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Withdrawal of nifedipine capsules: jeopardising the treatment of acute severe hypertension in pregnancy?

Mark A Brown, Lesley M E McCowan, Robyn A North, Barry N Walters (for the Council of the Australasian Society for the Study of Hypertension in Pregnancy)

Short-acting oral nifedipine has been withdrawn from the Australian market because of reports of its adverse effects after long-term treatment in non-pregnant patients with heart disease. This will have a major impact on the treatment of acutely hypertensive pregnant women, in whom the drug has proven to be safe, effective and easy to administer. Should pregnant women be forced to use less suitable agents, thus threatening their own and their babies' health?

(MJA 1997; 166: 640-643)

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Introduction - Antihypertensive medications in pregnancy - Adverse effects of nifedipine - Risk-benefit analysis of nifedipine in pregnancy - Withdrawal of nifedipine from the Australian market - Conclusions - Acknowledgement - References - Authors' details

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Introduction

 Pre-eclampsia is the development of hypertension after 20 weeks' gestation in a woman with no known history of hypertension or renal disease, whose blood pressure was normal in the first half of the pregnancy and returns to normal after delivery.1 Despite advances in maternal and neonatal care, it remains an important cause of maternal morbidity (and sometimes mortality) and of fetal prematurity, growth retardation and perinatal death. The dangers of cerebral haemorrhage in pre-eclampsia and of convulsions (eclampsia) have led to the belief that severe hypertension (systolic blood pressure 170 mmHg and/or diastolic blood pressure 110 mmHg) should be treated promptly in pre-eclamptic women. However, the ability to treat acute hypertensive crises in pregnancy is about to be retarded considerably because of recommendations by the Australian Drug Evaluation Committee (ADEC) to withdraw short-acting nifedipine capsules,2 one of the most common drugs for treating acute severe hypertension in pregnancy, effective from 1 May 1997.  

Antihypertensive medications in pregnancy

 There are only a few options for the treatment of acute severe hypertension in pregnancy.
  • Nifedipine (given orally or sublingually) and hydralazine (given intravenously or, sometimes, intramuscularly) are the most commonly used agents. They have both been endorsed for use for severe hypertension in pregnancy by the Australasian Society for the Study of Hypertension in Pregnancy (ASSHP) on the basis of clinical studies and extensive clinical experience by members of the ASSHP and other societies.1
  • Intravenous diazoxide was one of the earliest drugs to be used.3 It is effective but can cause sudden maternal hypotension, maternal hyperglycaemia and fetal hypoglycaemia, uterine atony and fetal distress. It is best given as incremental small-dose boluses to avoid a sudden drop in blood pressure.
  • Intravenous labetalol has been used less widely but is at least as effective as intravenous diazoxide.3 Its safety in preterm infants has been questioned,4 with higher perinatal mortality than in subjects given hydralazine in one study.
  • Intravenous glyceryl trinitrate is a potential candidate for treating severe hypertension in pregnancy.5 It has not yet been used widely and there is a risk that its predominant venodilator effect could reduce preload and compromise an already threatened cardiac output.6
Intravenous sodium nitroprusside is an excellent drug for acute severe hypertension, but its use in pregnancy is precluded by the risk of fetal cyanide toxicity.7  

Adverse effects of nifedipine

 Unfortunately, some authors fail to discriminate between pregnant and non-pregnant subjects when providing recommendations about the continued use of nifedipine capsules. For example, Grossman et al. did a MEDLINE search of articles from 1966 to 1994 using the terms "side-effects" and "nifedipine" to document serious adverse effects with oral or sublingual nifedipine.8 They recommended that, given the seriousness of the reported adverse cardiac events and the lack of any clinical documentation attesting to a benefit, the use of nifedipine capsules for hypertensive emergencies and pseudoemergencies should be abandoned. Only one case of fetal distress was reported in this review9 (although we have noted three other cases), in a pregnant woman whose blood pressure fell from 150/115 mmHg to 90/55 mmHg, hardly a surprising event and one which could have occurred with any drug which lowered the blood pressure to this extent.

A more disturbing report by Rehman et al. noted that 98% of hospitalised patients receiving nifedipine capsules failed to have a bedside evaluation and only half had had their blood pressure followed up within an hour of treatment.10 This is poor medical practice and a good reason to improve medical education, but not a reason to withdraw a drug from the market.  

Risk-benefit analysis of nifedipine in pregnancy

 Many small studies, comprising a total of about 150 pregnant women, have shown that nifedipine will acutely lower maternal blood pressure within 30 minutes of administration, without compromising the fetus.11-22 In studies involving approximately 200 pregnant women treated with nifedipine over a longer period, no adverse fetal effects were recorded.12,23-27 Three case reports (of four patients) have, at the same time, reported the potential risk of sudden hypotension following the use of nifedipine in severe pre-eclampsia, particularly when combined with magnesium sulfate (used parenterally as convulsion prophylaxis in pre-eclampsia).9,28,29 However, in a more recent prospective study, 10 women with severe pre-eclampsia already receiving intravenous magnesium sulfate were given between 10 mg and 40 mg nifedipine orally. Blood pressure was well controlled in each woman, none had significant hypotension and there was no fetal distress.30

Sudden hypotension has been reported with other antihypertensive drugs used to acutely lower blood pressure in pregnancy, including hydralazine.3,31 The risk of sudden hypotension with any form of acute antihypertensive therapy can be minimised by concomitant plasma volume expansion1,20,32 and avoidance of diuretics, as pre-eclampsia is a volume-contracted state compared with normal pregnancy.33 Several studies have found that nifedipine lowers maternal blood pressure without adversely affecting uteroplacental blood flow.13,14,17,23,34

Several studies have compared intravenous hydralazine with nifedipine in pre-eclampsia;12,19,20,35 all showed nifedipine to be of equal or greater efficacy and safety for both mother and fetus. Visser and Wallenburg observed similar maximum reductions in blood pressure during administration of each drug, but greater falls in pulmonary capillary wedge pressure as well as increased occurrence of fetal distress in women receiving hydralazine.20 In one randomised trial, there were fewer preterm infants and less acute fetal distress in the group of women given nifedipine than in the group of women given intravenous and then oral hydralazine.12 The most recent and largest studies showed that maternal and fetal outcomes were similar in pregnant women with severe hypertension (diastolic blood pressure > 120 mmHg) who received either sublingual nifedipine or intravenous hydralazine.36 The authors concluded that sublingual nifedipine may be advantageous "for use by midwives who work in rural areas where speed is essential in reducing acute hypertension . . ."

Nifedipine also relaxes the myometrium, and therefore has a potentially important role in the treatment of preterm labour. In five separate randomised trials involving a total of 290 women, nifedipine was as effective as ritodrine for tocolysis and was associated with fewer serious maternal side effects.37-41 No adverse fetal effects were attributable to nifedipine in studies reporting on more than 350 women treated with the drug in preterm labour.42 Recent prospective data have provided further support for the safety of nifedipine, even when used in early pregnancy.43  

Withdrawal of nifedipine from the Australian market

 The "position of comfort" -- that nifedipine can be used safely and easily in an emergency (before insertion of an intravenous cannula) -- has been lost. The plan to withdraw nifedipine capsules arose out of concern over the potential adverse effects (myocardial infarction, death) in non-pregnant patients with hypertension and ischaemic heart disease receiving long-term treatment with the drug.44-46 In New Zealand, the Ministry of Health has stated that nifedipine and some other calcium antagonists are contraindicated in pregnancy.47 There is no basis for this pronouncement in studies of nifedipine use in human pregnancy.

As nifedipine was never officially listed in the Australian Register of Therapeutic Goods for use in pregnancy, clinicians cannot argue to retain the drug for the treatment of hypertension in pregnancy. The simple solution could be to accept defeat and rely on parenteral hydralazine. However, the most recent preparation of this drug is not marketed for intramuscular use (presumably because of its variable absorption), so that treatment must be delayed until an intravenous cannula is inserted. This delay adds to the dangers of severe hypertension for the pregnant woman. Moreover, it has been speculated that parenteral hydralazine will also be withdrawn shortly as it has been superseded by better drugs with fewer side-effects in non-pregnant patients.

We now face the following situation: nifedipine capsules have been withdrawn from sale, and it is possible that intravenous hydralazine and diazoxide will also be withdrawn from the Australian market. Intravenous labetalol is not available in Australia, and magnesium sulfate, while known to have some blood pressure lowering effects, is not a sufficiently powerful antihypertensive agent for treatment of severe hypertension in pre-eclampsia. Therefore, intravenous sodium nitroprusside and glyceryl trinitrate will be the only agents left for the treatment of acute severe hypertension in pregnancy. The former can induce fetal cyanide toxicity, while the latter has been subject to far fewer studies in pregnancy than nifedipine, hydralazine or diazoxide -- and both drugs require highly skilled dose titration.

Why do pregnant women now face the very real prospect that we will no longer be able to treat their severe hypertension as efficiently as before? In part, this relates to the bureaucratic nature of administering such matters -- if a drug has not been officially listed for an approved indication in the Australian Register of Therapeutic Goods (and nifedipine was never listed for use in pregnancy), then, despite widespread clinical use for that purpose, it can be withdrawn from the market by the pharmaceutical regulatory authorities. To be fair, this is probably the safest approach overall. At the same time, however, this situation highlights deficiencies in clinical and scientific interaction among clinicians, pharmaceutical companies and government agencies. The pharmaceutical company concerned has long known that nifedipine was being used for treating severe hypertension in pregnancy. They, of course, could not endorse such an action, but could have worked with clinicians to study the clinical outcomes in a proper manner, leading to an application for approval of a new indication. They chose not to do so. We clinicians are as much at fault here for not taking such an initiative when the company failed to do so.

ADEC tried to balance these issues in its most recent consideration of the problem, but had no option other than to withdraw nifedipine capsules from sale. In New Zealand, nifedipine capsules are now available only in hospitals, which limits the access of rural practitioners to this drug.

Perhaps this situation should force us to reconsider the speed at which we need to lower blood pressure in pre-eclampsia. Pregnancy outcomes are very good when severe hypertension is treated rapidly (over 20-30 minutes) and cerebral haemorrhage and eclampsia are now relatively rare. This does not mean there is necessarily a causal relationship between such treatment and the low rates of intracerebral haemorrhage and eclampsia. However, it would be difficult to prove a causal relationship because of the rarity of these complications as well as the ethical problems involved in randomising severly hypertensive pregnant women to a trial comparing rapid reductions in blood pressure (e.g., using nifedepine) with slower reductions (e.g., using oral clonidine or methyldopa).  

Conclusions

 The "best case" scenario is that withdrawal from sale of nifedipine capsules and intramuscular hydralazine will leave Australian clinicians with only intravenous diazoxide and intravenous hydralazine to fill an essential therapeutic niche (with intravenous labetalol still available in New Zealand). None of these drugs can be given urgently in hospitals without resident medical staff, and even in the larger tertiary hospitals resident medical staff can be delayed in other wards or operating theatres. Such delays could result in serious complications for the pregnant woman and her baby.

The "worst case" scenario is that none of these drugs (nifedipine, labetalol, hydralazine or diazoxide) will be available for the treatment of acute severe hypertension in pregnancy. Pregnant women will then suffer from inadequate treatment or be exposed to the side effects of the remaining antihypertensive drugs, which are currently not recommended for use in pregnancy.

Is all this enough to justify continued availability of short-acting nifedipine in pregnant women in Australia and New Zealand? Most clinicians would rapidly respond "yes" as they continue to practise medicine as both an art and a science. The "art" of using nifedipine successfully in pregnancy is well known to most of us, but, although the above review of the available literature shows that nifidepine capsules are as safe as any other drugs currently used to treat acute severe hypertension in pregnancy, we have failed to gather the science to a sufficient extent. We hope our patients will not suffer as a result of our combined shortfalls.  

Acknowledgement

 We thank Mrs Jodie Hendley for assistance in preparing this manuscript.  

References
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(Received 26 Aug 1996, accepted 28 Jan 1997)

Authors' details

Departments of Medicine, Renal Medicine and Obstetrics, St George Hospital, Kogarah, NSW.
Mark A Brown, FRACP, MD, Associate Professor of Medicine.
Department of Obstetrics and Gynaecology, University of Auckland School of Medicine, National Women's Hospital, Auckland, NZ.
Lesley M E McCowan, FRCOG, FRNZCOG, Senior Lecturer in Obstetrics and Gynaecology;
Robyn A North, PhD, FRACP, Senior Lecturer in Obstetric Medicine.
King Edward Memorial Hospital for Women, Perth, WA.
Barry N Walters, FRACP, Physician in Obstetric Medicine.

Council of the Australasian Society for the Study of Hypertension in Pregnancy, 145 Macquarie Street, Sydney, NSW 2000.

No reprints will be available. Correspondence: Dr M A Brown, Departments of Medicine, Renal Medicine and Obstetrics, St George Hospital, Kogarah, NSW 2217.

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