The Fetal Medicine Foundation has funded and coordinated several major multicentre randomized trials to investigate the potential value of interventions in the prevention of preeclampsia, preterm birth and macrosomia.

Prevention of preeclampsia

• Aspirin (150 mg/day) started from 12 weeks of gestation can substantially reduce the risk of preterm preeclampsia
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  Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia

  Rolnik DL, Wright D, Poon LC, O'Gorman N, Syngelaki A, de Paco Matallana C, Akolekar R, Cicero S, Janga D, Singh M, Molina FS, Persico N, Jani JC, Plasencia W, Papaioannou G, Tenenbaum-Gavish K, Meiri H, Gizurarson S, Maclagan K, Nicolaides KH

  N Engl J Med 2017;377:613-622

  The objectives of this study were to examine if the prophylactic use of low-dose aspirin from the first-trimester of pregnancy in women at increased risk for preterm PE can reduce the incidence of the disease. In the ASPRE trial (Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-Based Preeclampsia Prevention) women with singleton pregnancies had screening by means of an algorithm that combines maternal factors, mean arterial pressure (MAP), uterine-artery pulsatility index (UTPI), and maternal serum placental growth factor (PLGF) and pregnancy-associated plasma protein A (PAPP-A) at 11-13 weeks’ gestation. Screening was carried out in 26,941 pregnancies. Those with an estimated risk for preterm PE of >1 in 100 were invited to participate in a double-blind trial of aspirin (150 mg/day) vs. placebo from 11 to 14 until 36 weeks’ gestation.

  Preterm PE, which was the primary outcome, occurred in 1.6% (13/798) participants in the aspirin group, as compared with 4.3% (35/822) in the placebo group (odds ratio in the aspirin group with adjustment for the effect of the estimated risk for preterm-PE at screening and participating center 0.38; 95% confidence interval, 0.20 to 0.74). The incidence of PE at <34 weeks was reduced by 82%. The trial showed that aspirin had no significant effect in reducing the risk of term PE. Adherence was good, with a reported intake of 85% or more of the required number of tablets in 79.9% of the participants. There were no significant between-group differences in the incidence of neonatal adverse outcomes or other adverse events.

  It was concluded that treatment with low-dose aspirin in women at high risk for preterm PE reduces substantially the incidence of this disease.

• Aspirin (150 mg/day) started from 23 weeks of gestation does not reduce the risk of preeclampsia
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  Randomized controlled trial using low-dose aspirin in the prevention of pre-eclampsia in women with abnormal uterine artery Doppler at 23 weeks' gestation

  Yu CK, Papageorghiou AT, Parra M, Palma Dias R, Nicolaides KH; Fetal Medicine Foundation second trimester screening group.

  Ultrasound Obstet Gynecol 2003;22:233-9  pdf

  In this study we tested the hypothesis that in women identified as being at high-risk for pre-eclampsia, because of impaired flow in the uterine arteries, the prophylactic use of low-dose aspirin from 23 weeks of gestation can reduce the incidence of PE. We used color and pulsed Doppler to measure the flow in the uterine arteries in 19,950 singleton pregnancies at 22-24 weeks of gestation. Those women exhibiting increased impedance were recruited into a randomized study of aspirin 150 mg per day or placebo. We compared the two groups for the incidence of PE and the other consequences of impaired placentation.

  The screening study identified 844 women (4.2%) as being at high risk of uteroplacental insufficiency. After exclusion and refusal, 560 women were randomly allocated to aspirin 150 mg or placebo per day until 36 weeks' gestation. There were no significant differences between the aspirin and placebo groups in either the incidence of PE (18% vs. 19%, P = 0.6) or PE requiring delivery below 34 weeks (6% vs. 8%, P = 0.36). Furthermore, the administration of aspirin did not significantly alter the incidence of preterm delivery (24% vs. 27%, P = 0.46), birth weight below the 5th centile (22% vs. 24%, P = 0.4), perinatal death (3% vs. 1%, P = 0.33) or placental abruption (4% vs. 2%, P = 0.12).

  It was concluded that in pregnancies with impaired placentation, as demonstrated by increased impedance to flow in the uterine arteries, the daily administration of 150 mg aspirin after 23 weeks of gestation does not prevent the subsequent development of PE.

• Pravastatin (20 mg/day) started from 36 weeks of gestation does not reduce the risk of term preeclampsia
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  Pravastatin Versus Placebo in Pregnancies at High Risk of Term Preeclampsia

  Döbert M, Varouxaki AN, Mu AC, Syngelaki A, Ciobanu A, Akolekar R, De Paco Matallana C, Cicero S, Greco E, Singh M, Janga D, Del Mar Gil M, Jani JC, Bartha JL, Maclagan K, Wright D, Nicolaides KH

  Circulation 2021;144:670-679  pdf

  The objective of the trial was to examine if prophylactic use of pravastatin from 35-37 weeks of gestation in women at increased risk for preeclampsia can reduce the incidence and severity of the disease. Effective screening for term preeclampsia is provided by a combination of maternal factors with measurements of mean arterial pressure, serum placental growth factor, and serum soluble fms-like tyrosine kinase-1 at 35 to 37 weeks of gestation, with a detection rate of ≈75% at a screen-positive rate of 10%. Screening was carried out in 29,816 singleton pregnancies. Those with an estimated risk for preeclampsia of >1 in 20 were invited to participate in a double-blind trial of pravastatin (20 mg/day) vs. placebo from 35 to 37 until delivery or 41 weeks.

  Preeclampsia which was the primary outcome of the trial, occurred in 14.6% (80 of 548) of participants in the pravastatin group and in 13.6% (74 of 543) in the placebo group. Allowing for the effect of risk at the time of screening and participating center, the mixed-effects Cox regression showed no evidence of an effect of pravastatin (hazard ratio for statin/placebo, 1.08 [95% CI, 0.78-1.49]; P=0.65). There was no evidence of interaction between the effect of pravastatin, estimated risk of preeclampsia, pregnancy history, adherence, and aspirin treatment. There was no significant between-group difference in the incidence of any secondary outcomes, including gestational hypertension, stillbirth, abruption, delivery of small for gestational age neonates, neonatal death, or neonatal morbidity. There was no significant between-group difference in the treatment effects on serum placental growth factor and soluble fms-like tyrosine kinase-1 concentrations 1 and 3 weeks after randomization. Adherence was good, with reported intake of ≥80% of the required number of tablets in 89% of participants. There were no significant between-group differences in neonatal adverse outcomes or other adverse events.

  It was concluded pravastatin in women at high risk of term preeclampsia did not reduce the incidence of delivery with preeclampsia.

Prevention of preterm birth

• Progesterone (200 mg/day) in women with short cervix can substantially reduce the risk of preterm birth
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  Progesterone and the risk of preterm birth among women with a short cervix

  Fonseca EB, Celik E, Parra M, Singh M, Nicolaides KH; Fetal Medicine Foundation Second Trimester Screening Group

  N Engl J Med 2007;357:462-9  pdf

  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.

• Progesterone (600 mg/day) in women with twin pregnancies does not reduce the risk of preterm birth
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  Early vaginal progesterone versus placebo in twin pregnancies for the prevention of spontaneous preterm birth: a randomized, double-blind trial

  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

  Am J Obstet Gynecol 2021;224:86.e1-86.e19  pdf

  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.

  A meta-analysis, which included the above and other trials in twin pregnancies, was carried out by Conde-Agudelo A, Romero R, Rehal A, Brizot ML, Serra V, Da Fonseca E, Cetingoz E, Syngelaki A, Perales A, Hassan SS, Nicolaides KH (vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in twin gestations: a systematic review and meta-analysis. Am J Obstet Gynecol. 2023 May 15:S0002-9378(23)00317-4). The study showed that vaginal progesterone does not prevent preterm birth, nor does it improve perinatal outcomes in unselected twin gestations (8 studies; 3274 women). However, among twin gestations with a transvaginal sonographic cervical length <30 mm (6 studies; 306 women), vaginal progesterone was associated with a significant decrease in the risk of preterm birth occurring at <32 gestational weeks (relative risks, 0.48-0.65), and of neonatal morbidity and mortality. However, more evidence is needed before recommending this intervention to this subset of patients.

• Cervical cerclage in women with short cervix does not reduce the risk of preterm birth
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  Cervical cerclage for prevention of preterm delivery in women with short cervix: randomised controlled trial

  To MS, Alfirevic Z, Heath VC, Cicero S, Cacho AM, Williamson PR, Nicolaides KH; Fetal Medicine Foundation Second Trimester Screening Group

  Lancet 2004;363:1849-53  pdf

  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 women with short cervix does not reduce the risk of preterm birth
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  A Randomized Trial of a Cervical Pessary to Prevent Preterm Singleton Birth

  Nicolaides KH, Syngelaki A, Poon LC, Picciarelli G, Tul N, Zamprakou A, Skyfta E, Parra-Cordero M, Palma-Dias R, Rodriguez Calvo J

  N Engl J Med 2016;374:1044-52  pdf

  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 twin pregnancies does not reduce the risk of preterm birth
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  Cervical pessary placement for prevention of preterm birth in unselected twin pregnancies: a randomized controlled trial

  Nicolaides KH, Syngelaki A, Poon LC, de Paco Matallana C, Plasencia W, Molina FS, Picciarelli G, Tul N, Celik E, Lau TK, Conturso R

  Am J Obstet Gynecol 2016;214:3.e1-9  pdf

  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 improves management
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  Targeted therapy for threatened preterm labor based on sonographic measurement of the cervical length: a randomized controlled trial

  Alfirevic Z, Allen-Coward H, Molina F, Vinuesa CP, Nicolaides K

  Ultrasound Obstet Gynecol 2007;29:47-50  pdf

  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.

Prevention of macrosomia

• Metformin in obese women does not reduce the risk of macrosomia but it reduces the risk of preeclamsia
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  Metformin versus Placebo in Obese Pregnant Women without Diabetes Mellitus

  Syngelaki A, Nicolaides KH, Balani J, Hyer S, Akolekar R, Kotecha R, Pastides A, Shehata H

  N Engl J Med 2016;374:434-43  pdf

  The MOP trial was designed to test the hypothesis that metformin, compared to placebo, would reduce birth weight and pregnancy complications in non-diabetic pregnant women with a BMI >35 kg/m2. The trial was conducted in three NHS maternity hospitals in the United Kingdom. Eligible women were randomized in a 1:1 ratio to either metformin or placebo, using computer generated random numbers.

  In total 400 women participated in the study. There was no significant between-group difference in the median neonatal birth-weight z score. However, the median maternal gestational weight gain was lower in the metformin group than in the placebo group (4.6 kg [interquartile range, 1.3 to 7.2] vs. 6.3 kg [interquartile range, 2.9 to 9.2], P<0.001), as was the incidence of PE (3.0% vs. 11.3%; odds ratio, 0.24; 95% confidence interval, 0.10 to 0.61; P=0.001). The incidence of side effects was higher in the metformin group than in the placebo group. There were no significant between-group differences in the incidence of gestational diabetes, large-for-gestational-age neonates, or adverse neonatal outcomes.

  It was concluded that among women without diabetes who have a BMI of more than 35, the antenatal administration of metformin reduces maternal weight gain and PE, but not neonatal birth weight.