IJG-07941; No of Pages 4 International Journal of Gynecology and Obstetrics xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
Maintenance tocolysis with oral micronized progesterone for prevention of preterm birth after arrested preterm labor Manju Choudhary a,⁎, Amita Suneja a, Neelam B. Vaid a, Kiran Guleria a, M.M.A. Faridi b a b
Department of Obstetrics and Gynaecology, University College of Medical Sciences and Guru Tegh Bahadur Hospital, Delhi, India Department of Pediatrics, University College of Medical Sciences and Guru Tegh Bahadur Hospital, Delhi, India
a r t i c l e
i n f o
Article history: Received 29 August 2013 Received in revised form 21 January 2014 Accepted 27 March 2014 Keywords: Maintenance tocolysis Oral micronized progesterone Preterm labor
a b s t r a c t Objective: To evaluate the efficacy of maintenance therapy with oral micronized progesterone (OMP) for prolongation of pregnancy in cases of arrested preterm labor. Methods: Ninety women at 24–34 weeks of singleton pregnancy with intact membranes and arrested preterm labor were randomly allocated to receive OMP (n = 45) or placebo (n = 45) daily until 37 weeks or delivery, whichever was earlier. Outcome parameters were compared using Student t test, χ2 test, Fisher exact test, and log-rank χ2 test. Results: OMP significantly prolonged the latency period (33.29 ± 22.16 vs 23.07 ± 15.42 days; P = 0.013). Log-rank analysis revealed a significant difference in mean time to delivery between the 2 groups (P = 0.014). There were significantly fewer preterm births (33% vs 58%; P = 0.034) and low birth weight neonates (37% vs 64%; P = 0.017), and significantly higher mean birth weight (2.44 ± 0.58 vs 2.14 ± 0.47 kg; P = 0.009) in the OMP group. Perinatal outcomes and adverse effects were similar in the 2 groups. Conclusion: Maintenance tocolysis with OMP significantly prolonged pregnancy and decreased the number of preterm births. Clinical Trial Registry of India: CTRI/2011/10/002043. © 2014 Published by Elsevier Ireland Ltd. on behalf of International Federation of Gynecology and Obstetrics.
1. Introduction Preterm birth is the leading cause of neonatal morbidity and mortality, accounting for 10% of neonatal mortality worldwide [1]. The accepted treatment of preterm labor is acute tocolysis, which may prolong gestation by 2–7 days—providing time for corticosteroid administration and maternal transport to a facility with a neonatal intensive care unit (ICU). Considerable debate remains as to whether maintenance tocolysis is appropriate after initial tocolysis for spontaneous preterm labor. Various drugs with different dosage schedules and routes have been used for maintenance tocolysis (β-agonists, calcium-channel blockers, magnesium, and atosiban) but no significant prolongation of pregnancy or improved perinatal outcome has been noted [2–5]. Progesterone has been widely used as a uterine sedative in the prevention of preterm labor but it has not been investigated thoroughly for maintenance tocolysis. Few recent studies support the use of progesterone as a maintenance tocolytic [6–9]. Currently, there is insufficient evidence to advocate progesterone for maintenance tocolysis among women with preterm labor, as the
⁎ Corresponding author at: Department of Obstetrics and Gynaecology, UCMS and GTB Hospital, Delhi 110095, India. Tel.: +91 9868482424; fax: +91 11 22590495. E-mail address: [email protected] (M. Choudhary).
number of trials comparing progesterone and placebo or other tocolytic drugs is small. More trials are needed for better assessment of the efficacy of progesterone as a maintenance tocolytic agent. The aim of the present study was to evaluate the efficacy of maintenance therapy with oral micronized progesterone for prolongation of pregnancy in cases of arrested preterm labor. 2. Materials and methods A double-blind, randomized, placebo-controlled trial was conducted at the Department of Obstetrics and Gynaecology and the Department of Pediatrics at University College of Medical Sciences (UCMS) and Guru Teg Bahadur Hospital, Delhi, India, from October 1, 2010, to April 30, 2012. Ethical clearance was obtained from the institutional ethics committee. Pregnant women at 24–34 weeks of singleton pregnancy were recruited after successful tocolysis with nifedipine therapy. Women with multiple pregnancies, premature rupture of membranes, prepartum hemorrhage, fetal growth restriction, fetal distress, fetal congenital anomalies, and history of tocolytic treatment were excluded from the study. After written informed consent was obtained, all women with threatened preterm labor underwent detailed history-taking pertaining to risk factors for preterm labor and examination (general physical examination, obstetric examination, speculum examination, vaginal
http://dx.doi.org/10.1016/j.ijgo.2014.01.019 0020-7292/© 2014 Published by Elsevier Ireland Ltd. on behalf of International Federation of Gynecology and Obstetrics.
Please cite this article as: Choudhary M, et al, Maintenance tocolysis with oral micronized progesterone for prevention of preterm birth after arrested preterm labor, Int J Gynecol Obstet (2014), http://dx.doi.org/10.1016/j.ijgo.2014.01.019
2
M. Choudhary et al. / International Journal of Gynecology and Obstetrics xxx (2014) xxx–xxx
examination, and Bishop score). Preterm labor was defined as 4 contractions per 20 minutes or 8 per 60 minutes associated with progressive change in cervix or cervical dilation of more than 1 cm or at least 80% cervical effacement [10]. All women with threatened preterm labor received intravenous hydration therapy (500 mL of intravenous lactated Ringer solution), betamethasone (12 mg intramuscularly, followed by another 12 mg after 24 hours), and tocolysis with nifedipine per hospital protocol (initial dose of 20 mg, followed by 10–20 mg every 4–6 hours). Nifedipine tocolysis was continued until uterine contractions had subsided for at least 12 hours. After the arrest of preterm labor, patients were recruited for the study within 48 hours of acute tocolysis. Arrested preterm labor was defined as no uterine contractions for at least 12 hours on nifedipine tocolysis. Recruited women underwent routine obstetric investigations and special investigations (hemoglobin with total leucocyte count; urine culture and sensitivity; high vaginal swab culture and sensitivity). The purpose of the urine culture and the high vaginal swab culture was to detect infections and treat them accordingly. For double-blinding, women were randomly allocated by a third party in a 1:1 ratio into 2 groups—micronized progesterone or placebo— using computer-generated random number tables. Each participant was assigned a consecutive serial number from 1. Precoded, opaque, sealed envelopes containing capsules for 7 days (200 mg of oral micronized progesterone or placebo) were given to the patients on a weekly basis. Study drugs were provided by the pharmaceutical company, and similar-looking placebo was prepared in the Department of Pharmacology at UCMS using lactose as filler. Once a patient had been stable in the hospital for 48 hours after stopping nifedipine, she was discharged with instructions regarding signs and symptoms of preterm labor. Each woman was given drugs for 1 week at each visit and was asked to take a capsule orally once daily at bed time, from recruitment to 37 weeks or delivery, whichever was earlier. Weekly follow-up was carried out for signs and symptoms of preterm labor and any fresh complaint related to adverse effects of the medication. Both the patient and the investigator were blinded to the study medication. Compliance in taking medication was checked by asking participants to return empty envelopes to the third party on a weekly basis. Decoding of sealed envelopes was carried out at the time of data analysis. Participants were divided into 2 groups: group 1 (patients taking the active drug) and group 2 (patients taking placebo).
The primary outcome parameter was prolongation of pregnancy/ latency period (i.e. days gained until delivery). Secondary outcome parameters were number of preterm births, birth weight, gestational age at delivery, readmission for preterm labor, neonatal ICU admission, neonatal ICU stay, and neonatal morbidity (respiratory distress syndrome, sepsis, necrotizing enterocolitis, and early neonatal mortality). For the sample size calculation, we assumed a standard deviation of 12 days, based on data from a previous study of maintenance tocolysis [6]. Forty-two patients per group were needed to detect a 12-day difference in time gained during pregnancy at a significance level of 5% and power of 80%. Statistical analysis was performed using χ2 and Fisher exact tests for qualitative variables and unpaired Student t test for quantitative variables. Kaplan–Meier survival analysis and log-rank test were used to compare the 2 survival curves. P b 0.05 was considered to be statistically significant. SPSS version 20 (IBM, Armonk, NY, USA) was used for statistical analysis. 3. Results Ninety women with arrested preterm labor were recruited for the study and randomized to group 1 (progesterone group; n = 45) or group 2 (placebo group; n = 45). Two participants from group 1 and 3 from group 2 were lost to follow-up during the study period; their data were analyzed via intention-to-treat analysis by replacing the missing values with the means (Fig. 1). The groups were matched with respect to age, parity, and presence of risk factors for preterm birth. All clinical characteristics at recruitment were matched between the groups. Mean gestational age at recruitment was 31.91 weeks in group 1 and 32.42 weeks in group 2 (P = 0.20) (Table 1). The mean latency period was significantly longer in group 1 (33.29 ± 22.16 vs 23.07 ± 15.42 days; P = 0.013). There was a significant difference in mean time to delivery between the groups; the Kaplan–Meier plot depicted significantly more undelivered women in group 1 at each specific time point until delivery (P = 0.014; log-rank χ2 = 6.06; Fig. 2). Mean gestational age at delivery was higher in group 1 (P = 0.07). In group 1, most patients delivered at 37 weeks or later (28 [62%]), while most patients in group 2 delivered at 34–36 weeks (17 [38%]) (P = 0.01). There were significantly fewer preterm births in group 1 than in group 2 (P = 0.03) (Table 2).
160 women with preterm labor received nifedipine tocolysis 70 patients excluded (failure to arrest preterm labor, adverse effects of nifedipine, rupture of membranes, obstetric/fetal complications)
90 patients randomized to study groups
Group 1 (n=45) Study group (progesterone)
Group 2 (n=45) Placebo group
2 patients lost to follow-up
43 patients completed the study
3 patients lost to follow-up
42 patients completed the study
Fig. 1. Flow diagram of study participants.
Please cite this article as: Choudhary M, et al, Maintenance tocolysis with oral micronized progesterone for prevention of preterm birth after arrested preterm labor, Int J Gynecol Obstet (2014), http://dx.doi.org/10.1016/j.ijgo.2014.01.019
M. Choudhary et al. / International Journal of Gynecology and Obstetrics xxx (2014) xxx–xxx Table 1 Comparison of baseline characteristics between groups (n = 90).a Characteristics
Group 1: progesterone (n = 45)
Group 2: placebo (n = 45)
Age, y Parity 0 1 ≥2 History of previous preterm birth Presence of any risk factor for preterm birthb Gestational age, wk Cervical dilation, cm Cervical effacement, % Bishop score
24.11 ± 2.386
23.71 ± 2.928
16 (36) 22 (49) 5 (11) 6 (13)
16 (36) 21 (47) 5 (11) 2 (4)
17 (38)
18 (40)
31.91 ± 2.09 1.67 ± 0.36 55 ± 19.96 4.18 ± 1.07
32.42 ± 1.65 1.65 ± 0.33 49.00 ± 17.85 4.02 ± 1.09
P value 0.479 0.994
0.265 N0.99 0.202 0.784 0.136 0.484
a
Values are given as mean ± SD or number (percentage) unless otherwise indicated. History of preterm birth, first-trimester abortion, second-trimester abortion, genitourinary infection, addiction. b
Mean birth weight was higher in group 1 than in group 2 (P = 0.009). Most neonates in both groups were appropriate for gestational age, and there was no significant difference in Apgar score at birth or 5 minutes between the groups (Table 3). The incidence of low birth weight neonates was significantly lower in group 1 (P = 0.01). There were no significant differences between the groups with regard to neonatal ICU admission (P N 0.99), neonatal ICU stay (P = 0.60), respiratory distress syndrome (P = 0.77), sepsis (P = 0.67), or neonatal mortality (P N 0.99). There was 1 (2.2%) neonatal death in each group. The cause of death was severe prematurity with respiratory distress syndrome in group 1, and sepsis and pulmonary hemorrhage in group 2. Most patients did not report any adverse effects; 4 women in each group experienced headache, epigastric pain, and acne. Symptoms of preterm labor recurred in 46 patients; these women continued on the same medication and did not receive a different therapy. 4. Discussion In the present study, 200 mg of oral micronized progesterone was used because of its adequate bioavailability and fewer adverse effects compared with a 400-mg dose. The micronized form increases oral absorption and has comparable efficacy to that of vaginal progesterone [11]. The literature reports comparable plasma concentrations of
3
Table 2 Gestational age at delivery, number of preterm births, and readmission for preterm labor (n = 90).a Outcome parameters
Group 1: progesterone Group 2: placebo P value (n = 45) (n = 45)
Gestational age at delivery, wk 28–31 + 6 32–33 + 6 34–36 + 6 ≥37 Preterm birth, %
36.79 ± 2.64 2 (4) 6 (13) 7 (16) 28 (62) 15 (33)
a
35.90 ± 2.00 0 (0) 9 (20) 17 (38) 16 (36) 26 (58)
0.076 0.014
0.034
Values are given as mean ± SD or number (percentage) unless otherwise indicated.
progesterone with 200 mg of oral micronized progesterone and 400 mg of vaginal progesterone (30 vs 17–34 ng/mL) [12]. The vaginal route was not selected in the present study because it is associated with vaginal irritation and unpleasant vaginal discharge [13]. The oral route has better compliance. In the present study, the mean latency period was significantly longer among women treated with progesterone compared with the placebo group. This is consistent with results from other studies [6–8]. A trial by Borna and Sahabi [6] showed significant prolongation of mean latency period with progesterone (36.1 ± 17.9 days in progesterone group vs 24.5 ± 27.2 days in control group; P = 0.037). A randomized controlled trial by Sharami et al. [7] also showed that progesterone therapy resulted in a longer latency period (23.88 ± 18.01 vs 16.67 ± 12.9 days; P = 0.004). In addition, Arikan et al. [8] found that micronized progesterone treatment resulted in a longer latency period (32.1 ± 17.8 vs 21.2 ± 16.3 days; P b 0.05). The beneficial effect of oral micronized progesterone on prolongation of pregnancy was shown by the survival analysis in the present study, which depicted significantly larger numbers of undelivered women in the progesterone group at each specific time point until delivery compared with placebo. Prolongation of latency period with progesterone can be explained by various mechanisms resulting in uterine quiescence. Progesterone relaxes myometrial smooth muscle, blocks the action of oxytocin, inhibits the formation of gap junctions and prostaglandin synthesis, and has anti-inflammatory properties [14–17]. In the present study, mean gestational age at delivery was 1 week later in the progesterone group than in the placebo group, although this difference was not significant. This is consistent with results from the double-blind randomized controlled trial by Sharami et al. [7]. The
Table 3 Neonatal outcome parameters at birth.a,b
Fig. 2. Kaplan–Meier survival curve of time until delivery between the progesterone group and the placebo group.
Outcome parameters
Group 1: progesterone Group 2: placebo P value (n = 43) (n = 42)
Birth weight, kg Appropriate for gestational age Small for gestational age Large for gestational age Apgar score b7 at birth Apgar score b7 at 5 minutes Low birth weight Respiratory distress syndrome Sepsis Hyperbilirubinemia Otherc NICU admission Duration of NICU stay, d Median (interquartile range) Neonatal mortality
2.44 ± 0.58 40 (93) 2 (5) 1 (2) 4 (9) 1 (2) 16 (37) 6 (14) 2 (5) 2 (5) 1 (2) 10 (23) 4.70 ± 3.72 4.0 (1.75–7.75) 1 (2)
2.14 ± 0.47 42 (100) 0 (0) 0 (0) 1 (2) 0 (0) 27 (64) 7 (17) 3 (7) 0 (0) 2 (5) 9 (21) 5.89 ± 4.25 4.0 (3.0–8.0) 1 (2)
0.009 0.241
0.360 N0.99 0.017 0.771 0.676 0.494 0.616 N0.99 0.604d N0.99
Abbreviation: NICU, neonatal intensive care unit. a Values are given as mean ± SD or number (percentage) unless otherwise indicated. b Per-protocol analysis. c Hypoglycemia, hypothermia, and hemorrhagic diseases of newborns. d Mann–Whitney U test.
Please cite this article as: Choudhary M, et al, Maintenance tocolysis with oral micronized progesterone for prevention of preterm birth after arrested preterm labor, Int J Gynecol Obstet (2014), http://dx.doi.org/10.1016/j.ijgo.2014.01.019
4
M. Choudhary et al. / International Journal of Gynecology and Obstetrics xxx (2014) xxx–xxx
2 other relevant randomized controlled trials [6,8]—which were not double-blind—revealed a significant prolongation of gestational age at delivery with progesterone. The progesterone group had significantly higher birth weight, significantly fewer preterm births, and significantly fewer low birth weight neonates. However, neonatal morbidity and mortality were similar between the groups. Lack of significant improvement in neonatal outcome could have been because the sample size was calculated to determine a difference in latency period and, therefore, did not have sufficient power to demonstrate a significant difference in perinatal morbidity and mortality. To account for this, future studies based on combined sample size to detect maternal and neonatal outcome are needed. Another reason for similar neonatal outcome could have been that mean gestational age at recruitment was relatively late (31–32 weeks) and most adverse neonatal outcomes are seen in earlier gestation (before 30 weeks); therefore, we may have missed significant differences in adverse perinatal outcome in extreme prematurity. Further studies focusing on women at less than 30 weeks of pregnancy and with larger samples would provide valuable data on the use of oral micronized progesterone for maintenance tocolysis. In conclusion, maintenance tocolysis with oral micronized progesterone significantly prolonged pregnancy and decreased the number of preterm births. The present results support the use of micronized progesterone as a maintenance tocolytic for prolongation of pregnancy in cases of arrested preterm labor. Conflict of interest The authors have no conflicts of interest. References [1] Reducing Perinatal and Neonatal Mortality. Child Health Research Project Special Report. http://www.harpnet.org/doc/spec3.pdf. Published October 1999. Accessed April 6, 2012.
[2] Dodd JM, Crowther CA, Dare MR, Middleton P. Oral betamimetics for maintenance therapy after threatened preterm labour. Cochrane Database Syst Rev 2006;1: CD003927. [3] Carr DB, Clark AL, Kernek K, Spinnato JA. Maintenance oral nifedipine for preterm labor: a randomized clinical trial. Am J Obstet Gynecol 1999;181(4):822–7. [4] Han S, Crowther CA, Moore V. Magnesium maintenance therapy for preventing preterm birth after threatened preterm labour. Cochrane Database Syst Rev 2010;7: CD000940. [5] Papatsonis D, Flenady V, Liley H. Maintenance therapy with oxytocin antagonists for inhibiting preterm birth after threatened preterm labour. Cochrane Database Syst Rev 2009;1:CD005938. [6] Borna S, Sahabi N. Progesterone for maintenance tocolytic therapy after threatened preterm labour: a randomised controlled trial. Aust N Z J Obstet Gynaecol 2008;48(1):58–63. [7] Sharami SH, Zahiri Z, Shakiba M, Milani F. Maintenance therapy by vaginal progesterone after threatened Idiopathic Preterm Labor: A randomized placebo-controlled double-blind trial. Int J Fertil Steril 2010;4(2):45–50. [8] Arikan I, Barut A, Harma M, Harma IM. Effect of progesterone as a tocolytic and in maintenance therapy during preterm labor. Gynecol Obstet Invest 2011;72(4): 269–73. [9] Facchinetti F, Paganelli S, Comitini G, Dante G, Volpe A. Cervical length changes during preterm cervical ripening: effects of 17-alpha-hydroxyprogesterone caproate. Am J Obstet Gynecol 2007;196(5):453.e1–4. [10] Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Rouse D, Spong CY. Preterm Birth. In: Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Rouse D, Spong CY, editors. Williams Obstetrics. 23rd ed. Philadelphia, PA: McGraw Hill Professional; 2009. p. 804–31. [11] Loose-Mitchell DS, Stancel GM. Estrogen and Progestins. In: Goodman LS, Hardman JG, Limbird LE, Gilman AG, editors. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw-Hill; 2001. p. 1617–21. [12] Silver RI, Rodriguez R, Chang TS, Gearhart JP. In vitro fertilization is associated with an increased risk of hypospadias. J Urol 1999;161(6):1954–7. [13] Simon JA. Micronized progesterone: vaginal and oral uses. Clin Obstet Gynecol 1995;38(4):902–14. [14] How H, Huang ZH, Zuo J, Lei ZM, Spinnato II JA, Rao CV. Myometrial estradiol and progesterone receptor changes in preterm and term pregnancies. Obstet Gynecol 1995;86(6):936–40. [15] Henderson D, Wilson T. Reduced binding of progesterone receptor to its nuclear response element after human labor onset. Am J Obstet Gynecol 2001;185(3): 579–85. [16] Garfield RE, Saade G, Buhimschi C, Buhimschi I, Shi L, Shi SQ, et al. Control and assessment of the uterus and cervix during pregnancy and labour. Hum Reprod Update 1998;4(5):673–95. [17] Challis JRG. Characteristics of Parturition. In: Creasy RK, Resnick R, editors. MaternalFetal Medicine. 4th ed. Philadelphia, PA: W.B. Saunders; 1999. p. 484–97.
Please cite this article as: Choudhary M, et al, Maintenance tocolysis with oral micronized progesterone for prevention of preterm birth after arrested preterm labor, Int J Gynecol Obstet (2014), http://dx.doi.org/10.1016/j.ijgo.2014.01.019
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
Maintenance tocolysis with oral micronized progesterone for prevention of preterm birth after arrested preterm labor Manju Choudhary a,⁎, Amita Suneja a, Neelam B. Vaid a, Kiran Guleria a, M.M.A. Faridi b a b
Department of Obstetrics and Gynaecology, University College of Medical Sciences and Guru Tegh Bahadur Hospital, Delhi, India Department of Pediatrics, University College of Medical Sciences and Guru Tegh Bahadur Hospital, Delhi, India
a r t i c l e
i n f o
Article history: Received 29 August 2013 Received in revised form 21 January 2014 Accepted 27 March 2014 Keywords: Maintenance tocolysis Oral micronized progesterone Preterm labor
a b s t r a c t Objective: To evaluate the efficacy of maintenance therapy with oral micronized progesterone (OMP) for prolongation of pregnancy in cases of arrested preterm labor. Methods: Ninety women at 24–34 weeks of singleton pregnancy with intact membranes and arrested preterm labor were randomly allocated to receive OMP (n = 45) or placebo (n = 45) daily until 37 weeks or delivery, whichever was earlier. Outcome parameters were compared using Student t test, χ2 test, Fisher exact test, and log-rank χ2 test. Results: OMP significantly prolonged the latency period (33.29 ± 22.16 vs 23.07 ± 15.42 days; P = 0.013). Log-rank analysis revealed a significant difference in mean time to delivery between the 2 groups (P = 0.014). There were significantly fewer preterm births (33% vs 58%; P = 0.034) and low birth weight neonates (37% vs 64%; P = 0.017), and significantly higher mean birth weight (2.44 ± 0.58 vs 2.14 ± 0.47 kg; P = 0.009) in the OMP group. Perinatal outcomes and adverse effects were similar in the 2 groups. Conclusion: Maintenance tocolysis with OMP significantly prolonged pregnancy and decreased the number of preterm births. Clinical Trial Registry of India: CTRI/2011/10/002043. © 2014 Published by Elsevier Ireland Ltd. on behalf of International Federation of Gynecology and Obstetrics.
1. Introduction Preterm birth is the leading cause of neonatal morbidity and mortality, accounting for 10% of neonatal mortality worldwide [1]. The accepted treatment of preterm labor is acute tocolysis, which may prolong gestation by 2–7 days—providing time for corticosteroid administration and maternal transport to a facility with a neonatal intensive care unit (ICU). Considerable debate remains as to whether maintenance tocolysis is appropriate after initial tocolysis for spontaneous preterm labor. Various drugs with different dosage schedules and routes have been used for maintenance tocolysis (β-agonists, calcium-channel blockers, magnesium, and atosiban) but no significant prolongation of pregnancy or improved perinatal outcome has been noted [2–5]. Progesterone has been widely used as a uterine sedative in the prevention of preterm labor but it has not been investigated thoroughly for maintenance tocolysis. Few recent studies support the use of progesterone as a maintenance tocolytic [6–9]. Currently, there is insufficient evidence to advocate progesterone for maintenance tocolysis among women with preterm labor, as the
⁎ Corresponding author at: Department of Obstetrics and Gynaecology, UCMS and GTB Hospital, Delhi 110095, India. Tel.: +91 9868482424; fax: +91 11 22590495. E-mail address: [email protected] (M. Choudhary).
number of trials comparing progesterone and placebo or other tocolytic drugs is small. More trials are needed for better assessment of the efficacy of progesterone as a maintenance tocolytic agent. The aim of the present study was to evaluate the efficacy of maintenance therapy with oral micronized progesterone for prolongation of pregnancy in cases of arrested preterm labor. 2. Materials and methods A double-blind, randomized, placebo-controlled trial was conducted at the Department of Obstetrics and Gynaecology and the Department of Pediatrics at University College of Medical Sciences (UCMS) and Guru Teg Bahadur Hospital, Delhi, India, from October 1, 2010, to April 30, 2012. Ethical clearance was obtained from the institutional ethics committee. Pregnant women at 24–34 weeks of singleton pregnancy were recruited after successful tocolysis with nifedipine therapy. Women with multiple pregnancies, premature rupture of membranes, prepartum hemorrhage, fetal growth restriction, fetal distress, fetal congenital anomalies, and history of tocolytic treatment were excluded from the study. After written informed consent was obtained, all women with threatened preterm labor underwent detailed history-taking pertaining to risk factors for preterm labor and examination (general physical examination, obstetric examination, speculum examination, vaginal
http://dx.doi.org/10.1016/j.ijgo.2014.01.019 0020-7292/© 2014 Published by Elsevier Ireland Ltd. on behalf of International Federation of Gynecology and Obstetrics.
Please cite this article as: Choudhary M, et al, Maintenance tocolysis with oral micronized progesterone for prevention of preterm birth after arrested preterm labor, Int J Gynecol Obstet (2014), http://dx.doi.org/10.1016/j.ijgo.2014.01.019
2
M. Choudhary et al. / International Journal of Gynecology and Obstetrics xxx (2014) xxx–xxx
examination, and Bishop score). Preterm labor was defined as 4 contractions per 20 minutes or 8 per 60 minutes associated with progressive change in cervix or cervical dilation of more than 1 cm or at least 80% cervical effacement [10]. All women with threatened preterm labor received intravenous hydration therapy (500 mL of intravenous lactated Ringer solution), betamethasone (12 mg intramuscularly, followed by another 12 mg after 24 hours), and tocolysis with nifedipine per hospital protocol (initial dose of 20 mg, followed by 10–20 mg every 4–6 hours). Nifedipine tocolysis was continued until uterine contractions had subsided for at least 12 hours. After the arrest of preterm labor, patients were recruited for the study within 48 hours of acute tocolysis. Arrested preterm labor was defined as no uterine contractions for at least 12 hours on nifedipine tocolysis. Recruited women underwent routine obstetric investigations and special investigations (hemoglobin with total leucocyte count; urine culture and sensitivity; high vaginal swab culture and sensitivity). The purpose of the urine culture and the high vaginal swab culture was to detect infections and treat them accordingly. For double-blinding, women were randomly allocated by a third party in a 1:1 ratio into 2 groups—micronized progesterone or placebo— using computer-generated random number tables. Each participant was assigned a consecutive serial number from 1. Precoded, opaque, sealed envelopes containing capsules for 7 days (200 mg of oral micronized progesterone or placebo) were given to the patients on a weekly basis. Study drugs were provided by the pharmaceutical company, and similar-looking placebo was prepared in the Department of Pharmacology at UCMS using lactose as filler. Once a patient had been stable in the hospital for 48 hours after stopping nifedipine, she was discharged with instructions regarding signs and symptoms of preterm labor. Each woman was given drugs for 1 week at each visit and was asked to take a capsule orally once daily at bed time, from recruitment to 37 weeks or delivery, whichever was earlier. Weekly follow-up was carried out for signs and symptoms of preterm labor and any fresh complaint related to adverse effects of the medication. Both the patient and the investigator were blinded to the study medication. Compliance in taking medication was checked by asking participants to return empty envelopes to the third party on a weekly basis. Decoding of sealed envelopes was carried out at the time of data analysis. Participants were divided into 2 groups: group 1 (patients taking the active drug) and group 2 (patients taking placebo).
The primary outcome parameter was prolongation of pregnancy/ latency period (i.e. days gained until delivery). Secondary outcome parameters were number of preterm births, birth weight, gestational age at delivery, readmission for preterm labor, neonatal ICU admission, neonatal ICU stay, and neonatal morbidity (respiratory distress syndrome, sepsis, necrotizing enterocolitis, and early neonatal mortality). For the sample size calculation, we assumed a standard deviation of 12 days, based on data from a previous study of maintenance tocolysis [6]. Forty-two patients per group were needed to detect a 12-day difference in time gained during pregnancy at a significance level of 5% and power of 80%. Statistical analysis was performed using χ2 and Fisher exact tests for qualitative variables and unpaired Student t test for quantitative variables. Kaplan–Meier survival analysis and log-rank test were used to compare the 2 survival curves. P b 0.05 was considered to be statistically significant. SPSS version 20 (IBM, Armonk, NY, USA) was used for statistical analysis. 3. Results Ninety women with arrested preterm labor were recruited for the study and randomized to group 1 (progesterone group; n = 45) or group 2 (placebo group; n = 45). Two participants from group 1 and 3 from group 2 were lost to follow-up during the study period; their data were analyzed via intention-to-treat analysis by replacing the missing values with the means (Fig. 1). The groups were matched with respect to age, parity, and presence of risk factors for preterm birth. All clinical characteristics at recruitment were matched between the groups. Mean gestational age at recruitment was 31.91 weeks in group 1 and 32.42 weeks in group 2 (P = 0.20) (Table 1). The mean latency period was significantly longer in group 1 (33.29 ± 22.16 vs 23.07 ± 15.42 days; P = 0.013). There was a significant difference in mean time to delivery between the groups; the Kaplan–Meier plot depicted significantly more undelivered women in group 1 at each specific time point until delivery (P = 0.014; log-rank χ2 = 6.06; Fig. 2). Mean gestational age at delivery was higher in group 1 (P = 0.07). In group 1, most patients delivered at 37 weeks or later (28 [62%]), while most patients in group 2 delivered at 34–36 weeks (17 [38%]) (P = 0.01). There were significantly fewer preterm births in group 1 than in group 2 (P = 0.03) (Table 2).
160 women with preterm labor received nifedipine tocolysis 70 patients excluded (failure to arrest preterm labor, adverse effects of nifedipine, rupture of membranes, obstetric/fetal complications)
90 patients randomized to study groups
Group 1 (n=45) Study group (progesterone)
Group 2 (n=45) Placebo group
2 patients lost to follow-up
43 patients completed the study
3 patients lost to follow-up
42 patients completed the study
Fig. 1. Flow diagram of study participants.
Please cite this article as: Choudhary M, et al, Maintenance tocolysis with oral micronized progesterone for prevention of preterm birth after arrested preterm labor, Int J Gynecol Obstet (2014), http://dx.doi.org/10.1016/j.ijgo.2014.01.019
M. Choudhary et al. / International Journal of Gynecology and Obstetrics xxx (2014) xxx–xxx Table 1 Comparison of baseline characteristics between groups (n = 90).a Characteristics
Group 1: progesterone (n = 45)
Group 2: placebo (n = 45)
Age, y Parity 0 1 ≥2 History of previous preterm birth Presence of any risk factor for preterm birthb Gestational age, wk Cervical dilation, cm Cervical effacement, % Bishop score
24.11 ± 2.386
23.71 ± 2.928
16 (36) 22 (49) 5 (11) 6 (13)
16 (36) 21 (47) 5 (11) 2 (4)
17 (38)
18 (40)
31.91 ± 2.09 1.67 ± 0.36 55 ± 19.96 4.18 ± 1.07
32.42 ± 1.65 1.65 ± 0.33 49.00 ± 17.85 4.02 ± 1.09
P value 0.479 0.994
0.265 N0.99 0.202 0.784 0.136 0.484
a
Values are given as mean ± SD or number (percentage) unless otherwise indicated. History of preterm birth, first-trimester abortion, second-trimester abortion, genitourinary infection, addiction. b
Mean birth weight was higher in group 1 than in group 2 (P = 0.009). Most neonates in both groups were appropriate for gestational age, and there was no significant difference in Apgar score at birth or 5 minutes between the groups (Table 3). The incidence of low birth weight neonates was significantly lower in group 1 (P = 0.01). There were no significant differences between the groups with regard to neonatal ICU admission (P N 0.99), neonatal ICU stay (P = 0.60), respiratory distress syndrome (P = 0.77), sepsis (P = 0.67), or neonatal mortality (P N 0.99). There was 1 (2.2%) neonatal death in each group. The cause of death was severe prematurity with respiratory distress syndrome in group 1, and sepsis and pulmonary hemorrhage in group 2. Most patients did not report any adverse effects; 4 women in each group experienced headache, epigastric pain, and acne. Symptoms of preterm labor recurred in 46 patients; these women continued on the same medication and did not receive a different therapy. 4. Discussion In the present study, 200 mg of oral micronized progesterone was used because of its adequate bioavailability and fewer adverse effects compared with a 400-mg dose. The micronized form increases oral absorption and has comparable efficacy to that of vaginal progesterone [11]. The literature reports comparable plasma concentrations of
3
Table 2 Gestational age at delivery, number of preterm births, and readmission for preterm labor (n = 90).a Outcome parameters
Group 1: progesterone Group 2: placebo P value (n = 45) (n = 45)
Gestational age at delivery, wk 28–31 + 6 32–33 + 6 34–36 + 6 ≥37 Preterm birth, %
36.79 ± 2.64 2 (4) 6 (13) 7 (16) 28 (62) 15 (33)
a
35.90 ± 2.00 0 (0) 9 (20) 17 (38) 16 (36) 26 (58)
0.076 0.014
0.034
Values are given as mean ± SD or number (percentage) unless otherwise indicated.
progesterone with 200 mg of oral micronized progesterone and 400 mg of vaginal progesterone (30 vs 17–34 ng/mL) [12]. The vaginal route was not selected in the present study because it is associated with vaginal irritation and unpleasant vaginal discharge [13]. The oral route has better compliance. In the present study, the mean latency period was significantly longer among women treated with progesterone compared with the placebo group. This is consistent with results from other studies [6–8]. A trial by Borna and Sahabi [6] showed significant prolongation of mean latency period with progesterone (36.1 ± 17.9 days in progesterone group vs 24.5 ± 27.2 days in control group; P = 0.037). A randomized controlled trial by Sharami et al. [7] also showed that progesterone therapy resulted in a longer latency period (23.88 ± 18.01 vs 16.67 ± 12.9 days; P = 0.004). In addition, Arikan et al. [8] found that micronized progesterone treatment resulted in a longer latency period (32.1 ± 17.8 vs 21.2 ± 16.3 days; P b 0.05). The beneficial effect of oral micronized progesterone on prolongation of pregnancy was shown by the survival analysis in the present study, which depicted significantly larger numbers of undelivered women in the progesterone group at each specific time point until delivery compared with placebo. Prolongation of latency period with progesterone can be explained by various mechanisms resulting in uterine quiescence. Progesterone relaxes myometrial smooth muscle, blocks the action of oxytocin, inhibits the formation of gap junctions and prostaglandin synthesis, and has anti-inflammatory properties [14–17]. In the present study, mean gestational age at delivery was 1 week later in the progesterone group than in the placebo group, although this difference was not significant. This is consistent with results from the double-blind randomized controlled trial by Sharami et al. [7]. The
Table 3 Neonatal outcome parameters at birth.a,b
Fig. 2. Kaplan–Meier survival curve of time until delivery between the progesterone group and the placebo group.
Outcome parameters
Group 1: progesterone Group 2: placebo P value (n = 43) (n = 42)
Birth weight, kg Appropriate for gestational age Small for gestational age Large for gestational age Apgar score b7 at birth Apgar score b7 at 5 minutes Low birth weight Respiratory distress syndrome Sepsis Hyperbilirubinemia Otherc NICU admission Duration of NICU stay, d Median (interquartile range) Neonatal mortality
2.44 ± 0.58 40 (93) 2 (5) 1 (2) 4 (9) 1 (2) 16 (37) 6 (14) 2 (5) 2 (5) 1 (2) 10 (23) 4.70 ± 3.72 4.0 (1.75–7.75) 1 (2)
2.14 ± 0.47 42 (100) 0 (0) 0 (0) 1 (2) 0 (0) 27 (64) 7 (17) 3 (7) 0 (0) 2 (5) 9 (21) 5.89 ± 4.25 4.0 (3.0–8.0) 1 (2)
0.009 0.241
0.360 N0.99 0.017 0.771 0.676 0.494 0.616 N0.99 0.604d N0.99
Abbreviation: NICU, neonatal intensive care unit. a Values are given as mean ± SD or number (percentage) unless otherwise indicated. b Per-protocol analysis. c Hypoglycemia, hypothermia, and hemorrhagic diseases of newborns. d Mann–Whitney U test.
Please cite this article as: Choudhary M, et al, Maintenance tocolysis with oral micronized progesterone for prevention of preterm birth after arrested preterm labor, Int J Gynecol Obstet (2014), http://dx.doi.org/10.1016/j.ijgo.2014.01.019
4
M. Choudhary et al. / International Journal of Gynecology and Obstetrics xxx (2014) xxx–xxx
2 other relevant randomized controlled trials [6,8]—which were not double-blind—revealed a significant prolongation of gestational age at delivery with progesterone. The progesterone group had significantly higher birth weight, significantly fewer preterm births, and significantly fewer low birth weight neonates. However, neonatal morbidity and mortality were similar between the groups. Lack of significant improvement in neonatal outcome could have been because the sample size was calculated to determine a difference in latency period and, therefore, did not have sufficient power to demonstrate a significant difference in perinatal morbidity and mortality. To account for this, future studies based on combined sample size to detect maternal and neonatal outcome are needed. Another reason for similar neonatal outcome could have been that mean gestational age at recruitment was relatively late (31–32 weeks) and most adverse neonatal outcomes are seen in earlier gestation (before 30 weeks); therefore, we may have missed significant differences in adverse perinatal outcome in extreme prematurity. Further studies focusing on women at less than 30 weeks of pregnancy and with larger samples would provide valuable data on the use of oral micronized progesterone for maintenance tocolysis. In conclusion, maintenance tocolysis with oral micronized progesterone significantly prolonged pregnancy and decreased the number of preterm births. The present results support the use of micronized progesterone as a maintenance tocolytic for prolongation of pregnancy in cases of arrested preterm labor. Conflict of interest The authors have no conflicts of interest. References [1] Reducing Perinatal and Neonatal Mortality. Child Health Research Project Special Report. http://www.harpnet.org/doc/spec3.pdf. Published October 1999. Accessed April 6, 2012.
[2] Dodd JM, Crowther CA, Dare MR, Middleton P. Oral betamimetics for maintenance therapy after threatened preterm labour. Cochrane Database Syst Rev 2006;1: CD003927. [3] Carr DB, Clark AL, Kernek K, Spinnato JA. Maintenance oral nifedipine for preterm labor: a randomized clinical trial. Am J Obstet Gynecol 1999;181(4):822–7. [4] Han S, Crowther CA, Moore V. Magnesium maintenance therapy for preventing preterm birth after threatened preterm labour. Cochrane Database Syst Rev 2010;7: CD000940. [5] Papatsonis D, Flenady V, Liley H. Maintenance therapy with oxytocin antagonists for inhibiting preterm birth after threatened preterm labour. Cochrane Database Syst Rev 2009;1:CD005938. [6] Borna S, Sahabi N. Progesterone for maintenance tocolytic therapy after threatened preterm labour: a randomised controlled trial. Aust N Z J Obstet Gynaecol 2008;48(1):58–63. [7] Sharami SH, Zahiri Z, Shakiba M, Milani F. Maintenance therapy by vaginal progesterone after threatened Idiopathic Preterm Labor: A randomized placebo-controlled double-blind trial. Int J Fertil Steril 2010;4(2):45–50. [8] Arikan I, Barut A, Harma M, Harma IM. Effect of progesterone as a tocolytic and in maintenance therapy during preterm labor. Gynecol Obstet Invest 2011;72(4): 269–73. [9] Facchinetti F, Paganelli S, Comitini G, Dante G, Volpe A. Cervical length changes during preterm cervical ripening: effects of 17-alpha-hydroxyprogesterone caproate. Am J Obstet Gynecol 2007;196(5):453.e1–4. [10] Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Rouse D, Spong CY. Preterm Birth. In: Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Rouse D, Spong CY, editors. Williams Obstetrics. 23rd ed. Philadelphia, PA: McGraw Hill Professional; 2009. p. 804–31. [11] Loose-Mitchell DS, Stancel GM. Estrogen and Progestins. In: Goodman LS, Hardman JG, Limbird LE, Gilman AG, editors. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw-Hill; 2001. p. 1617–21. [12] Silver RI, Rodriguez R, Chang TS, Gearhart JP. In vitro fertilization is associated with an increased risk of hypospadias. J Urol 1999;161(6):1954–7. [13] Simon JA. Micronized progesterone: vaginal and oral uses. Clin Obstet Gynecol 1995;38(4):902–14. [14] How H, Huang ZH, Zuo J, Lei ZM, Spinnato II JA, Rao CV. Myometrial estradiol and progesterone receptor changes in preterm and term pregnancies. Obstet Gynecol 1995;86(6):936–40. [15] Henderson D, Wilson T. Reduced binding of progesterone receptor to its nuclear response element after human labor onset. Am J Obstet Gynecol 2001;185(3): 579–85. [16] Garfield RE, Saade G, Buhimschi C, Buhimschi I, Shi L, Shi SQ, et al. Control and assessment of the uterus and cervix during pregnancy and labour. Hum Reprod Update 1998;4(5):673–95. [17] Challis JRG. Characteristics of Parturition. In: Creasy RK, Resnick R, editors. MaternalFetal Medicine. 4th ed. Philadelphia, PA: W.B. Saunders; 1999. p. 484–97.
Please cite this article as: Choudhary M, et al, Maintenance tocolysis with oral micronized progesterone for prevention of preterm birth after arrested preterm labor, Int J Gynecol Obstet (2014), http://dx.doi.org/10.1016/j.ijgo.2014.01.019
