Abstract
Introduction
Preterm birth is the most common cause of neonatal morbidity and mortality. Women with twin pregnancies and a short cervical length are at high risk for preterm birth. Vaginal progesterone and cervical pessary have been proposed as potential strategies to reduce preterm birth in this high‐risk population. Therefore, we aimed to compare the effectiveness of cervical pessary and vaginal progesterone in improving developmental outcomes of children born to women with twin pregnancies and mid‐trimester short cervical length.
Material and methods
This was a follow‐up study (NCT04295187) of all children at 24 months of age, born from women treated with cervical pessary or progesterone to prevent preterm birth in a randomized controlled trial (NCT02623881). We used a validated Vietnamese version of Ages & Stages Third Edition Questionnaires (ASQ‐3) and a red flag questionnaire. In surviving children, we compared the mean ASQ‐3 scores, abnormal ASQ‐3 scores, the number of children with any abnormal ASQ‐3 scores and red flag signs between the two groups. We reported the composite outcome of perinatal death or survival with any abnormal ASQ‐3 score in offspring. These outcomes were also calculated in a subgroup of women with a cervical length ≤28 mm (<25th percentile).
Results
In the original randomized controlled trial, we randomized 300 women to pessary or progesterone. After counting the number of perinatal deaths and lost to follow‐up, 82.8% parents in the pessary group and 82.5% parents in progesterone group returned the questionnaire. The mean ASQ‐3 scores of the five skills and red flag signs did not differ significantly between the two groups. However, the percentage of children having abnormal ASQ‐3 scores in fine motor skills was significantly lower in the progesterone group (6.1% vs 1.3%, P = 0.01). There were no significant differences in the composite outcome of perinatal death or survival with any abnormal ASQ‐3 score in unselected women and in those with cervical length ≤28 mm.
Conclusions
Cervical pessary and vaginal progesterone may have comparable effects on developmental outcomes in children at ≥24 months of age, born to women with twin pregnancies and short cervical length. However, this finding could be likely due to a lack of study power.
Keywords: ASQ‐3, cervical pessary, developmental outcomes, red flag signs, twin pregnancy, vaginal progesterone
Vaginal progesterone and cervical pessary have been proposed as potential strategies to reduce preterm birth in women with twin pregnancies and a short cervix. Our results suggested that the impact of cervical pessary and progesterone on the brain development of young children via Red flag and Ages & Stages Third Edition Questionaires (ASQ‐3) are mostly comparable.
Abbreviations
- ASQ‐3
Ages & Stages Third Edition Questionnaire
- CI
confidence interval
- CL
cervical length
- PTB
preterm birth
- RCT
randomized controlled trial
Key message.
Vaginal progesterone and cervical pessary have been proposed as potential strategies to reduce preterm birth in women with twin pregnancies and a short cervix. The impact of cervical pessary and progesterone on the brain development of young children via Red flag and Ages & Stages Third Edition Questionnaires (ASQ‐3) are mostly comparable.
1. INTRODUCTION
Preterm birth (PTB) is the most common cause of neonatal morbidity and mortality worldwide 1 and the second‐leading cause of death in children <5 years of age. 2 , 3 , 4 Women with twin pregnancies and a short cervical length (CL) are at extremely high risk for PTB. 5 Vaginal progesterone 6 , 7 and cervical pessary 8 , 9 , 10 , 11 , 12 have been proposed as potential strategies to reduce PTB in this high‐risk population. It has been shown that the universal use of progesterone in women with twin pregnancies did not reduce PTB rate, 7 , 13 , 14 but it might reduce PTB and neonatal complications in women with a short CL. 7 In contrast, another meta‐analysis showed that progesterone could only improve some secondary outcomes, regardless of CL. 11 A recent meta‐analysis showed that current evidence does not support the use of pessary to prevent PTB or to improve perinatal outcomes in women with twin pregnancies, regardless of CL. 15 However, this meta‐analysis only included a small number of trials, and heterogeneity between trials was identified. 15
In view of the significant impact of PTB and the promising but controversial effects of both pessary and progesterone, we have recently conducted a randomized controlled trial (RCT) directly comparing the effectiveness of these two interventions in women with twin pregnancies and a CL <38 mm. 16 Our data showed that pessary and progesterone resulted in similar treatment effects in the prevention of PTB <34 weeks. However, secondary endpoints as well as a prespecified subgroup analysis indicated that women with a cervix ≤28 mm (≤25th percentile) might benefit more from pessary. 16 The economic analysis performed alongside this RCT also showed that the costs per morbidity‐free survival neonate were significantly lower in the pessary group. 17
In addition to beneficial clinical outcomes and the cost‐effectiveness of interventions, their consequences are an important issue. Data of long‐term outcomes on twin children born to women with a CL <38 mm, is limited, with evidence from two trials assessed progesterone in unselected twin pregnancies 18 , 19 and one assessed pessary in women with a short CL, 20 both compared with no intervention. We, therefore, compared developmental outcomes in children born to women with twin pregnancies and a CL <38 mm, who participated in an RCT comparing pessary and progesterone. 16
2. MATERIAL AND METHODS
This was a follow‐up study of a RCT 16 performed at My Duc Hospital, Ho Chi Minh City, Vietnam. Women with twin pregnancies were eligible to participate in the original RCT if they were asymptomatic, at 16–22 weeks' gestation and had a CL <38 mm at transvaginal ultrasound. The 38‐mm cut‐off in this trial was based on the result of the Dutch study that reported in patients with a CL <25th percentile (<38 mm), the pessary significantly reduced preterm delivery and improved perinatal outcomes as compared with no intervention. 9 As this was a RCT in a research setting, such a relatively high cut‐off would allow us to assess a potential clinical relevant cut‐off that would probably be <38 mm. After written informed consent, women were randomly assigned (1:1 ratio) to receive a pessary (Arabin®, Dr Arabin GmbH & Co. KG) or 400‐mg vaginal progesterone (Cyclogest® 400 mg, Actavis) once daily at bedtime. In this follow‐up study, we included all children born from the original RCT who were aged ≥24 months and whose parents agreed to participate.
We used the Red flag and Ages & Stages Third Edition Questionnaires (ASQ‐3) as screening tools to assess child development. The ASQ‐3 instrument is designed to detect a developmental delay in children and to be completed by parents. 21 , 22 , 23 The questionnaire covers five areas of child development, including communication, gross motor, fine motor, problem‐solving, and personal‐social skills. Each area is assessed by six questions on developmental milestones, which are assigned a score of 0 (not yet able), 5 (sometimes able), or 10 (fully able). The maximum total score in each area is 60, with lower scores indicating less attainment of developmental milestones. 21 A score ≤2 standard deviations below the mean score on at least one domain was considered abnormal development. 23 In this study, we used the Vietnamese language version, which has been validated by an expert committee.
The Red flag questionnaire is designed to provide healthcare professionals working with young children (up to 6 years of age) and their families with a quick reference guide to help identify developmental concerns at an early stage. 24 , 25 , 26 This questionnaire is recommended to be used together with a screening tool, such as the ASQ‐3. 26 It was classified into three age groups: for children from 2 to <3 years of age (composed of five items: unclear speech, not speaking in three‐word sentences, not understanding simple instruction, not making eye contact, and losing skills); for children from 3 to <4 years of age (composed of five items: not being able to jump in place, speaking unclearly, not playing make‐believe, not being able to retell a favorite story and losing skills); and for children from 4 years old onwards (composed of four items: being easily distracted, having extreme behaviors, not talking about daily activities or experiences, and losing skills). Children presenting with any red flag indicators were suspected of developmental disorders. In this study, all children showing any abnormality were investigated further by a specialist.
To identify potentially eligible participants, researchers reviewed data of all children born from the original RCT to check the possible occurrence of death of one or both twins before contacting the parents. All couples of whom at least one of the twins was alive after discharge were contacted by telephone, postal mail, or e‐mail. Consent forms, questionnaires, and detailed instructions were sent to those who were successfully contacted. An interview via telephone was performed to record the red flag signs. At the end of the interview, the experienced pediatricians explained to the parents how to answer the ASQ‐3 questionnaire at home. Completed questionnaires were returned via postal mail, e‐mail, or instant messenger. For those who preferred to come to the hospital, children were examined by experienced pediatricians to record the red flag signs and physical development. Parents were also explained how to answer the ASQ‐3 questionnaires by themselves. The total score of both questionnaires was adjusted for child age.
The endpoints for this follow‐up analysis were developmental outcomes of all live births and the composite outcome of perinatal death or survival with any abnormal ASQ‐3 score of all live births born to women treated with pessary or progesterone.
2.1. Statistical analyses
Baseline characteristics of women and children participating in the follow‐up study were analyzed using descriptive statistics. Abnormal scores, mean scores of ASQ‐3 and red flag signs were analyzed according to randomization in the original RCT for all surviving children that could be assessed at ≥24 months of age and in the subgroup of women with a CL ≤28 mm (≤25th percentile of the original RCT). We used t‐test, Mann–Whitney U‐test, Chi‐square test or Fisher's exact test to compare the two groups' differences when appropriate. The between‐group difference, with 95% confidence interval (CI), was calculated.
We also evaluated the effect of pessary compared with progesterone on the composite outcome of perinatal death or survival with any abnormal ASQ‐3 score in the offspring of all randomized women in the original RCT. This was also calculated in the subgroup of women with CL ≤28 mm. For this outcome, we assumed that children lost to follow‐up had the same percentage of ASQ‐3 abnormal scores as the followed‐up group. Additionally, number needed to treat or number needed to harm were calculated. All statistical analyses were performed using the R statistical package (R version 3.3.3, R Foundation for Statistical Computing). P‐value <0.05 was considered to indicate statistical significance.
2.2. Ethics statement
The original RCT (NCT02623881) was approved by the hospital ethics committee. This follow‐up study was approved by the hospital ethics committee (04/20/ĐĐ‐BVMĐ, February 18, 2020) and registered at ClinicalTrials.gov (NCT04295187). A written informed consent was obtained from all parents participating in the study.
3. RESULTS
In the original RCT, 300 women were randomly assigned to the pessary group (150 women, 300 fetuses) or progesterone group (150 women, 300 fetuses). Two women in the pessary group (4 fetuses) and one woman in the progesterone group (2 fetuses) were lost to follow‐up. At the time of discharge, there were 21 children in the pessary group (13 women) and 17 children in the progesterone group (11 women) who had died due to stillbirth or neonatal death (Figure 1).
FIGURE 1.
Study flowchart.
In the pessary group, of the 140 women (275 children) approached, there were 116 (82.8%) women (229 children) returned fully completed questionnaires. Corresponding figures in the progesterone group were 143 women (281 children) and 118 (82.5%) women (232 children) (Figure 1). For the subgroup of women with a CL ≤28 mm, fully completed questionnaires were returned by 35 (85.4%) women (70 children) in the pessary group and 27 (87.1%) women (53 children) in the progesterone group (Figure S1).
Baseline demographic and clinical characteristics of women participating in the follow‐up study were comparable between the two groups (Table 1). There were significantly lower risks of low birthweight, respiratory distress syndrome and admission to neonatal intensive care unit (NICU) in neonates born to women treated with pessary. At the end of follow‐up, the mean age, mean height and weight of children were comparable between the two groups (Table 1).
TABLE 1.
Baseline demographic, clinical characteristics of women at entry of original RCT and neonatal characteristics of children participating in the follow‐up study.
| Characteristics | Pessary (n = 116) | Progesterone (n = 118) | Between‐group difference (95% CI) |
|---|---|---|---|
| Maternal baseline demographics | |||
| Age, years | 31.7 ± 5.0 | 32.1 ± 4.9 | ‐ |
| Body mass index, kg/m2 | 20.9 ± 2.3 | 20.8 ± 2.0 | ‐ |
| Nulliparous, n (%) | 98 (84.5) | 105 (89.0) | ‐ |
| Maternal clinical characteristics | |||
| Eclampsia/HELLP, n (%) | 1 (0.9) | 1 (0.8) | ‐ |
| Hypertension, n (%) | 15 (12.9) | 14 (11.9) | ‐ |
| Mode of delivery, n (%) | |||
| Cesarean | 105 (90.5) | 102 (86.4) | ‐ |
| Spontaneous | 11 (9.5) | 16 (13.6) | ‐ |
| Gestational age at delivery, weeks | 36.4 ± 2.0 | 35.9 ± 2.1 | ‐ |
| <28 weeks | 1 (0.9) | 1 (0.8) | ‐ |
| <34 weeks | 12 (10.3) | 20 (16.9) | ‐ |
| <37 weeks | 51 (44.0) | 68 (57.6) | ‐ |
| n = 229 | n = 232 | ||
|---|---|---|---|
| Neonatal characteristics of children | |||
| Birthweight, g | 2434.3 ± 447.7 | 2327.4 ± 461.1 | 107 (23.8, 190.1) |
| Low birthweight (<2500 g), n (%) | 104 (45.4) | 137 (59.1) | −13.6 (−23.1, −4.2) |
| Very low birthweight (<1500 g), n (%) | 9 (3.9) | 10 (4.3) | −0.4 (−4.4, 3.6) |
| Congenital anomalies, n (%) | 1 (0.4) | 3 (1.3) | −0.9 (−3, 1.3) |
| Periventricular leukomalacia, n (%) | 0 (0) | 0 (0) | ‐ |
| Respiratory distress syndrome, n (%) | 21 (9.2) | 39 (16.8) | −7.6 (−14.2, −1.1) |
| Bronchopulmonary dysplasia, n (%) | 0 (0) | 0 (0) | ‐ |
| Intraventricular hemorrhage, n (%) | 1 (0.4) | 2 (0.9) | −0.4 (−2.3, 1.5) |
| Necrotizing enterocolitis, n (%) | 6 (2.6) | 13 (5.6) | −3 (−7, 1.1) |
| Proven sepsis, n (%) | 14 (6.1) | 26 (11.2) | −5.1 (−10.6, 0.4) |
| NICU admission, n (%) | 26 (11.4) | 49 (21.1) | −9.8 (−16.9, −2.7) |
| Child characteristics at completion of questionnaires | |||
| Age, months | 37.2 ± 3.7 | 37.7 ± 3.9 | −0.6 (−1.2, 0.1) |
| Weight, kg | 15.2 ± 2.8 | 15.2 ± 2.7 | 0 (−0.6, 0.5) |
| Height, cm | 95.6 ± 5.8 | 95.8 ± 5.9 | −0.2 (−1.3, 0.9) |
| BMI, kg/m2 | 16.6 ± 2.7 | 16.7 ± 2.6 | −0.2 (−0.7, 0.3) |
Note: Values are mean ± standard deviation or number of patients (%).
Abbreviations: CI, confidence interval; RCT, randomized controlled trial.
The mean ASQ‐3 scores of the five skills did not differ significantly between the pessary and progesterone groups. However, the percentage of children having abnormal ASQ‐3 scores of fine motor skills was significantly higher in pessary group (Table 2). The proportion of children with any abnormal ASQ‐3 scores was comparable in the pessary group and the progesterone group (Table 2). There were no significant differences in any abnormal red flag signs between the two groups (Table 3).
TABLE 2.
Ages & Stages Third Edition (ASQ‐3) scores and proportion of children with abnormal scores.
| Pessary (n = 229) | Progesterone (n = 232) | Between‐group difference (95% CI) | |
|---|---|---|---|
| ASQ‐3 mean scores | |||
| Communication | 53.2 ± 11 | 53.8 ± 8.7 | −0.5 (−2.3, 1.3) |
| Gross motor | 57 ± 5.6 | 56.3 ± 6.8 | 0.7 (−0.4, 1.9) |
| Fine motor | 45.9 ± 13.9 | 45.4 ± 12.4 | 0.6 (−1.8, 3) |
| Problem solving | 54.3 ± 9.3 | 54.4 ± 9 | −0.1 (−1.8, 1.6) |
| Personal‐social | 51.5 ± 10.1 | 50.4 ± 8.8 | 1.1 (−0.6, 2.8) |
| Abnormal ASQ‐3 scores | |||
| Communication | 13 (5.7) | 7 (3) | 2.7 (−1.5, 6.8) |
| Gross motor | 2 (0.9) | 5 (2.2) | −1.3 (−3.9, 1.4) |
| Fine motor | 14 (6.1) | 3 (1.3) | 4.8 (1, 8.7) |
| Problem solving | 7 (3.1) | 8 (3.4) | −0.4 (−4, 3.2) |
| Personal‐social | 16 (7) | 7 (3) | 4 (−0.4, 8.4) |
| Any abnormal ASQ‐3 | 22 (9.6) | 14 (6) | 3.6 (−1.8, 8.9) |
Note: Values are number of patients (%).
Abbreviation: CI, confidence interval.
TABLE 3.
Red flag questionnaire findings.
| Pessary (n = 229) | Progesterone (n = 232) | Between‐group difference (95% CI) | |
|---|---|---|---|
| From 24 to < 36 months | |||
| Child has very unclear speech | 1 (0.4) | 1 (0.4) | 0 (−1.2, 1.2) |
| Does not understand simple instruction | 0 (0) | 1 (0.4) | ‐ |
| Does not speak in short sentences | 2 (0.9) | 6 (2.6) | −1.7 (−4.5, 1.1) |
| Does not make eye contact | 2 (0.9) | 1 (0.4) | 0.4 (−1.5, 2.3) |
| Loses skills he/she once had | 0 (0) | 0 (0) | ‐ |
| From 36 to < 48 months | |||
| Cannot jump in place | 1 (0.4) | 5 (2.2) | −1.7 (−4.2, 0.8) |
| Does not play pretend or make‐believe | 4 (1.7) | 2 (0.9) | 0.9 (−1.6, 3.4) |
| Speaks unclearly | 2 (0.9) | 0 (0) | ‐ |
| Cannot retell a favorite story | 13 (5.7) | 11 (4.7) | 0.9 (−3.6, 5.4) |
| Loses skills he/she once had | 1 (0.4) | 0 (0) | ‐ |
| From 48 months onwards | |||
| Cannot focus on one activity for more than 5 minutes | 0 (0.0) | 0 (0.0) | ‐ |
| Cannot talk about daily activities or experiences | 0 (0.0) | 0 (0.0) | ‐ |
| Shows extreme behaviors (unusually fearful, aggressive, shy or sad) | 0 (0.0) | 0 (0.0) | ‐ |
| Loses skills he/she once had | 0 (0.0) | 0 (0.0) | ‐ |
| Red flags | 13 (5.7) | 17 (7.3) | −1.7 (−6.6, 3.3) |
Note: Values are number of patients (%).
Abbreviation: CI, confidence interval.
In a subgroup of women with a CL ≤28 mm, baseline demographic and clinical characteristics were comparable between the two groups (Table S1). At the time of discharge, seven children in the pessary group (four women) and seven children in the progesterone group (four women) had died due to stillbirth or neonatal death. There were significantly lower risks of low birthweight, respiratory distress syndrome, neonatal sepsis,and NICU admission in neonates born to women treated with pessary (Table S1). In the children born to women with CL ≤28 mm, there were no significant differences in the mean ASQ‐3 scores of the five skills and the percentage of children with any abnormal ASQ‐3 score between pessary group and progesterone group (Table S2). The proportion of children with any abnormal red flag findings was comparable between two groups (Table S3).
The composite outcome of perinatal death or survival with any abnormal ASQ‐3 score for all randomized women in the original RCT was also calculated. In the pessary group, 21 of 296 children died, leading to 275 survival children (229 children were followed up and 46 children were lost to follow‐up). In the progesterone group, the corresponding figures were 17 of 298 and 281 (232 and 49), respectively. The abnormal outcomes in children lost to follow‐up were extrapolated, based on the percentage of abnormal child outcomes in children followed up in the pessary and progesterone groups (9.6% and 6.0%, respectively). The estimated composite outcome of perinatal death or survival with any abnormal ASQ‐3 occurred in 47 children (15.9%) in the pessary group vs 35 children (11.7%) children in the progesterone group (RR 1.35, 95% CI 0.90–2.03) (Table 4). In the subgroup of children born to women with CL ≤28 mm, the estimated composite outcome of abnormal ASQ‐3 or perinatal death occurred in 12 children (12.8%) in the pessary group vs 11 (15.7%) in the progesterone group (RR 0.81; 95% CI 0.38–1.73) (Table 4).
TABLE 4.
Composite outcome of perinatal death or any abnormal ASQ‐3 in the offspring of all randomized women in the original RCT and in a subgroup of women with CL ≤28 mm.
| Pessary | Progesterone | Relative risk (95% CI) | |
|---|---|---|---|
| Unselected group | n = 296 | n = 298 | |
| Composite outcome of abnormal ASQ‐3 or perinatal death | 47 (15.9) | 35 (11.7) | 1.35 (0.90, 2.03) |
| Subgroup with CL ≤ 28 mm | n = 94 | n = 70 | |
| Composite abnormal ASQ‐3 scores | 12 (12.8) | 11 (15.7) | 0.81 (0.38,1.73) |
Note: Values are number of patients (%).
Abbreviation: CI, confidence interval.
4. DISCUSSION
This follow‐up study was conducted in a randomized setting, comparing developmental outcomes of children at ≥24 months of age, born to women with twin pregnancies and a CL <38 mm who were randomized to pessary or 400‐mg progesterone. Our data showed that ASQ‐3 mean scores and red flag signs were comparable between the two groups. However, the percentage of children with abnormal scores in fine motor skills were significantly higher in the pessary group. In the subgroup of women with CL ≤28 mm, there was no significant difference between the pessary and progesterone group in the protective effect on developmental outcomes of children. When combined perinatal death or survival with any abnormal ASQ‐3 outcome, we found no improvement in this composite outcome both in unselected women and in women with a CL ≤28 mm.
This study evaluated the effects of cervical pessary and vaginal progesterone on children's development, with more than 80% response rate in both groups. The fact that this issue was investigated in children born to women participating in an RCT 16 made our findings more reliable. Another strength of our study is the relatively long in utero exposure to progesterone (15.9 ± 1.7 weeks) and high compliance (97%) compared with other studies. 18 , 19 However, some limitations also need to be taken into account. First, even though a follow‐up rate >80% is a reasonable response rate, there is still a substantial risk of bias. We assumed that children lost to follow‐up showed the same percentage of ASQ‐3 abnormal scores as the group that was followed up. This assumption was based on the comparable characteristics of children who participated in this follow‐up study and those of children whose parents refused to participate and those with incompleted questionnaires returned. The maternal baseline demographics were also comparable between the two groups (Table S4). Secondly, we only used questionnaires as screening tool for developmental delay and behavioral problems, not additional physical developmental tests or behavioral observations. However, the ASQ‐3 and Red flag questionnaire are widely used in follow‐up studies and validated in several countries. Last, the power calculations used in the original RCT do not apply to the current analysis, which analyzed a different population (babies vs women in the RCT) and used different endpoints (developmental measures vs live birth rate in the RCT). With a sample size of 229 children in the pessary group and 232 children in the progesterone group and a significance level of 0.05 (two‐sided), the current study had 31% power to detect a difference of 3.6% in any abnormal ASQ‐3 rates between the two groups. The corresponding figures in the rates of abnormal communication, abnormal gross motor, abnormal fine motor, abnormal problem solving and abnormal personal‐social skills were 30% power (for a difference of 2.7%), 92% power (for a difference of 1.3%), 83% power (for a difference of 4.8%), 5% power (for a difference of 0.4%), 5% power (for a difference of 0.4%) and 52% power (for a difference of 4%), respectively. Therefore, the lack of statistical significance for between‐group comparisons is likely due to a lack of study power.
Prevention of PTB has been considered a priority worldwide. 27 A number of RCTs and meta‐analyses have been conducted to assess the effectiveness of progesterone and pessary 7 for PTB prevention, with controversial findings. 7 , 8 , 9 , 10 , 11 In addition to beneficial clinical outcomes, long‐term follow‐up of children is of particular importance because serious sequelae from perinatal complications frequently only manifest themselves after several years. 28 Unfortunately, this kind of study is not very common 29 and data on the long‐term effect of progesterone and pessary on children born to women with twin pregnancies and a short CL is limited. Moreover, there are no published data so far making a direct comparison between the development of children in pessary and progesterone groups, with women with either singleton or twin pregnancies.
In the longest follow‐up to date of 8‐year‐old children born to women with unselected twin pregnancies, the authors reported a statistically significantly higher mean ASQ‐3 score in the progesterone group than the placebo group. 19 However, this positive finding was not supported by another study, where health outcomes of children at 3–6 years born to women with unselected twin pregnancies treated with progesterone vs placebo were assessed. 18 Long‐term outcomes in offspring of women treated with pessary vs expectant management were reported in two studies. 20 , 30 In the longest follow‐up study to date, data showed that pessary did not improve any child outcome in surviving children at age 4, regardless of CL. However, the risk of composite outcome of death or abnormal child was significantly reduced in women with a CL <38 mm treated with pessary. 20
Our study directly compared developmental outcomes of children at ≥24 months of age, born to women with twin pregnancies and short CL, treated with progesterone or pessary in a randomized setting. There was no significant difference observed in any red flag questionnaire parameters or in ASQ‐3 mean scores of five areas between the two groups. However, our data suggest that treatment with progesterone significantly decreased the proportion of children with abnormal ASQ‐3 scores of fine motor skills. It should be noted that there might be a high probability of pure chance for this finding. However, this could also be related to a higher mean age in the progesterone group, although there was no significant difference, compared with the pessary group at the end of the follow‐up. This finding needs to be clarified in the future.
In our study, the number of children having red flag signs in both groups was low. It should be noted that the number of children in the progesterone group having abnormalities in ASQ‐3 range from 1.3% to 3.4%. In another follow‐up study, where the authors reported the total ASQ‐3 score <10th percentile, this figure ranged from 5.3% to 8%. 19 Again, these data show that there may be no major concerns about the potential harm to children born to women exposed to progesterone.
Our results also suggested that the impact of cervical pessary and progesterone on the brain development of young children (37.2 ± 3.7 vs 37.7 ± 3.9, respectively) are mostly comparable. However, it remains possible that the potential impact of cervical pessary and progesterone on brain development has not been captured in previous follow‐up studies 18 , 19 or ours, as children have been too young to determine this. We strongly encourage researchers who have carried out randomized trials on progesterone and pessary to perform a follow‐up study at later ages, eg after the age of 5, with appropriate diagnostic outcome measures and larger sample size. Moreover, the long‐term effect of pessary and progesterone on children born to women with a CL ≤28 mm should be explored.
5. CONCLUSION
This follow‐up study in children born to women with twin pregnancies and a CL <38 mm who were randomized to 400‐mg progesterone or pessary showed that at ≥2 years of age, the mean ASQ‐3 and the composite outcome of perinatal death or survival with any abnormal ASQ‐3 were comparable between the two groups. More data are needed to draw a firm conclusion.
AUTHOR CONTRIBUTIONS
The study was designed by VTT Tran, NA Nguyen, NT Nguyen, BW Mol and VQ Dang. Statistical analysis was performed by TD Pham. The first draft of this paper was written by VTT Tran, NA Nguyen and NT Nguyen. The paper was reviewed and edited by all the authors. VTT Tran, NA Nguyen, NT Nguyen, Vinh Q. Dang and Toan D. Pham had full access to all the data in the study. All authors had final responsibility for the decision to submit and assume responsibility for the accuracy and completeness of the analyses and the consistent adherence of this report to the research protocol.
FUNDING INFORMATION
The study was funded by My Duc Hospital.
CONFLICT OF INTEREST STATEMENT
LNV has received speaker and conference fees from Merck Sharpe and Dohme, and a grant, speaker, conference and scientific board fees from Ferring. BWM has acted as a paid consultant to Merck, ObsEva and Guerbet, and is the recipient of grant money from an NHMRC Investigator Grant. VQD has received a grant from Merck Sharpe and Dohme. The other authors have stated explicitly that there are no conflicts of interest in connection with this article.
Supporting information
Figure S1.
Table S1.
Table S2.
Table S3.
Table S4.
ACKNOWLEDGMENTS
Our special thanks go to the clinicians, nurses and administrative assistants for their help with participant recruitment and data collection.
Tran VTT, Nguyen NA, Nguyen NT, et al. Development of children born to women with twin pregnancies treated with cervical pessary or vaginal progesterone: Follow‐up of a randomized controlled trial. Acta Obstet Gynecol Scand. 2023;102:626‐634. doi: 10.1111/aogs.14545
Van T. T. Tran and Nghia A. Nguyen contributed equally to this work.
REFERENCES
- 1. Saigal S, Doyle LW. An overview of mortality and sequelae of preterm birth from infancy to adulthood. Lancet. 2008;371:261‐269. [DOI] [PubMed] [Google Scholar]
- 2. Blencowe H, Cousens S, Oestergaard MZ, et al. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet. 2012;379:2162‐2172. [DOI] [PubMed] [Google Scholar]
- 3. Liu L, Oza S, Hogan D, et al. Global, regional, and national causes of under‐5 mortality in 2000‐15: an updated systematic analysis with implications for the sustainable development goals. Lancet. 2016;388:3027‐3035. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Allotey J, Zamora J, Cheong‐See F, et al. Cognitive, motor, behavioural and academic performances of children born preterm: a meta‐analysis and systematic review involving 64 061 children. BJOG. 2018;125:16‐25. [DOI] [PubMed] [Google Scholar]
- 5. Kindinger LM, Poon LC, Cacciatore S, et al. The effect of gestational age and cervical length measurements in the prediction of spontaneous preterm birth in twin pregnancies: an individual patient level meta‐analysis. BJOG. 2016;123:877‐884. [DOI] [PubMed] [Google Scholar]
- 6. Serra V, Perales A, Meseguer J, et al. Increased doses of vaginal progesterone for the prevention of preterm birth in twin pregnancies: a randomised controlled double‐blind multicentre trial. BJOG. 2013;120:50‐57. [DOI] [PubMed] [Google Scholar]
- 7. Schuit E, Stock S, Rode L, et al. Effectiveness of progestogens to improve perinatal outcome in twin pregnancies: an individual participant data meta‐analysis. BJOG. 2015;122:27‐37. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Goya M, de la Calle M, Pratcorona L, et al. Cervical pessary to prevent preterm birth in women with twin gestation and sonographic short cervix: a multicenter randomized controlled trial (PECEP‐twins). Am J Obstet Gynecol. 2016;214:145‐152. [DOI] [PubMed] [Google Scholar]
- 9. Liem S, Schuit E, Hegeman M, et al. Cervical pessaries for prevention of preterm birth in women with a multiple pregnancy (ProTWIN): a multicentre, open‐label randomised controlled trial. Lancet. 2013;382:1341‐1349. [DOI] [PubMed] [Google Scholar]
- 10. Nicolaides KH, Syngelaki A, Poon LC, et al. Cervical pessary placement for prevention of preterm birth in unselected twin pregnancies: a randomized controlled trial. Am J Obstet Gynecol. 2016;214(3):e1‐e9. [DOI] [PubMed] [Google Scholar]
- 11. Jarde A, Lutsiv O, Park CK, et al. Preterm birth prevention in twin pregnancies with progesterone, pessary, or cerclage: a systematic review and meta‐analysis. BJOG. 2017;124:1163‐1173. [DOI] [PubMed] [Google Scholar]
- 12. Berghella V, Dugoff L, Ludmir J. Prevention of preterm birth with pessary in twins (PoPPT): a randomized controlled trial. Ultrasound Obstet Gynecol. 2017;49:567‐572. [DOI] [PubMed] [Google Scholar]
- 13. Rehal A, Benkő Z, De Paco MC, et al. 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(1):86.e1‐86.e19. [DOI] [PubMed] [Google Scholar]
- 14. Dodd JM, Grivell RM, OBrien CM, Dowswell T, Deussen AR. Prenatal administration of progestogens for preventing spontaneous preterm birth in women with a multiple pregnancy. Cochrane Database Syst Rev. 2019;2019(11). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Conde‐Agudelo A, Romero R, Nicolaides KH. Cervical pessary to prevent preterm birth in asymptomatic high‐risk women: a systematic review and meta‐analysis. Am J Obstet Gynecol. 2020;223:42‐65. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Dang VQ, Nguyen LK, Pham TD, et al. Pessary compared with vaginal progesterone for the prevention of preterm birth in women with twin pregnancies and cervical length less than 38 mm: a randomized controlled trial. Obstet Gynecol. 2019;133:459‐467. [DOI] [PubMed] [Google Scholar]
- 17. Le KD, Nguyen LK, Nguyen LTM, Mol BWJ, Dang VQ. Cervical pessary vs vaginal progesterone for prevention of preterm birth in women with twin pregnancy and short cervix: economic analysis following randomized controlled trial. Ultrasound Obstet Gynecol. 2020;55:339‐347. [DOI] [PubMed] [Google Scholar]
- 18. McNamara HC, Wood R, Chalmers J, et al. STOPPIT baby follow‐up study: the effect of prophylactic progesterone in twin pregnancy on childhood outcome. PLoS One. 2015;10:e0122341. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Vedel C, Larsen H, Holmskov A, et al. Long‐term effects of prenatal progesterone exposure: neurophysiological development and hospital admissions in twins up to 8 years of age. Ultrasound Obstet Gynecol. 2016;48:382‐389. [DOI] [PubMed] [Google Scholar]
- 20. Simons NE, van de Beek C, van der Lee JH, et al. Child outcomes after placement of a cervical pessary in women with a multiple pregnancy: a 4‐year follow‐up of the ProTWIN trial. Acta Obstet Gynecol Scand. 2019;98:1292‐1300. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Jane Squires P, Twombly E, Diana Bricker P, LaWanda Potter MS. ASQ‐3 User's Guide. 3rd ed. Brookes; 2009. [Google Scholar]
- 22. Kerstjens JM, Bos AF, ten Vergert EM, de Meer G, Butcher PR, Reijneveld SA. Support for the global feasibility of the ages and stages questionnaire as developmental screener. Early Hum Dev. 2009;85:443‐447. [DOI] [PubMed] [Google Scholar]
- 23. Steenis LJ, Verhoeven M, Hessen DJ, van Baar AL. Parental and professional assessment of early child development: the ASQ‐3 and the Bayley‐III‐NL. Early Hum Dev. 2015;91:217‐225. [DOI] [PubMed] [Google Scholar]
- 24. Dosman CF, Andrews D, Goulden KJ. Evidence‐based milestone ages as a framework for developmental surveillance. Paediatr Child Health. 2012;17:561‐568. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Scharf RJ, Scharf GJ, Stroustrup A. Developmental milestones. Pediatr Rev. 2016;37:25‐37. [DOI] [PubMed] [Google Scholar]
- 26. CDC.gov: CDC's developmental milestones. https://www.cdc.gov/ncbddd/actearly/milestones/index.html [19 December 2021]
- 27. WHO . Born to soon: The Global action report on Preterm Birth. 2012. https://apps.who.int/iris/bitstream/handle/10665/44864/9789241503433_eng.pdf;jsessionid=B36785D079DF4800698E8DAD502AC72B?sequence=1 (19 December 2021)
- 28. Voller SMB. Follow‐up care for high‐risk preterm infants. Pediatr Ann. 2018;47:e142‐e146. [DOI] [PubMed] [Google Scholar]
- 29. Teune MJ, van Wassenaer AG, Malin GL, et al. Long‐term child follow‐up after large obstetric randomised controlled trials for the evaluation of perinatal interventions: a systematic review of the literature. BJOG. 2013;120:15‐22. [DOI] [PubMed] [Google Scholar]
- 30. Van't Hooft J, van der Lee JH, Opmeer BC, et al. Pessary for prevention of preterm birth in twin pregnancy with short cervix: 3‐year follow‐up study. Ultrasound Obstet Gynecol. 2018;51:621‐628. [DOI] [PubMed] [Google Scholar]
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Supplementary Materials
Figure S1.
Table S1.
Table S2.
Table S3.
Table S4.