CASE REPORT

Maternal hypoxia associated with nifedipinefor threatened preterm labour

Ryan Hodgesa, Andrea Barkehall-Thomasb,*, Christine Tippettb

Case report

A 31 year old woman, gravida 3 para 1, presented at 32

weeks of gestation with threatened preterm labour. She had

an asymptomatic ventricular septal defect diagnosed and

subjected to incomplete surgical repair in childhood. De-

spite this, she had good pre-pregnancy exercise tolerance

and did not suffer dyspneic episodes. Her obstetric history

included a first trimester termination of pregnancy and a

subsequent normal vaginal delivery of a healthy female

infant. She recalled some shortness of breath that prolonged

her hospital stay by seven days after that delivery.

In this pregnancy, an echocardiogram undertaken in early

pregnancy showed normal left ventricular size and function

and she was asymptomatic until she presented at 32 weeks.

She reported sudden onset of episodic lower back and

suprapubic pain consistent with uterine contractions but

without associated vaginal bleeding, rupture of membranes

or dysuria. She was haemodynamically stable, with no

clinical evidence of infection or placental abruption. Re-

peated vaginal examination showed no cervical change

(1 cm dilated, 1 cm long). She received betamethasone, three

20 mg doses of nifedipine orally, 20 minutes apart, for

preterm labour tocolysis, and 1 g amoxicillin intravenously

for bacterial endocarditis prophylaxis.

Within 10 minutes of the second dose of nifedipine, she

experienced shortness of breath with no associated chest

pain, cough, haemoptysis, fever or calf pain. Her symptoms

worsened overnight and by 20 hours post nifedipine, the

respiratory distress necessitated transfer to the intensive

care unit. On examination the patient had a pulse rate of

120 per minute, blood pressure 130/65 and was afebrile.

The respiratory rate was 32 per minute and mild cyanosis,

bilateral peripheral oedema and raised jugular venous

pressure (10 cm) were evident. There was a loud systolic

murmur at the left sternal edge, consistent with her known

ventricular septal defect, right ventricular heave, and de-

creased breath sounds at the bases of both lungs. Her calves

were soft and non-tender. Abdominal examination revealed

a soft uterus, symphysis–fundal height consistent with

gestation, and a cephalic presentation with a fixed position

four-fifths above the brim.

Her arterial oxygen saturation was 93% on room air

(95% on 6 L O2/minute) and arterial blood gas analysis

revealed a PO2 of 76 mmHg, a metabolic acidosis [pH 7.34,

HCO3 11 mmol/L (21–30)], a compensatory respiratory

alkalosis (PCO2 21 mmHg) and an increased anion gap

of 23 mmol/L. She had 3+ ketones in the urine, normal

serum lactate 1.0 mmol/L (0.5–2.0) and urea 2.0 mmol/L

(2.5–7.8). Despite an elevated D-dimer assay 0.44 units

(<0.20) and electrocardiograph changes consistent with a

pulmonary embolism (a deep S wave in lead I, a Q wave

and an inverted T wave in lead III), venous thromboem-

bolism was excluded by a normal ventilation–perfusion

(V–Q) lung scan and Doppler ultrasound of the leg veins.

A therapeutic heparin infusion was commenced but ceased

after the negative V–Q scan.

Normal chest X-ray, sputum culture and atypical serology

excluded pneumonia and a mid-stream specimen of urine

revealed no growth on culture. The white cell count was 13.3

� 109/L, normal for pregnancy and post-corticosteroids.1

There was no evidence of placental abruption with a normal

obstetric ultrasound revealing growth consistent with ges-

tation and Kleihauer–Betke test revealed no evidence of a

feto-maternal haemorrhage. Transthoracic echocardiogram

showed hyperdynamic systolic function with normal left

and right ventricle size, no evidence of cardiomyopathy,

mildly dilated right atrium consistent with pregnancy and a

small perimembranous ventricular septal defect with a

restricted left to right shunt. Troponin I was not elevated

(<0.04 Ag/L) to indicate myocardial ischaemia. The fetus

was active with a normal cardiotocogram.

With conservative management the unexplained dyspnea

and hypoxia gradually settled and she was discharged seven

days later with uneventful weekly antenatal clinic review.

She went into spontaneous labour at 36 weeks plus five days

gestation and delivered a healthy female infant weighing

BJOG: an International Journal of Obstetrics and GynaecologyApril 2004, Vol. 111, pp. 380–381

D RCOG 2004 BJOG: an International Journal of Obstetrics and Gynaecology www.blackwellpublishing.com/bjog

aDepartment of Obstetrics and Gynaecology, Monash

University, Clayton, Victoria, AustraliabMaternal–Fetal Medicine Unit, Monash Medical Centre,

Southern Health, Clayton, Victoria, Australia

* Correspondence: Dr A. Barkehall-Thomas, Maternal–Fetal Medicine

Unit, Monash Medical Centre, Clayton, Victoria 3168, Australia.

DOI: 10 .1111 / j . 1471 -0528 .2004 .00092 .x

2700 g. She received 20 mg furosemide intravenously in

addition to 5 IU syntocinon in the third stage of labour as a

precaution for possible pulmonary oedema. Her delivery

and postnatal recovery was uneventful and the aetiology of

her hypoxia remained undiagnosed.

Discussion

Nifedipine, a calcium channel blocker, has recently been

advocated, with atosiban (an oxytocin antagonist) as a

tocolytic of choice by the RCOG.2 It is an attractive alter-

native to beta-adrenergic agonists and non-selective cyclo-

oxygenase inhibitors because of comparable effectiveness

and fewer maternal or fetal adverse effects.3 The incidence

of significant pulmonary oedema with beta-adrenergic ago-

nists is estimated at 1:350–1:400 treated patients, with more

than 25 maternal deaths in the literature.4

A meta-analysis has reported that, compared with beta-

adrenergic agonists, there are fewer interruptions of treat-

ment with nifedipine due to maternal adverse effects and

therapy is more effective in prolonging pregnancy, results

in fewer cases of neonatal respiratory distress syndrome

and fewer transfers to NICU.4 Nifedipine is also advanta-

geous due to a relative lack of influence on A–V conduc-

tion and maternal cardiac output.5

This case report highlights that nifedipine is nevertheless

not without risk, particularly in a woman with an underly-

ing, albeit asymptomatic and stable, cardiac anomaly. The

increased cardiac demands of pregnancy are well appreci-

ated: hormonally mediated increases in blood volume, red

cell mass and heart rate result in a major increase in cardiac

output6 coupled with increased myocardial oxygen de-

mand. Pre-existing cardiac anomalies may compromise

the ability to meet this demand and may be associated with

cardiac decompensation, particularly in later pregnancy, as

the major increase in cardiac output peaks during the

second trimester and remains constant until term.6

We believe that in this case, the native vulnerability of

her ventricular septal defect with the additional cardiovas-

cular stress of pregnancy potentially compromised her car-

diac status. The uninvestigated dyspnea following the first

pregnancy may have indicated borderline decompensation

at that time. In this current pregnancy, the further demands

of corticosteroids of increased extracellular volume, in-

creased systemic vascular resistance and increased cardiac

contractility,7 coupled with the negative inotropic effects of

nifedipine, led to more significant cardiac embarrassment.

The cause of her hypoxia is not clear. Pulmonary embo-

lism, pneumonia, cardiomyopathy, obstructive or restrictive

airways disease and ischaemic heart disease were unlikely

on the basis of history, examination and investigations. The

close-time relationship between corticosteroids and nifed-

ipine and the development of respiratory distress and the

spontaneous recovery all point towards a drug effect. One

small study suggested that nifedipine raised pulmonary

artery pressures in non-pregnant patients with underlying

lung disease and pulmonary hypertension.8 It is unlikely

that corticosteroid therapy would have contributed, as this

has been associated with a reduction in pulmonary arterial

pressure and pulmonary vascular resistance.9

We alert the reader to the fact that women with cardio-

vascular disease or any medical condition contraindicating

tocolysis were excluded from the trials evaluating the effi-

cacy and safety of nifedipine use for preterm labour.5,10–12

This case poses an interesting dilemma of assessing the

suitability of a patient for nifedipine with known cardiac

disease even when entirely asymptomatic and stable; we

believe this is a setting for caution. It articulates well the

significant impact of pregnancy itself on the cardiovascular

system, and how sensitive its workings are to the added

insult of a little hole and a few red pills.

References

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Accepted 12 December 2003

CASE REPORT 381

D RCOG 2004 Br J Obstet Gynaecol 111, pp. 380–381