Best Practice Research Clinical Obstetrics and Gynaecology Vol

Best Practice & Research Clinical Obstetrics and Gynaecology Vol. 21, No. 5, pp. 857– 868, 2007 Andrew Bisits Conjoint Senior Lecture and Director of Obstetrics Faculty of Health, University of Newcastle, Australia

It has long been the desire of clinicians to have therapies that can interrupt premature labour and allow the delivery of more mature infants with lower morbidity and mortality, time to use antenatal corticosteroids and transfer to tertiary care centres for delivery.

CURRENT TOCOLYTIC AGENTS IN USE

1332 women There was a significant decrease in the number of women giving birth within 48 h of administration of the b 2 agonist There were significant increases in maternal adverse effects: chest pain dyspnoea tachycardia palpitations tremor headaches hypokalaemia hyperglycaemia nausea/vomiting nasal stuffiness And in other studies there were maternal deaths

There were no effects on perinatal deaths, respiratory distress (RDS), cerebral palsy (CP), neonatal death, infant death and necrotizing enterocolitis (NEC). Only one trial reported neonatal length of hospital stay. There is no evidence of improved neonatal outcomes with ß 2 agonists, but an association with severe maternal morbidity and mortality. Increase in cephalic presentation at delivery. Reduced incidence of caesarean section. The most marked effect was in multiparous women.

Mg. SO has historically been most used in North America, with only sparse and poor quality evidence supporting its use. Reviewed 23 trials with > 2000 women but only nine trials were rated as high quality. All trials and the nine high quality trials showed no effect on PTD < 48 h after the administration of Mg. SO compared with placebo, no therapy or other tocolytics All trials showed an increase in fetal and paediatric death, which was unexpected. 4 4

No beneficial effect was seen for neonatal morbidity, including RDS, NEC or proven infection and reduction of CP. Crowther et al concluded that there was no evidence supporting the use of Mg. SO as a tocolytic agent. King repeating in 2004 that there was clear evidence from RCTs that its use as a tocolytic should be abandoned as there was an association with a higher risk of perinatal death. 4

34 women, Panter Indomethacin, No increases in perinatal mortality or morbidity, namely NEC, bronchopulmonary dysplasia (BPD), interventricular haemorrhage (IVH) and periventricular leucomalacia (PVL). There was no evidence of any benefits from indomethacin. However, it can also be concluded that there were no detrimental effects.

Macones : indomethacin to be an effective tocolytic in delaying PTD for >48 h, 7 -10 days, 37 weeks, and decreasing low birthweight. There may be an increased rate of IVH and NEC, but it is not possible to pool the results for neonatal outcomes. Premature closure of the ductus arteriosus occurs in 10 -50% of fetuses exposed to indomethacin. It is more prevalent in later gestations (>32 weeks) and if additional maternal treatment is longer than 48 h. These effects can be reversible but pathological effects on fetal myocardial function have been reported (endocardial ischaemia, papillary muscle dysfunction, cardiac failure and death).

NSAIDs cont. From several researches(Suarez & Loe & etc. ) the authors stated: ‘We cautiously conclude that use of indomethacin at less than 34 weeks of gestation for tocolysis does not appear to increase the risk of adverse neonatal outcomes’.

NSAIDs cont. Sulindac: 95 women (46 given sulindac and 49 placebo controls) There were no outcome but there was a reduction in amniotic fluid index (AFI) and deepest pocket of liquor at 14 days. The possibility of cyclooxygenase-2 (COX-2) inhibitors as possible tocolytic agents has been investigated by several teams but the withdrawal of rofecoxib has prevented a thorough evaluation.

Nitric oxide donors The possibility of glyceryl trinitrate or nitric oxide (NO) donors as tocolytics had great appeal. O’Grady et al, who reported a 100% successful tocolysis. Duckitt and Thornton : 466 women : NO donors did reduce the risk of delivering before 37 weeks but did not delay delivery prior to 32 or 34 completed weeks, nor improve neonatal outcome, they were significantly more likely to cause headache They concluded there was insufficient evidence to support NO donors for tocolysis.

Nitric oxide donors Bisits et al : 233 women Comparing IV b 2 agonists with glyceryl trinitrate (GTN) dermal patches. GTN being less efficacious Fewer side effects were noted with GTN.

From 1980 Papatsonis et al: compare oral nifedipine or IV ritodrine Nifedipine was associated with lower rates of admission rates to NICU & RDS & ICH & and neonatal jaundice Nifedipine was associated with significant increase in mean gestational age at birth and a higher mean birth weight.

King et al : CCBs are more effective than ß 2 agonists with less maternal side effects and reduced neonatal morbidity. Most trials have used oral treatments for maintenance up to 34 -37 weeks. The results show decreased delivery within 7 days , decreased delivery before 34 weeks , reduced adverse maternal drug reaction , reduced RDS & NEC &IVH & admition to NICU & neonatal jaundice. Concerns have been raised regarding maternal cardiovascular side effects resulting from nifedipine therapy.

It has also been argued that nifedipine is not associated with severe hypotensionm other than that attributed to the underlying maternal condition because the maternal hypotension far outlasted the known half-life of oral nifedipine.

Atosiban([1 -deamino-2 -D-Tyro(OEt)-4 -Thr-8 -Orn] oxytocin) is a competitive oxytocin receptor antagonist. Goodwin et al : 112 women : Only a small number of women at <28 weeks were recruited. A significant decrease in uterine contraction frequency was seen over a 2 -h period in the atosiban subjects. Romero et al recruited 551 patients: compare atosiban with placebo The percentages of patients remaining undelivered at 24 h, 48 h and 7 days were significantly higher in the atosiban group than in the control group. Atosiban was less effective at <28 weeks and the incidence of fetal deaths was higher at <24 weeks.

Moutquin et al reported a RCT of 363 women who received atosiban and 379 a b mimetic (ritodrine, salbutamol or terbutaline). There were no significant differences for delivery at 48 h or 7 days. There were reduced maternal side effects (particularly cardiovascular) in the atosiban group but no differences in neonatal/infant outcomes. Significantly fewer women required alternative therapy in the atosiban group. 31

Papatsonis et al : 1695 women : Compared with placebo, atosiban did not reduce the incidence of preterm birth or improve neonatal outcome. There are lots of researches about Atosiban and the results are different.

Fetal fibronectin Ultrasound measurement of cervical length (Their combined results were better in predicting PTD. )

Atosiban is a combined vasopressin V 1 A/oxytocin receptor antagonist. Recently, a highly selective oxytocin receptor antagonist (barusiban) has been described. Barusiban would appear in theoretical and in vivo studies to be more effective than atosiban.

WASHINGTON CLARK HILL Department of Obstetrics and Gynecology, University of South Florida, 2004

Any treatment of preterm labor in the multiple gestation must include the administration of corticosteroids. The meta-analysis conducted by Crowley showed that the use of antenatal corticosteroids reduced significantly the incidence and severity of neonatal respiratory distress syndrome. Antenatal corticosteroids also reduce the incidence of intraventricular hemorrhage, necrotizing enterocolitis and neonatal mortality. 35

Vicenc¸ Cararach European Journal of Obstetrics & Gynecology and Reproductive Biology 2006 Badalona, Spain Catalonia, Spain

Ritodrine provides more effective tocolysis within the first 48 h of preterm labor than nifedipine. Although nifedipine was initially less effective than ritodrine in the first 2 days, similar perinatal results were obtained with a significantly lower rate of secondary effects than with ritodrine treatment.

Nifedipine and atosiban should be considered as first-line tocolytic agents instead of b agonists, based on equal or superior efficacy and superior adverse events profiles.

Katie M. Groom 2007 Auckland, New Zealand

Antibiotics may be beneficial in some women for preventing preterm birth but in others they may be associated with an increased risk and therefore should only be used with caution. Progesterone is likely to be the best potential drug at present for prevention of preterm birth.

EDWARD HAYES 2007 Jefferson University, Obstetrics and Gynecology, Philadelphia, Pennsylvania American Journal of Obstetrics and Gynecology, Volume 195, Issue 6

Based on 25 clinical trials (total n=1870 patients), Nifedipine is the most cost-effective tocolytic and should be used as ‘‘first-line’’ therapy for tocolysis in the U. S.

S. G. Oei University of Technology, Eindhoven Netherlands European Journal of Obstetrics & Gynecology and Reproductive Biology 126 (2006) 137– 145

Firstly, calcium channel blockers should not be combined with intravenous b-agonists. Secondly, intravenous nicardipine or high oral doses of nifedipine (>150 mg/day) should be avoided in cases of cardiovascular compromised pregnant women and/or multiple gestations. In all cases, blood pressure should be monitored and cardiotocography recorded during the administration of immediate release tablets and chewing the tablets should be avoided.

Comparing nifedipine with placebo