cord; 5 full-thickness disc samples (1 at the cord insertion, 1 in central tissue that appeared abnormal on gross examination, 2 from central tissue, and 1 at the margin of visible abnormal areas on gross examination). All pathologic examinations were done by a single pathologist. Placental lesions (which were considered in this work) were classified into maternal or fetal origin lesions. Maternal origin lesions included placental findings that were consistent with maternal under-perfusion vascular and villous changes. Maternal origin vascular lesions included acute atherosis and mural hypertrophy; maternal villous changes included increased syncytial knots, villous agglutination, increased intervillous fibrin deposition, and villous infarcts. Placental fetal origin lesions, which were also consistent with the term fetal thromboocclusive disease, were divided into vascular and villous changes. Fetal origin vascular lesions were considered to be thrombosis of chorionic plate and stem villous vessels; villous changes included avascular villi. In addition, villitis of unknown cause or chronic villitis , which was defined as placental inflammatory changes in fetal blood vessels that were recorded separately.
Statistical analysis
Data are presented as mean ± SD or median and range as appropriate. Data analysis was performed with the SPSS software (version 15.0; SPSS Inc, Chicago, IL). Analysis of variance was used to compare independent nonparametric categoric variables among the 3 groups (PIH, FGR, and combined). A probability value of < .05 was considered significant.
Results
Of the 202 patients who were included in the study, 64 women (32%) were in the PIH group, 99 women (49%) were in the normotensive FGR group, and 39 women (19%) were in the combined group. Maternal characteristics are summarized in Table 1 . Mean maternal age in the FGR group was significantly lower, 30.1 ± 5.5 years, compared with the PIH and combined groups (33 ± 5.4 and 32.8 ± 5.8 years, respectively). Gravidity and parity did not differ among the groups. Patients in the FGR group had a lower body mass index (22.5 ± 4.7 kg/m 2 ), compared with the other 2 groups (PIH, 27.7 ± 8 kg/m 2 ; combined, 26 ± 6.5 kg/m 2 ; P < .001). This difference in body mass index remained after the exclusion of women with GDM and pregestational DM from the study groups ( P = .001). The rate of the different hypertensive disorders was significantly higher in the PIH and combined groups, as expected from the study design. The rate of other maternal chronic disease (asthma, epilepsy, hypothyroidism) was similar in the 3 groups; however, DM (GDM and pregestational DM) was significantly higher in the PIH group (25%), compared with the FGR and combined groups (3% and 5.3%, respectively). There was no significant difference in pregestational DM in the PIH (3.1%), FGR (0), and combined (2.5%) groups. The rate of thrombophilia was not significantly different among the study groups (1.6%, 3%, and 2.6% in the PIH, FGR, and combined groups, respectively).
| Characteristic | Group | P value | ||
|---|---|---|---|---|
| Pregnancy-induced hypertension (n = 64) | Fetal growth restriction (n = 99) | Combined (n = 39) | ||
| Maternal age, y a | 33 ± 5.4 | 30.1 ± 5.5 | 32.8 ± 5.8 | .002 |
| Gravidity, n a | 2.3 ± 1.9 | 2.2 ± 1.4 | 2.8 ± 2.4 | .280 |
| Parity, n a | 0.97 ± 1.3 | 0.86 ± 1.0 | 0.9 ± 1.3 | .854 |
| Body mass index, kg/m 2 a | 27.7 ± 8.0 | 22.5 ± 4.7 | 26.0 ± 6.5 | < .001 |
| Smoking, % b | 14.1 | 27.6 | 23.1 | .131 |
| Diabetes mellitus, % c | 25 | 3 | 5 | < .001 |
| Chronic hypertension, % | 40.6 | 0 | 15.4 | < .001 |
| Pregnancy-induced hypertension, % | 21.9 | 0 | 15.4 | < .001 |
| Preeclampsia, % | 68.8 | 0 | 71.8 | < .001 |
| Gestational age, wk a | 36.6 ± 3 | 38 ± 2.2 | 34 ± 4 | < .001 |
| Cesarean delivery, % | 81.3 | 63.6 | 71.8 | .054 |
| Birthweight percentile a | 46.5 ± 28.5 | 5.3 ± 2.4 | 5.7 ± 2.8 | < .001 |
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