Br Med J (Clin Res Ed): first published as 10.1136/bmj.283.6288.395 on 8 August 1981. Downloaded from BRITISH LONDON, SATURDAY 8 AUGUST 1981 MEDICAL JOURNAL

Drug treatment of premature labour

When an obstetrician is faced with a patient in premature In each individual case careful clinical assessment is needed labour the immediate aim is to prolong the pregnancy and so to to decide whether the option of premature delivery is improve the prognosis for the fetus. Several beta-sympatho- preferable to continuation of the pregnancy-as may be the mimetic agents are now being used to suppress premature case with intrauterine infection, abruptio placentae, or retarda- labour, but the benefit and risks of such treatment are far from tion of intrauterine growth. Moreover, drugs should probably clear. Most of the clinical trials have been of ritodrine hydro- not be used to suppress labour after spontaneous rupture ofthe chloride; the conclusions have not been universally favourable. membranes; the treatment may well be ineffective and the Two studies,1 2 for example, found no differences between onset of contractions may indicate the presence of infection, patients treated with ritodrine and placebo, but the numbers when delivery is in the best interests of mother and fetus. In were small. One larger study3 found that bed rest and sedation abruptio placentae there is at least a theoretical risk that were as effective at postponing delivery as three different relaxation of the uterus may exacerbate the bleeding, and regimens of ritodrine, but this report was criticised on the antepartum haemorrhage should be regarded as a relative ground that the controls had lower Bishop scores (for the state contraindication to treatment. of the cervix) at the start of treatment than those treated Even after the patient has been selected as a suitable candi- with ritodrine.4 date for suppression of uterine activity the difficult and In contrast to these studies others have reported that important problem remains of distinguishing between "true" 9 ritodrine,5-7 terbutaline,' and isoxsuprine10 are all more and "false" labour. By the time cervical effacement and http://www.bmj.com/ effective at postponing delivery in threatened premature dilatation are obvious it may be too late for effective inhibition labour than either placebo or ethanol. The evidence is less of uterine activity; if, on the other hand, drugs are used at the convincing that the pharmacological suppression of premature earliest opportunity many patients will be overtreated. labour passes the more stringent test of reducing perinatal Injudicious selection of cases may explain why, in West mortality. Merkatz et all' pooled the data from 11 different Germany, one million ampoules and six million tablets of one centres in the United States, and found that the incidence of beta-sympathomimetic agent were used during one year'2- neonatal death (5%O) and respiratory distress syndrome (11%) without any noticeable improvement in perinatal mortality. in 187 mothers treated with ritodrine were significantly less Ideally, before treatment is begun, the patient should have a on 28 September 2021 by guest. Protected copyright. than the respective figures of 13% and 20%O in 122 controls; period of assessment, using tocography where available, to but these conclusions must be viewed with some caution judge the frequency and regularity ofuterine contractions. because the different numbers in the two groups suggest that Even after premature labour has been arrested the recur- selection bias could have influenced the results. The lack of rence rate is high, and oral maintenance treatment may be of information on the long-term outcome of the child after value in prolonging the pregnancy.9 13 On the other hand, treatment of premature labour is serious: preventing the drugs have not been shown to help women at "high risk" of morbidity of prematurity may be just as important as reducing developing premature labour-possibly owing to the great mortality, and this aspect should be given more attention in difficulty of selecting the individual who will go into labour future investigations. prematurely. Despite the inconclusive nature of the published evidence Once the decision to use drug treatment has been made, the the clinician still has to decide when to use drug treatment for best choice would appear to be one of the beta2-sympatho- premature labour. Merkatz et all' made the important point mimetic drugs. Ethanol is less effective than ritodrine in that in their series improvement in neonatal mortality was suppressing uterine activity6 7 and induces unpleasant side limited to those who were treated before 33 weeks ofgestation. effects of headache and nausea. Prostaglandin-synthetase Both the risks of prematurity and the potential benefits of inhibitors suppress uterine activity'4 but cannot be recom- treatment decrease rapidly as pregnancy advances; but the mended until more is known about the possible risk, shown in gestational age that should be chosen as the limit for treatment animals, that they induce premature closure of the ductus will depend on the quality of the neonatal services in any arteriosus." Magnesium sulphate suppresses uterine activity particular area. more effectively than ethanol'6 and may yet prove to have a

C BRITISH MEDICAL JOURNAL 1981. All reproduction rights reserved. VOLUME 283 NO 6288 PAGE 395 396 BRITISH MEDICAL JOURNAL VOLUME 283 8 AUGUST 1981 Br Med J (Clin Res Ed): first published as 10.1136/bmj.283.6288.395 on 8 August 1981. Downloaded from place in the management of premature labour. Ritodrine has been studied more extensively than the other beta2-sympa- Treatment of acute thomimetic agents, but one report found very little difference mountain sickness in side effects between ritodrine and fenoterol.17 Further studies will be required to see whether there are any subtle, but possibly important, differences between the different beta- For centuries it has been known that persons who climb to high sympathomimetic drugs. Furthermore, beta-mimetics are not altitude are likely to suffer from acute mountain sickness. The harmless. They may cause acute pulmonary oedema in the symptoms ofthe mild form include headache, nausea, anorexia, mother when used in conjunction with corticosteroids to and weakness and are experienced by half of people ascending induce maturity of the fetal lung.18-20 They also induce above 14 000 feet. Nearly 5% suffer from the severe form with tachycardia, palpitations, and hypotension and should not be cerebral or pulmonary oedema.' It is seen in climbers, soldiers, used in patients with heart disease or hyperthyroidism.21 and skiers but, most frequently, in trekkers, partly because of In an earlier leading article22 we described the use of drugs in their large numbers, and partly because they usually live at the management of preterm labour as "usually unnecessary, sea level and do not leave sufficient time to acclimatise. In frequently ineffective, and occasionally harmful." Little has the Himalayas alone over 200 000 men and women undertake changed since then. Nevertheless, prematurity remains a major high-altitude treks each year, and their numbers are rapidly cause of perinatal death and further controlled trials, probably increasing. multicentre ones, are required before the treatment of prema- Doctors need, therefore, both to understand mountain ture labour can be put on a rational basis. sickness and to be able to treat it. Unfortunately the underlying cause of acute mountain sickness is not clear, though hypoxia, 1 Walters WAW, Wood C. A trial of oral ritodrine for the prevention of alkalosis, exercise, and alterations in the production of cere- premature labour. BrJ Obstet Gynaecol 1977 ;84 :26-30. brospinal all 2 Spellacy WN, Cruz AC, Birk SA, Buhi WC. Treatment of premature fluid may be relevant.2 Hypoxia has been thought labor with ritodrine: a randomized controlled study. Obstet Gynecol unlikely to be the sole cause, but in a recent controlled study3 1979 ;54 :220-3. the symptoms of mountain sickness were shown to be highly 3 Larsen JF, Hansen MK, Hesseldahl H, et al. Ritodrine in the treatment of correlated with arterial In preterm labour. A clinical trial to compare a standard treatment with hypoxia. the same individuals three regimens involving the use of ritodrine. Br J Obstet Gynaecol arterial hypoxia also correlated with proteinuria4 and cerebral 1980;87 :949-57. performance tests. Since hypoxia can cause cerebral oedema5 'Heyting A. Ritodrine in the treatment of preterm labour. A clinical trial and may cause pulmonary oedema,6 7 most of the to compare a standard treatment with three regimens involving the use features of ofritodrine. BrJ' Obstet Gynaecol 1980 ;87 :1056. acute mountain sickness could be attributed solely to oxygen Wesselius-de Casparis A, Thiery M, Yo Le Sian A, et al. Results of lack. Acute mountain sickness is less well correlated with double-blind multicentre study with ritodrine in premature labour. alkalosis3 and occurs in the absence of exercise.2 These Br MedJ' 1971 ;iii :144-7. aspects 6 Fuchs F. Prevention of prematurity. Am J Obstet Gynecol 1976;126:809- must be of secondary importance. 17. If hypoxia is the main cause of acute mountain sickness then 7 Lauersen NH, Merkatz IR, Tejani N, et al. Inhibition of premature increasing oxygen supply to the tissues should help. Breathing labour. A multicenter comparison of ritodrine and ethanol. Am J Obster Gynecol 1977;127:837-45. from oxygen apparatus may be beneficial7 but in terms of 8 Ingermarsson I. Effect of terbutaline on premature labor. A double-blind trekking to altitude it is impracticable. There has, therefore, placebo-controlled study. AmJ' Obstet Gynecol 1976;125:520-4. been considerable interest in drug treatment. Acetazolamide ' Brown SM, Tejani NA. Tebutaline sulfate in the prevention of recurrence has been shown in several studies2 3 8 to reduce arterial of premature labor. Obstet Gynecol 1981 ;57 :22-5. http://www.bmj.com/ 10 Csapo Al, Herezeg J. Arrest of premature labor by isoxsuprine. Am J hypoxia at altitude and now this has been linked with the Obstet Gynecol 1977;129:482-91. degree of acute mountain sickness.3 The clinical features ofthe Merkatz IR, Peter JB, Barden TP. Ritodrine hydrochloride. A beta- illness are subjective, but the pronounced reduction in mimetic agent for use in preterm labour. II. Evidence of efficacy. Obstet Gynecol 1980;56:7-12. altitude proteinuria of those taking acetazolamide indicates its 12 Fifth Study Group of the Royal College of Obstetricians and Gynae- beneficial effect on the body. cologists. Beta-adrenergic agonists. In: Anderson A, Beard R, Brudenell The drug probably acts by causing a metabolic acidosis JM, Dunn PM, eds. Preterm labour. Proceedings of the Fifth Study Group of the Royal College of Obstetricians and Gynaecologists 1977. leading to an increased hypoxic drive to ventilation and London: Royal College of Obstetricians and Gynaecologists, 1978: thereby increased tissue oxygenation. More potent analogues on 28 September 2021 by guest. Protected copyright. 134-220. of acetazolamide may be preferable, and methylprogesterone 13 Creasy RK, Golbus MS, Laros RK Jr, Parer JT, Roberts JM. Oral ritodrine maintenance in the treatment of preterm labour. Am J Obstet might also be useful.9 The appropriate dosage ofthe drugs and Gynecol 1980;137:212-9. their relation to hypoxia need to be assessed, particularly at 14 Zuckerman H, Reiss U, Rubinstein I. Inhibition of human premature night when profound oxygen desaturation occurs.'0 Other labor by indomethacin. Obstet Gynecol 1974;44 :787-92. 15 Sharpe GL, Thalme B, Larsson KS. Studies on closure of the ductus drugs tried in acute mountain sickness include spironolactone arteriosus. XI. Ductal closure in utero by a prostaglandin synthetase and frusemide. These drugs have been aimed at reducing the inhibitor. Prostaglandins 1974;8:363-8. fluid retention, but they have no effect on tissue oxygenation, 16 Steer CM, Petrie RH. A comparison of magnesium sulfate and alcohol for the prevention of premature labor. AmJ7 Obstet Gynecol 1977 ;129 :1-4. and none has been of proved benefit." 17 Richter R, Hinselmann MJ. The treatment of threatened premature labor Use of acetazolamide as a prophylactic for acute mountain by betamimetic drugs: a comparison of fenoterol and ritodrine. Obstet sickness should help to reduce much of the suffering of those Gynecol 1979;53:81-7. who and live at altitude and 18 Elliott HR, Abdulla U, Hayes PJ. Pulmonary oedema associated with trek, climb, high by increasing ritodrine infusion and betamethasone administration in premature mental alertness might even decrease mountaineering labour. Br MedJr 1978;ii:799-800. accidents. It is, however, not a panacea. Acetazolamide does 19 Tinga DJ, Aarnoudse JG. Post-partum pulmonary oedema associated have occasional severe side effects as with treat- with preventive therapy for premature labour. Lancet 1979 ;i :1026. and, oxygen 20 Stubblefield PG. Pulmonary edema occurring after therapy with dexa- ment, is unlikely to be of much use in the established case. methasone and terbutaline for premature labor: a case report. Am J People will still suffer from acute mountain sickness if they Obstet Gynecol 1978;132:341-2. ascend too fast. 21 Barden TP, Peter JB, Merkatz IR. Ritodrine hydrochloride: a beta- mimetic agent for use in preterm labor. I. Pharmacology, clinical history, administration, side effects, and safety. Obstet Gynecol 1980 ;56 :1-6. Hackett PH, Rennie D, Levine HD. The incidence, importance, and 22 Anonymous. Drugs in threatened preterm labour. Br Medy 1979 ;i :71. prophylaxis of acute mountain sickness. Lancet 1976 ;ii : 1149-54,5.