Use of Tocolytics and Birth Outcome foetal heart rate evaluation.6 Ritodrine induced higher foetal heart


rates, lower long-term variation and also lower low-to-high-frequency ratios compared with atosiban. There was no difference in Apgar score between atosiban and ritodrine.


The Canadian Preterm Labour Investigator Group presented data on infant morbidity at 18 months in those with pre-term delivery.7


infants and calcium-channel blockers used as tocolytics.16 They did


This publication dates from 1992 and neonatal outcome has drastically changed since then. The Canadian group compared placebo with intravenous ritodrine. There was a slight but not significant trend towards an improved Bayley psychomotor development index score at 18 months of age among the infants in the ritodrine-treated group.


Ritodrine is well-known to cause hyperglycaemia in the mother, but cases of severe hyperinsulinaemic hypoglycaemia in the neonate have also been published.8


In recent years it has become clear that


long-term ritodrine tocolysis may be a risk factor for cerebral palsy in pre-term infants. In a cohort study of 922 infants, Takanashy et al. found in a multiple logistic model that long-term ritodrine tocolysis was associated with the development of cerebral palsy (OR 8.62, 95% CI 2.18–33.97).9


This result clearly warrants further investigation and could be an important factor when deciding which tocolytic to use. On the other hand, Weintraub et al. found that infants exposed to ritodrine tocolysis had a significantly lower risk of grade III–IV periventricular/intraventricular haemorrhage after adjustment for other variables (OR 0.3, 95% CI 0.2–0.6).10


Ozcan et al. in an


older report did not find any difference in neonatal intraventricular periventricular haemorrhage between those exposed to ritodrine, magnesium sulphate or nifidipine, but their study included only 44 patients.11


Indomethacin is a very effective tocolytic that should not be used after 34 gestational weeks (if any tocolytic should ever be used at that age) due to the risk that the ductus arteriosus will close. In a meta-analysis on the effect of antenatal indomethacin on neonatal outcome, Amin et al. concluded that antenatal indomethacin may be associated with an increased risk of periventricular leucomalacia (OR 2.0, 95% CI 1.3–3.1) and necrotising enterocolitis (OR 2.2, 95% CI 1.1–4.2).12


It should therefore be used judiciously for tocolysis.


Former reports on lethal kidney failure are only confirmed for non-steroidal anti-inflammatory drugs and cyclo-oxygenase inhibitors other than indomethacin. Doyl et al. reported a significantly higher rate of intraventricular haemorrhage when indomethacin was used, but the significance was lost in a meta-analysis.13


Calcium-channel blockers, mainly nifedipine, are used off-label for tocolysis. One trial currently in progress is studying neonatal morbidity up to six months after sustained tocolysis in early labour, comparing nifedipine with placebo.14


No results are yet available.


De Heus et al. studied the effect of atosiban and nifedipine on foetal movements, heart rate and blood flow.15


They found no significant


effect of either tocolytic on foetal heart rate and movement parameters over a five-day study period. Neither tocolytic significantly changed the umbilical artery blood flow.


Nguon et al. performed a case–control study to determine a possible association between intraventricular haemorrhage in very premature


EUROPEAN OBSTETRICS & GYNAECOLOGY


not find a significant association between the use of a calcium- channel blocker and an increased risk of intraventricular haemorrhage in premature infants of a gestational age


Magnesium sulphate should not be as considered a tocolytic, but it may have a role in neuroprotection in women entering pre-term labour. A systematic review by Doyle et al. showed that the risk of cerebral palsy in the children of women receiving magnesium sulphate was substantially reduced compared with those receiving placebo (RR 0.69, 95% CI 0.54–0.87).18


There was also a significant


reduction in the rate of substantial gross motor dysfunction. If planning to use magnesium sulphate for long-term tocolysis, obstetricians should consider the effects of prolonged maternal magnesium administration on the neonate.


Yokoyama et al. measured lower serum calcium levels and mean serum alkaline phosphatase in neonates who received antenatal magnesium sulphate compared to controls.19


This means that the


potential long-term metabolic effects on neonatal bone should be considered. In a case report, Wedig et al. noted serious bone deminiralisation after maternal treatment with intravenous magnesium from 22–30 weeks gestation.20


Atosiban is the latest drug in the tocolysis field and has been specifically designed to halt premature labour. To date, no serious foetal or neonatal side effects have been published. However, when comparing atosiban with nifedipine, the neonatal outcome with nifedipine was slightly better, as mentioned above.17


Atosiban did not


result in foetal changes in heart rate or heart rate variability. Papatsonis et al. performed a systematic meta-analysis on the oxytocine-receptor antagonist for inhibiting pre-term labour, compared with placebo.21 Atosiban did not improve neonatal outcome and in one trial there was an increase in infant death at 12 months, but this was probably because this trial randomised significantly more women to atosiban before gestation of 26 weeks.


In conclusion, in recent years neonatal treatment has improved considerably. Survival is no longer the issue and the expected quality of life of neonates will increasingly influence obstetric decisions. It is for this reason that long-term follow-up studies of neonates born after different tocolytic treatments are needed. n


Yves Jacquemyn is a Professor of Obstetrics and Gynaecology and Head of the Department of Obstetrics and Gynaecology at Antwerp University Hospital. He is actively involved in perinatal research and the prevention of prematurity and pre-term labour. Previously, he worked for several years in a large regional hospital taking care of socially deprived women and high-risk pregnancy, and his main research objectives are still social inaqualities and high-risk


pregnancy. Professor Jacquemyn studied medicine at Antwerp University, where he also completed his specialisation in obstetrics and gynaecology. His PhD thesis was on ethnic differences in perinatal outcome in Belgium.


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