- Email: [email protected]
The frequency and severity of placental findings in women with preeclampsia are gestational age dependent
The frequency and severity of placental findings in women with preeclampsia are gestational age dependent Julie S. Moldenhauer, MD,a Jerzy Stanek, MD,b Carri Warshak, MD,a Jane Khoury, MS,a and Baha Sibai, MDa Cincinnati, Ohio OBJECTIVE: The purpose of this study was to evaluate placental lesions found in women with preeclampsia compared with normotensive control subjects and to determine whether the presence of these lesions are related to gestational age at delivery. STUDY DESIGN: Placental disease of women with preeclampsia at 24 to 42 weeks of gestation was compared with the placental disease of normotensive gestational age–matched control subjects. The placental lesions that were studied specifically included decidual arteriolopathy, thrombi in the fetal circulation, central infarction, intervillous thrombi, and hypermaturity of villi. Data analysis involved the v2 test, the Student t test, and logistic regression; odds ratios and CIs were estimated. RESULTS: Placentas from women with preeclampsia (n = 158) and normotensive control subjects (n = 156) were evaluated. Among women with preeclampsia, 67% had severe disease. Placental lesions were studied according to gestational age at delivery: < 28, 28 to 32, 33 to 36, and $37 weeks of gestation. Of the placental lesions that were studied, decidual arteriolopathy (odds ratio, 23.8, 95% CI 10.0-57.0), hypermaturity of villi (odds ratio, 12.4; 95% CI 5.3-29.2), intervillous thrombi (odds ratio, 1.95;95% CI 1.0-3.7), central infarction (odds ratio, 5.9; 95% CI 3.1-11.1), and thrombi in the fetal circulation (odds ratio, 2.8; 95% CI 1.2-6.6) were found to have significantly higher rates in the preeclamptic group. In contrast, the rate of chorioamnionitis was significantly lower in the preeclamptic group (odds ratio, 0.2; 95% CI 0.1-0.4). The rates of abruptio placentae and meconium staining were not different between the two groups. Within the preeclamptic group, the rates of decidual arteriolopathy (P < .0001), central infarction (P = .0001), and hypermaturity of villi (P < .0001) were higher the earlier the gestational age at delivery. CONCLUSION: Placentas in women with preeclampsia have increased amounts of disease. The rate is increased with lower gestational ages at the time of delivery for women with preeclampsia. (Am J Obstet Gynecol 2003;189:1173-7.)
Key words: Preeclampsia, preterm, term, placenta, disease Preeclampsia is a common medical complication of pregnancy that affects 6% to 7% of nulliparous patients.1,2 Preeclampsia typically occurs after 20 weeks of gestation and accounts for a large portion of maternal and neonatal morbidity and deaths.3 Because neonatal outcome is related directly to the gestational age at delivery,4 prolonging gestation has been shown to be an acceptable treatment plan in properly chosen patients, provided that the clinical aspects of the preeclampsia remain stable.5,6 From the aDepartment of Obstetrics and Gynecology, University of Cincinnati Medical Center, Cincinnati, Ohio, USA, and the bDepartment of Pathology, University of Cincinnati Medical Center, Cincinnati, Ohio, USA. Presented at the Sixty-Ninth Annual Meeting of the Central Association of Obstetrics and Gynecology, Las Vegas, Nev, October 2002. Received for publication January 13, 2003; revised March 20, 2003; accepted May 2, 2003. Reprint requests: Baha M. Sibai, MD, Department of Obstetrics and Gynecology, University of Cincinnati College of Medicine, 231 Albert Sabin Way ML 0526, Cincinnati, OH 45267-0526. E-mail: [email protected] Ó 2003, Mosby, Inc. All rights reserved. 0002-9378/2003 $30.00 + 0 doi:10.1067/S0002-9378(03)00576-3
In patients who require delivery, the indication is due to fetal concerns in most cases, which infers an abnormal placental pathologic process.7 Prolonging gestation in patients with severe preeclampsia and intrauterine growth retardation has not been shown to improve neonatal outcome,8 which once again implies a pathologic process that involves the placenta. When preeclampsia occurs earlier in gestation and requires preterm delivery, it is believed that the underlying pathologic insult is more severe than when it occurs at term. It is possible that the mechanism of disease is different in those pregnancies that are complicated by preeclampsia at term compared with those pregnancies that are preterm. Preeclampsia affects both the mother and the fetus. The placenta acts as the interface between these two compartments. Placental disease of patients with a diagnosis of preeclampsia in preterm gestations has been well studied.9-11 The lesions that are found commonly in preeclampsia have been designated to belong to pathophysiologic groups that are dependent on their mechanistic effect, including vascular lesions, occlusive lesions, and inflammation. In particular, the vascular 1173
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and occlusive lesions have the potential to alter uteroplacental/fetal blood flow and to have an impact on neonatal outcome. The presence of these lesions have also been shown to correlate with intrauterine growth restriction in the preterm fetus.12 It has been shown that, in patients with preeclampsia at term without severe growth restriction, placental histomorphometry results are similar to the results of normotensive control subjects, which supports the theory that, in these cases, a compensatory mechanism exists and protects uteroplacental blood flow.13 If this protective mechanism exists in the term pregnancy and not the preterm pregnancy, this could lead to the worsening status in the preterm pregnancy and could mandate delivery. Comparing the placental disease in patients with a diagnosis of preeclampsia at term versus those patients with a diagnosis of preeclampsia and are delivered prematurely may help to elucidate the underlying pathologic process. The purpose of this study was to determine whether pathologic differences exist between the placentae of women with preeclampsia throughout gestation compared with normotensive control subjects.
Material and methods A case control study of placental disease was performed at the University of Cincinnati Medical Center, with the approval of the Institutional Review Board. Patients who were delivered of singleton pregnancies from July 1, 1994, through December 31, 2000, and who were identified from an established placental disease database were considered eligible. Maternal medical records were reviewed to confirm the diagnosis of preeclampsia and gestational age at the time of delivery. Gestational age– matched normotensive control subjects who were delivered for other obstetric indications were identified by the presence of placental disease. Patients in the control group had no diagnosis of preeclampsia, insulin-dependent diabetes mellitus, chronic hypertension, or connective tissue disease. Those who were delivered preterm were delivered because of either preterm labor, preterm rupture of membranes, incompetent cervix, or vaginal bleeding with possible abruptio placentae. Maternal age at delivery, parity, race, and mode of delivery was extracted from maternal chart review. The diagnosis of preeclampsia was confirmed by chart review, and the classification was assigned on the basis of established criteria.14 Mild preeclampsia was defined as blood pressure of $140 mm Hg systolic and $90 mm Hg diastolic, with proteinuria ($300 mg/24 hours or $2+ on dipstick). Severe preeclampsia was defined as blood pressure of $160 mm Hg systolic and $110 mm Hg diastolic with proteinuria. Patients with the diagnosis of HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome met criteria previously
October 2003 Am J Obstet Gynecol
established.15 A diagnosis of eclampsia required the presence of seizure activity in patients with preeclampsia. Placental examination was performed according to the recommendations of the American Society of Clinical Pathologists.16,17 Specifically, after the membranes and umbilical cord were removed, the placentas were weighed, measured, and sliced. Sections of all grossly identifiable lesions and, in addition, at least two fullthickness sections from the paracentral region of the placenta and sections of the membrane roll and umbilical cord were taken for histologic examination. The pathologic diagnoses were defined as follows18:
1. Decidual arteriolopathy: presence of at least one of the two lesions. a. Deficient placentation: absence of replacement of the media of decidual spiral arterioles by trophoblast (ie, persistence of thick muscular arterioles in the deciduas parietalis or basalis) beyond 20 weeks of gestation. b. Acute atherosis: presence of foamy cells in the walls of decidual spiral arterioles that were replaced by eosinophilic hyaline material. c. These changes may be associated with decidual lymphocytic vasculitis, thrombosis, and decidual necrosis. 2. Placental hypermaturity: taking into consideration that normal placentas are characterized by a feature called heterogenous maturation, heterogenous placental hypermaturity was diagnosed only in preterm pregnancies when the morphologic characteristic of term placentas (predominance of small terminal villi over intermediate villi, syncytial knotting) was observed. All cases of homogenous (diffuse) hypermaturity were regarded as abnormal. Homogenous hypermaturity is characteristic of preplacental or some forms of postplacental hypoxia; heterogeneous hypermaturity is encountered in uteroplacental hypoxia of preeclampsia.19 3. Intervillous thrombus (thrombohematoma): Villusfree, nodular focus of coagulated blood in the intervillous space. 4. Infarction: localized area of ischemic villous necrosis. 5. Thrombi in the fetal circulation: yhrombotic occlusion of fetal villous stem artery that produces a sharply delineated area of villous avascularity/fibrosis. 6. Chorioamnionitis: presence of acute inflammation (neutrophils) at least in the extravillous trophoblast of the extraplacental membranes (stage I [ie, chorionitis]); higher stages include the presence of neutrophils in the chorionic mesoderm (stage II), amniotic mesoderm (stage III), and associated amniotic necrosis (stage IV). 7. Meconium staining: presence of fine nonrefractile pigment in extraplacental membranes, chorionic
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Table I. Maternal demographic data
Maternal age (y)* Nulliparous (%) African American (%) Operative delivery (%)
Table II. Gestational age at time of delivery
Normotensive (n = 156)
Preeclampsia (n = 158)
P value
25.3 ± 6.6 28.4 47.1 43.9
23.4 ± 6.8 50.0 49.6 65.3
.017 .001 NS .003
Weeks
Normotensive (n = 156)
Preeclampsia (n = 158)
< 28 28-32 33-36 $37
23 42 39 52
25 45 36 52
Data are presented as number of subjects. NS, Not significant. *Data are presented as mean
± SD.
plate, or umbilical cord (free pigment or in macrophages). 8. Abruptio placentae: presence of hemosiderin laden macrophages that signify chronic abruption or retroplacental hematoma. Data were managed and analyzed with the use of SAS software SAS Institute (Cary, NC). Clinical characteristics were compared between the study and control group with the use of the Student t test or the v2 test, as appropriate. The presence of pathologic features was compared between the study group and the normotensive control group with the use of the v2 test. Multiple logistic regression was used to look at the effect of gestational age, preeclampsia, and the associated interaction for each of the pathologic features. Odds ratios and associated CIs were estimated. Results We evaluated 158 placentas of women with preeclampsia and 156 placentas of gestational age–matched normotensive control subjects. Maternal age at delivery, parity, race, and mode of delivery are presented in Table I. Women in the study group had a lower mean maternal age, were more likely to be nulliparous, and required operative delivery. Table II shows the gestational ages of the two study groups. In the control group, 104 women were delivered preterm (44% with preterm labor, 29% with preterm premature rupture of membranes, and 4% with incompetent cervix). The distribution of the preeclamptic diagnoses by gestational age is presented in Table III. Women who were delivered prematurely with preeclampsia had higher rates of severe disease, including HELLP syndrome and eclampsia (P < .0001). As shown in Table IV, the rates of placental lesions between the placentas of women with preeclampsia are compared with the rates for normotensive control subjects. The rates of placental lesions were significantly higher in the preeclamptic group. In contrast, the rate of chorioamnionitis was significantly lower in the preeclampsia group. There was no difference in the rates of meconium staining or abruptio placentae between the two groups. As shown in Table V, the rates of placental lesions within the preeclamptic group according to gestational age at
Table III. Gestational age at delivery by severity in women with preeclampsia
Weeks
Mild (n = 53)
< 28 28-32 33-36 $37
0 2 (3.8%) 11 (20.8%) 40 (75.5%)
Severe (n = 66) 13 27 15 11
(19.7%) (40.9%) (22.7%) (16.7%)
HELLP syndrome (n = 29) 10 (34.5%) 14 (48.3%) 5 (17.2%) 0
Eclampsia (n = 10) 2 2 5 1
(20.0%) (20.0%) (50.0%) (10.0%)
delivery are presented. The rates of decidual arteriolopathy, central infarction, and hypermaturity of villi were higher the earlier the gestational age at the time of delivery. Interestingly, we found that chorioamnionitis increased with increasing gestational age in patients with preeclampsia. The rate of meconium staining also increased with increasing gestational age. Abruptio placentae was not associated with gestational age. As shown in Table VI, the rates of placental lesions within the control group are presented according to gestational age at delivery for comparison with the preeclamptic group. The rates of placental lesions within this group do not show a correlation with gestational age. The rates of chorioamnionitis and abruptio placentae were not statistically significant among the gestational ages within the control group. As expected, the rate of meconium staining increased with increasing gestational age in the control group and in the preeclamptic group. Logistic regression was used to observe the differential association between gestational age and placental lesion for the preeclamptic group versus the control group. There was statistically significant interaction for hypermaturity of villi (P = .026) and chorioamnionitis (P = .014), borderline for central infarction (P = .056), and no statistically significant interaction for arteriolopathy, intervillous thrombi, fetal thrombi, abruptio placentae, and meconium staining. Comment The findings in this study support the hypothesis that placental lesions are more common in the placentae of women with preeclampsia, particularly at early gestational ages. These pathologic abnormalities could explain the various clinical manifestations in women with severe
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October 2003 Am J Obstet Gynecol
Table IV. Placental disease in preeclampsia versus normotensive control subjects Normotensive (n = 156) Arteriolopathy Hypermaturity of villi Intervillous thrombi Central infarction Fetal thrombi Abruptio placentae Chorioamnionitis Meconium staining
7 7 17 15 8 9 67 33
Preeclampsia (n = 158)
(4.5%) (4.5%) (10.9%) (9.6%) (5.1%) (5.8%) (42.9%) (21.2%)
72 52 30 59 21 12 26 31
Odds ratio (95% CI)
(45.6%) (32.9%) (19.0%) (37.3%) (13.3%) (7.6%) (16.5%) (19.6%)
23.80 12.39 1.95 5.90 2.84 1.34 0.24 0.92
(9.96-57.01) (5.26-29.16) (1.02-3.73) (3.12-11.14) (1.22-6.63) (0.55-3.29) (0.14-0.42) (0.51-1.66)
Table V. Placental disease according to gestational age at delivery in patients with preeclampsia Weeks gestation Disease
< 28 (n = 25)
Arteriolopathy Hypermaturity of villi Intervillous thrombi Central infarction Fetal thrombi Abruptio placentae Chorioamnionitis Meconium staining
21 14 7 15 5 2 2 1
28-32 (n = 45)
(84.0%) (56.0%) (28.0%) (60.0%) (20.0%) (8.7%) (8.0%) (4.0%)
23 24 5 24 5 4 3 4
33-36 (n = 36)
(51.1%) (53.3%) (11.1%) (53.3%) (11.1%) (9.5%) (6.7%) (8.9%)
18 12 8 10 6 2 4 7
$ 37 (n = 52)
(50.0%) (33.3%) (22.2%) (27.8%) (16.7%) (5.1%) (11.1%) (19.4%)
10 2 10 10 5 1 17 19
(19.2%) (3.8%) (19.2%) (19.2%) (9.6%) (1.9%) (32.7%) (36.5%)
P value < .0001 < .0001 .336 < .0001 .355 .114 .001 < .0001
Table VI. Placental disease according to gestational age at delivery in normotensive control subjects Weeks gestation Disease Arteriolopathy Hypermaturity of villi Intervillous thrombi Central infarction Fetal thrombi Abruptio placentae Chorioamnionitis Meconium staining
< 28 (n = 23) 1 1 2 1 1 2 16 1
(4.4%) (4.4%) (8.7%) (4.4%) (4.4%) (8.0%) (69.6%) (4.4%)
28-32 (n = 42) 4 3 2 4 2 3 17 3
(9.5%) (7.1%) (4.8%) (9.5%) (2.6%) (6.7%) (40.5%) (7.1%)
preeclampsia. For example, in some women with preeclampsia, the disease manifests with maternal factors such as uncontrolled hypertension or eclampsia. In other women, evidence of fetal compromise including intrauterine growth restriction or oligohydramnios can be seen. This is also the reason that women who have the disease early are more likely to be delivered preterm.7,8 Placental abnormalities tend to be more frequent and severe as compared with women who are allowed to be delivered at term. Moreover, our findings could explain the various success rates that are reported in the literature in women with severe preeclampsia remote from term being treated expectantly.5-7 If a woman has evidence of intrauterine growth retardation or oligohydramnios, the success rate of prolonging the gestation beyond 48 hours is minimal.8 We speculate that, in these women, the placental findings are so severe that prolonging the gestation will not be successful because most women will be delivered for fetal indications.
33-36 (n = 39) 2 (5.1%) 0 3 (7.7%) 6 (15.4%) 1 (2.6%) 4 (11.1%) 10 (25.6%) 5 (12.8%)
$ 37 (n = 52) 3 10 4 4 3 24 24
0 (5.8%) (19.2%) (7.7%) (7.7%) (5.8%) (46.2%) (46.2%)
P value .113 .890 .057 .711 .531 .839 .150 < 0.0001
Our findings are consistent with previous studies that have shown increased rates of vaso-occlusive lesions in the placentae of women with preterm preeclampsia.9-11 In the study by Teasdale,13 the placentas of women who were delivered at term with growth-restricted infants were compared with the placentas of normal term control subjects. He found that there were no significant pathologic differences between the preeclamptic placentae and the control placentae. Therefore, the hypothesis was that compensatory mechanisms exist to keep the disease from progressing to severe. We believe this to be true on the basis of our finding of decreased disease in our term placentas compared with the preterm placentas. Within the control group, women were delivered both at term and preterm for obstetric indications other than hypertensive disorders. Patients at term were mostly normal laboring women. Any patients who were delivered at early gestational ages are clearly not normal pregnancies and, by definition, will have underlying disease. These
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patients were delivered for indications that included spontaneous preterm labor, premature rupture of membranes, chorioamnionitis, abruptio placentae, and nonreassuring fetal status, among others. This is supported by our findings of a very high rate of chorioamnionitis in the control group. Therefore, they inherently have a pathologic process occurring that required early delivery. The fact that we did not find any statistical significance in the rate of abruptio placentae in women with preeclampsia versus normotensive control subjects is due to the increased disease in our control subjects, particularly chorioamnionitis, which is known to be associated with abruptio placentae.20 In summary, there are different pathologic mechanisms that are responsible for the placental findings in the term versus preterm placentae of women with preeclampsia. This could possibly be explained by the fact that, in the preeclamptic pregnancies that proceed to term, compensatory mechanisms exist to allow adequate uteroplacental blood flow and that those patients were delivered early may lack such compensatory mechanisms. These compensatory mechanisms may depend on the degree and severity of the lack of placental vascular adaptation early in pregnancy.
6.
7.
8.
9.
10.
11.
12.
13. 14.
15.
REFERENCES 1. Sibai BM, Caritis SN, Thom E, Klebanoff M, McNellis D, Rocco L, et al. Prevention of preeclampsia with low-dose aspirin in healthy, nulliparous pregnant women. N Engl J Med 1993;329:1213-8. 2. Levine RJ, Hauth JC, Curet LB, Sibai BM, Catalano PM, Morris CD, et al. Trial of calcium to prevent preeclampsia. N Engl J Med 1997;337:69-76. 3. American College of Obstetricians and Gynecologists. Hypertension in pregnancy. Washington (DC): The College, 1996. Technical bulletin No.: 219. 4. Friedman SA, Schiff E, Kao L, Sibai BM. Neonatal outcome after preterm delivery for preeclampsia. Am J Obstet Gynecol 1995; 172:1785-92. 5. Odendaal HJ, Pattinson RC, Bam R, Grove D, Kotze JvW. Aggressive or expectant management for patients with severe preeclampsia
16.
17. 18. 19. 20.
between 28-34 weeks’ gestation: a randomized controlled trial. Obstet Gynecol 1990;76:1070-5. Sibai BM, Mercer BM, Schiff E, Friedman SA. Aggressive versus expectant management of severe preeclampsia at 28 to 32 weeks’ gestation: a randomized controlled trial. Am J Obstet Gynecol 1994;171:818-22. Hall DR, Odendaal HJ, Kirsten GF, Smith J, Grove D. Expectant management of early onset, severe preeclampsia: perinatal outcome. BJOG 2000;107:1258-64. Chammas MF, Nguyen TM, Li MA, Nuwayhid BS, Castro LC. Expectant management of severe preterm preeclampsia: Is intrauterine growth restriction an indication for immediate delivery? Am J Obstet Gynecol 2000;183:853-8. Salafia CM, Pezzullo JC, Lopez-Zeno JA, Simmens S, Minior VK, Vintzileos AM. Placental pathologic features of preterm preeclampsia. Am J Obstet Gynecol 1995;173:1097-105. Salafia CM, Pezzullo JC, Ghidini A, Lopez-Zeno JA, Whittington SS. Clinical correlations of patterns of placental pathology in preterm preeclampsia. Placenta 1998;19:67-72. Khong TY. Acute atherosis in pregnancies complicated by hypertension, small-for-gestational-age infants, and diabetes mellitus. Arch Pathol Lab Med 1991;115:722-5. Salafia CM, Minior VK, Pezzullo JC, Popek EJ, Rosenkrantz TS, Vintzileos AM. Intrauterine growth restriction in infants of less than thirty-two weeks’ gestation: associated placental pathologic features. Am J Obstet Gynecol 1995;173:1049-57. Teasdale F. Histomorphometry of the human placenta in maternal preeclampsia. Am J Obstet Gynecol 1985;152:25-31. American College of Obstetricians and Gynecologists. Diagnosis and management of preeclampsia and eclampsia. Washington (DC): The College, 2002. Practice bulletin No.: 33. Audibert F, Friedman SA, Frangieh AY, Sibai BM. Clinical utility of strict diagnostic criteria for the HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome. Am J Obstet Gynecol 1996;175:460-4. Langston C, Kaplan C, Macpherson T, Manci E, Peevy K, Clark B, et al. Practice guideline for examination of the placenta: developed by the Placental Pathology Practice Guideline Development Task Force of the College of American Pathologists. Arch Pathol Lab Med 1997;121:449-76. Gersell DJ. ASCP survey on placental examination: American Society of Clinical Pathologists. Am J Clin Pathol 1998;109:127-43. Benirschke K, Kaufmann P. Pathology of the human placenta. 3rd ed. New York: Springer-Verlag, 1995. Kingdom JC, Kaufmann P. Oxygen and placental villous development: origins of fetal hypoxia. Placenta 1997;18:613-21. Rana A, Sawhney H, Gopalan S, Panigrahi D, Nijhawan R. Abruptio placentae and chorioamnionitis-microbiological and histologic correlation. Acta Obstet Gynecol Scand 1999;78:363-6.
Key words: Preeclampsia, preterm, term, placenta, disease Preeclampsia is a common medical complication of pregnancy that affects 6% to 7% of nulliparous patients.1,2 Preeclampsia typically occurs after 20 weeks of gestation and accounts for a large portion of maternal and neonatal morbidity and deaths.3 Because neonatal outcome is related directly to the gestational age at delivery,4 prolonging gestation has been shown to be an acceptable treatment plan in properly chosen patients, provided that the clinical aspects of the preeclampsia remain stable.5,6 From the aDepartment of Obstetrics and Gynecology, University of Cincinnati Medical Center, Cincinnati, Ohio, USA, and the bDepartment of Pathology, University of Cincinnati Medical Center, Cincinnati, Ohio, USA. Presented at the Sixty-Ninth Annual Meeting of the Central Association of Obstetrics and Gynecology, Las Vegas, Nev, October 2002. Received for publication January 13, 2003; revised March 20, 2003; accepted May 2, 2003. Reprint requests: Baha M. Sibai, MD, Department of Obstetrics and Gynecology, University of Cincinnati College of Medicine, 231 Albert Sabin Way ML 0526, Cincinnati, OH 45267-0526. E-mail: [email protected] Ó 2003, Mosby, Inc. All rights reserved. 0002-9378/2003 $30.00 + 0 doi:10.1067/S0002-9378(03)00576-3
In patients who require delivery, the indication is due to fetal concerns in most cases, which infers an abnormal placental pathologic process.7 Prolonging gestation in patients with severe preeclampsia and intrauterine growth retardation has not been shown to improve neonatal outcome,8 which once again implies a pathologic process that involves the placenta. When preeclampsia occurs earlier in gestation and requires preterm delivery, it is believed that the underlying pathologic insult is more severe than when it occurs at term. It is possible that the mechanism of disease is different in those pregnancies that are complicated by preeclampsia at term compared with those pregnancies that are preterm. Preeclampsia affects both the mother and the fetus. The placenta acts as the interface between these two compartments. Placental disease of patients with a diagnosis of preeclampsia in preterm gestations has been well studied.9-11 The lesions that are found commonly in preeclampsia have been designated to belong to pathophysiologic groups that are dependent on their mechanistic effect, including vascular lesions, occlusive lesions, and inflammation. In particular, the vascular 1173
1174 Moldenhauer et al
and occlusive lesions have the potential to alter uteroplacental/fetal blood flow and to have an impact on neonatal outcome. The presence of these lesions have also been shown to correlate with intrauterine growth restriction in the preterm fetus.12 It has been shown that, in patients with preeclampsia at term without severe growth restriction, placental histomorphometry results are similar to the results of normotensive control subjects, which supports the theory that, in these cases, a compensatory mechanism exists and protects uteroplacental blood flow.13 If this protective mechanism exists in the term pregnancy and not the preterm pregnancy, this could lead to the worsening status in the preterm pregnancy and could mandate delivery. Comparing the placental disease in patients with a diagnosis of preeclampsia at term versus those patients with a diagnosis of preeclampsia and are delivered prematurely may help to elucidate the underlying pathologic process. The purpose of this study was to determine whether pathologic differences exist between the placentae of women with preeclampsia throughout gestation compared with normotensive control subjects.
Material and methods A case control study of placental disease was performed at the University of Cincinnati Medical Center, with the approval of the Institutional Review Board. Patients who were delivered of singleton pregnancies from July 1, 1994, through December 31, 2000, and who were identified from an established placental disease database were considered eligible. Maternal medical records were reviewed to confirm the diagnosis of preeclampsia and gestational age at the time of delivery. Gestational age– matched normotensive control subjects who were delivered for other obstetric indications were identified by the presence of placental disease. Patients in the control group had no diagnosis of preeclampsia, insulin-dependent diabetes mellitus, chronic hypertension, or connective tissue disease. Those who were delivered preterm were delivered because of either preterm labor, preterm rupture of membranes, incompetent cervix, or vaginal bleeding with possible abruptio placentae. Maternal age at delivery, parity, race, and mode of delivery was extracted from maternal chart review. The diagnosis of preeclampsia was confirmed by chart review, and the classification was assigned on the basis of established criteria.14 Mild preeclampsia was defined as blood pressure of $140 mm Hg systolic and $90 mm Hg diastolic, with proteinuria ($300 mg/24 hours or $2+ on dipstick). Severe preeclampsia was defined as blood pressure of $160 mm Hg systolic and $110 mm Hg diastolic with proteinuria. Patients with the diagnosis of HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome met criteria previously
October 2003 Am J Obstet Gynecol
established.15 A diagnosis of eclampsia required the presence of seizure activity in patients with preeclampsia. Placental examination was performed according to the recommendations of the American Society of Clinical Pathologists.16,17 Specifically, after the membranes and umbilical cord were removed, the placentas were weighed, measured, and sliced. Sections of all grossly identifiable lesions and, in addition, at least two fullthickness sections from the paracentral region of the placenta and sections of the membrane roll and umbilical cord were taken for histologic examination. The pathologic diagnoses were defined as follows18:
1. Decidual arteriolopathy: presence of at least one of the two lesions. a. Deficient placentation: absence of replacement of the media of decidual spiral arterioles by trophoblast (ie, persistence of thick muscular arterioles in the deciduas parietalis or basalis) beyond 20 weeks of gestation. b. Acute atherosis: presence of foamy cells in the walls of decidual spiral arterioles that were replaced by eosinophilic hyaline material. c. These changes may be associated with decidual lymphocytic vasculitis, thrombosis, and decidual necrosis. 2. Placental hypermaturity: taking into consideration that normal placentas are characterized by a feature called heterogenous maturation, heterogenous placental hypermaturity was diagnosed only in preterm pregnancies when the morphologic characteristic of term placentas (predominance of small terminal villi over intermediate villi, syncytial knotting) was observed. All cases of homogenous (diffuse) hypermaturity were regarded as abnormal. Homogenous hypermaturity is characteristic of preplacental or some forms of postplacental hypoxia; heterogeneous hypermaturity is encountered in uteroplacental hypoxia of preeclampsia.19 3. Intervillous thrombus (thrombohematoma): Villusfree, nodular focus of coagulated blood in the intervillous space. 4. Infarction: localized area of ischemic villous necrosis. 5. Thrombi in the fetal circulation: yhrombotic occlusion of fetal villous stem artery that produces a sharply delineated area of villous avascularity/fibrosis. 6. Chorioamnionitis: presence of acute inflammation (neutrophils) at least in the extravillous trophoblast of the extraplacental membranes (stage I [ie, chorionitis]); higher stages include the presence of neutrophils in the chorionic mesoderm (stage II), amniotic mesoderm (stage III), and associated amniotic necrosis (stage IV). 7. Meconium staining: presence of fine nonrefractile pigment in extraplacental membranes, chorionic
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Table I. Maternal demographic data
Maternal age (y)* Nulliparous (%) African American (%) Operative delivery (%)
Table II. Gestational age at time of delivery
Normotensive (n = 156)
Preeclampsia (n = 158)
P value
25.3 ± 6.6 28.4 47.1 43.9
23.4 ± 6.8 50.0 49.6 65.3
.017 .001 NS .003
Weeks
Normotensive (n = 156)
Preeclampsia (n = 158)
< 28 28-32 33-36 $37
23 42 39 52
25 45 36 52
Data are presented as number of subjects. NS, Not significant. *Data are presented as mean
± SD.
plate, or umbilical cord (free pigment or in macrophages). 8. Abruptio placentae: presence of hemosiderin laden macrophages that signify chronic abruption or retroplacental hematoma. Data were managed and analyzed with the use of SAS software SAS Institute (Cary, NC). Clinical characteristics were compared between the study and control group with the use of the Student t test or the v2 test, as appropriate. The presence of pathologic features was compared between the study group and the normotensive control group with the use of the v2 test. Multiple logistic regression was used to look at the effect of gestational age, preeclampsia, and the associated interaction for each of the pathologic features. Odds ratios and associated CIs were estimated. Results We evaluated 158 placentas of women with preeclampsia and 156 placentas of gestational age–matched normotensive control subjects. Maternal age at delivery, parity, race, and mode of delivery are presented in Table I. Women in the study group had a lower mean maternal age, were more likely to be nulliparous, and required operative delivery. Table II shows the gestational ages of the two study groups. In the control group, 104 women were delivered preterm (44% with preterm labor, 29% with preterm premature rupture of membranes, and 4% with incompetent cervix). The distribution of the preeclamptic diagnoses by gestational age is presented in Table III. Women who were delivered prematurely with preeclampsia had higher rates of severe disease, including HELLP syndrome and eclampsia (P < .0001). As shown in Table IV, the rates of placental lesions between the placentas of women with preeclampsia are compared with the rates for normotensive control subjects. The rates of placental lesions were significantly higher in the preeclamptic group. In contrast, the rate of chorioamnionitis was significantly lower in the preeclampsia group. There was no difference in the rates of meconium staining or abruptio placentae between the two groups. As shown in Table V, the rates of placental lesions within the preeclamptic group according to gestational age at
Table III. Gestational age at delivery by severity in women with preeclampsia
Weeks
Mild (n = 53)
< 28 28-32 33-36 $37
0 2 (3.8%) 11 (20.8%) 40 (75.5%)
Severe (n = 66) 13 27 15 11
(19.7%) (40.9%) (22.7%) (16.7%)
HELLP syndrome (n = 29) 10 (34.5%) 14 (48.3%) 5 (17.2%) 0
Eclampsia (n = 10) 2 2 5 1
(20.0%) (20.0%) (50.0%) (10.0%)
delivery are presented. The rates of decidual arteriolopathy, central infarction, and hypermaturity of villi were higher the earlier the gestational age at the time of delivery. Interestingly, we found that chorioamnionitis increased with increasing gestational age in patients with preeclampsia. The rate of meconium staining also increased with increasing gestational age. Abruptio placentae was not associated with gestational age. As shown in Table VI, the rates of placental lesions within the control group are presented according to gestational age at delivery for comparison with the preeclamptic group. The rates of placental lesions within this group do not show a correlation with gestational age. The rates of chorioamnionitis and abruptio placentae were not statistically significant among the gestational ages within the control group. As expected, the rate of meconium staining increased with increasing gestational age in the control group and in the preeclamptic group. Logistic regression was used to observe the differential association between gestational age and placental lesion for the preeclamptic group versus the control group. There was statistically significant interaction for hypermaturity of villi (P = .026) and chorioamnionitis (P = .014), borderline for central infarction (P = .056), and no statistically significant interaction for arteriolopathy, intervillous thrombi, fetal thrombi, abruptio placentae, and meconium staining. Comment The findings in this study support the hypothesis that placental lesions are more common in the placentae of women with preeclampsia, particularly at early gestational ages. These pathologic abnormalities could explain the various clinical manifestations in women with severe
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Table IV. Placental disease in preeclampsia versus normotensive control subjects Normotensive (n = 156) Arteriolopathy Hypermaturity of villi Intervillous thrombi Central infarction Fetal thrombi Abruptio placentae Chorioamnionitis Meconium staining
7 7 17 15 8 9 67 33
Preeclampsia (n = 158)
(4.5%) (4.5%) (10.9%) (9.6%) (5.1%) (5.8%) (42.9%) (21.2%)
72 52 30 59 21 12 26 31
Odds ratio (95% CI)
(45.6%) (32.9%) (19.0%) (37.3%) (13.3%) (7.6%) (16.5%) (19.6%)
23.80 12.39 1.95 5.90 2.84 1.34 0.24 0.92
(9.96-57.01) (5.26-29.16) (1.02-3.73) (3.12-11.14) (1.22-6.63) (0.55-3.29) (0.14-0.42) (0.51-1.66)
Table V. Placental disease according to gestational age at delivery in patients with preeclampsia Weeks gestation Disease
< 28 (n = 25)
Arteriolopathy Hypermaturity of villi Intervillous thrombi Central infarction Fetal thrombi Abruptio placentae Chorioamnionitis Meconium staining
21 14 7 15 5 2 2 1
28-32 (n = 45)
(84.0%) (56.0%) (28.0%) (60.0%) (20.0%) (8.7%) (8.0%) (4.0%)
23 24 5 24 5 4 3 4
33-36 (n = 36)
(51.1%) (53.3%) (11.1%) (53.3%) (11.1%) (9.5%) (6.7%) (8.9%)
18 12 8 10 6 2 4 7
$ 37 (n = 52)
(50.0%) (33.3%) (22.2%) (27.8%) (16.7%) (5.1%) (11.1%) (19.4%)
10 2 10 10 5 1 17 19
(19.2%) (3.8%) (19.2%) (19.2%) (9.6%) (1.9%) (32.7%) (36.5%)
P value < .0001 < .0001 .336 < .0001 .355 .114 .001 < .0001
Table VI. Placental disease according to gestational age at delivery in normotensive control subjects Weeks gestation Disease Arteriolopathy Hypermaturity of villi Intervillous thrombi Central infarction Fetal thrombi Abruptio placentae Chorioamnionitis Meconium staining
< 28 (n = 23) 1 1 2 1 1 2 16 1
(4.4%) (4.4%) (8.7%) (4.4%) (4.4%) (8.0%) (69.6%) (4.4%)
28-32 (n = 42) 4 3 2 4 2 3 17 3
(9.5%) (7.1%) (4.8%) (9.5%) (2.6%) (6.7%) (40.5%) (7.1%)
preeclampsia. For example, in some women with preeclampsia, the disease manifests with maternal factors such as uncontrolled hypertension or eclampsia. In other women, evidence of fetal compromise including intrauterine growth restriction or oligohydramnios can be seen. This is also the reason that women who have the disease early are more likely to be delivered preterm.7,8 Placental abnormalities tend to be more frequent and severe as compared with women who are allowed to be delivered at term. Moreover, our findings could explain the various success rates that are reported in the literature in women with severe preeclampsia remote from term being treated expectantly.5-7 If a woman has evidence of intrauterine growth retardation or oligohydramnios, the success rate of prolonging the gestation beyond 48 hours is minimal.8 We speculate that, in these women, the placental findings are so severe that prolonging the gestation will not be successful because most women will be delivered for fetal indications.
33-36 (n = 39) 2 (5.1%) 0 3 (7.7%) 6 (15.4%) 1 (2.6%) 4 (11.1%) 10 (25.6%) 5 (12.8%)
$ 37 (n = 52) 3 10 4 4 3 24 24
0 (5.8%) (19.2%) (7.7%) (7.7%) (5.8%) (46.2%) (46.2%)
P value .113 .890 .057 .711 .531 .839 .150 < 0.0001
Our findings are consistent with previous studies that have shown increased rates of vaso-occlusive lesions in the placentae of women with preterm preeclampsia.9-11 In the study by Teasdale,13 the placentas of women who were delivered at term with growth-restricted infants were compared with the placentas of normal term control subjects. He found that there were no significant pathologic differences between the preeclamptic placentae and the control placentae. Therefore, the hypothesis was that compensatory mechanisms exist to keep the disease from progressing to severe. We believe this to be true on the basis of our finding of decreased disease in our term placentas compared with the preterm placentas. Within the control group, women were delivered both at term and preterm for obstetric indications other than hypertensive disorders. Patients at term were mostly normal laboring women. Any patients who were delivered at early gestational ages are clearly not normal pregnancies and, by definition, will have underlying disease. These
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patients were delivered for indications that included spontaneous preterm labor, premature rupture of membranes, chorioamnionitis, abruptio placentae, and nonreassuring fetal status, among others. This is supported by our findings of a very high rate of chorioamnionitis in the control group. Therefore, they inherently have a pathologic process occurring that required early delivery. The fact that we did not find any statistical significance in the rate of abruptio placentae in women with preeclampsia versus normotensive control subjects is due to the increased disease in our control subjects, particularly chorioamnionitis, which is known to be associated with abruptio placentae.20 In summary, there are different pathologic mechanisms that are responsible for the placental findings in the term versus preterm placentae of women with preeclampsia. This could possibly be explained by the fact that, in the preeclamptic pregnancies that proceed to term, compensatory mechanisms exist to allow adequate uteroplacental blood flow and that those patients were delivered early may lack such compensatory mechanisms. These compensatory mechanisms may depend on the degree and severity of the lack of placental vascular adaptation early in pregnancy.
6.
7.
8.
9.
10.
11.
12.
13. 14.
15.
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