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*Correspondence: Dr H. Helmer, Department of Obstetrics and Gynecology, General Hospital Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.
The purpose of this retrospective study is to evaluate the effects of atosiban (Tractocile available in Austria since February 2000) for routine treatment of women with threatened preterm delivery. The advantage of this drug compared to other tocolytic agents is its specific action on reproductive tissues without the accompanying severe side effects. Women (n= 208) were retrospectively evaluated. Diagnoses at admission were preterm labour (n= 117), preterm rupture of membranes (n= 65), incompetent cervix (n= 19) and vaginal bleeding (n= 7). Gestational age was between weeks 21 and 33 of pregnancy. Preterm labour was defined as ≥4 uterine contractions/30 min and cervical length <30 mm examined by vaginal ultrasound and/or detection of vaginal fetal fibronectin. Tocolytic effectiveness was determined as the number of women having a diagnosis of preterm labour who were still pregnant after 48 hours and after 7 days. The influence on the frequency of contractions before and 3–12 hours after the start of treatment was assessed. Maternal side effects, perinatal and neonatal morbidity and transfers to the NICU were also evaluated. The proportion of women who remained undelivered was 78.7% after 48 hours, and 64.3% after 7 days. Atosiban decreased the frequency of contractions from 5.4/30 min before treatment to 1.6 contractions/30 min after the start of treatment. At the initial bolus application, 20.2% of women presented drug-related side effects, such as nausea, vertigo and flush over a short period of 1–2 minutes. During infusion, side effects possibly related to atosiban could be detected in 6% of women. Mean length of stay was 11.8 days in the NICU and 30.9 days in intermediate care. Twenty-three children developed intraventricular haemorrhage (I–IV). In conclusion, atosiban is an effective tocolytic drug in the treatment of preterm labour and preterm rupture of the membranes. It has significantly less side effects due to its lack of cardiovascular activity.
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The World Health Organisation reports that each year around 210 million women become pregnant1. Among the 130 million or so births, some 10–15% require rapid and skilled intervention. It is estimated that preterm birth and/or low birth weight is the third most important (24%) cause of newborn deaths. In developed countries, low birth weight is associated with about 75% of early neonatal mortality2. Low birth weight also contributes significantly to infant and childhood morbidity.
The second and third trimesters of pregnancy are vital for maturation of the fetal lungs. If this maturation is halted by early delivery, the chances of survival for the neonate are reduced and the possibility of morbidity including neurodevelopmental handicap, cerebral palsy, seizure disorders and non-neurological disorders, such as bronchopulmonary dysplasia and retinopathy, is higher.
Corticosteroids given prior to preterm birth are effective in preventing respiratory distress syndrome and neonatal mortality3. Delaying delivery by tocolytics to achieve a full course of corticosteroids for lung maturation, and to transfer the fetus in utero to a tertiary feto-maternal unit has been verified. In an effort to examine the effectiveness of any tocolytic compared with a placebo or no tocolytic for preterm labour, Gyetvai et al.4 published a systematic review demonstrating that the use of beta-agonists, indomethacin, atosiban and ethanol was associated with statistically significant decreases in the likelihood of delivery within 24 hours, 48 hours and 7 days. In large, randomised, double-blind trials, atosiban has demonstrated similar tocolytic effectiveness as beta-agonists but has the advantage of generating almost no side effects due to its specific effect on uterine tissues5–7. In January 2000, the European Agency for the Evaluation of Medical Products (EMEA) authorised atosiban for use in clinical practice. Atosiban has been used in our department as the first line tocolytic drug in women with threatened preterm delivery since April 2000. In the context of a post marketing surveillance study we evaluated the use of atosiban in everyday clinical practice.
Material and Methods
Two hundred and eight women were retrospectively evaluated; diagnoses at admission were preterm labour (n= 117), preterm rupture of membranes (n= 65), incompetent cervix (n= 19) and vaginal bleeding (n= 7). Gestational age was between 21 and 33 completed weeks of pregnancy. Preterm labour was defined as ≥4 uterine contractions/30 min and the fulfilment of at least one of the following two criteria: (1) cervical length <30 mm examined by vaginal ultrasound, (2) detection of vaginal fetal fibronectin by immunoassay (Fetal Fibronectin, Adeza Biomedical, California, USA). Preterm premature rupture of the membranes (PPROM) was proven by using a commercially available immunoassay test evaluating the concentration of dephosphorylised insulin growth factor binding protein-1 in the vaginal secretion (Actim PROM Test, Medix Biochemica OY, Kauniainen, Finland).
Incompetent cervix was diagnosed by observing visible fetal membranes using specula in the absence of regular uterine contractions. Atosiban was administered according to the recommended protocol with an initial bolus of 6.75 mg followed by a high saturation infusion of 18 mg/hour over 3 hours and a lower concentrated infusion of 6 mg/hour over a period of 15–45 hours. Additionally, the number of cycles following this regimen was recorded. Additional cycles were administered when regular uterine contractions and/or an ongoing cervical dilatation/effacement was observed after 48 hours. The decision to administer rescue therapy using the beta-agonist, hexoprenaline, as an alternative tocolytic drug, was made if uterine contractions continued and/or cervical dilatation/effacement was not halted within 1–6 hours after the start of atosiban treatment.
Tocolytic effectiveness was determined as the number of women diagnosed with preterm labour who were still pregnant after 48 hours and after 7 days. Twenty-seven multiple pregnancies have been evaluated separately for tocolytic effectiveness. The influence on the frequency of contractions before and 3–12 hours after the start of treatment was assessed. The interval between the start of treatment and delivery was recorded. In 170 women, vaginal swabs were evaluated for bacterial vaginosis according to the criteria of Nugent8. Antibiotic treatment was performed in all women with PPROM, preterm labour, cervical incompetence or vaginal bleeding; women received antibiotics if the serum C-reactive protein was >2 mg/dl and/or in the presence of a leukocyte count >16,000. Further indications for antibiotic treatment included the presence of bacterial vaginosis or amnionitis assessed by amniocentesis. Maternal side effects, mode of delivery, pH values, Apgar score, perinatal and neonatal mortality, morbidity and the transfer rate to the NICU were also evaluated.
After 48 hours and 7 days, 78.7% and 64.3% of women with threatened preterm delivery had not been delivered, respectively (Figs. 1 and 2). In 19 twin and eight triplet pregnancies, 77.8% had not been delivered after 48 hours and 69.2% were still pregnant after 7 days. One hundred and fifty four of the 207 women (74.4%) received tocolytic treatment with atosiban over a time period between 18 and 48 hours, 14.4% were treated with two cycles and 11.2% received three or more cycles. Rescue therapy with an alternative tocolytic drug (hexoprenaline) was indicated in 32% of all treatments. The frequency of alternative tocolytic treatment was higher (39%) at very early gestational ages (<24 weeks) whereas at later gestational ages (29–33 weeks) the frequency was reduced to 29%. In women with regular uterine contractions, atosiban decreased the frequency of contractions from 5.4 contractions/30 min before treatment to 1.6 contractions/30 min in an interval of 3–12 hours after the start of treatment (Fig. 3).
The overall mean number of days gained after the start of tocolysis was 31 days, whereas in the subgroup of women with PPROM the interval until delivery was 9.3 days and in women with preterm labour 41.0 days (Fig. 4). Bacterial vaginosis was present at admission in 7.6% of women.
At the initial bolus application, 20.2% of women presented drug-related side effects as nausea, vertigo and flush over a short period of 1–2 minutes. During infusion, 6% of women experienced side effects, which were possibly related to atosiban. Regarding mode of delivery, 61% of women were delivered by caesarean section while 39% gave birth spontaneously. The mean Apgar score was 7.61 after 1 min and 8.75 after 5 min. Arterial pH of the umbilical cord showed a mean of 7.25 and the venous mean pH was 7.32. The mean length of stay at the NICU was 11.8 days, and at intermediate care it was 30.9 days. Perinatal mortality was 5.0% at gestational ages between 24 and 27 weeks. Twenty-three out of 130 infants investigated developed signs of intraventricular haemorrhage, of which seven were grade 3 to 4.
In this retrospective analysis atosiban was shown to be an effective and safe tocolytic drug in the treatment of preterm labour and PPROM. This could be demonstrated for singleton as well as for multiple pregnancies. Typical maternal and fetal side effects associated with beta-agonist treatment were avoided. Only 6% of all women reported side effects during infusion therapy, which could be related to atosiban. However, 20.2% of the women reported side effects during the initial bolus administration. We found a significant decrease in side effects when we changed the dosage regimen for the administration of the bolus from 1 minute to an interval of 3 minutes. Extending this to even longer periods could not be recommended since the half-life of atosiban is approximately 16 min.
There are divergent opinions about the use of any tocolytic drug in women with PPROM. We believe that the use of tocolytics in these women is justified before 32 weeks gestation to achieve lung maturation and to allow antibiotic treatment. In an effort to diagnose intrauterine infection in women with PPROM we routinely performed amniocentesis if technically possible.
There is a well known correlation between the presence of bacterial vaginosis and preterm labour or PPROM. Mainly in very early gestational ages, an ascending infection is held responsible for causing these pathologies. We believe that the low incidence of bacterial vaginosis at admission in our collective was due to the fact that ascending infection had taken place during earlier gestation. Unfortunately we had no previous results of vaginal swabs in these women.
We would also like to point out the use of vaginal ultrasonography and fetal fibronectin to define a high-risk group for preterm delivery in women with preterm contractions. It could be shown that the use of these diagnostic tools could reduce the admission rates without influencing the neonatal outcome. Digital examination of the cervix should be avoided especially in women with PPROM.
As has been demonstrated on many occasions, preterm labour occurs at the end of a cascade of biochemical pathways. We cannot expect to prevent the inevitable outcome of preterm labour and thus a tocolytic drug can only achieve temporary symptomatic relief of this condition. However, this delay can be critical in terms of providing the opportunity to transfer the baby in utero to NICU where the administration of corticosteroids enables the fetal lungs to mature. At early gestations, between 23 and 26 weeks, delaying delivery for one day is associated with a 3% increase in survival9, therefore, attempts to suppress preterm labour are certainly not futile. However, there are principal controversies concerning the use of tocolytics since a direct benefit for the neonate could not be demonstrated. Following the medical principle ‘primum non nocere’ (‘first, do no harm’) a drug with the least side effects should be used, a situation which is best accomplished with atosiban.