Severe preeclampsia in the second trimester: Recurrence risk and long-term prognosis

Severe preeclampsia in the second trimester: Recurrence risk and long-term prognosis

Severe preeclampsia in the second trimester: Recurrence risk and long-term prognosis Baha M. Sibai, MD, Brian Mercer, MD, and Cern Sarinoglu, MD Memph...

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Severe preeclampsia in the second trimester: Recurrence risk and long-term prognosis Baha M. Sibai, MD, Brian Mercer, MD, and Cern Sarinoglu, MD Memphis, Tennessee A total of 125 women with severe preeclampsia that developed in the second trimester underwent follow-up for an average of 5.4 years. Seventeen women had no further pregnancies and 108 had 169 subsequent pregnancies: 59 (35%) were normotensive and 110 (65%) were complicated by preeclampsia (32% of these developing in the second trimester, 32% at 28 to 36 weeks, and 36% at 37 to 40 weeks). Overall, 21% of subsequent pregnancies were complicated by severe preeclampsia in the second trimester. Forty-four patients (35%) had chronic hypertension, the highest incidence being in those with recurrent severe preeclampsia in the second trimester and the lowest in those with only normotensive subsequent pregnancies (67% vs 4%, P < 0.0001). Long-term maternal complications included two maternal deaths and two other patients with end-stage renal disease requiring dialysis. We conclude that these women are at increased risk for repeat preeclampsia, particularly in the second trimester, and are at increased risk for chronic hypertension and maternal mortality and morbidity. (AM J OSSTET GVNECOL 1991 ;165:1408-12.)

Key words: Preeclampsia, second trimester, recurrence, chronic hypertension Severe preeclampsia developing in the second trimester is a rare complication of pregnancy. These pregnancies are usually associated with increased perinatal mortality and morbidity. 1·3 In addition, such pregnancies are associated with significant maternal morbidity: pulmonary edema, disseminated intravascular coagulopathy, hypertensive encephalopathy, convulsions, and acute renal failure. 1, 2, 4 Counseling of the patient whose pregnancy is complicated by severe preeclampsia during the second trimester is a difficult task for the obstetrician, because there are no data regarding risk of recurrence and long-term maternal outcome. We previously reported that women having severe preeclampsia-eclampsia in their first pregnancy are at increased risk for having preeclampsia in subsequent pregnancies and at increased risk for chronic hypertension later in life. s However, very few patients studied in that report had severe preeclampsia in the second trimester. The purpose of this study is to report subsequent pregnancy outcome and remote maternal prognosis in 125 women with severe preeclampsia that developed in the second trimester.

Material and methods The study population consisted of 125 women who had severe preeclampsia during the second trimester From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Tennessee, Memphis. Received for publication December 12, 1990; revised April 1 ,1991; accepted April 10, 1991. Reprint requests: Baha M. Sibai, MD, 853 jefferson Ave., Room E102, Memphis, TN 38103. 6/1/30373

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(18 to 27 weeks' gestation). The diagnosis and management in these cases were previously described. 1. 2 All patients were delivered during the index pregnancy at the E.H. Crump Women's Hospital and Perinatal Center, Memphis. Patients with preexisting diabetes mellitus, connective tissue disease, or sickle cell disease and those with inadequate medical follow-up were excluded. Inclusion criteria included adequate medical follow-up for a minimum of 2 years after delivery of the index pregnancy. Pregnancy outcome in subsequent pregnancies was reviewed with regard to gestational age at time of delivery, incidence of preeclampsia, and perinatal outcome. Only pregnancies delivered beyond the first trimester are included in this analysis. The diagnosis of chronic hypertension was based on the presence of documented hypertension (either before index pregnancy or on follow-up) for which the patient received antihypertensive therapy. Maternal blood pressure measurements were performed with the patient in the sitting position after 5 minutes of quiet rest; the arm used was in a roughly horizontal position at heart level. The fifth (disappearance) Korotkoff sound was used to determine the diastolic blood pressure. All patient records were carefully and extensively reviewed by B.M.S. In the majority of cases (90%) the patients were seen and followed up by B.M.S. In other cases hospital records and the records of other medical providers were accepted only if they were determined to be adequate. Maternal blood pressure recordings were obtained at 6 to 8 weeks post partum and then once every year. Data analysis was done with the use of X2 and odds ratios; p < 0.05 was considered significant.

Vo lume 165 Nu mber 5. Part I

Subsequent outcome after second-trimester preeclampsia

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40 35

35

Normotensive

ISJ Preeclampsia

30 25

;:R. 0

20 15 10 5

0 $

27

28-36

37-40

Weeks' Gestation

Subsequent Pregnancy Outcome (n=169) Fig. I. Pregnancy outcome in 108 women who had subsequent pregnancies: 35 % were normotensive and 65% were complica ted by preeclampsia.

Results

Table I summarizes the clinical findings in the index pregnancy among the 125 women studied. The i2 5 women underwent follow-up for an average of 5.44 years (range, 2 to 12). Seventeen women had no further pregnancies, and 108 had 169 subsequent pregnancies (range, one tofour per patient). In 59 (35%) of these pregnancies the women were normotensive, whereas 110 (65%) were complicated by preeclampsia. Of those complicated by preeclampsia, it developed in the second trimester in 35 (32 %), at 28 to 36 weeks in 35 (32%), and at 37 to 40 weeks in 40 (36%) . Fig. 1 summarizes the overall incidence of preeclampsia in subsequent pregnancies according to gestational age at the time of onset. Overall, 21 % of subsequent pregnancies were complicated by severe preeclampsia in the second trimester. The 169 subsequent pregnancies resulted in 170 births (one set of twins). There were 22 stillbirths and six neonatal deaths, for an overall perinatal loss of 16.5 %. Eleven (6.5%) of the pregnancies were complicated by abru ptio placentae, and 39 (23%) were complicated by fetal growth retardation (birth weight < 10th percentile for gestational age). T able II summarizes the pregnancy outcome in subsequent pregnancies according to whether the women were normotensive or had preeclamps ia. T here were two perinatal deaths in the normotensive group; one was a stillbirth at 32 weeks' gestation (normal findings on autopsy), and one was a neonatal death after preterm delivery at 24 weeks' gestation due to premature rup-

Table I. Clinical findings at time of index pregnancy Maternal age (yr, mean!: SO) Maternal age <25 yr No .

%

Nu lli parous No. %

Black

No.

%

Gestational age at onset (wk. mean!: SO) Gestational age at deli very (wk, mean!: SO) Birth weight (gm, mean!: SO)

23.6 !: 4.9

80 64 101

80

83

66

25 .3 ± 1.7 26.8 ± 1.8 70 1 ± 173

ture of membranes. In addition, the majority of poor pregnancy outcomes in the preeclamptic group were in those who had repeat second-trimester preeclampsia. Atotal o f 44 patients had chronic hypertension; 21 of these women had chronic hypertension before the index pregnancy (one of them also had glomerulonephritis). T he other 23 patients had evidence of chronic hypertension on follow-up . The average time interval from delivery to the development of h ypertension in these patients was 6.1 years (range, 1 to 11 ). Seven (41 %) of the 17 women with no subsequent pregnancies had chronic hypertension; six of these had chron ic hypertension before the index pregnancy and the other patients had chronic hypertension on follow-

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November 1991 Am J Obstet Gynecol

Table II. Pregnancy outcome in subsequent pregnancies Intrauterine growth retardation No.

Normotensive Preeclampsia ~27 wk* 28-36 wk 37-40 wk

I

4 35 20 11 4

Perinatal loss

%

No.

6.8 31.5 55.1 31.4 10

2 26 23 3 0

I

Abruptio placentae

%

No.

3.4 23.4 63.9 8.6

1 10 5 3 2

I

% 1.7 9.1 14.3 8.6 5.0

*n = 36 (one set of twins).

Table III. Presence of chronic hypertension according to subsequent pregnancy outcome (N = 108 women) Chronic hypertension Outcome

Normotensive Preeclampsia ~27 wk 28-36 wk 37-40 wk

*p <

No. of patients

No.

I

4*

25 83 27 30 26

%

36 18 12 6

43 67* 40 23

0.0001; odds ratio, 48: 1.

Table IV. Development of chronic hypertension on follow-up according to subsequent pregnancy outcome (N = 93*) Chronic hypertension Outcome

Normotensive Preeclampsia ~27 wk 28-36 wk 37-40 wk

No. of patients

No.

25 68 20 25 23

I

% 4t

21 11 7 3

31 55t 28 19

*Excludes 15 patients with previous chronic hypertension. tp < 0.0002; odds ratio, 29.3: 1.

up. On the other hand, 37 (34%) of the 108 with subsequent pregnancies had chronic hypertension, 15 before the index pregnancy, whereas the other 22 patients had chronic hypertension on follow-up. A total of 93 patients without evidence of chronic hypertension before the index pregnancy had subsequent pregnancies on follow-up. Eighty-nine were normotensive, and four had persistent elevations of blood pressure 6 to 8 weeks after delivery of the index pregnancy. The latter four patients had chronic hypertension that developed after 1 to 3 years of follow-up. The remaining 89 patients who were normotensive post par-

tum had a total of 130 subsequent pregnancies. In 58 (45%) of these pregnancies the women were normotensive, whereas 72 (55%) pregnancies were complicated by preeclampsia. Among these, preeclampsia developed in the second trimester in 20 (28%), at 28 to 36 weeks in 25 (35%) and at 37 to 40 weeks in 27 (37%). Table III describes the frequency of chronic hypertension, according to subsequent pregnancy outcome among the 108 women studied. The incidence of chronic hypertension was significantly higher in those women, who had subsequent preeclampsia than in those who were normotensive in subsequent pregnancies (43% vs 4%, P < 0.0001; odds ratio, 18.4: 1). The highest incidence of chronic hypertension was in those women with recurrent severe preeclampsia in the second trimester (67%). The data were subsequently analyzed after the 15 women who had chronic hypertension before the index pregnancy were excluded. Table IV describes the incidence of chronic hypertension diagnosed on followup, according to outcome in subsequent pregnancies. Again, the incidence of chronic hypertension was significantly higher in women who had subsequent preeclampsia as compared with those with only normotensive subsequent pregnancies (31 % vs 4%, P < 0.005; odds ratio, 10.7: 1). In addition, the highest incidence of chronic hypertension was among women with recurrent severe preeclampsia in the second trimester (55%). In four patients serious maternal complications developed during the follow-up period; two of them died and two patients had end-stage renal disease necessitating dialysis. All four patients had long-standing chronic hypertension, and three of the four had the index pregnancy complicated by abruptio placentae, fetal death, disseminated intravascular coagulation, and acute renal failure. One patient had acute renal failure caused by bilateral cortical necrosis immediately after delivery of the index pregnancy. This patient had no subsequent pregnancies. The other three patients had subsequent pregnancies that were complicated by severe preeclampsia in the second trimester; one of them died of a cerebrovascular accident 5 years after

Volume 165 Number 5, Part I

the index pregnancy (3 months after the recurrent second-trimester preeclampsia). One patient had three consecutive pregnancies complicated by preeclampsia in the second trimester (two of which also were complicated by acute renal failure). She required dialysis 7 years after the index pregnancy and eventually died at 9 years 5 months after the first episode. In the remaining patient with preexisting glomerulonephritis end-stage renal disease developed about 2Y2 years after the index pregnancy and is currently on dialysis after 5 years of follow-up.

Comment Two recent studies revealed that women who have preeclampsia in their first pregnancy are at increased risk for having preeclampsia in subsequent pregnancies. 5 . 6 In addition, both studies found that the risk of having preeclampsia in subsequent pregnancies is related to the time of onset of preeclampsia during the first pregnancy. However, neither of these studies described the risks for women with severe preeclampsia that develops in the second trimester. The results of this study show that women with severe preeclampsia that develops in the second trimester are at very high risk for severe preeclampsia in subsequent pregnancies. In such women 65% of all subsequent pregnancies were complicated by preeclampsia. It is important to emphasize that 21 % of all subsequent pregnancies were complicated by severe preeclampsia in the second trimester and 2 I % were complicated by severe preeclampsia at 28 to 36 weeks' gestation. Thus these patients should be informed of the high likelihood of severe preeclampsia and poor perinatal outcome in subsequent pregnancies. Women considering pregnancy should be instructed to seek prenatal care early in the first trimester. In addition, they should be seen more frequently, starting in the second trimester, so that the onset of hypertension can be detected as early as possible. Moreover, such patients might be good candidates for receiving low-dose aspirin during pregnancy to prevent the onset of early preeclampsia.? Patients with severe preeclampsia that develops remote from term are at increased risk of chronic hypertension and undiagnosed underlying renal disease.'. 6. 8.9 Ihle et aL8 studied renal function at 6 weeks to 6 months post partum in 84 patients with severe preeclampsia that developed at 24 to 36 weeks' gestation. Maternal evaluation included a 24-hour urine study, urine microscopy, intravenous pyelography, and renal biopsy when appropriate. The authors found a high incidence of renal disease and essential chronic hypertension (90%). In two thirds of these patients the lesion was glomerulonephritis, mostly of the immunoglobulin A variety. They concluded that such women usually have underlying renal disease that should be

Subsequent outcome after second-trimester preeclampsia

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evaluated after delivery. In contrast, Lin et aL 9 reported on the pregnancy outcome and prognosis in 157 women in whom the etiology of hypertensive complications of pregnancy was determined by postpartum renal biopsies. The authors found that most of the women (62%) who were delivered before 37 weeks' gestation had the renal resion of preeclampsia. The results of this study show that patients having severe preeclampsia in the second trimester have a significantly high incidence of chronic hypertension. This incidence is significantly higher in those having subsequent hypertensive pregnancies. In addition, the incidence is highest in those with severe preeclampsia that again develops in the second trimester. On the other hand, patients who are normotensive in subsequent pregnancies have an extremely low incidence of chronic hypertension on follow-up (Table IV). This information may be useful for the counseling of such patients about subsequent medical follow-up . It is important to emphasize that women having severe preeclampsia in the second trimester are at increased risk for long-term maternal morbidity or for mortality. Two of these women died; one death was due to a cerebrovascular accident and one was a result of end-stage renal disease. In addition, end-stage renal disease necessitating dialysis developed in two other patients. All four serious complications developed in women with long-standing, preexisting chronic hypertension. Interestingly, only three of these four patients had subsequent pregnancies, and all subsequent pregnancies were complicated by severe preeclampsia in the second trimester. Thus such patients should be informed about these risks and should be counseled regarding close medical follow-up in the future. In summary, patients with severe preeclampsia that develops in the second trimester should be considered at increased risk for severe preeclampsia in subsequent pregnancies and at increased risk for chronic hypertension . In addition, women with recurrent severe preeclampsia that develops in the second trimester are at increased risk for maternal mortality and morbidity later in life. REFERENCES 1. Sibai BM, Taslimi M, Abdella TN, Brooks TF, et al. Maternal and perinatal outcome of conservative management of severe preeclampsia in midtrimester. AM J OBSTET GvNECOL 1985;152:32-7. 2. Sibai BM, Akl S, Fairlie F, Moretti M. A protocol for managing severe preeclampsia in the second trimester. AM J OBSTET GVNECOL 1990; 163:733-8. 3. Odendaal HJ, Pattinson RC, Dutoit R. Fetal and neonatal outcome in patients with severe preeclampsia before 34 weeks. S Afr Med J 1987;71:555-8. 4. Sibai BM, Villar MA , Mabie Be. Acute renal failure in hypertensive disorders of pregnancy. AM J OBSTET Gv-· NECOL 1990;162:777-83. 5. Sibai BM, EI-Nazer A, Gonzalez-Ruiz A. Severe preeclampsia-eclampsia in young primigravid women: subsequent

Sibai, Mercer, and Sarinoglu

pregnancy outcome and remote prognosis. AM J OBSTET GVNECOL 1986;155:1011-6. 6. Lindeberg S, Axelsson 0, Jomer U, et al. A prospective controlled five-year followup study of primiparas with gestational hypertension. Acta Obstet Gynecol Scand 1988;67:605-9. 7. Beaufils M, Donsimoni R, U zan S, et al. Prevention of pre-

November 1991 Am J Obstet Gynecol

eclampsia by early antiplatelet therapy. Lancet 1985;2: 840-2. 8. Ihle BU, Long P, Oats J. Early onset preeclampsia: recognition of underlying renal disease. BMJ 1987 ;294:79-81. 9. Lin CC, Lindheimer MD, River P, Moawad AH. Fetal outcome in hypertensive disorders of pregnancy. AM J OBSTET GVNECOL 1982;142:255-60.

A case report of prostaglandin E2 termination of pregnancy complicated by Cushing's syndrome Monica A. Buescher, MD, Howard D. McClamrock, MD, and Eli Y. Adashi, MD Baltimore, Maryland A case of Cushing's syndrome caused by an adrenal adenoma seen at 10 weeks' gestation is described. The pregnancy was terminated at 18 weeks' gestation, representing the first reported case of therapeutic termination of pregnancy in Cushing's syndrome with prostaglandin E2 vaginal suppositories. (AM J OBSTET GVNECOL 1991;165:1412-3.)

Key words: Cushing's syndrome in pregnancy, hypertension in pregnancy A case of Cushing's syndrome associated with an adrenal adenoma at 10 weeks' gestation is reported.

Case report A 28-year-old black woman, gravida 3, para 2, was referred to University Hospital for termination of pregnancy at 13 weeks' gestation with a presumptive diagnosis of Cushing's syndrome. The patient was first admitted to a community hospital at 10 weeks' gestation for evaluation of hypertension. At this time blood pressure was 206/150 mm Hg with otherwise unremarkable findings at physical examination. She denied any history of hypertension or serious medical illness and had last been examined by a physician 7 months earlier. Menses had been regular to date. Laboratory parameters were obtained; hemoglobin value, serum electrolyte levels, serum creatinine level, creatinine clearance value, and thyroid and liver function test results were normal. One-hour glucose tolerance testing with a 50 gm load was elevated at 176 mgl dl. Twenty-four-hour urinary metanephrine levels were normal. Evaluation From. the Department of Obstetrics and Gynecology, University of Maryland School of Medicine. Received for publication March 12, 1991; revised April 19, 1991; accepted April 24, 1991. Reprint requests: Howard D. McClamrock, MD, Assistant Professor, Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, The University of Maryland, 22 S. Greene St., Baltimore, MD 21201. 6/1130676

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of the adrenal axis revealed an evening serum cortisol level of 33.1 IJ-gi dl, 24-hour urinary free cortisol level of 1000 IJ-g, and a 24-hour urinary 17 -hydroxycorticosteroid value of 13.1 mg. These values were interpreted as normal for pregnancy. The patient was discharged after antihypertensive therapy was adequately established. She was seen by the visiting obstetric consultant in the outpatient clinic at 13 weeks' gestation. The patient appeared lethargic and admitted to easy fatigability. Blood pressure was poorly controlled at 1801120 mm Hg. Physical examination was unchanged except for the presence of moon facies and purple striae over the abdomen and upper and lower extremities. The abdomen was protuberant. Presumptive diagnosis of Cushing'S syndrome was made on the basis of the findings at physical examination and the previously determined adrenal studies. The patient indicated at this time her wish to terminate the pregnancy, and she was referred to the tertiary care center for continuing evaluation and pregnancy termination. The patient was lost to follow-up until 17 weeks' gestation, at which time she was admitted to University Hospital. Biochemical evaluation revealed frank diabetes with fasting blood glucose levels of 150 to 200 mg/dl. Repeat evaluation of adrenal function confirmed the previously noted elevation: Diurnal variation of serum cortisol was abolished with a morning level of 71.8 mg/dl and an evening level of 59.6 mg/dl. Twenty-four-hour urinary free cortisol level