Int J Gynecol Obstet, 1992, 38: 195-199

195

International Federation of Gynecology and Obstetrics

Maternal antihypertensive therapy with beta-blockers with poor outcome in very-low birthweight infants R. Kaajaa, V. Hiilesmaa”,

K. Holmaa

associated

and A-L. JBrvenpZib

‘First and Second Departments of Obstetrics and Gynaecology, Helsinki University Central Hospital and hCity Maternity Hospital, Helsinki, (Finland)

(Received October 5th, 1991) (Revised and accepted January 9th, 1992)

Abstract The progress of 36 very-low birthweight (I 1500 g) infants born to mothers with pregnancy-induced hypertonia or pre-eclampsia was studied. During the first year of hfe, 7 out of 19 infants died when the mothers’ antihypertensive regimen included beta-blockers. Four of the deaths occurred within 15 days. There were no deaths in 16 infants whose mothers were treated with other antihypertensive treatment (P = 0.006). These results suggest that maternal beta-blocker therapy may have adverse effects on the very-low birthweight infants.

Keywords:

Antihypertensive therapy; Betablockers; Very-low birthweight infants. Introduction

Early-onset maternal hypertension is a known risk factor for premature birth, perinatal mortality, and growth retardation [l-4]. An early delivery, usually by cesarean section, is necessary in these cases for maternal and/or fetal indications. In addition, verylow birthweight children suffer from neurologic dysfunctions more often in later life than normal birthweight children [5-71. Beta-blockers were started to be used for 0020-7292/92/$05.00 @ 1992 International

Federation of Gynecology and Obstetrics Printed and Published in Ireland

treatment of hypertonic disorders in pregnancy in the late 1970s. While considered safe in full-term pregnancies [8], little is known about their possible effects upon the very premature and very-low birthweight infants. To determine the possible effect of maternal antihypertensive therapy we studied retrospectively the long-term outcome for 36 consecutive very-low birthweight infants born to mothers with high blood pressure during pregnancy. Patients and methods

The study was undertaken at the Departments of Obstetrics and Gynaecology, and Pediatrics between 1979 and 1985. During this period, the use of beta-blockers was gradually introduced in pregnant patients while older antihypertensive drugs, such as clonidine, diuretics, hydralazine and methyldopa, were still in use. The data were retrieved from the records of 36 consecutive very-low birthweight infants born during that period. These infants are regularly followed up until 6 years of age at the pediatric clinic, The criteria for inclusion in the study were birthweight of 1500 g or less, and maternal pregnancy-induced hypertonia or preeclampsia treated with antihypertensive agents. Mothers with an underlying disease Article

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known to interfere with pregnancy outcome, i.e. essential hypertension, diabetes, systemic lupus erythematosus, or renal disease, were excluded. Hypertensive disorders were classified either (1) as pregnancy-induced hypertension where diastolic blood pressure was > 90 mmHg, and systolic blood pressure > 140 mmHg on two occasions more than 6 h apart, or (2) as pre-eclampsia with the same criteria of blood pressure associated with proteinuria of 0.5 g or more in 24 h. The mothers with proteinuria were further divided into two subgroups, (a) those excreting less than 3 g in 24 h and (b) those excreting 3 g or more. Proteinuria of 3 g or more in 24 h is generally considered as a sign of nephrotic syndrome. Mean arterial pressures were calculated by adding one-third of the pulse pressure to the diastolic reading. Mean arterial pressures l-2 weeks before treatment and during treatment were calculated for each patient (Table 2). The mothers were allotted into two groups according to their antihypertensive treatment, (I) those whose regimen included betablockers, and (II) those whose regimen did not include beta-blockers. From the infants’ medical charts we determined gestational age, birthweight, occurrence of respiratory distress, need and duration of respirator therapy, psychomotor outcome and details of the infant deaths. Diagnosis of the respiratory distress syndrome (RDS) was based on tachypnea, grunting, a need for oxygen for more than 24 h, and typical X-ray changes [9]. A diagnosis of bronchopulmonary dysplasia (BPD) was based on the criteria of Northway et al. [lo]. Small-for-gestational-age (SGA) infants were defined as having a birthweight below the 10th percentile for the gestational age [I 11. The rest of the infants were defined as appropriate for gestational age (AGA). The children were assessed as normal or handicapped; the latter being defined as a disability that interfered with normal life (cerebral palsy, blindness, mental retardation) according to Kitchen et al. [ 121. Cranial ultraInt J Gynecol Obstet 38

sound was used only after its introduction in 1982. Statistical analysis included the t-test or Mann-Whitney U-test for continuous variables. Dichotomous data were analysed by x2-test or by Fisher’s exact probability test. A P-value of 0.05 or less was considered to indicate statistical significance. Results There were no significant differences between the two treatment groups with regard to maternal age, parity, history of preeclampsia in previous pregnancies, and frequency of smokers (Table 1). Pregnancy-induced hypertension was diagnosed in 8 of the pregnancies, and preeclampsia in the remaining 27. The severity of the maternal hypertensive disease was similar in the two treatment groups as assessed by occurrence and degree of proteinuria as well as by mean arterial pressure values before and during treatment (Table 2). Early in the study period hypertensive pregnant patients were primarily treated with hydralazine, clonidine, methyldopa, or diuretics whereas later on the therapy was more often with beta-blockers. The purpose for combination of the drugs was either to decrease side-effects (e.g. metoprolol for reflectory tachycardia caused by hydralazine) or inefficacy of monotherapy. The beta-blockers used were either beta-lselective metoprolol (in 15 mothers) or non-

Table 1.

Maternal characteristics.

Age years, mean (SD) No. of primiparae Hypertensive disorder in a previous pregnancy Smokers

Beta-blocker n= 19

Other antihypertensive n = 16

29.6 (4.2) 7

27.4 (5.7) 6

2 2

I 5

The differences are not statistically significant as tested using the r-test, X*-test, and Fisher’s exact probability test.

Maternal beta-blockers Table 2.

Characteristics of maternal hypertensive disease. Beta-blocker n= 19

Pregnancy-induced hypertonia without proteinuria Pre-eclampsia dU-prot r3 g dU-prot c3 g Mean arterial pressure mmHg; mean (SD) Before treatment During treatment Duration of treatment days; mean (range)

3

I1 3

8 5

12 (l-60)

123 (8) 115 (8) 11 (l-37)

Mean arterial pressure = diastolic + (systolic - diastolic)/3. The differences are not statistically significant as tested using the r-test, &test, and Mann-Whitney U-test.

selective propranolol (in 4 mothers); a total of 19 patients took beta-blockers. A betablocker was given alone in 2 cases, combined with hydralazine in 13, and combined with both hydralazine and clonidine in 4. Antihypertensive medication not including a beta-blocker was taken by 16 mothers (hydralazine alone in 11 cases, hydralazine combined with clonidine in 3, hydralazine combined with methyldopa in 1, and diuretics in 1). The dose of metoprolol was 100-200 mg/day, and that of hydralazine 30- 150 mg/day. The duration of antihypertensive treatment was similar in both groups (Table 2). No statistically significant differences were observed in gestational ages, birthweights, proportion of small for date babies, oneminute Apgar scores, neither in the incidences of respiratory distress syndrome, bronchopulmonary dysplasia, and in need of respirator therapy (Table 3). We did not systematically record the blood pressures of the infants. Seven out of 19 infants died in the group where the mothers treatment included a betablocker while there were no deaths in the

infants

197

Characteristics of the infants. Maternal treatment

Other antihypertensive n = 16

5

126 (9) 116 (7)

Table 3.

and very-low birthweight

Gestation (weeks), mean (SD) Birth weight (g), mean (SD) Birth weight less than 1000 g (n) Apgar score at 1 min, mean (SD) Male/female (n) SGA/AGA (n) RDS (n) Respirator therapy (n)

Beta-blocker n= 19

Other antihypertensive n = 17

31.2(2.3)

31.2(1.7)

1113(275)

llO2(234)

6

4

6.0 (2.7) 9110 1217 8 14

6.2 (2.7) 819 12/S 7 9

The differences are not statistically significant as tested by the &test and r-test.

group where only other types of antihypertensive drugs were used (P = 0.006; Table 4). No significant difference was found in the incidence of psychomotor impairment (Table 4). The age at death varied from 7 to 2 18 days, and the causes were pulmonary or cerebrovascular complications (Table 5). Four of the infant deaths occurred within 15 days of life, and in 3 of the these cases the infant had a birthweight of less than 700 g. Discussion Our study suggests that in pregnancies leading to the birth of a very-low birthweight

TahIe 4.

Neonatal outcome according to maternal treatment.

Normal Infant death Psychomotor impairment

Beta-blocker n= 19

Other antihypertensive n = 17

9 7’ 3

15 0* 2

*Fisher’s exact probability test, P = 0.006.

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Table 5.

Details of the seven infant deaths.

Gestation, completed weeks

Birthweight, grams

Cause of death

Age at death, days

Duration of treatment, days

26 28 28 29 29 29 36

600 685 615 1100 1080 985 1480

RDS & IVH RDS & IVH RDS & IVH IVH BPD BPD Encephalopathia

I I 15 12 28 120 218

4 23 35 60 18 13 17

RDS, respiratory distress syndrome; IVH, intraventricular hemorrhage; BPD, bronchopulmonary

infant maternal beta-blocker therapy is associated with higher mortality than that observed for other types of maternal antihypertensive therapy. Although the treatment groups were not randomized, no significant differences were observed in the potential confounding factors, such as the severity on the maternal hypertonic or pre-eclampic disease, degree of prematurity, proportion of growth-retarded infants, or other important parameters known to increase the risks. An explanation could be impaired adaptation of the infants’ sympathico-adrenal system to the postnatal environment due to antenatal administration of the beta-blocking agent. Eliot et al. [13] found significant elevations of the plasma catecholamine concentrations in the venous blood of full term infants as an element in extra-uterine adaptation. It is probable that this occurs in preterm infants, too. Experimental studies have shown that the adaptation of fetus relies heavily on greatly increased sympathico-adrenal activity in asphyxia [ 141. Beta 1-adrenoreceptor blocking as a result of maternal medication could be hazardous to the asphyctic newborn [14]. Lieberman et al. [15] have also reported that beta-adrenergic blockade could harm the hypoxic fetus in hypertensive pregnancies complicated by placental insufficiency. In the healthy, full term newborn infant, blood levels of metoprolol are reported to increase almost fourfold during the first hours of extrauterine life [ 161.This could be explained either by redistribution of the drug as a Int J Gynecol Obstet 38

dysplasia.

consequence of haemodynamic changes at birth, or by the relative immaturity of the liver of the newborn [16]. The concentration of metoprolol can even be higher in an asphyctic than in a healthy newborn infant. In fetal asphyxia, a weak base such as metoprolol can accumulate in the acidotic fetus because of the enhanced pH gradient between the mother and the fetus [ 16,171 and prevent the postnatal adaptation of the sympathicoadrenal system. The study reported here suggests that maternal beta-blocker therapy could have adverse effects on the very-low birthweight infant. The four deaths occurring within 15 days after birth could be at least partly related to maternal beta-blocker therapy. Three of these infants had a birthweight of below 700 g which can have an additional effect on the poor prognosis. Two of the infants born to mothers who took other antihypertensives also were below 700 g birthweight, developed RDS but survived. We therefore suggest that, in pregnancies in which delivery of an infant weighing less than 1500 g is likely, the dosages of beta-blockers should be kept low, or another drug, not influencing the sympathico-adrenal system, should be given. Being retrospective, the present study can only show the association, not a causal relationship, between the maternal use of betablockers and poor fetal outcome. Prospective controlled, and randomized studies are needed to find the safest antihypertensive treat-

Maternal beta-blockers

ment for the serious early-onset pre-eclamptic disease. 11

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3 4

5

6

Hendrics CH, Brenner WE: Toxemia of pregnancy. Relationship between fetal weight, fetal survival, and the maternal state. Am J Obstet Gynecol 109: 225, 1971. Chesley LC: Hypertension disorders in pregnancy. In: Principles of Medical Therapy in Pregnancy, 1st edn (ed N Cleicher) p 75 1. Plenum Medical Book Company, New York and London, 1985. Chamberlain G: Raised blood pressure in pregnancy. The foetus in hypertension. Br J Hosp Med 26: 127, 1980. Brazy JE, Grimm JK, Little V: Neonatal manifestations of severe maternai hypertension occurring before the thirty-sixth week of pregnancy. J Pediatr 100: 265, 1982. Michelsson K, Lindahl E, Parre M, Helenius M: Nineyear follow-up of infants weighing 1500 g or less at birth. Acta Paediatr Stand 73: 835, 1984. Lefebvre F, Bard H, Veilleux A, Martell C: Outcome at school age of children with birthweights of 1000 g or less. Dev Med Child Neural 30: 170, 1988. Lloyd BW, Wheldall K, Perks D: Controlled study of intelligence and school performance of very low-birthweight children from a defined geographical area. Dev Med Child Neural 30: 36, 1988. Rubin PC: Beta-blockers in pregnancy. N Engl J Med 305: 1323, 1981. Martin RJ, Klaus MH, Fanaroff A: Respiratory problems. In: Care of the High-Risk Neonate, 3rd ed (eds Klaus, FanarofF) p 171, W.B. Saunders Company, Philadelphia, 1986. Northway WH, Rosan RC, Porter D: Pulmonary disease following respirator therapy of hyaline-membrane disease

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Broncho-pulmonary dysplasia. N Engl J Med 276: 357, 1967. Usher R, McLean F: Intrauterine growth of live-born caucasian infants at sea level: standards obtained from measurments in 7 dimensions of infants born between 25 and 44 weeks of gestation. J Pediatr 74: 901, 1969. Kitchen WH, Ford GW, Richards AC, et al.: Children of birth weight < 1000 g: changing outcome between ages 2 and 5 years. J Pediatr 110: 283, 1987. Eliot RJ, Lam R, Leake RJ et al.: Plasma catecholamine concentrations in infants at birth and during the first 48 hours of life. J Pediatr 2: 311, 1980. Kjellmer I, Dagbjartsson A, Hrbek A et al.: Maternal beta-adrenoreceptor blockade reduces fetal tolerance to asphyxia. A study in pregnant sheep. Acta Obstet Gynecol Stand Suppl 118: 75, 1984. Lieberman BA, Stirrat GM, Cohen S et al.: The possible adverse effect of propranolol on the foetus in pregnancies complicated by severe hypertension. Br J Obstet Gynecol 85: 678, 1978. Lindeberg S, Sandstrom B, Lundborg P, Regardh C-G: Disposition of the adrenergic blocker metoprolol in the late-pregnant woman, amniotic fluid, the cord blood and the neonate. Acta Obstet Gynecol Stand Suppl 118: 61, 1984. Brown WU, Bell GC, A1pe.r M: Acidosis, local anesthetics, and newborn. Obstet Gynecol 48: 27, 1976.

Address for reprints:

R. Kaaja Departments of Obstetrics and Gynecology Helsinki University Central Hospital 0290 Helsinki, Finland

Article

Maternal antihypertensive therapy with beta-blockers associated with poor outcome in very-low birthweight infants.

The progress of 36 very-low birthweight (less than or equal to 1500 g) infants born to mothers with pregnancy-induced hypertonia or pre-eclampsia was ...
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