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Meta-Analysis
. 2015 Jun 5;2015(6):CD001992.
doi: 10.1002/14651858.CD001992.pub3.

Cyclo-oxygenase (COX) inhibitors for treating preterm labour

Hanna E Reinebrant  1 , Cynthia Pileggi-Castro, Carla L T Romero, Rafaela A N Dos Santos, Sailesh Kumar, João Paulo Souza, Vicki Flenady
Affiliations
Meta-Analysis

Cyclo-oxygenase (COX) inhibitors for treating preterm labour

Hanna E Reinebrant et al. Cochrane Database Syst Rev. .

Abstract

Background: Preterm birth is a major cause of perinatal mortality and morbidity. Cyclo-oxygenase (COX) inhibitors inhibit uterine contractions, are easily administered and appear to have few maternal side effects. However, adverse effects have been reported in the fetus and newborn as a result of exposure to COX inhibitors.

Objectives: To assess the effects on maternal and neonatal outcomes of COX inhibitors administered as a tocolytic agent to women in preterm labour when compared with (i) placebo or no intervention and (ii) other tocolytics. In addition, to compare the effects of non-selective COX inhibitors with COX-2 selective inhibitors.

Search methods: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (24 August 2014). We also contacted recognised experts and searched reference lists of retrieved studies.

Selection criteria: All published and unpublished randomised trials in which COX inhibitors were used for tocolysis for women in labour between 20 and 36 completed weeks' gestation.

Data collection and analysis: Two review authors independently evaluated methodological quality and extracted data. We sought additional information from study authors. Results are presented using risk ratio (RR; dichotomous data) and mean difference (MD; continuous data) with 95% confidence interval (CI). The number needed to treat for benefit (NNTB) and the number needed to treat for harm (NNTH) were calculated for statistically different categorical outcomes.

Main results: With the addition of seven studies with a total of 684 women, this review now includes outcome data from 20 studies including 1509 women. The non-selective COX inhibitor indomethacin was used in 15 studies. The overall quality of the included studies was considered moderate to low.Three small studies (102 women), two of which were conducted in the 1980's, compared COX inhibition (indomethacin only) with placebo. No difference was shown in birth less than 48 hours after trial entry (average RR 0.20, 95% CI 0.03 to 1.28; two studies with 70 women). Indomethacin resulted in a reduction in preterm birth (before completion of 37 weeks of gestation) in one small study (36 women) (RR 0.21, 95% CI 0.07 to 0.62; NNTB 2, 95% CI 2 to 4); and an increase in gestational age at birth (average MD 3.59 weeks, 95% CI 0.65 to 6.52; two studies with 66 women) and birthweight (MD 716.34 g, 95% CI 425.52 to 1007.16; two studies with 67 infants). No difference was shown in measures of neonatal morbidity or neonatal mortality.Compared with betamimetics, COX inhibitors resulted in a reduction in birth less than 48 hours after trial entry (RR 0.27, 95% CI 0.08 to 0.96; NNTB 7, 95% CI 6 to 120; two studies with 100 women) and preterm birth (before completion of 37 weeks of gestation) (RR 0.53, 95% CI 0.28 to 0.99; NNTB 6, 95% CI 4 to 236; two studies with 80 women) although no benefit was shown in terms of neonatal morbidity or mortality. COX inhibition was also associated with fewer maternal adverse affects compared with betamimetics (RR 0.19, 95% CI 0.11 to 0.31; NNTB 3, 95% CI 2 to 3; five studies with 248 women) and maternal adverse effects requiring cessation of treatment (average RR 0.09, 95% CI 0.02 to 0.49; NNTB 5, CI 95% 5 to 9; three studies with 166 women).No differences were shown when comparing COX inhibitors with magnesium sulphate (MgSO4) (seven studies with 792 women) or calcium channel blockers (CCBs) (two studies with 230 women) in terms of prolonging pregnancy or for any fetal/neonatal outcomes. There were also no differences in very preterm birth (before completion of 34 weeks of gestation) and no maternal deaths occurred in the one study that reported on this outcome. However COX inhibitors resulted in fewer maternal adverse affects when compared with MgSO4 (RR 0.39, 95% CI 0.25 to 0.62; NNTB 11, 95% CI 9 to 17; five studies with 635 women).A comparison of non-selective COX inhibitors versus any COX-2 inhibitor (two studies with 54 women) did not demonstrate any differences in maternal, fetal or neonatal outcomes.No data were available to assess COX inhibitors compared with oxytocin receptor antagonists (ORAs). Further, no data were available on extremely preterm birth (before 28 weeks of gestation), longer-term infant outcomes or costs.

Authors' conclusions: In this review, no clear benefit for COX inhibitors was shown over placebo or any other tocolytic agents. While some benefit was demonstrated in terms of postponement of birth for COX inhibitors over placebo and betamimetics and also maternal adverse effects over betamimetics and MgSO4, due to the limitations of small numbers, minimal data on safety, lack of longer-term outcomes and generally low quality of the studies included in this review, we conclude that there is insufficient evidence on which to base decisions about the role of COX inhibition for women in preterm labour. Further well-designed tocolytic studies are required to determine short- and longer-term infant benefit of COX inhibitors over placebo and other tocolytics, particularly CCBs and ORAs. Another important focus for future studies is identifying whether COX-2 inhibitors are superior to non-selective COX inhibitors. All future studies on tocolytics for women in preterm labour should assess longer-term effects into early childhood and also costs.

PubMed Disclaimer

Conflict of interest statement

All authors declared no conflict of interest.

Figures

1
1
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
2
2
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1 COX inhibitors compared with placebo, Outcome 1 Birth less than 48 hours after trial entry.
1.2
1.2. Analysis
Comparison 1 COX inhibitors compared with placebo, Outcome 2 Neonatal mortality.
1.3
1.3. Analysis
Comparison 1 COX inhibitors compared with placebo, Outcome 3 Preterm birth (before completion of 37 weeks of gestation).
1.4
1.4. Analysis
Comparison 1 COX inhibitors compared with placebo, Outcome 4 Birth less than 7 days after trial entry.
1.5
1.5. Analysis
Comparison 1 COX inhibitors compared with placebo, Outcome 5 Gestational age (weeks).
1.6
1.6. Analysis
Comparison 1 COX inhibitors compared with placebo, Outcome 6 Birthweight (g).
1.7
1.7. Analysis
Comparison 1 COX inhibitors compared with placebo, Outcome 7 Apgar score less than 7 at 5 minutes.
1.8
1.8. Analysis
Comparison 1 COX inhibitors compared with placebo, Outcome 8 Admission to neonatal intensive care unit.
1.9
1.9. Analysis
Comparison 1 COX inhibitors compared with placebo, Outcome 9 Respiratory distress syndrome.
1.10
1.10. Analysis
Comparison 1 COX inhibitors compared with placebo, Outcome 10 Chronic lung disease.
1.11
1.11. Analysis
Comparison 1 COX inhibitors compared with placebo, Outcome 11 Persistent pulmonary hypertension of the newborn.
1.12
1.12. Analysis
Comparison 1 COX inhibitors compared with placebo, Outcome 12 Intraventricular haemorrhage Grades III or IV.
1.13
1.13. Analysis
Comparison 1 COX inhibitors compared with placebo, Outcome 13 Necrotising enterocolitis.
1.14
1.14. Analysis
Comparison 1 COX inhibitors compared with placebo, Outcome 14 Neonatal sepsis.
1.15
1.15. Analysis
Comparison 1 COX inhibitors compared with placebo, Outcome 15 Premature closure of the ductus arteriosus.
1.16
1.16. Analysis
Comparison 1 COX inhibitors compared with placebo, Outcome 16 Patent ductus arteriosus.
1.17
1.17. Analysis
Comparison 1 COX inhibitors compared with placebo, Outcome 17 Maternal adverse effects.
1.18
1.18. Analysis
Comparison 1 COX inhibitors compared with placebo, Outcome 18 Postpartum haemorrhage.
1.19
1.19. Analysis
Comparison 1 COX inhibitors compared with placebo, Outcome 19 Chorioamnionitis or endometritis.
1.20
1.20. Analysis
Comparison 1 COX inhibitors compared with placebo, Outcome 20 Caesarean section.
2.1
2.1. Analysis
Comparison 2 COX inhibitors compared with any other tocolytic (subgrouped by type of tocolytic), Outcome 1 Birth less than 48 hours after trial entry.
2.2
2.2. Analysis
Comparison 2 COX inhibitors compared with any other tocolytic (subgrouped by type of tocolytic), Outcome 2 Neonatal mortality.
2.3
2.3. Analysis
Comparison 2 COX inhibitors compared with any other tocolytic (subgrouped by type of tocolytic), Outcome 3 Very preterm birth (before completion of 34 weeks of gestation).
2.4
2.4. Analysis
Comparison 2 COX inhibitors compared with any other tocolytic (subgrouped by type of tocolytic), Outcome 4 Maternal death.
2.5
2.5. Analysis
Comparison 2 COX inhibitors compared with any other tocolytic (subgrouped by type of tocolytic), Outcome 5 Preterm birth (before completion of 37 weeks of gestation).
2.6
2.6. Analysis
Comparison 2 COX inhibitors compared with any other tocolytic (subgrouped by type of tocolytic), Outcome 6 Birth less than 7 days after trial entry.
2.7
2.7. Analysis
Comparison 2 COX inhibitors compared with any other tocolytic (subgrouped by type of tocolytic), Outcome 7 Pregnancy prolongation (days).
2.8
2.8. Analysis
Comparison 2 COX inhibitors compared with any other tocolytic (subgrouped by type of tocolytic), Outcome 8 Gestational age (weeks).
2.9
2.9. Analysis
Comparison 2 COX inhibitors compared with any other tocolytic (subgrouped by type of tocolytic), Outcome 9 Birthweight (g).
2.10
2.10. Analysis
Comparison 2 COX inhibitors compared with any other tocolytic (subgrouped by type of tocolytic), Outcome 10 Antenatal corticosteroids ‐ any.
2.11
2.11. Analysis
Comparison 2 COX inhibitors compared with any other tocolytic (subgrouped by type of tocolytic), Outcome 11 Respiratory distress syndrome.
2.12
2.12. Analysis
Comparison 2 COX inhibitors compared with any other tocolytic (subgrouped by type of tocolytic), Outcome 12 Apgar score less than 7 at 5 minutes.
2.13
2.13. Analysis
Comparison 2 COX inhibitors compared with any other tocolytic (subgrouped by type of tocolytic), Outcome 13 Admission to neonatal intensive care unit.
2.14
2.14. Analysis
Comparison 2 COX inhibitors compared with any other tocolytic (subgrouped by type of tocolytic), Outcome 14 Duration of neonatal intensive care unit stay.
2.15
2.15. Analysis
Comparison 2 COX inhibitors compared with any other tocolytic (subgrouped by type of tocolytic), Outcome 15 Use of mechanical ventilation.
2.16
2.16. Analysis
Comparison 2 COX inhibitors compared with any other tocolytic (subgrouped by type of tocolytic), Outcome 16 Duration of mechanical ventilation (days).
2.17
2.17. Analysis
Comparison 2 COX inhibitors compared with any other tocolytic (subgrouped by type of tocolytic), Outcome 17 Persistent pulmonary hypertension of the newborn.
2.18
2.18. Analysis
Comparison 2 COX inhibitors compared with any other tocolytic (subgrouped by type of tocolytic), Outcome 18 Intraventricular haemorrhage ‐ all grades.
2.19
2.19. Analysis
Comparison 2 COX inhibitors compared with any other tocolytic (subgrouped by type of tocolytic), Outcome 19 Intraventricular haemorrhage Grades III or IV.
2.20
2.20. Analysis
Comparison 2 COX inhibitors compared with any other tocolytic (subgrouped by type of tocolytic), Outcome 20 Other major cerebral abnormality.
2.21
2.21. Analysis
Comparison 2 COX inhibitors compared with any other tocolytic (subgrouped by type of tocolytic), Outcome 21 Retinopathy of prematurity Grades III or IV.
2.22
2.22. Analysis
Comparison 2 COX inhibitors compared with any other tocolytic (subgrouped by type of tocolytic), Outcome 22 Necrotising enterocolitis.
2.23
2.23. Analysis
Comparison 2 COX inhibitors compared with any other tocolytic (subgrouped by type of tocolytic), Outcome 23 Neonatal sepsis.
2.24
2.24. Analysis
Comparison 2 COX inhibitors compared with any other tocolytic (subgrouped by type of tocolytic), Outcome 24 Oligohydramnios.
2.25
2.25. Analysis
Comparison 2 COX inhibitors compared with any other tocolytic (subgrouped by type of tocolytic), Outcome 25 Premature closure of the ductus arteriosus.
2.26
2.26. Analysis
Comparison 2 COX inhibitors compared with any other tocolytic (subgrouped by type of tocolytic), Outcome 26 Patent ductus arteriosus.
2.27
2.27. Analysis
Comparison 2 COX inhibitors compared with any other tocolytic (subgrouped by type of tocolytic), Outcome 27 Neonatal renal failure.
2.28
2.28. Analysis
Comparison 2 COX inhibitors compared with any other tocolytic (subgrouped by type of tocolytic), Outcome 28 Maternal adverse effects.
2.29
2.29. Analysis
Comparison 2 COX inhibitors compared with any other tocolytic (subgrouped by type of tocolytic), Outcome 29 Maternal adverse effects requiring cessation of treatment.
2.30
2.30. Analysis
Comparison 2 COX inhibitors compared with any other tocolytic (subgrouped by type of tocolytic), Outcome 30 Chorioamnionitis or endometritis.
2.31
2.31. Analysis
Comparison 2 COX inhibitors compared with any other tocolytic (subgrouped by type of tocolytic), Outcome 31 Caesarean section.
3.1
3.1. Analysis
Comparison 3 Non‐selective COX inhibitors compared with selective COX‐2 inhibitors, Outcome 1 Birth less than 48 hours after trial entry.
3.2
3.2. Analysis
Comparison 3 Non‐selective COX inhibitors compared with selective COX‐2 inhibitors, Outcome 2 Neonatal mortality.
3.3
3.3. Analysis
Comparison 3 Non‐selective COX inhibitors compared with selective COX‐2 inhibitors, Outcome 3 Preterm birth (before completion of 37 weeks of gestation).
3.4
3.4. Analysis
Comparison 3 Non‐selective COX inhibitors compared with selective COX‐2 inhibitors, Outcome 4 Birth less than 7 days after trial entry.
3.5
3.5. Analysis
Comparison 3 Non‐selective COX inhibitors compared with selective COX‐2 inhibitors, Outcome 5 Gestational age (weeks).
3.6
3.6. Analysis
Comparison 3 Non‐selective COX inhibitors compared with selective COX‐2 inhibitors, Outcome 6 Birthweight (g).
3.7
3.7. Analysis
Comparison 3 Non‐selective COX inhibitors compared with selective COX‐2 inhibitors, Outcome 7 Respiratory distress syndrome.
3.8
3.8. Analysis
Comparison 3 Non‐selective COX inhibitors compared with selective COX‐2 inhibitors, Outcome 8 Intraventricular haemorrhage Grades III or IV.
3.9
3.9. Analysis
Comparison 3 Non‐selective COX inhibitors compared with selective COX‐2 inhibitors, Outcome 9 Intraventricular haemorrhage ‐ all grades.
3.10
3.10. Analysis
Comparison 3 Non‐selective COX inhibitors compared with selective COX‐2 inhibitors, Outcome 10 Necrotising enterocolitis.
3.11
3.11. Analysis
Comparison 3 Non‐selective COX inhibitors compared with selective COX‐2 inhibitors, Outcome 11 Apgar score less than 7 at 5 minutes.
3.12
3.12. Analysis
Comparison 3 Non‐selective COX inhibitors compared with selective COX‐2 inhibitors, Outcome 12 Admission to neonatal intensive care unit.
3.13
3.13. Analysis
Comparison 3 Non‐selective COX inhibitors compared with selective COX‐2 inhibitors, Outcome 13 Use of mechanical ventilation.
3.14
3.14. Analysis
Comparison 3 Non‐selective COX inhibitors compared with selective COX‐2 inhibitors, Outcome 14 Neonatal sepsis.
3.15
3.15. Analysis
Comparison 3 Non‐selective COX inhibitors compared with selective COX‐2 inhibitors, Outcome 15 Premature closure of the ductus arteriosus.
3.16
3.16. Analysis
Comparison 3 Non‐selective COX inhibitors compared with selective COX‐2 inhibitors, Outcome 16 Oligohydramnios.
3.17
3.17. Analysis
Comparison 3 Non‐selective COX inhibitors compared with selective COX‐2 inhibitors, Outcome 17 Maternal adverse effects.
3.18
3.18. Analysis
Comparison 3 Non‐selective COX inhibitors compared with selective COX‐2 inhibitors, Outcome 18 Antepartum haemorrhage.
3.19
3.19. Analysis
Comparison 3 Non‐selective COX inhibitors compared with selective COX‐2 inhibitors, Outcome 19 Chorioamnionitis or endometritis.
3.20
3.20. Analysis
Comparison 3 Non‐selective COX inhibitors compared with selective COX‐2 inhibitors, Outcome 20 Caesarean section.
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Update of

References

References to studies included in this review

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Carlan 1995 {published data only}
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Gamissans 1984 {published data only}
    1. Gamissans O, Balasch J. Prostaglandin synthetase inhibitors in the treatment of preterm labor. In: Fuchs F, Stubblefield PG editor(s). Preterm Birth: Causes, Prevention and Management. New York: Macmillan, 1984:223‐48.
Groom 2005 {published data only}
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Hallak 1992 {published data only}
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    1. Hallak M, Moise KJ, Lira N, Dorman KF, O'Brian Smith E, Cotton DB. The effect of tocolytic agents (indomethacin and terbutaline) on fetal breathing and body movements: a prospective, randomized, double‐blind, placebo‐controlled clinical trial. American Journal of Obstetrics and Gynecology 1992;167(4):1059‐63. - PubMed
    1. Hallak M, Moise KJ, O'Brian Smith E, Cotton DB. The effects of indomethacin and terbutaline on human fetal umbilical artery velocimetry: a randomized double‐blind study. American Journal of Obstetrics and Gynecology 1993;168(1 Pt 2):348. - PubMed
    1. Hallak M, Moise KJ, O'Brian Smith E, Cotton DB. The effects of indomethacin and terbutaline on human fetal umbilical artery velocimetry: a randomized, double‐blind study. American Journal of Obstetrics and Gynecology 1993;168(3):865‐8. - PubMed
Humphrey 2001 {published data only}
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Jain 2006 {published data only}
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Katz 1983 {published data only}
    1. Katz Z, Lancet M, Yemini M, Mogilner BM, Feigl A, Ben‐Hur H. Treatment of premature labor contractions with combined ritodrine and indomethacine. International Journal of Gynecology & Obstetrics 1983;21:337‐42. - PubMed
Mital 1992 {published data only}
    1. Khuteta RP, Garg S, Bhargava A. Mefanimic acid in prevention of premature labour. 12th FIGO World Congress of Gynecology and Obstetrics; 1988 October 23‐28; Brazil. 1988:222.
    1. Mital P, Garg S, Khuteta RP, Khuteta S, Mital P. Mefenamic acid in prevention of premature labour. Journal of the Royal Society of Health 1992;112(5):214‐6. - PubMed
Newton 1991 {published data only}
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    1. Ridgway L, Wright J, Newton E. The effect of indomethacin on fetal heart biometry. American Journal of Obstetrics and Gynecology 1991;164:349.
Rasanen 1995 {published data only}
    1. Jouppila P, Rasanen J. Response of the fetal hemodynamics to different maternal prostaglandin synthetase inhibitors. Proceedings of 14th European Congress of Perinatal Medicine; 1994 June 5‐8; Helsinki, Finland. 1994:Abstract no: 269.
    1. Jouppila P, Rasanen J. Response to the fetal hemodynamics to different maternal prostaglandin synthetase inhibitors. International Journal of Gynecology & Obstetrics 1994;46:48.
    1. Rasanen J, Jouppila P. Fetal cardiac function and ductus arteriosus during indomethacin and sulindac therapy for threatened preterm labor: a randomized study. American Journal of Obstetrics and Gynecology 1995;173(1):20‐5. - PubMed
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References to studies awaiting assessment

Castillo 1988 {published data only}
    1. Castillo JM, Alonso J, Hernandez‐Garcia JM, Sancho B, Martinez V. Study of biochemical and biophysical modifications produced on pregnant women treated in threatened of premature labor with ritodrine and indometacine. 12th World Congress of Gynecology and Obstetrics; 1988 Oct 23‐28; Rio de Janeiro, Brazil. 1988:20.
Mesdaghinia 2012 {published data only}
    1. Mesdaghinia E, Mesdaghinia A, Hashemi T, Sooky Z, Mousavi GA. Comparing the effects fo indomethacin and magnesium‐sufate in the treatment of preterm labor. Feyz, Journal of Kashan University of Medical Sciences 2012;16(2):95‐101.
    1. Sooky Z. Comparison of delaying in premature labour by indomethacin and Mg sulphate in pregnant women referred to maternity hospital. IRCT Iranian Registry of Clinical Trials (www.irct.ir) (accessed 6 December 2010) 2010.

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References to other published versions of this review

King 2005
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