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Eur. J. Obstet. Gynecol. Reprod. Biol., 23 (1986) 341-348 Elsevier 341 EJOOO400 Factors predictive of perinatal outcome in pregnancies complicated by hypertension P.-F. Plouin, G. Chatellier, G. B&art, D. Hillion, A. Moynot, C. Tchobroutsky, M. Beaufils, S. Uzan and P. Blot Department of Hypertension, Hspital Broussais, Paris, Groupe de Recherches Epidemiologiques SW la Mere et I’Enfani (INSERM U-149). Paris, France, Department of Nephrology, H??pital Intercommunal, Poissy, Departments of Obstetrics, H;pital Saint Vincent de Paul and Hspital du Port-Rqyal, Paris, France, Departments of Nephrologv and Obstetrics, Hi?piral Tenon, Paris, France, and Unique Universitaire Baudelocque, Paris. France Accepted for publication 27 August 1986 Summary Perinatal outcome and various indicators of perinatal risk were analyzed in a prospective study of 268 pregnant women with hypertension. Poor perinatal out- come was defined by stillbirth (n = 13), neonatal death (n = 2), and in surviving babies, by birth before 32 weeks or a birthweight below 1500 g (n = 13). In multivariate analysis, proteinuria and onset of hypertension between the 27th and 36th weeks of amenorrhea were the only two independent indicators of poor outcome (relative risks of 4.0 and 3.7, p < 0.001 and p < 0.01 respectively). Both these indicators were more frequent in mothers with no history of pre-pregnancy hypertension. Hypertension; Perinatal mortality and morbidity; Plasma urate concentration; Proteinuria; Relative risk Intruduction Hypertension, which occurs frequently during pregnancy [l-4], is considered by a World Health Organization Expert Committee to be the major cause of premature birth and perinatal death [5]. However, hypertension in pregnancy is a complex disease whose outcome cannot be precisely predicted from maternal blood pressure. Poor perinatal outcome is more reliably predicted by the occurrence of proteinuria Correspondence: Pierre-Frmpis Plouin, Department of Hypertension, HiSpita Broussais, 96 rue Didot, 75674 Paris Cedex 14, France. 0028-2243/86/$03.50 0 1986 Elsevier Science Publishers B.V. (Biomedical Division)

Factors predictive of perinatal outcome in pregnancies complicated by hypertension

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Eur. J. Obstet. Gynecol. Reprod. Biol., 23 (1986) 341-348

Elsevier

341

EJOOO400

Factors predictive of perinatal outcome in pregnancies complicated by hypertension

P.-F. Plouin, G. Chatellier, G. B&art, D. Hillion, A. Moynot, C. Tchobroutsky, M. Beaufils, S. Uzan and P. Blot

Department of Hypertension, Hspital Broussais, Paris, Groupe de Recherches Epidemiologiques SW la Mere et I’Enfani (INSERM U-149). Paris, France, Department of Nephrology, H??pital Intercommunal, Poissy,

Departments of Obstetrics, H;pital Saint Vincent de Paul and Hspital du Port-Rqyal, Paris, France,

Departments of Nephrologv and Obstetrics, Hi?piral Tenon, Paris, France,

and Unique Universitaire Baudelocque, Paris. France

Accepted for publication 27 August 1986

Summary

Perinatal outcome and various indicators of perinatal risk were analyzed in a prospective study of 268 pregnant women with hypertension. Poor perinatal out- come was defined by stillbirth (n = 13), neonatal death (n = 2), and in surviving babies, by birth before 32 weeks or a birthweight below 1500 g (n = 13). In multivariate analysis, proteinuria and onset of hypertension between the 27th and 36th weeks of amenorrhea were the only two independent indicators of poor outcome (relative risks of 4.0 and 3.7, p < 0.001 and p < 0.01 respectively). Both these indicators were more frequent in mothers with no history of pre-pregnancy hypertension.

Hypertension; Perinatal mortality and morbidity; Plasma urate concentration; Proteinuria; Relative risk

Intruduction

Hypertension, which occurs frequently during pregnancy [l-4], is considered by a World Health Organization Expert Committee to be the major cause of premature birth and perinatal death [5]. However, hypertension in pregnancy is a complex disease whose outcome cannot be precisely predicted from maternal blood pressure. Poor perinatal outcome is more reliably predicted by the occurrence of proteinuria

Correspondence: Pierre-Frmpis Plouin, Department of Hypertension, HiSpita Broussais, 96 rue Didot,

75674 Paris Cedex 14, France.

0028-2243/86/$03.50 0 1986 Elsevier Science Publishers B.V. (Biomedical Division)

342

[2,3] or high plasma urate levels [6] than by blood pressure levels. The time at which blood pressure rises above normal levels could also have some prognostic implica- tions. In a prospective survey of 2996 mothers documented as normotensive in early pregnancy, some of us found that in cases subsequently complicated by gestational hypertension, fetal growth retardation was more frequent when hypertension began early in the third trimester than when it began in the second trimester or later than the 35th week of amenorrhea [7]. However, urate levels were not studied in this survey, nor could the prognostic value of the data of onset of hypertension be extrapolated to other groups of pregnant women or to more severe criteria of poor perinatal outcome.

We therefore planned a prospective, cooperative study to examine, in relation to perinatal outcome, the evolution of blood pressure levels, plasma urate concentra- tions, and, proteinuria in pregnancies complicated by hypertension, whether gesta- tional or diagnosed before pregnancy.

Patients and methods

The maternity wards of five obstetric units in or near Paris were asked to refer pregnant hypertensive women to one of the five physicians cooperating in the study. The criteria used to select subjects for this study were (1) mother’s knowledge of at least one blood pressure reading before pregnancy, (2) two blood pressure readings during the current pregnancy of 140/90 mmHg or more before referral, (3) referral before the termination of pregnancy, and (4) a singleton pregnancy.

Medical history (including blood pressure during the 12 months before preg- nancy, and history of hypertension), obstetric history, blood pressure, proteinuria and plasma urate concentrations during pregnancy and after delivery, and items relevant to perinatal outcome were collected in a computerized record. In accor- dance with WHO recommendations for pregnant patients [5], blood pressure was measured in the sitting position with a mercury sphygmomanometer, diastolic blood pressure being recorded at the muffling of sounds. Proteinuria was considered present when a dip-test gave a positive reaction of 2 + or more. Gestational hypertension was defined by the absence of a personal history of hypertension outside pregnancy or oral contraception, whereas chronic hypertension was defined as a positive history. The time of onset of hypertension was defined as the gestational age, in weeks of amenorrhea, at the first blood pressure reading of 140/90 mmHg or more without treatment, or at the beginning of antihypertensive treatment. Poor perinatal outcome was defined .either by perinatal death, or, in surviving babies, by a birthweight of less than 1500 g, and/or a gestational age at birth of 32 weeks or less.

Poor or favorable outcomes and cases of gestational or chronic hypertension were compared using a r-test for quantitative variables and either a x2 test or a Fisher exact test for qualitative variables. The parameters which were shown to be significantly correlated with outcome in the univariate analysis were combined, using stepwise logistic regression analysis [8], in order to assess which set of parameters best predicted a poor fetal outcome.

343

Results

Between June 1982 and June 1983, 315 mothers were referred. Twenty-six records

were excluded because they concerned either mothers unaware of any blood pressure reading before pregnancy (n = 13) or twin pregnancies (n = 13). Twenty-one

eligible mothers (7.3%) were lost to follow-up before delivery. These mothers did not differ significantly from those included in the study as regards mean age (30.3 _+ 4.2

vs. 29.5 f 5.2 yr), parity (rate of primigravidae: 47.6% vs. 38.4%) or the proportion

with chronic hypertension (47.6% vs. 34.0%).

Pregnancy was terminated by spontaneous abortion in three cases and by

stillbirth (n = 13) or neonatal death (n = 2) in fifteen. Thirteen surviving newborns

were severely premature or underweight (born at or before the 32nd week or below

1500 g). In Table I, 265 pregnancies (excluding the 3 abortions) are classified according to

perinatal outcome. Gestational hypertension, a first reading above 140/90 mmHg between weeks 27 and 36, proteinuria, and plasma urate concentrations above 360

pmol/l were more frequent in pregnancies with poor outcome than in the others

(p -c 0.001). The presence of a plasma urate concentration of 360 pmol/l or more was closely associated with the presence of proteinuria (x2 = 45.3, p < 0.001). Poor outcome was also associated with lower systolic pressure levels at booking ( p = 0.02)

higher maximum blood pressure levels in pregnancy (p -c O.OOl), later onset of

TABLE I

Items associated with perinatal outcome

A poor outcome was defined as death, birthweight < 1500 g, and/or gestational age at birth 5 32 weeks.

Results are expressed as means rf SD or the number (W) of pregnancies.

Poor outcome Good outcome p

(n=28) (n = 237)

No. (%) with

gestational hypertension

Blood pressure at

booking (mmHg)

at week

Onset of hypertension at week

No. (%) with onset in weeks 28-35

Highest blood pressure (mmHg)

at week

No. (%) given hypotensive drugs

started at week

Post-natal blood

pressure (mmHg)

No. (%) with a proteinuria 2 2 +

Maximum plasma urate (rmol/l) a

No. (%) with plasma

mate z 360 pmol/l a

27 (96.4)

125/78+_ 15/12

8.3 I 6.2

26.5 + 7.8

15 (53.6)

187/113 k 29/20

28.2 i 8.5

18 (64.3)

26.4k6.3

130/79* 21/13

17 (60.7)

392 + 100

13 (59.1)

148 (62.4)

134/82+_ 19/13

9.1 i 5.0

18.7& 12.5

35 (14.8)

164/‘101 k 20/12

27.3 k 11.6

186 (7X.5)

21.0+ 13.1

134/83 f 17,‘12

43 (18.1)

304 & 88

41 (20.3)

< 0.001

0.02 NS

NS

i 0.01

i 0.001

< O.OOl/ < 0.001

NS

NS

< 0.01

NS/NS

< 0.001

< 0.001

i 0.001

’ Plasma urate concentrations not available in 41 cases.

344

TABLE II

Parameters predictive of poor perinatal outcome

Stepwise logistic analysis of 216 records with complete data.

Parameter Regression coefficient

Proteinuria 2 2+ 0.687 Onset of hypertension

during weeks 28-35 0.650 Plasma urate

concentration 2 360 pmol/l 0.474

’ 95% confidence limits of relative risk in parentheses.

Relative risk ’

4.0 (1.3-12.4)

3.7 (1.3-10.8)

2.6 (0.8-7.9)

p value

c 0.001

< 0.01

0.08

TABLE III

Perinatal outcome, parameters predictive of poor perinatal outcome, and various characteristics of mothers with gestational and chronic hypertension

Results expressed as means+ SD or the number (W) of mothers.

Gestational hypertension (n =177)

Chronic P hypertension (n = 91)

Perinatal outcome Gestational age (wk) Birthweight (g) Stillbirths 2 22 wk Neonatal deaths

Total mortality Surviving babies born s32wkor <15OOg

Parameters predictive of poor outcome No. (%) with proteinuria > 2 + No. (Q) with onset of hypertension during wk 28-35 Maximum plasma urate (rmol/l) No. with urates 2 360 pmol/l

Miscellaneous

Age (yr) No. (S) of primigravidae No. (W) with previous early or late fetal loss Last documented systolic pressure before pregnancy (mmHg) Blood pressure at booking (mmHg) First reading 2 140/90 (mmHg) Onset of hypertension at week Highest blood pressure (mmHg)

at week No. (W) smoking during pregnancy Postnatal blood pressure (mmHg) Postnatal plasma urate (f.tmol/l)

.37.7&3.2 38.9 + 1.6 2929+859 2 967 k 571

13 0 2 0

15 0

12 1

47 (26.6) 14 (15.4)

41 (23.2) 322 + 101 43 (29.5)

9 (9.9) 297 + 75

12 (15.2)

29.2 + 5.3 67 (37.9)

29.9 k 4.9 36 (39.6)

48 (43.6) 27 (49.1)

122*12 129/77 f 16/12 153/94+ 14/10 21.9k11.7

166/102 k 12/14 28.3 + 10.8 20 (11.3)

125/83 + 19/13 274 + 63

142+19 143/87 k 22/13 155/96 f 18/12 14.4+ 12.2

166/103 f 25/14 25.2k2.1 17 (18.7)

133/89 + 17/12 283 f 72

< 0.01

NS

< 0.001

= 0.04

= 0.06

< 0.01 = 0.06

0.02

NS NS

NS

< 0.001 0.001/0.001

NS/NS < 0.001 NS/NS < 0.05 NS

0.01/0.001 NS

345

hypertension (p < 0.01) and higher plasma urate concentrations (p < 0.001). No other item was found to be significantly related to outcome.

The stepwise logistic regression analysis was performed with perinatal outcome as the dependent variable, and with the variables significantly related to perinatal outcome as the covariates (plasma urate was included as a binary variable: < 360 or 2 360 pmol/l) (Table II). Proteinuria of 2 + or more and the onset of hypertension between the 27th and the 36th weeks of amenorrhea were found to be the only two independent indicators of poor perinatal outcome (relative risks of 4.0, p < 0.001, and 3.7, p < 0.01 respectively). The relative risk associated with a plasma urate concentration 2 360 pmol/l was 2.6 (p = 0.08).

Table III compares perinatal outcome, the. distribution of items associated with outcome, and various maternal characteristics in 177 pregnancies with gestational hypertension and 91 with chronic hypertension. Pregnancy was terminated by spontaneous abortion in two cases of the former and one of the latter. In the remaining cases, the mean duration of pregnancy was shorter in gestational than in chronic hypertension (p < O.Ol), but the mean birthweight was similar in both groups. Perinatal deaths occurred in gestational hypertension but not in chronic hypertension ( p < 0.001). In surviving babies, the number of severely premature or underweight newborns was higher in pregnancies complicated by gestational hyper- tension (p = 0.04). Proteinuria, plasma urate 2 360 and onset of hypertension between weeks 27 and 36 were more frequent in gestational than in chronic hypertension (p = 0.06, p = 0.02 and p < 0.01 respectively). As expected, blood pressure readings before and after pregnancy or at booking were significantly higher in chronic than in gestational hypertension, and rose above 140/90 mmHg earlier in chronic hypertension. However, during pregnancy, levels of the first abnormal blood pressure reading as well as the highest blood pressure were virtually identical in both groups. Of the mothers who had had a previous pregnancy, a large proportion had experienced spontaneous abortion or intrauterine death, the rates being similar in gestational and chronic hypertension.

Discussion

The present work is based on an analysis of hypertensive pregnancies with high levels of perinatal mortality and morbidity. The results underline the well-known association of proteinuria and high urate levels with perinatal outcome, and confirm that the onset of hypertension between the 27th and 36th weeks of amenorrhea is an independent indicator of poor pregnancy outcome. They suggest that gestational hypertension, in which proteinuria and/or onset of high blood pressure during weeks 28 to 35 is frequent, has more severe perinatal consequences than chronic hypertension.

The perinatal mortality rate associated with hypertensive pregnancy was higher in this series (5.7%) than in other surveys: it was 3.8% in the report of Svensson et al. [9], and ranged, depending on the absence or presence of proteinuria, from 1.9 to 5.5% in Aberdeen [lo], from 3.1 to 5.3% in the Collaborative Perinatal Project [3] and from 1.3 to 4.1% in the Child Health and Development Study [2]. The frequent cases of mild hypertension in which blood pressure returns to normal either

346

spontaneously or through minor alterations in the subjects’ activity are included in the epidemiologic records [l-3,9,10] but in the present work were probably excluded by the referral procedure. A selection bias is not, however, a likely explanation for our findings regarding perinatal outcome, since the relative risks associated with the major prognostic predictors were in the expected range. Thus, the relative risk associated with proteinuria ranged from 2.5 to 5.5 in previous papers [2,3,9,10] and was 4.0 in this report. As regards the relative risk of poor outcome associated with onset of hypertension early in the third trimester, this ranged from 2.3 without proteinuria to 3.8 with traces of proteinuria in the Collaborative Perinatal Project [3] in terms of mortality, and from 3.0 to 4.7 in our previous survey in terms of morbidity [7], compared to 3.7 in the present work.

Our data are in good agreement with the well-known prognostic value of proteinuria in hypertensive pregnancies [l-3,7,9], as well as with the report of Redman et al. [6] on the relationship between perinatal outcome and plasma urate concentrations. Interestingly, Redman et al. [6] found that this relationship was closest between 24 and 32 weeks, which introduces the concept of a temporal risk factor in hypertensive pregnancy. This concept was also mentioned by Friedman and Neff [3] in their analysis of the Perinatal Collaborative Project. From discrimi- nant analysis of 98 variables, including age, parity, race, smoking habits, blood pressure and proteinuria, they noticed that when diastolic blood pressure reached 85 mmHg between the 28th and 32nd weeks, it was associated with a significant increase in fetal deaths, whether or not proteinuria was present. Accordingly, some of us [7] found that intrauterine growth retardation was significantly more frequent in gestational hypertension when its onset occurred between the 27th and 36th weeks, than when it occurred before the 28th week or after the 35th. This higher morbidity persisted in the results of multivariate analysis, irrespective of other risk factors such as proteinuria, obstetric history or smoking. Taken together, these data suggest that proteinuria, hyperuricemia and impaired fetal health are different expressions of a specific hypertensive disease occurring most frequently early in the third trimester.

Although many papers have dealt with the differences between the outcome in non-proteinuric hypertension and pre-eclampsia [l-3,7,9,10], few have compared fetal outcomes in gestational and chronic hypertension [2,9], probably because it is difficult to distinguish between them. In fact, the only sure way of doing so is to refer to pre-pregnancy readings. Since these are often not available, an approximate diagnosis is inferred from blood pressure readings made during the first half of pregnancy: readings of 140/90 mmHg or more before the 21st week suggest that the hypertensive disease is chronic, whereas normal blood pressure early in pregnancy followed by hypertension is considered gestational hypertension [ll]. This indirect criterion was used in two previous studies [2,9]. In one of them, Page and Christianson [2] surveyed 12954 mothers, including 307 with gestational hyperten- sion and 440 with chronic hypertension, and found that only in chronic hyperten- sion was the perinatal death rate higher than in normotensive pregnancies. However, in their study, chronic hypertension was defined as an average mean blood pressure (diastolic plus one-third pulse pressure) of 90 mmHg or more during the fifth and sixth months of pregnancy: thus, they included as cases of chronic hypertension

347

some patients who developed hypertension in the second half of pregnancy. In the

second study, Svensson et al. [9] followed 109 mothers with late non-proteinuric hypertension and 102 considered to have chronic hypertension on the basis of blood pressure 2 140/90 mmHg no later than the 20th week, and reported that perinatal mortality was higher in both gestational and chronic hypertension than in controls (3.8 vs. 0.8%). In the present work, gestational hypertension was defined by the absence of a known history of pre-pregnancy hypertension, and chronic hyperten-

sion by the presence of such a history. All hypertensive mothers were aware of a blood pressure reading before pregnancy, and about 90% could report at least one

blood pressure reading within the last 12 months. The average blood pressure

reported before pregnancy was in good agreement with the actual blood pressure

readings obtained at booking or at the post-natal visit. At variance with the series of

Page and Christianson and Svensson et al. [2,9], we found that gestational hyperten-

sion was more frequent than chronic hypertension among our hypertensive mothers.

This was in fact expected, since in a nation-wide French population sample [4], 9%

of parous women reported a history of hypertension in pregnancy (the frequency of

chronic plus gestational hypertension), while the prevalence of chronic hypertension among non-pregnant women in the same age group (20-39 yr) was estimated at

close to 2% [12]. A second difference between our findings and those of the studies quoted above [2,9] is that in the present work the perinatal outcome was more severe

in gestational than in chronic hypertension. This finding is due, at least in part, to the more frequent occurrence of proteinuria, hyperuricemia and onset of hyperten-

sion during weeks 28-35 in mothers with gestational hypertension. The aims and design of the present work do not allow the formal conclusion that

gestational hypertension is more harmful for the fetus than chronic hypertension,

since our series is not population-based and the definition of gestational hyperten-

sion used is based on history. Thus defined, gestational hypertension per se has a

limited prognostic value, since the type of hypertension was not found to be an

independent predictor of poor outcome in multivariate analysis. Nevertheless, onset of hypertension in the 28th to the 35th weeks can obviously be expected more

frequently in cases where blood pressure rises during the second half of pregnancy.

Consequently, gestational hypertension is certainly a major contributor to perinatal

morbidity and mortality in pregnancies complicated by hypertension.

Acknowledgement

The analyses of data were supported by a grant from la Fondation pour la Recherche Medicale.

References

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2 Page EW, Christianson R. Influence of blood pressure changes with or without proteinuria upon

outcome of pregnancy. Am J Obstet Gynecol 1976; 126: 821-829.

3 Friedman EA, Neff RK. Classification of hypertension in pregnancy. In: Pregnancy hypertension, a

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169-175.

4 Rumeau-Rouquette C. Naltre en France. EnquCtes nationales sur la grossesse et l’accouchement. Paris, Editions INSERM, 1979.

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