Hypertension in pregnancy: maternal and fetal outcomes according to laboratory and clinical features

With the current emphasis on outpatient management of pregnant women with non-proteinuric hypertension,² clinicians require readily available clinical and laboratory parameters as indicators of the likely outcome of pregnancies complicated by hypertension. Such information is often difficult to obtain because of the selective nature of cases and complications reported by high-risk tertiary-care obstetric units, and is confounded by the varying treatments given to pregnant women before referral.^3,4

Our study examined prospectively the maternal and fetal outcomes in women with hypertension in pregnancy, and the associated clinical and laboratory features. In particular, we sought to determine whether complications were greater if the woman had hyperuricaemia, severe hypertension and/or proteinuria, was nulliparous, or presented with hypertension early in the pregnancy. We also sought to determine which clinical and laboratory features were associated with severe pre-eclampsia.

Indications for referral were:

• Hypertension failing to settle after overnight rest in hospital, or repeated measurement in a day-only unit;

• The presence of proteinuria or other abnormal urinalysis, abnormal biochemistry (serum electrolytes and creatinine levels, liver function tests) or thrombocytopenia;

• Recurrent admissions for hypertension; or

• A suspected secondary cause for hypertension.

The definitions, classifications and complications of hypertension in pregnancy used in our study were those of the Australasian Society for the Study of Hypertension in Pregnancy (ASSHP) (Boxes 1 and 2).⁵

The maternal biochemical and haematological data used in our analysis were those recorded immediately before delivery. Complications were those having occurred by the time of discharge from hospital or by the postpartum check-up (after three months).

Each patient's management was overseen by one physician (M A B) in conjunction with the patient's obstetrician. A standardised management protocol was followed by all staff during the course of this study (Box 3).

For initial bivariate analyses, the frequency of adverse events within groups was tested by χ² analysis and, where significant, by 2 x 2 contingency tables. Biochemical and haematological indices and birthweights were compared using Student's t tests, and significance assessed using Hochberg's method for interpreting multiple comparisons.

The maternal-outcome variable was severity of pre-eclampsia. Logistic regression analysis was used to analyse the following variables as predictors of severe pre-eclampsia: parity; gestation at presentation; age; plasma uric acid level; serum albumin, haemoglobin and haematocrit levels; and diabetes. Proteinuria, platelet count and serum creatinine levels were not analysed because abnormalities of these form part of the diagnosis of severe pre-eclampsia.

Fetal-outcome variables were birthweight, small-for-gestational-age (SGA) and perinatal mortality (PNM). Each of the following variables was analysed as a predictor of poor fetal outcome: maternal complications, age, parity, diabetes, gestation at presentation and laboratory data. Multiple regression analysis was used for birthweight and logistic regression analysis for SGA and PNM.

For regressions, backward elimination was used until all remaining predictors were statistically significant (P < 0.05).

There were 825 women (70%) with pre-eclampsia (mild, 502; severe, 323), 82 (7%) with superimposed pre-eclampsia, 223 (19%) with essential hypertension, and 53 (4%) with secondary hypertension (predominantly renal disease).

Oral antihypertensive medications were given to 563 women (48%), additional parenteral antihypertensives were required by 281 (24%), and 339 (29%) received no antihypertensive medications. Thirteen women (1%) received "prophylactic" low-dose aspirin.

Five women (0.4%) required dialysis during or after pregnancy and four women (0.3%) had convulsions. Seventy-three women (6%) had pre-existing or gestational diabetes mellitus.

Of the 1242 babies born to the women in the study, there were 15 perinatal deaths (12 per 1000 hypertensive pregnancies). There was one maternal death (0.08%) in a 29-year-old woman who presented at 29 weeks' gestation with severe pre-eclampsia and who delivered immediately and died unexpectedly the next day. Despite autopsy, the cause of death was not established.

Severe hypertension was significantly associated with higher maternal complication rates and earlier gestation at delivery than mild hypertension (Box 4). This group of women had babies of a lower average birthweight, a higher proportion of SGA babies and a higher perinatal mortality rate.

Proteinuria was significantly associated with similar maternal and fetal complication rates as severe hypertension, and the proportion of SGA babies was similar to non-proteinuric hypertension (Box 4).

Parity did not affect maternal complication rates, except for a higher prevalence of severe hypertension and liver disease in nulliparae (Box 5).

Early gestation at presentation with hypertension (at or before 32 weeks' gestation) was significantly associated with a higher prevalence of proteinuria than later presentation (Box 5).

Multivariate analysis
Severe pre-eclampsia was associated with low serum albumin (odds ratio [OR], 0.93; 95% confidence interval [CI], 0.90-0.97; P = 0.0001), primiparity (OR, 0.51; 95% CI, 0.33-0.79; P = 0.002) and the absence of diabetes (OR, 0.21; 95% CI, 0.05-0.93; P = 0.04).

SGA was associated with severe pre-eclampsia (OR, 2.5; 95% CI, 1.6-3.9; P = 0.0001), high maternal haemoglobin levels (OR, 3.7; 95% CI, 1.1-12.8; P = 0.04) and low platelet counts (OR, 1.4; 95% CI, 1.1-1.8; P = 0.02).

Birthweight was positively associated with gestation at presentation (regression coefficient [β], 41; standard error [SE], 5; P < 0.0001) and serum albumin levels (β, 28; SE, 5; P < 0.0001) and inversely associated with severe hypertension (β, 2193; SE, 69; P < 0.005) and severe pre-eclampsia (β, 2311; SE, 60; P < 0.0001).

Perinatal mortality was associated only with low serum albumin levels (OR, 0.88; 95% CI, 0.82-0.95; P < 0.0003), but there were too few perinatal deaths to support a useful formal analysis.

Maternal and fetal outcomes were better for women with essential hypertension than for the other groups. Twenty-seven per cent (or 10% if proteinuria was included in the diagnosis) of women with essential hypertension developed superimposed pre-eclampsia.

Women with superimposed pre-eclampsia delivered their babies earlier, had babies with lower average birthweights, significantly more SGA babies and significantly higher rates of all maternal complications than women with essential hypertension alone.

Women with secondary (predominantly renal) hypertension had similar maternal and fetal outcomes to women with superimposed pre-eclampsia (data available from author).

During the study period, 12% of all confinements were complicated by hypertension, which is either similar to or higher than previous reports.^8-11 Hjertberg et al. noted a 5% incidence of hypertension in pregnancy, of whom 83% had hypertension de novo in pregnancy.¹² In our study, 70% of women had pre-eclampsia (hypertension de novo in pregnancy), 19% had essential hypertension alone, 7% had superimposed pre-eclampsia, and 4% had a renal or other secondary cause. These results are similar to those from a smaller study in a tertiary referral unit.¹³

When analysed separately, hyperuricaemia, proteinuria and severe hypertension were associated with higher rates of all maternal and fetal complications, while parity was associated with severe hypertension and liver disease. Presentation before 32 weeks' gestation impacted negatively on fetal outcome. We have reported previously on the adverse impact of proteinuria on maternal and fetal outcomes.¹⁴

Hyperuricaemia is an established marker of severe pre-eclampsia, correlating histologically with the severity of renal lesions,¹⁵ and clinically with adverse fetal outcomes.¹⁶ We found that hyperuricaemia, when considered alone, was associated with higher maternal complication rates and fetal growth retardation, but, with multivariate analysis, was not a significant predictor of adverse maternal or fetal outcomes. Hyperuricaemia remains a useful marker of pre-eclampsia, but women with normal serum uric acid levels and pre-eclampsia may still develop complications.

Severe hypertension was confirmed by multivariate analysis to be associated with low birthweight babies, and, in univariate analysis, with a higher incidence of all fetal complications and a higher incidence of SGA babies. Therefore, the more severe the hypertension, the more the likelihood of fetal as well as maternal complications.

Pre-eclampsia has long been considered a disorder of primigravidae.¹⁷ However, it is clear that pre-eclampsia does occur in second or subsequent pregnancies (particularly following a change of partner); in our study, approximately two-fifths of the women with pre-eclampsia were parous women. Parous women had a lower incidence of severe hypertension and liver disease when compared with nulliparae, but there were no other differences in outcomes between these groups. Therefore, equal risk to the fetus should be assumed in both groups of women once hypertension has developed in the second half of pregnancy.

The gestation at presentation in pre-eclampsia influences fetal outcome because of the likelihood of early delivery, but we are unaware of any prospective studies that relate gestation at presentation to maternal complication rates. Apart from proteinuria, maternal complication rates for women presenting before 33 weeks' gestation in our study were similar to those who presented later. Two retrospective studies have reported a higher incidence of maternal complications in women with pre-eclampsia of early onset.^18,19 Our patients presenting early with pre-eclampsia had milder disease than that reported by Sibai et al.²⁰ As expected, the earlier the gestation with pre-eclampsia the lower the birthweight (because gestation did not proceed as far as those presenting later), but the likelihood of having an SGA baby was not increased.

Although maternal diabetes was associated with a lower risk of severe pre-eclampsia, only 6% of our study population had diabetes. Therefore, it should not be assumed that diabetes protects pregnant women against severe pre-eclampsia.

The consistent relationship between low serum albumin levels and adverse maternal and fetal outcomes was independent of proteinuria and implies that hepatic albumin synthesis is altered in severe pre-eclampsia. The association between high maternal haemoglobin levels and SGA babies presumably reflects a reduced plasma volume and haemoconcentration, which is associated with poor fetal growth.²¹

In conclusion, for women with pre-eclampsia, the traditional clinical markers of proteinuria, parity and severe hypertension remain useful clinical indices of maternal risk, while severe pre-eclampsia, severe hypertension, elevated haemoglobin and low serum albumin levels portend increased fetal risk.

1. Crawford JS. Epidemic pre-eclampsia. Lancet 1987; 1: 329-330.
2. Tuffnell DJ, Lilford RJ, Buchan PC, et al. Randomised controlled trial of day care for hypertension in pregnancy. Lancet 1992; 339: 224-227.
3. Horvath JS, Korda A, Child A, et al. Hypertension in pregnancy. A study of 142 women presenting before 32 weeks' gestation. Med J Aust 1985; 143: 19-21.
4. Clarke M, Mason ES, Macvicar J, Clayton DG. Evaluating perinatal mortality rates: effects of referral and case mix. BMJ 1993; 306: 824-827.
5. Australasian Society for the Study of Hypertension in Pregnancy. Consensus Statement on Management of Hypertension in Pregnancy: Executive Summary. Med J Aust 1993; 158: 700-702.
6. Minitab [computer program], version 9.1. Pennsylvania State College: Minitab Inc, 1993.
7. BMDP [computer program]. Berkeley, Calif: University of California, 1990.
8. Martikainen AM, Heinonen KM, Saarikoski SV. The effect of hypertension in pregnancy on fetal and neonatal condition. Int J Gynaecol Obstet 1989; 30: 213-220.
9. Andrews WW, Cox SM, Sherman ML, Leveno KJ. Maternal and perinatal effects of hypertension at term. J Reprod Med 1992; 37: 73-76.
10. Safflas AF, Oldson DR, Franks AL, et al. Epidemiology of pre-eclampsia and eclampsia in the United States, 1979-1986. Am J Obstet Gynecol 1990; 163: 460-465.
11. Pietrantoni M, O'Brien WF. The current impact of the hypertensive disorders of pregnancy. Clin Exp Hypertens 1994; 16: 479-492.
12. Hjertberg R, Bellrage P, Hanson U. Conservative treatment of mild and moderate hypertension in pregnancy. Acta Obstet Gynecol Scand 1992; 71: 439-446.
13. Horvath JS, Phippard A, Henderson-Smart D, et al. High risk hypertensive pregnancies: maternal and foetal outcome. Clin Exp Hypertens Pregnancy 1983; B2: 21-28.
14. Brown MA, Buddle ML. The importance of non proteinuric hypertension in pregnancy. Hypertens Pregnancy 1995; 14: 57-65.
15. Pollak VE, Nettles JB. The kidney in toxemia of pregnancy: a clinical and pathologic study based on renal biopsies. Medicine (Baltimore) 1960; 39: 469-526.
16. Redman CWG, Beilin LJ, Bonnar J, Wilkinson PH. Plasma urate measurements in predicting fetal death in hypertensive pregnancy. Lancet 1976; 2: 1370-1373.
17. Chesley LC. Diagnosis of pre-eclampsia. Obstet Gynecol 1985; 65: 423-425.
18. Sibai BM, Taslimi M, Abdella TN, et al. Maternal and perinatal outcome of conservative management of severe pre-eclampsia in midtrimester. Am J Obstet Gynecol 1985; 152: 32-37.
19. Railton A, Allen DG. Management and outcome of pregnancy complicated by severe pre-eclampsia of early onset. S Afr Med J 1987; 72: 608-610.
20. Sibai BM, Mercer BM, Schiff E, Friedman SA. Aggressive versus expectant management of severe pre-eclampsia at 28 to 32 weeks' gestation: a randomized controlled trial. Am J Obstet Gynecol 1994; 171: 818-822.
21. Brown MA, Zammit VC, Mitar DM. Extracellular fluid volumes in pregnancy-induced hypertension. J Hypertens 1992; 10: 821-829.

No reprints will be available.
Correspondence: Associate Professor M A Brown, Department of Renal Medicine, St George Hospital, Kogarah, NSW 2217.
E-mail: "nest::brown"ATdodo.ssahs.unsw.edu.au