Prevention of preterm birth
The majority of babies born prematurely survive and develop normally. However, babies born before 34 weeks have a higher chance of dying soon after birth or becoming disabled than babies born at term. In singleton pregnancies the chance that a woman will go into labour and deliver before 34 weeks is about 1%. In twin pregnancies, the chance of such premature birth is 10-15%.
Vaginal progesterone in singletons
Fonseca EB, Celik E, Parra M, Singh M, Nicolaides KH; Fetal Medicine Foundation Second Trimester Screening Group. Progesterone and the risk of preterm birth among women with a short cervix. N Engl J Med 2007;357:462-9.
Previous randomized trials had shown that progesterone administration in women who previously delivered prematurely reduces the risk of recurrent premature delivery. Asymptomatic women found at midgestation to have a short cervix are at greatly increased risk for spontaneous early preterm delivery, and it was unknown whether progesterone reduces this risk in such women.
In this study, cervical length was measured by transvaginal ultrasonography at a median of 22 weeks of gestation (range, 20 to 25) in 24,620 pregnant women seen for routine prenatal care. Cervical length was 15 mm or less in 413 of the women (1.7%), and 250 (60.5%) of these 413 women were randomly assigned to receive vaginal progesterone (200 mg each night) or placebo from 24 to 34 weeks of gestation. The primary outcome was spontaneous delivery before 34 weeks. Spontaneous delivery before 34 weeks of gestation was less frequent in the progesterone group than in the placebo group (19.2% vs. 34.4%; relative risk, 0.56; 95% confidence interval [CI], 0.36 to 0.86). Progesterone was associated with a nonsignificant reduction in neonatal morbidity (8.1% vs. 13.8%; relative risk, 0.59; 95% CI, 0.26 to 1.25; P=0.17). There were no serious adverse events associated with the use of progesterone.
It was concluded that in women with a short cervix, treatment with progesterone reduces the rate of spontaneous early preterm birth.
A meta-analysis, which included the above and four other similar trials in singleton pregnancies, was carried out by Romero R, Nicolaides KH, Conde-Agudelo A, O'Brien JM, Cetingoz E, Da Fonseca E, Creasy GW, Hassan SS (an updated meta-analysis including data from the OPPTIMUM study. Ultrasound Obstet Gynecol 2016;48:308-17). The study showed that vaginal progesterone decreases preterm birth ≤ 34 weeks of gestation in women with a singleton pregnancy and a short cervix. The study assessed the efficacy of vaginal progesterone for the prevention of preterm birth and neonatal morbidity and mortality in asymptomatic women with a singleton gestation and a sonographic short cervix (cervical length ≤ 25 mm) in the mid-trimester. Data were available for 974 women. Vaginal progesterone, compared with placebo/no treatment, was associated with a statistically significant reduction in the risk of preterm birth occurring at < 28 to < 36 gestational weeks (RRs from 0.51 to 0.79), composite neonatal morbidity and mortality (RR, 0.59, 95% CI, 0.38-0.91) and some measures of neonatal morbidity, without any demonstrable deleterious effects on childhood neurodevelopment.
A meta-analysis of individual participant data, which included the above and five other similar trials in twin pregnancies, was carried out by Romero R, Conde-Agudelo A, El-Refaie W, Rode L, Brizot ML, Cetingoz E, Serra V, Da Fonseca E, Abdelhafez MS, Tabor A, Perales A, Hassan SS, Nicolaides KH (vaginal progesterone decreases preterm birth and neonatal morbidity and mortality in women with a twin gestation and a short cervix: an updated meta-analysis of individual patient data. Ultrasound Obstet Gynecol 2017;49:303-314). The study assessed the efficacy of vaginal progesterone for the prevention of preterm birth and neonatal morbidity and mortality in asymptomatic women with a twin gestation and a sonographic short cervix (cervical length ≤ 25 mm) in the mid-trimester. Data were available for 303 women (159 assigned to vaginal progesterone and 144 assigned to placebo/no treatment) and their 606 fetuses/infants. Vaginal progesterone, compared with placebo/no treatment, was associated with a significant reduction in the risk of preterm birth occurring at < 30 to < 35 gestational weeks, neonatal mortality and some measures of neonatal morbidity, without any demonstrable deleterious effects on childhood neurodevelopment.
Vaginal progesterone in twins
Rehal A, Benkő Z, De Paco Matallana C, Syngelaki A, Janga D, Cicero S, Akolekar R, Singh M, Chaveeva P, Burgos J, Molina FS, Savvidou M, De La Calle M, Persico N, Quezada Rojas MS, Sau A, Greco E, O’Gorman N, Plasencia W, Pereira S, Jani JC, Valino N, Del Mar Gil M, Maclagan K, Wright A, Wright D, Nicolaides KH. Early vaginal progesterone versus placebo in twin pregnancies for the prevention of spontaneous preterm birth: a randomized, double-blind trial. Am J Obstet Gynecol 2021;224:86.e1-86.e19.
Trials in unselected twin pregnancies had reported that vaginal administration of progesterone from mid gestation had no significant effect on the incidence of early preterm birth. Such apparent lack of effectiveness of progesterone in twins may be due to inadequate dosage or treatment that is started too late in pregnancy. In this trial it was hypothesized that among women with twin pregnancies, vaginal progesterone at a dose of 600 mg per day from 11 to 14 until 34 weeks' gestation, as compared with placebo, would result in a significant reduction in the incidence of spontaneous preterm birth between 24+0 and 33+6 weeks.
In this trial, which was conducted at 22 hospitals in England, Spain, Bulgaria, Italy, Belgium, and France, 582 women were assigned to the progesterone group and 587 in the placebo group. Spontaneous birth between 24+0 and 33+6 weeks occurred in 10.4% of participants in the progesterone group and in 8.2% in the placebo group (odds ratio in the progesterone group, adjusting for the effect of participating center, chorionicity, parity, and method of conception, 1.35; 95% confidence interval, 0.88-2.05; P=.17). In a post hoc time-to-event analysis, miscarriage or spontaneous preterm birth between randomization and 31+6 weeks' gestation was reduced in the progesterone group relative to the placebo group (hazard ratio, 0.23; 95% confidence interval, 0.08-0.69).
It was concluded that in women with twin pregnancies, universal treatment with vaginal progesterone does not reduce the incidence of spontaneous birth between 24+0 and 33+6 weeks' gestation. However, progesterone may reduce the risk of spontaneous birth before 32 weeks' gestation in women with a cervical length of <30 mm.
Cervical cerclage in singletons
To MS, Alfirevic Z, Heath VC, Cicero S, Cacho AM, Williamson PR, Nicolaides KH; Fetal Medicine Foundation Second Trimester Screening Group. Cervical cerclage for prevention of preterm delivery in women with short cervix: randomised controlled trial. Lancet 2004;363:1849-53.
Cervical cerclage has been widely used in the past 60 years to prevent early preterm birth and its associated neonatal mortality and morbidity. Results of randomised trials have not generally lent support to this practice, but this absence of benefit may be due to suboptimum patient selection, which was essentially based on obstetric history. A more effective way of identifying the high-risk group for early preterm delivery might be by transvaginal sonographic measurement of cervical length. We undertook a multicentre randomised controlled trial to investigate whether, in women with a short cervix identified by routine transvaginal scanning at 22-24 weeks' gestation, the insertion of a Shirodkar suture reduces early preterm delivery.
Cervical length was measured in 47,123 women. The cervix was 15 mm or less in 470, and 253 (54%) of these women participated in the study and were randomised to cervical cerclage (127) or to expectant management (126). Primary outcome was the frequency of delivery before 33 completed weeks (231 days) of pregnancy. The proportion of preterm delivery before 33 weeks was similar in both groups, 22% (28 of 127) in the cerclage group versus 26% (33 of 126) in the control group (relative risk=0.84, 95% CI 0.54-1.31, p=0.44), with no significant differences in perinatal or maternal morbidity or mortality.
It was concluded that the insertion of a Shirodkar suture in women with a short cervix does not substantially reduce the risk of early preterm delivery. Routine sonographic measurement of cervical length at 22-24 weeks identifies a group at high risk of early preterm birth.
A meta-analysis, which included the above and four other similar trials, was carried out by Berghella V, Ciardulli A, Rust OA, To M, Otsuki K, Althuisius S, Nicolaides K, Roman A, Saccone G (Cerclage for Short Cervix on Ultrasound in Singleton Gestations without Prior Spontaneous Preterm Birth: a Systematic Review and Meta-analysis of Trials using individual patient-level data. Ultrasound Obstet Gynecol 2017;50:569-577). A total of 419 asymptomatic singleton gestations with transvaginal ultrasound cervical length <25 mm and without prior spontaneous preterm birth were analyzed. No statistically significant differences were found in PTB <35, <34, <32, <28, and <24 weeks, mean gestational age at delivery, preterm premature rupture of membranes, and neonatal outcomes, comparing women who were randomized in the cerclage group with those who were randomized in the control group, respectively.
Cervical pessary in singletons
Nicolaides KH, Syngelaki A, Poon LC, Picciarelli G, Tul N, Zamprakou A, Skyfta E, Parra-Cordero M, Palma-Dias R, Rodriguez Calvo J. A Randomized Trial of a Cervical Pessary to Prevent Preterm Singleton Birth. N Engl J Med 2016;374:1044-52.
This was a multicenter randomized controlled trial comparing pessary with expectant management, in singleton pregnancies with cervical length ≤25 mm at 20 - 24 weeks’ gestation. Women in both arms of the trial with cervical length <15 mm, at randomization or subsequent visits, were treated with vaginal progesterone. The primary outcome was spontaneous birth at <34 weeks.
A total of 932 women took part in the trial; 465 received cervical pessary and 467 had expectant management. There were no significant differences between the pessary and the control groups in the rate of spontaneous delivery before 34 weeks (12.0% and 10.8%, respectively; odds ratio in the pessarygroup, 1.12; 95% confidence interval, 0.75 to 1.69; P=0.57), in the rates of perinatal death (3.2% in the pessary group and 2.4% in the control group, P=0.42), adverse neonatal outcome (6.7% and 5.7%, respectively; P=0.55), or neonatal special care (11.6% and 12.9%, respectively; P=0.59). The incidence of new or increased vaginal discharge was significantly higher in the pessary group than in the control group.
It was concluded that among women with singleton pregnancies who had a short cervix, a cervical pessary does not result in a lower rate of spontaneous early preterm delivery than the rate with expectant management.
Cervical pessary in twins
Nicolaides KH, Syngelaki A, Poon LC, de Paco Matallana C, Plasencia W, Molina FS, Picciarelli G, Tul N, Celik E, Lau TK, Conturso R. Cervical pessary placement for prevention of preterm birth in unselected twin pregnancies: a randomized controlled trial. Am J Obstet Gynecol 2016;214:3.e1-9.
Twins are found in about 2% of pregnancies, but they account for about 25% of preterm births. The objective of this study was to test the hypothesis that the insertion of a cervical pessary in twin pregnancies would reduce the rate of spontaneous early preterm birth. This was a multicenter, randomized controlled trial in unselected twin pregnancies of cervical pessary placement from 20+0-24+6 weeks' gestation until elective removal or delivery vs. expectant management. Primary outcome was spontaneous birth <34 weeks.
A total of 1,180 women took part in the trial; 590 received cervical pessary and 590 had expectant management. There were no significant differences between the pessary and control groups in rates of spontaneous birth <34 weeks (13.6% vs. 12.9%; relative risk 1.054, 95% confidence interval [CI] 0.787-1.413; p=0.722), perinatal death (2.5% vs. 2.7%; relative risk 0.908, 95% CI 0.553-1.491; p=0.702), adverse neonatal outcome (10.0 vs. 9.2%; relative risk 1.094, 95% CI 0.851-1.407; p=0.524) or neonatal therapy (17.9% vs. 17.2%; relative risk 1.040, 95% CI 0.871-1.242; p=0.701). A post hoc subgroup analysis of 214 women with short cervix (≤25 mm) showed no benefit from the insertion of a cervical pessary.
It was concluded that in women with twin pregnancy, routine treatment with cervical pessary does not reduce the rate of spontaneous early preterm birth.
Cervical assessment in threatened preterm labor
Alfirevic Z, Allen-Coward H, Molina F, Vinuesa CP, Nicolaides K. Targeted therapy for threatened preterm labor based on sonographic measurement of the cervical length: a randomized controlled trial. Ultrasound Obstet Gynecol 2007;29:47-50.
False positive diagnosis of preterm labor is common. As a consequence, medications including corticosteroids to promote fetal lung maturity and tocolysis are prescribed unnecessarily. We tested the hypothesis that management of threatened preterm labor (PTL) based on measurement of cervical length (CL) by ultrasonography can reduce the number of women who receive inappropriate treatment.
Forty-one women with PTL for whom a clinical decision was made to prescribe antenatal corticosteroids and tocolysis were randomized to have their CL measured by transvaginal ultrasound (n=21) or to receive therapy as planned (n=20). Fourteen women in the ultrasound group had a CL >15 mm and the therapy was withheld, while the other seven with CL ≤15 mm were managed in the same way as the control group. Three women (14%) in the ultrasound group were treated inappropriately with antenatal corticosteroids because they remained undelivered for more than a week. This compared favorably with the control group where 18 out of 20 (90%) received corticosteroids unnecessarily (relative risk (RR) 0.16; 95% confidence interval (CI), 0.05-0.39). Tocolysis was given to only seven women (33.3%) in the ultrasound group compared with 20 (100%) in the control group (RR 0.3; 95% CI, 0.15-0.54). There were no babies in either group who were born prematurely without being given a full course of antenatal corticosteroid therapy.
It was concluded that women with TPL and CL >15 mm should not receive tocolysis. The issue of the safety of withholding corticosteroid therapy in this clinical scenario warrants further study.
A meta-analysis of individual participant data, which included the above and two other similar trials, was published by Berghella V, Palacio M, Ness A, Alfirevic Z, Nicolaides KH, Saccone G. Cervical length screening for prevention of preterm birth in singleton pregnancy with threatened preterm labor: systematic review and meta-analysis of randomized controlled trials using individual patient-level data. Ultrasound Obstet Gynecol 2017;49:322-329. A total of 287 singleton pregnancies with threatened PTL between 240 and 356 weeks were included, of which 145 were randomized to CL screening with knowledge of results and 142 to no knowledge of CL. Compared with the control group, women who were randomized to the known CL group had a significantly lower rate of PTB < 37 weeks (22.1% vs 34.5%; RR, 0.64, 95% CI 0.44-0.94) and a later gestational age at delivery. It was concluded that in singleton pregnancies with threatened PTL there is a significant association between knowledge of CL and lower incidence of PTB and later gestational age at delivery.