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Can We Reduce Preterm Births?

Posted on: Friday, 1 April 2005, 03:00 CST

Preterm birth, defined as birth before 37 wk of gestation occurs in about 10 per cent of all pregnancies. The infant born before term is functionally immature and therefore at higher risk of death and disability. Hyaline membrane disease, hypothermia, hypoglycaemia. and a greater susceptibility to infection are some of the problems associated with prematurity. Given these increased risks for the baby, it would seem appropriate for clinicians to attempt to stop the process of preterm birth.

Several conditions are known to be associated with preterm birth. For example, a woman with an over distended uterus due to multifoetal pregnancies or polyhydramnios is at increased risk of preterm labour. oilier conditions that increase the risk of preterm birth include hypertensive disorders in pregnancy, bleeding during pregnancy, pre-labour rupture of membranes and genital and urinary tract infections.

While routine antenatal care may not reduce preterm deliveries, some focussed interventions in the antenatal period may reduce preterm births. Screening for urinary tract infection in the antenatal clinic followed by treatment of asymptomatic bacteriuria reduces the risk of preterm delivery or low birth weight babies by 40 per cent [95% confidence interval (CI) 20-55%]1. The national intervention strategy of modifying life-style and reducing workload of pregnant women in France was associated with a reduction in preterm delivery rate from 7.9 per cent in 1971 to 4.1 per cent by 1 988-89. The reduction in preterm births before 32 wk was 69 per cent:. Although this strategy has not been tested in a randomized trial, preterm delivery rates in France are lower than in most countries of comparable social development.

However in some situations, it would be unwise to stop preterm birth. In women with life threatening conditions such as severe pre- eclampsia or placental abruption remote from term, preterm delivery actually benefits the mother. Similarly pre-term delivery is medically indicated if there is symptomatic chorioamnionitis fol lowing preterm pre-labour rupture of membranes. Unfortunately, there is no identifiable cause in about half of all women with preterm labour. This lack of an apparent cause or association in a significant proportion of women has implications for the management of preterm labour.

Another issue complicating decision-making and management is the diagnosis of preterm labour. Labour is conventionally diagnosed if uterine contractions are associated with progressive shortening and dilatation of the cervix. Uterine contractions may occur without significant changes in the cervix. Waiting to demonstrate progressive cervical dilatation before initiating treatment to stop labour may be too late. On the other hand, starting tocolytic medications to inhibit labour early may be associated with apparently higher success rates, but one may question if the diagnosis of preterm labour was correct in the first place. This problem also makes it difficult to interpret results of the numerous clinical trials of tocolytic therapy.

Beta mimetic drugs are perhaps the most commonly used tocolytic agents worldwide. Ethanol, magnesium sulphate, indomethacin, calcium channel blockers, nitric oxide donors and atobisan (an oxytocin antagonist) have also been used for inhibiting preterm labour. Overall, tocolytics prolong pregnancy3 with 40 per cent reduction (95% CI 5-62%) in risk of delivery within 7 days of tocolytic therapy. However, tocolytics are not associated with improved perinatal outcomes. Significant maternal side effects associated with tocolytic use include palpitations, nausea, tremor, hyperglycaemia and hypokalaemia leading to discontinuation of treatment.

In this issue of the Journal, Xiaomao Li and colleagues have done a systematic review of trials comparing ritodrine, a beta mimetic agent with placebo or magnesium sulphate for tocolysis in preterm labour4. The authors reviewed 20 randomized trials, six of which are from Chinese literature. Meta-analyses showed that ritodrine was nearly twice as good as placebo in delaying delivery by at least two days. There were no differences in the proportions of term births, low birth weight, severe respiratory morbidity or perinatal mortality. While meta-analysis of four trials published in English comparing ritodrine with magnesium sulphate did not show any difference in delaying delivery, meta-analysis of the six Chinese trials showed that delay of at least one day in delivery occurred in more women on ritodrine [Odds ratio (OR) 3.95; 95% CI 1.98-7.88]. Further neonatal death occurred less often in this group (OR 0.45; 95% CI 0.22-0.93), a finding consistent with the results of another systematic review of magnesium sulphate for tocolysis5. Ritodrine acted faster than magnesium sulphate in inhibiting uterine contractions. However, maternal side effects requiring discontinuation of treatment were more in the ritodrine arm.

The present report4 does not discuss the quality of the studies that were included in the meta-analysis. It is not clear if some of these studies were truly randomized and double-blinded. The authors have assumed that a placebo may have been used at least in some of the trials. The decision to do a sub-group analysis does not appear in the study design and may have been made post-hoc. However, even given these limitations, the findings are consistent with other systematic reviews on this topic3,5.

A delay of two days in delivery is significant not just from a statistical point of view, but also from a clinical point of view. While the effect of tocolysis on prevention of preterm birth is minimal if any, one intervention that has been shown to be of great benefit to the survival of the preterm baby is administration of corticosteroids to the mother6. Giving steroids to the mother before delivery reduces the odds of neonatal mortality by 40 per cent (95% CI 0.48-0.75). This intervention reduces respiratory distress syndrome and intraventricular haemorrhage in preterm infants. Gaining one or two days with tocolytics allows for steroids to promote accelerated maturation of the baby. This is perhaps the greatest advantage of using tocolysis - to buy time for the baby's systems to mature. Also in settings where nursery facilities are limited, tocolysis can also help in facilitating transfer of the mother to a centre with better perinatal facilities.

Calcium channel blockers7 appear to be preferable to beta mimetics not only in reducing the number of preterm deliveries within seven days of tocolytic therapy [Relative risk (RR) 0.76; 95% CI 0.6-0.97] but also because of less discontinuation for adverse drug reactions (RR 0.14; 95% CI 0.05-0.36). This group of drugs is associated with better neonatal outcomes - less respiratory distress syndrome, less necrotising enterocolitis, less intraventricular haemorrhage and less neonatal jaundice. These drugs are easily available and relatively inexpensive. However, further research should address the effects of different dosage regimens and formulations of calcium channel blockers on maternal and neonatal outcomes.

Inhibiting preterm labour is not always successful especially when labour is advanced. However, early recognition of preterm labour by the woman is important. While providing antenatal care, it is important for the caregiver to educate women and their families on the symptoms and signs of preterm labour and the need to seek appropriate care should preterm labour occur. While this may not directly influence the incidence of preterm labour, it will allow more women to receive antenatal steroids and thus improve survival of preterm babies.

References

1. Smaill F. Antibiotics for asymptomatic bacteriuria in pregnancy (Cochrane Review). In: The Cochrane library, Issue 4. 2003. Chichester. UK: John Wiley & Sons, Ltd.

2. Papiernik F. Prevention of preterm labour and delivery. Baillieres Clin Obstet Gynaecol 1993; 7 : 499-521.

3. Gyetvai K, Hannah ME, Hodnett ED, Ohlsson A. Tocolytics for preterm labor: a systematic review. Obstet Gvnecol 1999; 94 : 869- 77.

4. Li X, Zhang Y. Shi 7. Ritodrine in the treatment of preterm labour: a mata-analysis. Indian J Med Res 2005: 121 : 120-7.

5. Crowther CA, Hiller JE, Doyle LW. Magnesium for preventing preterm birth in threatened preterm labour (Cochrane Review). In: The Cochrane Library, Issue 4, 2004. Chichester, UK: John Wiley & Sons, Ltd.

6. Crowley P. Prophylactic corticosteroids for preterm births (Cochrane Review). In: The Cochrane Library, Issue 4, 2004. Chichester, UK: John Wiley & Sons, Ltd.

7. King JF, Flenady VJ, Papatsonis DN, Carbonne B. Calcium channel blockers for inhibiting preterm labour (Cochrane Review). In: The Cochrane Library, Issue 1, 2003. Chichester, UK: John Wiley & Sons, Ltd.

Matthews Mathai

Department of Obstetrics & Gynaecology

Christian Medical College

Vellore 632004, India

e-mail: mathaim@cmcvcllore.ac.in

Copyright Indian Council of Medical Research Feb 2005

Source: Indian Journal of Medical Research

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