Browsing by Author "Nicolaides, Kypros H."
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Item Early vaginal progesterone versus placebo in twin pregnancies for the prevention of spontaneous preterm birth: a randomized, double-blind trial.(American Journal of Obstetrics and Gynecology, 2021) Rehal, Anoop; Benkő, Zsófia; De Paco Matallana, Catalina; Gil Mira, María del Mar; Nicolaides, Kypros H.Background: In women with a singleton pregnancy and sonographic short cervix in midgestation, vaginal administration of progesterone reduces the risk of early preterm birth and improves neonatal outcomes, without any demonstrable deleterious effects on childhood neurodevelopment. In women with twin pregnancies the rate of spontaneous early preterm birth is 10-times higher than in singletons and in this respect all twins are at increased risk of preterm birth. However, six trials in unselected twin pregnancies reported that vaginal 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 which is started too late in pregnancy. Objective: The Early vaginal progesterone for the preVention of spontaneous prEterm birth iN TwinS: A randomized, placebo controlled, double-blinded trial (EVENTS) was designed to test the hypothesis that, among women with twin pregnancies, vaginal progesterone at a dose of 600 mg per day from 11-14 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. Methods: The trial was conducted at 22 hospitals in England, Spain, Bulgaria, Italy, Belgium and France. Women were randomly assigned in a 1:1 ratio, to receive either progesterone or placebo and in the random-sequence generation there was stratification according to participating center. Primary outcome was spontaneous birth between 24 +0 and 33+6 weeks’ gestation. Statistical analyses were performed on an intention-to-treat basis. Logistic regression analysis was used to determine the significance of difference in incidence of spontaneous birth between 24+0 and 33+6 weeks’ gestation between the progesterone and placebo groups, adjusting for the effect of participating centre, chrorionicity, parity and method of conception. Prespecified tests of treatment interaction effects with chrorionicity, parity, method of conception, compliance and cervical length at recruitment were performed. A post hoc analysis using mixed effects Cox regression was used for further exploration of the effect of progesterone on preterm birth. Results: We recruited 1,194 women between May 2017 and April 2019; 21 withdrew consent and 4 were lost to follow up, which left 582 in the progesterone group and 587 in the placebo group. Adherence was good, with reported intake of ≥80% of the required number of capsules in 81.4% of the participants. After excluding births before 24 weeks and indicated deliveries before 34 weeks, spontaneous birth between 24+0 and 33+6 weeks occurred in 10.4% (56/541) participants in the progesterone group and in 8.2% (44/538) in the placebo group (odds ratio in the progesterone group, adjusting for the effect of participating center, chrorionicity, parity and method of conception, 1.35; 95% CI 0.88 - 2.05; p=0.17). There was no evidence of interaction between the effects of treatment and chorionicity (p=0.28), parity (p=0.35) method of conception (p=0.56) and adherence (p=0.34); however, there was weak evidence of an interaction with cervical length (p=0.08) suggestive of harm to those with cervical length ≥30 mm (odds ratio 1.61, 95% CI 1.01-2.59) and potential benefit for those with cervical length <30 mm (odds ratio 0.56; 95% CI 0.20-1.60). There was no evidence of difference between the two treatment groups for stillbirth or neonatal death; neonatal complications; neonatal therapy; and poor fetal growth. In the progesterone group there were 1.4% (8/582) women and 1.9% (22/1,164) fetuses with at least one serious adverse event; the respective numbers for the placebo group were 1.2% (7/587) and 3.2% (37/1,174) (p=0.80 and p=0.06, respectively). In the 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% CI 0.08 - 0.69). Conclusions: In women with twin pregnancies universal treatment with vaginal progesterone did not reduce the incidence of spontaneous birth between 24+0 and 33+6 weeks’ gestation. Post hoc time to event analysis led to the suggestion that progesterone may reduce the risk of spontaneous birth <32 weeks in women with cervical length <30 mm and it may increase the risk for those with cervical length ≥30 mm.Item First-trimester screening for trisomies by cfDNA testing of maternal blood in singleton and twin pregnancies: factors affecting test failure.(Ultrasound in Obstetrics and Gynecology, 2019) Galeva, Slavyana; Gil Mira, María del Mar; Konstantinidou, Liountmila; Akolekar, Ranjit; Nicolaides, Kypros H.Objectives: To examine factors affecting the failure rate to obtain a result from (cf) DNA testing of maternal blood for fetal trisomies 21, 18 and 13 in singleton and twin pregnancies in the first trimester of pregnancy. Methods: This was a prospective study in 23,495 singleton and 928 twin pregnancies undergoing screening for fetal trisomies by targeted cfDNA testing at 10+0-14+1 weeks’ gestation. Multivariate regression analysis was used to determine significant predictors of failure to obtain a result after first sampling. Results: There was no result from cfDNA testing after first sampling in 3.4% (798/23,495) of singletons, 11.3% (91/806) of DC twins and in 4.9% (6/122) of MC twins. Multivariate logistic regression analysis demonstrated that the risk of test failure first, increased with increasing maternal age (odds ratio (OR) 1.02; 95% confidence interval (CI) 1.01, 1.04) and weight (OR 1.05; 95% CI 1.04, 1.05), decreasing gestational age (OR 0.85; 95% CI 0.79, 0.91) and serum PAPP-A (OR 0.56; 95% CI 0.49, 0.64) and free ß-hCG (OR 0.67; 95% CI 0.60, 0.74), second, was higher in women of Black (OR 1.72; 95% CI 1.33, 2.20) and South Asian (OR 1.99; 95% CI 1.56, 2.52) than White racial origin, in dichorionic twin (OR 1.75; 95% CI 1.34, 2.25) than singleton pregnancy and in in vitro fertilization (OR 3.82; 95% CI 3.19, 4.55) than natural conception and third, was lower in parous (OR 0.63; 95% CI 0.55, 0.74) than nulliparous women. Conclusions: Maternal age, weight, racial origin and parity, gestational age, dichorionicity, method of conception and serum levels of free ß-hCG and PAPP-A are independent predictors of cfDNA test failure. The risk of test failure is higher in dichorionic twin than in singleton pregnancies, mainly because a higher proportion of twins are conceived by in vitro fertilization and more of the women are nulliparous.Item Implementation of maternal blood cell-free DNA testing in early screening for aneuploidies.(Medizinische Genetik, 2019) Gil Mira, María del Mar; Nicolaides, Kypros H.Several externally blinded validation and implementation studies in the last 9 years have shown that it is now possible, through analysis of cell-free (cf) DNA in maternal blood, to effectively detect a high proportion of fetuses affected by trisomies 21, 18, and 13 at a much lower false-positive rate (FPR) than all other existing screening methods. This article is aimed at reviewing technical and clinical considerations for implementing cfDNA testing in routine practice, including methods of analysis, performance of the test, models for clinical implementation, and interpretation of results.Item Routine first-trimester screening for fetal trisomies in twin pregnancies: cell-free DNA test contingent on results from the combined test.(Ultrasound in Obstetrics and Gynecology, 2018) Galeva, Slavyana; Konstantinidou, Liountmila; Gil Mira, María del Mar; Akolekar, Ranjit; Nicolaides, Kypros H.Objective: To report on the routine clinical implementation of cell-free (cf)DNA analysis of maternal blood for trisomies 21, 18 and 13 contingent on the results of the first-trimester combined test in twin pregnancies. Methods: Screening for trisomies 21, 18 and 13 was carried out by a combination of maternal age, fetal nuchal translucency (NT) thickness, and serum free ß-hCG and PAPP-A at 11-13 weeks’ gestation in 959 twin pregnancies in two UK NHS hospitals. Women in the high-risk group (risk >1 in 100) were offered options of invasive testing, cfDNA testing or no further testing and those in the intermediate-risk group (risk 1 in 101 to 1 in 2500 in the first phase of the study and 1 in 101 to 1 in 500 in the second phase) were offered cfDNA or no further testing. The trisomic status of the pregnancies was determined by prenatal or postnatal karyotyping or examination of the neonates. Results: In 42 (4.4%) of the 959 pregnancies there was termination, miscarriage or stillbirth with no known karyotype or there was loss to follow up. The 917 pregnancies with known trisomic status of both twins, included 6 that were discordant for trisomy 21, 4 discordant for trisomy 18 and 896 with no trisomies 21, 18 or 13. Following combined screening, 47 (5.1%), 203 (22.2%) and 667 (72.7%) of the pregnancies were classified as high-risk, intermediate-risk and low-risk, respectively. The high-risk group included 5 (83.3%) cases of trisomy 21 and 3 (75.0%) of trisomy 18. The cfDNA test was carried out in 224 pregnancies and results were provided in 214 (95.5%); this group included 6 with trisomy 21, 3 with trisomy 18 and 206 with no trisomies 21, 18 or 13. The cfDNA test correctly classified as screen positive all 6 cases of trisomy 21 and 2 of the 3 with trisomy 18 and as screen negative for each of the trisomies all 206 unaffected pregnancies. Contingent screening, led to prenatal detection of all cases of trisomy 21 and 3 of 4 with trisomy 18. Conclusions: The study has demonstrated the feasibility of introducing cfDNA testing, contingent on the results of the first-trimester combined test for major trisomies, in a routine population of twin pregnancies.Item Screening for trisomies by cfDNA testing of maternal blood in twin pregnancy: update of the Fetal Medicine Foundation results and meta-analysis.(Ultrasound in Obstetrics and Gynecology, 2019) Gil Mira, María del Mar; Galeva, Slavyana; Jani, Jacques; Konstantinidou, Liountmila; Akolekar, Ranjit; Plana, María Nieves; Nicolaides, Kypros H.Objective: To report on the routine clinical implementation of cell-free (cf)DNA analysis of maternal blood for trisomies 21, 18 and 13 in twin pregnancies and to define the performance of the test by combining our results with those arising from systematic review of the literature. Methods: The data for the study were derived from prospective screening for trisomies 21, 18 and 13 in twin pregnancies at 10+0-14+1 weeks’ gestation. Two populations were included; first self-referred women to the Fetal Medicine Centre in London or Brugmann University Hospital in Brussels and second, women selected for the cfDNA test after routine first-trimester combined testing in one of two National Health Service hospitals in England. This dataset was used to determine the performance of screening for the three trisomies. Search of Medline, Embase, CENTRAL (The Cochrane Library), ClinicalTrials.gov and ICTRP (World Health Organization) was carried out to identify all peer-reviewed publications on clinical validation or implementation of maternal cfDNA testing for trisomies 21, 18 and 13 in twin pregnancies. Meta-analysis was then performed using our data and data from the studies identified by the literature search. Results: In our dataset of 997 twin pregnancies with a cfDNA result and known outcome, the test classified correctly 16 (94.1%) of the 17 cases of trisomy 21, 9 (90.0%) of 10 of trisomy 18, 1 (50.0%) of 2 of trisomy 13 and 963 (99.5%) of 968 cases without any of the three trisomies. The literature search identified 7 relevant studies, excluding our papers because their data are included in the current study. In the combined total of our study and the 7 studies identified by the literature search there were 56 trisomy 21 and 3,718 non-trisomy 21 twin pregnancies; the pooled weighted detection rate (DR) and false positive rate (FPR) were 98.2% (95% CI 83.2, 99.8%) and 0.05% (95% CI 0.01, 0.26%), respectively. In the combined total of 18 cases of trisomy 18 and 3,143 non-trisomy 18 pregnancies the pooled weighted DR and FPR were 88.9% (95% CI 64.8, 97.2%) and 0.03% (95% CI 0.00, 0.33%), respectively. For trisomy 13, there were only 3 affected cases and 2 (66.7%) of these were detected by the cfDNA test at FPR of 0.19% (5/2,569). Conclusions: Performance of cfDNA testing for trisomies 21 in twin pregnancies is similar to that reported for singleton pregnancies. The number of cases of trisomies 18 and 13 is too small for accurate assessment of predictive performance of the cfDNA test.