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Very preterm delivery is an obstetric complication associated with high perinatal morbidity and mortality, and survival of the preterm infant is related directly to gestational age at delivery. Survival increases from less than 50% before 24 weeks to more than 95% by 33 weeks' gestation and there is a corresponding inverse relationship between the risk of severe disability in survivors and gestational age at delivery1, 2. Complications from preterm birth, are not limited to the neonatal period, such as in retinopathy of prematurity, intraventricular hemorrhage, necrotizing enterocolitis, respiratory disorder and sepsis; they can also constitute sequelae such as abnormal neurophysiological development in early childhood and underachievement at school3–5.
In Austria and Denmark, multiple gestations account for approximately 2% of all pregnancies, but constitute at least 10% of cases of preterm delivery and more than half of admissions to neonatal intensive care units (NICUs). More than 25% of infants liveborn before 28 weeks' gestation are twins6, 7. Efforts to treat or prevent preterm delivery in twin gestations, with bed rest, antibiotics, tocolytics and cerclage, have not been effective8–10. In contrast, it is now well-established that progesterone treatment is effective in reducing preterm birth rates in women with singleton pregnancies and previous preterm birth, and potentially also in women with a short cervix11–18. As mechanisms for initiation of preterm labor or preterm shortening of the cervix may be different in twin compared with singleton pregnancies, results from singleton studies cannot be extrapolated to twin gestations. Hence, several studies on the preventive effect of progesterone on preterm birth in multiple gestations were planned following the publication of two large singleton trials in 200319, 20.
The PREDICT study was conducted in order to test the hypothesis that in twin gestations, treatment with progesterone pessaries, compared with placebo treatment, would reduce the rate of delivery before 34 weeks' gestation.
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During the study period 2256 women with twin pregnancies had a nuchal translucency scan at one of the 17 participating departments (Figure 1), and approximately 67% (n = 1507) of them were assessed for eligibility. Of the 1288 who were informed, 677 (52.6%) women were randomized. We stopped informing women about the trial when the sample size of 650 had been achieved (22 September 2008). Women already informed about the trial were, however, allowed to enter the trial until 31 October 2008. Outcome measures were available for 675 women, as one woman was lost to follow-up and another withdrew her consent; both women were from the placebo group. Baseline characteristics were comparable for the groups (Table 1). There were slightly more monochorionic gestations in the placebo group (16.6% vs. 12.9%) but the difference was not statistically significant (P = 0.19). Six women underwent cerclage placement before inclusion, two from the progesterone group (2/334) and four from the placebo group (4/343).
Table 1. Baseline characteristics for women with twin pregnancies who were eligible to participate in the trial
|Characteristic||Progesterone group (n = 334)||Placebo group (n = 343)||Decliners who filled out background questionnaire (n = 403)|
|Maternal age (years)||32.0 ± 4.5||31.9 ± 4.4||31.9 ± 4.3|
|Nulliparous||169/333 (50.8)||193/343 (56.3)||222/399 (55.6)|
|Previous delivery before 34 weeks||5/333 (1.5)||10/343 (2.9)||5/399 (1.3)|
|Previous delivery between 34 and 37 weeks||17/333 (5.1)||11/343 (3.2)||10/399 (2.5)|
|Previous miscarriage after 12 weeks||8/333 (2.4)||11/343 (3.2)||19/399 (4.8)|
|Previous miscarriage before 12 weeks||77/333 (23.1)||76/343 (22.2)||77/399 (19.3)|
|Body mass index (kg/m2)||22.6 (20.6–26.0)||22.7 (20.6–25.7)||22.7 (20.8–25.7)|
|Completed ≥ 12 years in school*||231/328 (70.4)||266/339 (78.5)||294/398 (73.9)|
|Marital status|| || || |
| Married||199/333 (59.8)||205/342 (59.9)||232/403 (57.6)|
| Unmarried but cohabiting||127/333 (38.1)||133/342 (38.9)||149/403 (37.0)|
| Living alone||7/333 (2.1)||4/342 (1.2)||22/403 (5.5)|
|Fertility treatment||156/334 (46.7)||163/343 (47.5)||198/402 (49.3)|
|Previous progesterone treatment in current pregnancy†||106/333 (31.8)||120/342 (35.1)||130/402 (32.3)|
| Do not remember||2/333 (0.6)||4/342 (1.2)||25/402 (6.2)|
|Smoking before pregnancy||88/333 (26.4)||88/342 (25.7)||91/403 (22.6)|
|Smoking during pregnancy||36/333 (10.8)||33/342 (9.6)||39/403 (9.7)|
|Monochorionic||43/334 (12.9)||57/343 (16.6)||48/432 (11.1)|
|Medical disorders before pregnancy||77/333 (23.1)||72/342 (21.1)||67/383 (17.5)|
|Gestational age at randomization (days)||146.0 (139–157)||146.5 (139–158)||154.0 (138–164)‡|
Amongst the 611 women who were informed about the trial but did not participate, 403 filled out the background questionnaire. A total of 85 women did not respond regarding participation in the trial. Decliners and participants were comparable with respect to baseline characteristics (Table 1).
The mean (SD) gestational age at delivery was 252 (19.6) days in the progesterone group vs 251 (19.1) days in the placebo group (P = 0.43). The rate of the primary outcome of delivery before 34 weeks' gestation was 15.3% in the progesterone group and 18.5% in the placebo group (OR, 0.8 (95% CI, 0.5–1.2)). Figure 2 shows a Kaplan–Meier plot comparing the proportion of women remaining pregnant between randomization and delivery in the two treatment groups. The estimated distributions were similar (P = 0.65). Categorical maternal outcomes as well as pregnancy outcomes are shown in Table 2. There were no statistically significant differences between the two groups, except for risk of emergency Cesarean section, which was reduced in the progesterone group (OR, 0.7 (95% CI, 0.5–0.9). The number of days of maternal hospitalization was comparable between the two groups: median, 9 (interquartile range, 2–82) days for the progesterone group and median, 9 (interquartile range, 1–92) days in the placebo group (P = 0.42). In 17 pregnancies, a fetus or infant died. These included nine pregnancies (13 fetuses/infants) in the progesterone group and eight pregnancies (12 fetuses/infants) in the placebo group (OR, 1.1 (95% CI, 0.4–2.9)). One woman from the progesterone group and one woman from the placebo group received cerclage as cointervention after inclusion.
Figure 2. Proportions of women remaining pregnant from randomization to delivery in the two treatment groups (progesterone group (_____) and placebo group (·····)) were similar (log rank test, P = 0.65).
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Table 2. Maternal and twin pregnancy outcomes according to treatment group: progesterone (n = 334) or placebo (n = 341)
|Outcome||Progesterone group (n (%))||Placebo group (n (%))||Odds ratio (95% CI)|
|Gestational age at delivery|| || || |
| < 22 weeks||1/334 (0.3)||1/341 (0.3)||1.0 (0.1–16.4)|
| < 28 weeks||9/334 (2.7)||7/341 (2.1)||1.3 (0.5–3.6)|
| < 32 weeks||24/334 (7.2)||31/341 (9.1)||0.8 (0.4–1.3)|
| < 34 weeks||51/334 (15.3)||63/341 (18.5)||0.8 (0.5–1.2)|
| < 34 weeks, spontaneous delivery||42/334 (12.6)||53/341 (15.5)||0.8 (0.5–1.2)|
| < 34 weeks, induced delivery||9/334 (2.7)||10/341 (2.9)||1.0 (0.4–2.3)|
| < 37 weeks||158/334 (47.3)||179/341 (52.5)||0.8 (0.6–1.1)|
|Delivery by Cesarean section||207/332 (62.3)||232/338 (68.6)||0.8 (0.5–1.0)|
| Emergency Cesarean section||109/332 (32.8)||141/338 (41.7)||0.7 (0.5–0.9)|
| Planned Cesarean section||98/332 (29.5)||91/338 (26.9)||1.1 (0.8–1.6)|
|Number of pregnancies with 2, 1 or 0 liveborn infants|| || || |
| 2||330/334 (98.8)||336/341 (98.5)||1.2 (0.3–4.6)|
| 1||3/334 (0.9)||3/341 (0.9)||1.0 (0.2–5.1)|
| 0||1/334 (0.3)||2/341 (0.6)||0.5 (0.0–5.6)|
|Miscarriage||1/334 (0.3)||1/341 (0.3)||1.0 (0.1–16.4)|
|Intrauterine death*||2/334 (0.6)||2/341 (0.6)||1.0 (0.1–7.3)|
|Infant death during delivery|| || || |
| One infant||1/334 (0.3)||1/341 (0.3)||1.0 (0.1–16.4)|
| Both infants||0/334 (−)||1/341 (0.3)||NA|
|Corticosteroid treatment for fetal lung maturation||76/334 (22.8)||97/341 (28.4)||0.7 (0.5–1.0)|
|Tocolytic therapy||41/333 (12.3)||60/341 (17.6)||0.7 (0.4–1.0)|
|Maternal adverse outcome|| || || |
| Gestational diabetes||16/332 (4.8)||12/341 (3.5)||1.4 (0.6–3.0)|
| Increased liver enzymes||11/332 (3.3)||25/341 (7.3)||0.4 (0.2–0.9)|
| Pre-eclampsia||27/332 (8.1)||30/341 (8.8)||0.9 (0.5–1.5)|
| Thromboembolic event||0/332 (0)||1/341 (0.3)||NA|
The mean birth weight was comparable for the two groups: 2468 g in the progesterone group versus 2418 g in the placebo group (P = 0.41). Table 3 shows that neonatal outcomes did not differ between the two groups. Six infants in the progesterone group were born with malformations of the extremities, whereas there were none in the placebo group. The affected cases constituted: four infants with pes equinovarus, of which two were diagnosed by ultrasound before randomization; one infant with malformation of three fingers on one hand; one infant with bilateral contractures of hands. In the latter case, valproate embryopathy was suspected.
Table 3. Neonatal outcome in twin pregnancies according to treatment group: progesterone (n = 664) or placebo (n = 678)
|Outcome||Progesterone group (n or n (%))||Placebo group (n or n (%))||Odds ratio (95% CI)|
|Birth weight|| || || |
| < 2500 g||306/659 (46.4)||357/677 (52.9)||0.8 (0.6–1.0)|
| < 1500 g||36/659 (5.5)||48/677 (7.1)||0.8 (0.4–1.4)|
|Apgar score < 7 at 5 min||10/648 (1.5)||14/669 (2.1)||0.7 (0.3–1.7)|
|Infant death||9/664 (1.4)||8/678 (1.2)||1.2 (0.3–4.0)|
| Death during delivery||1||3|| |
| Neonatal death (within 28 days after delivery)||7||2|| |
| Death after 28 days, but in relation to NICU admittance||0||2|| |
| Sudden infant death||1*||1†|| |
|Congenital or chromosomal anomalies||25/663 (3.8)||27/677 (4.0)||1.0 (0.5–1.7)|
| Abdomen||1||0|| |
| CNS||2||1|| |
| Extremities||6||0|| |
| Heart||9||15|| |
| Chromosome/syndrome||2‡||5§|| |
| Thorax||1||1|| |
| Urogenital||6||8|| |
|Perinatal complication|| || || |
| Hypoglycemia||30/659 (4.6)||48/674 (7.1)||0.6 (0.4–1.1)|
| Intraventricular hemorrhage||10/659 (1.5)||6/674 (0.9)||1.7 (0.5–5.6)|
| Jaundice||106/659 (16.1)||116/674 (17.2)||0.9 (0.6–1.3)|
| Necrotizing enterocolitis||1/659 (0.2)||2/674 (0.3)||0.5 (0.0–5.6)|
| Patent ductus arteriosus||12/659 (1.8)||19/674 (2.8)||0.6 (0.3–1.5)|
| Respiratory distress syndrome||73/659 (11.1)||69/674 (10.2)||1.1 (0.7–1.7)|
| Retinopathy of prematurity||4/659 (0.6)||4/674 (0.6)||1.0 (0.2–4.8)|
| Septicemia||20/659 (3.0)||18/674 (2.7)||1.1 (0.5–2.4)|
|Admission to NICU||307/664 (46.2)||354/678 (52.2)||0.8 (0.6–1.1)|
|CPAP treatment of at least 24 h||105/659 (15.9)||121/674 (18.0)||0.9 (0.6–1.3)|
|Respirator treatment||12/659 (1.8)||12/674 (1.8)||1.0 (0.4–2.6)|
We received ASQs from 1050 (79.2%) of the liveborn children at 6 months of age; 78.8% from the progesterone group versus 79.7% from the placebo group. The mean ASQ score was 215 (SD, 37.5) in the progesterone group and 218 (SD, 36.7) in the placebo group (P = 0.45). A total of 991 (74.8%) children had an 18-month ASQ assessment, again with similar response rates in the two groups (76.8% vs 72.8%). The mean ASQ scores at 18 months were 193 (SD, 42.6) and 194 (SD, 40.6), respectively (P = 0.89). The proportion of infants with an 18-month ASQ score below the selected cut-off of 115 was 3.8% in the progesterone group vs 3.7% in the placebo group.
Table 4 shows side effects and compliance according to treatment. There were no significant differences in reported side effects. The mean number of pessaries returned after treatment was similar between the two groups. Nine women in the progesterone group and four women in the placebo group never started treatment because they changed their minds with respect to participation (n = 8), they miscarried or a fetus died in utero (n = 2) or they were withdrawn from the study (n = 3, one due to signs of TTTS, another due to Factor V Leiden homozygosity and the third because chorionicity had not been assessed before 16 weeks' gestation). These women all returned the boxes with pessaries unopened.
Table 4. Side effects and compliance in twin pregnancies according to treatment group: progesterone (n = 334) or placebo (n = 341)
| ||Progesterone group||Placebo group|
|Side effects*|| || |
|Central nervous system||32 (9.6)||39 (11.4)|
| Headache||13 (3.9)||17 (5.0)|
|Skin||11 (3.3)||10 (2.9)|
|Gastrointestinal||13 (3.9)||21 (6.2)|
|Reproductive system and breasts||194 (58.1)||213 (62.5)|
| Vaginal discharge||150 (44.9)||168 (49.3)|
| Vaginal itching||14 (4.2)||17 (5.0)|
|Miscellaneous||13 (3.9)||16 (4.7)|
|Compliance†|| || |
|Compliant||276 (82.6)||283 (83.0)|
|Not compliant because of:|| || |
| Side effect||23 (6.9)||25 (7.3)|
| Intrauterine death||2 (0.6)||1 (0.3)|
| Admission to hospital||6 (1.8)||7 (2.1)|
| Other reasons/unknown||18 (5.4)||21 (6.2)|
|Never started treatment (returned sealed box)||9 (2.7)||4 (1.2)|
|Number of pessaries used per woman (mean ± SD)||79.5 ± 24.9||78.9 ± 24.1|
The slightly larger proportion of monochorionicity in the placebo group can be explained in part by the fact that the randomization sequence allocated placebo treatment to the first monochorionic gestation randomized at each center. Combined with a low number of monochorionic inclusions in six centers, this allocation sequence yielded an excess placebo allocation of nine. In addition, one center unfortunately misclassified three gestations at randomization; two cases were randomized as monochorionic but review of patient files showed that they were actually dichorionic, and one case was randomized as dichorionic but was in fact monochorionic.
We performed subgroup analyses according to chorionicity on selected outcomes (these analyses were not prespecified). For dichorionic gestations, the mean gestational age at delivery or intrauterine death was 252 (SD, 20.8) days for the progesterone group vs 252 (SD, 19.8) days for the placebo group (P = 0.74), and the mean birth weight was similar in the two groups: 2475 (SD, 588) g and 2455 (SD, 547) g (P = 0.83). The mean gestational age at delivery or intrauterine death was 252 (SD, 14.1) days in the progesterone group vs 245 (SD, 22.0) days in the placebo group for monochorionic gestations (P = 0.08), and the rate of spontaneous delivery or intrauterine death before 34 weeks' gestation was 9.3% vs 15.8%, respectively (P = 0.39). The mean birth weight was 2420 (SD, 472) g compared with 2243 (SD, 589) g (P = 0.10). The proportion of infants with birth weight < 1500 g was 1.2% (1/84) in the progesterone group vs 13.2% (15/114) in the placebo group (OR, 0.1 (95% CI, 0.0–0.6)). Four infants died during delivery or within the first week of delivery amongst the monochorionic gestations. All four were from the placebo group, as were the six infants who had a 5-min Apgar score < 7. There were no statistically significant differences in other selected complications.
For decliners, the mean gestational age at delivery or intrauterine death was 248 (SD, 21.5) days for monochorionic gestations and the mean birth weight was 2367 (SD, 598) g. The corresponding figures were 253 (SD, 19.6) days and 2488 (SD, 529) g for dichorionic gestations. The rate of intrauterine death was 0.5% (3/611 pregnancies) and infant death (including stillbirth) was observed in 2.3% (28/1219) of infants. There were five cases of infants with foot malformations (5/601 pregnancies, 5/1202 infants) amongst women who were informed but not included. Information on malformations was missing in the Danish National Birth Register for 10 women who were informed but did not participate.
Other studies have reported intrauterine death or delivery before 34 weeks as the primary outcome27, 28. In our population, only one pregnancy with intrauterine death resulted in delivery after 34 weeks' gestation, whereas the other three cases delivered before 34 weeks. The rate of intrauterine death or delivery before 34 weeks in our population was therefore 51/334 (15.3%) in the progesterone group vs 64/341 (18.8%) in the placebo group (OR, 0.8 (95% CI, 0.5–1.2)). Figure 3 shows an updated version of the meta-analysis that was published in the Lancet in 200927, including our data as well as data from a recently published trial29. Inclusion of the newest data changed the pooled OR from 1.16 (95% CI, 0.89–1.51) to 1.06 (95% CI, 0.86–1.31).
Figure 3. Meta-analysis of the preventive effect of progesterone on delivery before 34 weeks' gestation in twin pregnancies. OR, odds ratio.
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This study is one of the largest trials to investigate the effect of progesterone treatment on prevention of preterm delivery in twin gestations. In accordance with previous trials27–31, we found that treatment with progesterone does not prevent preterm delivery. We are the first to provide a long-term follow-up on the twins, as we assessed infants from the study both 6 and 18 months after the estimated date of delivery via the ASQ. There was no difference between ASQ scores in the two groups, and our results therefore indicate that progesterone treatment is neither beneficial nor harmful to the infants. Whereas results from previous studies, including a recent meta-analysis27, have shown an increased but not statistically significant risk of preterm delivery in progesterone-treated women, our results did not indicate that progesterone treatment in twin gestations is harmful. In contrast, most ORs were < 1 although not significant. Inclusion of our study in the meta-analysis therefore changed the overall relative risk towards but not below 1, i.e. no effect of progesterone treatment. The rate of intrauterine death, stillbirth and infant death did not differ between the two treatment groups and was comparable to rates in women who were eligible but did not participate. All infants in the trial who were born with foot malformations were found amongst the progesterone-treated mothers. However, two of these cases were diagnosed before inclusion and the rate was comparable to the rate amongst eligible women who did not participate. In accordance with Norman et al.27, we found a preventive effect of progesterone on the risk of emergency Cesarean section, with an OR of 0.7 (95% CI, 0.5–0.9). A biological explanation for the possible association between vaginal progesterone treatment and a reduced risk of Cesarean section should be investigated.
The results from our trial can be generalized to most women with twin gestations in Denmark and Austria as women were included from 13 of the largest hospitals in Denmark, where 70% of Danish twins are delivered, and from four large centers in Austria, where approximately 50% of Austrian twins are delivered. We compared women who participated with women who were eligible but declined to participate and did not find any differences in baseline characteristics for these women. The overall rate of spontaneous delivery before 34 weeks' gestation of 14.1% corresponds to a previously estimated rate of spontaneous preterm delivery in a Danish population with approximately 15% monochorionic gestations25. It is noteworthy that nearly 30% of women with monochorionic gestations who were assessed for eligibility were excluded, mainly due to signs or diagnosis of TTTS. The population of monochorionic gestations in this trial therefore represents monochorionic pregnancies in which outcome is expected to be better than that in an unselected population. Approximately 10% of dichorionic gestations were excluded, mainly because the women did not speak Danish/German, they were planning to move, there were fetal malformations or intentional fetal reduction was performed.
As the proportion of monochorionic gestations was slightly higher in the placebo group, we performed subgroup analyses on dichorionic and monochorionic gestations separately. Surprisingly, the results from these subgroup analyses suggest that there may be an effect of progesterone treatment in monochorionic gestations, although the study was underpowered for the primary outcome. These analyses were, however, not prespecified and results should be interpreted with caution. As the monochorionic population in this trial represents a selected group of pregnancies, the rate of spontaneous very preterm delivery was low (approximately 12% overall). In addition, the mean gestational age at delivery or intrauterine death for women with monochorionic gestations who were found eligible but did not participate was higher than that for the placebo group but lower than that for the progesterone group. The mean gestational age at delivery or intrauterine death was similar in the progesterone group, placebo group and non-participants with dichorionic gestations. We do not believe that there is a biologically plausible explanation as to why an effect should be noticed in monochorionic gestations but not in dichorionic gestations. Norman et al.27 found a non-significant OR < 1 in monochorionic gestations, but an inverse but non-significant relation was found in dichorionic gestations (OR 1.7). Rouse et al.28 did not perform subgroup analyses according to chorionicity. A comparison of the effect of progesterone treatment in monochorionic and dichorionic gestations would require another study set-up or a meta-analysis.
We chose to use micronized natural progesterone in pessary form as a consequence of the positive results from the da Fonseca trial in 200319, in which a dosage of 100 mg was used in singleton gestations. We doubled the dose to 200 mg because our trial involved twin gestations, which would be expected to have higher endogenic progesterone production. In 2007, Fonseca et al. showed a positive effect on the risk of preterm delivery in women with a short cervix using the same pessaries with a dose of 200 mg18. The previously published trials including twin gestations have used micronized natural progesterone as gel27 and 17-alpha-hydroxyprogesterone caproate28–30.
The effect of the most common progesterone treatment modalities, therefore, has now been investigated and no study has found a significant effect of prevention of preterm delivery in twin gestations. It is noteworthy that in singleton gestations, a preventive effect of progesterone has been observed in high-risk women only, i.e. women with previous preterm delivery or short cervix at 23 weeks' gestation. It remains to be investigated if there is an effect of progesterone treatment on the risk of preterm delivery in twin gestations with a short cervix.