Abstract
BACKGROUND:
Current evidence indicates that administration of vaginal progesterone to women with a twin gestation and a short cervix reduces the risk of preterm birth occurring at early gestational ages and of neonatal morbidity and mortality. However, the potential long-term effects of prenatal administration of vaginal progesterone for preventing preterm birth on the psychopathological and cognitive profiles of twins remain unknown.
OBJECTIVE:
To evaluate the psychopathological and cognitive profiles at 6 to 9 years of age of surviving children born to mothers who participated in a randomized controlled trial that compared two different daily doses of vaginal progesterone (200 mg and 400 mg) to placebo to prevent preterm birth in dichorionic twin gestations.
STUDY DESIGN:
This is a follow-up study from a multicenter, double-blind, randomized controlled trial with three parallel groups (placebo, vaginal progesterone 200 mg/day, and vaginal progesterone 400 mg/day administered from 20 to 34 weeks of gestation or delivery, whichever came first; randomization ratio 1:1:1). The Child Behavior Checklist for ages 6 to 18 questionnaire and the Raven’s Colored Progressive Matrices test of non-verbal intelligence were applied to the participating mothers and their surviving children aged 6 to 9 years, respectively. The participant mothers, questionnaire collector, and database organizer were blinded to the intervention received in the original trial. The primary outcomes were behavioral, emotional, and social problems evaluated by the Child Behavior Checklist for ages 6 to 18 −18 questionnaire, and the intelligence coefficient percentile evaluated by the Raven’s Colored Progressive Matrices test. Analyses were performed on an intention-to-treat basis using descriptive and analytical tests. P values <0.05 were considered statistically significant.
RESULTS:
A total of 206 children born to 104 mothers (35.4% of those included in the original randomized controlled trial) were included in the study: 75 were exposed to vaginal progesterone 200 mg/d, 63 to vaginal progesterone 400 mg/d, and 68 to placebo. Overall, there were no significant differences in maternal sociodemographic, pregnancy and neonatal characteristics between participants and non-participants in the follow-up study, as well as between the three participating study groups. The mean scores of the 11 psychopathological syndrome scales evaluated by the Child Behavior Checklist for ages 6 to 18 questionnaire among children exposed to vaginal progesterone 200 mg/d, 400 mg/d or 200 & 400 mg/d were not significantly different to those among children exposed to placebo. There were no significant differences in the mean total Child Behavior Checklist score between the vaginal progesterone groups (31.08 ± 22.58 for the 200 mg/d group, 37.48 ± 28.59 for the 400 mg/d group, and 34.00 ± 25.60 for the 200 & 400 mg/d group) and the placebo group (34.60 ± 25.55) (P=0.38, 0.54, and 0.87, respectively). The mean percentiles of the Raven’s test were slightly higher among children exposed to vaginal progesterone 200 mg/d (63.11 ± 27.03) and 400 mg/d (60.40 ± 31.51) than among those exposed to placebo (59.40 ± 30.64) although these differences were not statistically significant (P = 0.44 and 0.85, respectively).
CONCLUSION:
Exposure to 200 or 400 mg/day of vaginal progesterone in the second half of pregnancy for preterm birth prevention, had no effect on the psychopathological and cognitive profiles of dichorionic twins at 6–9 years of age.
Keywords: behavioral outcomes, Child Behavior Checklist, childhood, cognition, cognitive development, neurodevelopment, pregnancy exposure, prematurity, preterm delivery, progesterone, progestins, progestogens, psychological development, Raven colored progressive matrices, twin pregnancy
INTRODUCTION
Compelling evidence indicates that vaginal progesterone reduces the risk of preterm birth and adverse perinatal outcomes in women with a singleton gestation and a midtrimester short cervix (≤25 mm), both with and without a history of spontaneous preterm birth.1–6 One randomized controlled trial7 and meta-analyses of individual patient data8 and aggregate data9 have reported that vaginal progesterone decreases the risk of preterm birth occurring at early gestational ages and of neonatal morbidity and mortality in twin gestations with a transvaginal sonographic short cervix (cervical length ≤25 or <30 mm). Based on this evidence, vaginal progesterone administration during the second half of pregnancy has been recommended to prevent preterm birth among women with a twin gestation and a short cervix.10–15
Progesterone plays a key role in regulating several molecular and cellular processes, such as myelination, neuroprotection, neuromodulation, learning and memory, and mood.16 It is also involved in critical developmental events, including cell differentiation and the formation of neural circuits.16 Findings from rodent models indicate that prenatal administration of progesterone decreases sexual behavior and may attenuate aggressive behavior in male offspring in adulthood,17,18 and increases aggressive behavior in female offspring.18 The prenatal exposure to 17α-hydroxyprogesterone caproate in rats has been associated with altered dopaminergic innervation of the prelimbic prefrontal cortex and impaired cognitive flexibility with increased perseveration later in life.19 In humans, it has been reported that prenatal exposure to lutocyclin, a synthetic progestogen, significantly affects sexual orientation in both males and females.20 A recent review that assessed the association between prenatal exposure to progestogens and adverse health outcomes in humans found that significant effects were reported in 12 of 24 studies measuring neurodevelopmental and behavior effects.21 However, no evidence of consistent effects was observed across studies on an outcome basis or across an individual neurological domain considered broadly (e.g., learning, memory).
Despite its extensive use, the long-term effects of prenatal exposure to vaginal progesterone on child neurodevelopment and behavior have barely been investigated. In singleton gestations, at least until 2 years of age, in utero exposure to vaginal progesterone does not have an effect on neurodevelopmental outcomes such as cognition assessed by the Denver II Developmental Screening Test,22 Bayley-III cognitive composite score,23,24 and behavioral measures.23,24 Beyond 2 years up to 6 years of age, only two follow-up studies25,26 of randomized controlled trials27,28 have evaluated the long-term effects of prenatal exposure to vaginal progesterone for preventing preterm birth on child neurodevelopment. Both studies25,26 reported no significant differences in neurodevelopmental outcomes at 4–6 years of age between twins exposed to vaginal progesterone and those exposed to placebo. A recent systematic review that evaluated the long-term effects of vaginal progesterone administration in the second and/or third trimester for preterm birth prevention on child neurodevelopment found no evidence of beneficial or harmful effects.29 However, the authors of this study concluded that there is an urgent need for follow-up studies on the potential effects of vaginal progesterone beyond early childhood.
The aim of our study was to assess the effects of prenatal administration of vaginal progesterone to prevent preterm birth on the psychopathological and cognitive profiles of dichorionic twins at 6–9 years of age.
MATERIAL AND METHODS
Study design and participants
This follow-up study evaluated the psychopathological and cognitive profiles of dichorionic diamniotic twins born to mothers who participated in a multicenter, double-blind randomized controlled trial (clinical trial registration: EudraCT 2004–004136-31) with three parallel groups (vaginal progesterone 200 and 400 mg/d, and placebo with a randomization ratio 1:1:1, administered from 20 to 34 weeks or delivery, whichever came first), for preterm birth prevention.30 In the original trial there were no significant differences in the rates of preterm birth and adverse perinatal outcomes between the three study groups.
All mothers who participated in the original randomized controlled trial30 and had at least one livebirth were invited to participate in this follow-up study. Figure shows a flowchart of the study population. In the original randomized controlled trial, 294 women were randomly assigned to receive vaginal progesterone 200 mg/d (98 women), or vaginal progesterone 400 mg/d (98 women), or placebo (98 women). A total of 190 women were not included in our follow-up study due to losses to follow-up (n = 74), refusal to participate or not responding (n =114), and neonatal death in both co-twins (n = 2). The final population for the follow-up study comprised 104 women (38 allocated to the vaginal progesterone 200 mg/d group, 32 allocated to the vaginal progesterone 400 mg/d group, and 34 allocated to the placebo group) and 206 children (two women had one perinatal death each; 75 exposed to vaginal progesterone 200 mg/d, 63 exposed to vaginal progesterone 400 mg/d, and 68 exposed to placebo).
FIGURE.
Flowchart of participants in the study.
Participating women and their children had to fill two follow-up questionnaires and they also agreed to perform a phone interview carried out by one of the authors (JA). The dichorionic twins included in this follow-up study were born between 2006 and 2008. The psychopathological evaluation of them was performed at 6–9 years of age. To assess whether this sample was representative of our whole initial series, we compared the baseline maternal and newborn characteristics between those mothers who agreed to respond (participants) and those who declined or were not available (non-participants). The protocol of this follow-up study was approved by the Hospital La Fe Ethics Committee in representation of the five participating centers. An informed consent was also signed by the parents participating in this follow-up study.
Procedures
Participant mothers, questionnaire collector, and database organizer were blinded to the intervention received in the original trial. The psychopathological and cognitive profiles of children were assessed by one trained psychiatrist using two tools: the Child Behavior Checklist for ages 6–18 (CBCL/6–18) questionnaire and the Raven’s colored progressive matrices test (RCPM) of non-verbal intelligence.
The CBCL/6–18,31 is a validated and widely used questionnaire with 112 items, filled by the parents, to assess in children and adolescents a variety of behavioral and emotional problems such as attention-deficit hyperactivity disorder, oppositional defiant disorder, conduct disorder, childhood depression, separation anxiety, childhood phobia, and a number of other childhood and adolescent issues. Responses are recorded on a Likert-type scale; higher scores indicate greater symptom severity. Similar items are grouped into syndrome scales (aggressive, anxious/depressed behavior, attention problems, rule-breaking behavior, somatic complaints, social problems, thought problems, and withdrawn/depressed). The Total CBCL score is calculated by summing the raw scores from all the syndrome scales and then converting that sum to a normalized T-score. T-scores have a mean of 50 and a standard deviation of 10. A T-score ≥64 is considered clinically significant and indicates that a child may have behavioral or emotional problems that warrant professional evaluation.31 The CBCL/6–18 has also been validated for the Spanish population.32
The RCPM, is a relatively quick, well-normed, highly reliable, and culture-free psychometric test of nonverbal reasoning abilities in children aged 5–11 years, performed directly by the children. It consists of 36 matrices divided into three sets (A, Ab, B), each comprising 12 problems increasing in complexity and difficulty. The participant is asked to complete the matrix by identifying the most appropriate solution out of six alternative options. Four distinct factors of intellectual abilities are measured by the RCPM: completion of simple continuous patterns (factor 1), completion of discrete patterns (factor 2), continuity and reconstruction of simple and complex structures (factor 3), and reasoning by analogy (factor 4). The test has been standardized and shows acceptable psychometric properties.33,34 An overall standard score was calculated and then it was converted to percentile ranks.
Outcomes
The primary outcomes were behavioral and emotional problems, and cognitive function, evaluated by the CBCL/6–18 questionnaire and the RCPM test, respectively.
Statistical analysis
Analyses were performed on an intention-to-treat basis. Univariate descriptive statistics were used to compare the characteristics and psychometric outcomes of the vaginal progesterone and the placebo groups. For outcomes of the children, within-twin pair correlation was taken into account by considering robust estimates of variance based on the generalized estimating equations method.35 We conducted a subgroup analysis aiming to discern variations in psychopathological and cognitive profiles between males and females in relation to the prenatal exposure to vaginal progesterone. Differences between groups were examined using the 2-sample Student t-test or the Mann-Whitney U test for continuous variables, and Chi-square (with Yates correction) or Fisher’s exact tests for categorical variables. The relationship between continuous variables was performed using the Pearson or the Spearman correlation coefficients (r and rs, respectively), where appropriate. P values <0.05 were considered statistically significant.
All statistical analyses were performed using SPSS version 20.0 (IBM Corp. Released 2011. Armonk, NY).
RESULTS
Baseline maternal sociodemographic and clinical characteristics of the 186 non-participant women were similar to those of the 104 participant women in the follow-up study, except for the frequency of chronic hypertension (6.7% vs 1.1% for participants and non-participants, respectively; P = 0.02) and induction of labor (19.2% vs 8.6% for participants and non-participants, respectively; P = 0.01) (Supplemental Table 1). There were no significant differences in neonatal characteristics between the participant and non-participant children in the follow-up study (Supplemental Table 2).
Table 1 shows the baseline sociodemographic and clinical characteristics of women participating in the follow-up study. There were no significant differences between the three study groups. In general, the neonatal characteristics of children who participated in the follow-up study were similar between the three study groups, except for a significantly lower gestational age at birth (35.3 ± 2.6 vs 36.5 ± 1.9 weeks; P = 0.002) and height at birth (45.1 ± 3.2 vs 46.3 ± 2.6 cm; P = 0.01) among children exposed to vaginal progesterone 200 mg/d, as compared to children exposed to placebo (Table 2).
TABLE 1.
Baseline sociodemographic and clinical characteristics of women participating in the follow-up study.
| Vaginal progesterone |
|||||
|---|---|---|---|---|---|
| Characteristic | 200 mg/d (n=38) | 400 mg/d (n=32) | Placebo (n=34) | P valuea | P valueb |
|
| |||||
| Maternal age, y | 33.9 ± 4.5 | 33.5 ± 4.2 | 33.4 ± 4.6 | 0.64 | 0.93 |
|
| |||||
| Body mass index, kg/m2 | 25.8 ± 4.5 | 26.0 ± 4.7 | 25.0 ± 3.9 | 0.42 | 0.35 |
|
| |||||
| Nulliparity | 25 (65.8) | 25 (78.1) | 27 (79.4) | 0.20 | 0.90 |
|
| |||||
| Previous preterm birth | 0 (0) | 1 (3.1) | 1 (2.9) | 0.46 | 0.97 |
|
| |||||
| Smoking during pregnancyc | 5 (13.2) | 6 (18.8) | 6 (17.6) | 0.60 | 0.91 |
|
| |||||
| Amniocentesis | 5 (13.2) | 2 (6.3) | 4 (11.8) | 0.86 | 0.45 |
|
| |||||
| Cervical length at 20 weeks of gestation, mm | 42.3 ± 6.4 | 40.8 ± 7.90 | 44.2 ± 5.7 | 0.18 | 0.05 |
|
| |||||
| Compliance, % | 81.8 ± 22.7 | 77.3 ± 32.1 | 87.5 ± 19.2 | 0.25 | 0.12 |
|
| |||||
| Tocolytic therapy use | 8 (21.1) | 7 (21.9) | 5 (14.7) | 0.49 | 0.45 |
|
| |||||
| Betamethasone use | 6 (15.8) | 5 (15.6) | 4 (11.8) | 0.62 | 0.65 |
|
| |||||
| Chronic hypertension | 5 (13.2) | 1 (3.1) | 1 (2.9) | 0.16 | 0.97 |
|
| |||||
| Gestational diabetes | 1 (2.6) | 3 (9.4) | 1 (2.9) | 0.94 | 0.30 |
|
| |||||
| Preterm PROM | 2 (5.3) | 1 (3.1) | 1 (2.9) | 0.63 | 0.97 |
|
| |||||
| Induction of labor | 6 (15.8) | 5 (15.6) | 9 (26.5) | 0.27 | 0.29 |
|
| |||||
| Cesarean delivery | 27 (71.1) | 18 (56.3) | 20 (58.8) | 0.29 | 0.83 |
Data presented as n (%) or mean ± SD.
PROM, premature rupture of membranes.
Comparison between vaginal progesterone 200 mg/day and placebo groups.
Comparison between vaginal progesterone 400 mg/day and placebo groups.
Women who smoked <10 cigarettes/day.
TABLE 2.
Neonatal characteristics of children participating in the follow-up study.
| Vaginal progesterone |
|||||
|---|---|---|---|---|---|
| Characteristic | 200 mg/d (n=75) | 400 mg/d (n=63) | Placebo (n=68) | P valuea | P valueb |
|
| |||||
| Gestational age at birth, weeks | 35.3 ± 2.6 | 36.2 ± 2.6 | 36.5 ± 1.9 | 0.002 | 0.45 |
|
| |||||
| Gestational age at birth <37 weeks | 25 (33.3) | 14 (22.2) | 16 (23.5) | 0.20 | 0.86 |
|
| |||||
| Gestational age at birth <34 weeks | 10 (13.3) | 3 (4.8) | 2 (2.9) | 0.05 | 0.59 |
|
| |||||
| Gestational age at birth <28 weeks | 0 | 1 (1.6) | 0 | NA | 0.47 |
|
| |||||
| Birthweight, g | 2225 ± 481 | 2426 ± 538 | 2327 ± 489 | 0.21 | 0.27 |
|
| |||||
| Height, cm | 45.1 ± 3.2 | 46.6 ± 2.8 | 46.3 ± 2.6 | 0.01 | 0.53 |
|
| |||||
| Apgar at 5 min | 9.7 ± 0.6 | 9.5 ± 0.9 | 9.7 ± 0.6 | 1.00 | 0.14 |
|
| |||||
| Umbilical artery pH | 7.3 ± 0.1 | 7.3 ± 0.1 | 7.3 ± 0.1 | 1.00 | 1.00 |
|
| |||||
| Respiratory distress syndrome | 15 (20.0) | 10 (15.9) | 6 (8.8) | 0.07 | 0.23 |
|
| |||||
| NICU admission | 13 (17.3) | 6 (9.5) | 5 (7.4) | 0.09 | 0.66 |
|
| |||||
| Mechanical ventilation | 7 (9.3) | 5 (7.9) | 1 (1.5) | 0.08 | 0.12 |
Data presented as n (%) or mean ± SD.
NA, not applicable; NICU, neonatal intensive care unit.
Comparison between vaginal progesterone 200 mg/day and placebo groups.
Comparison between vaginal progesterone 400 mg/day and placebo groups.
Table 3 depicts the psychopathological and cognitive profiles of dichorionic twins exposed in utero to vaginal progesterone 200 mg/d, 400 mg/d, or 200 & 400 mg/d and placebo at 6–9 years of age. Overall, there were no significant differences between the vaginal progesterone groups (200 mg/d, 400 mg/d or 200 & 400 mg/d) and the placebo group in the mean score of the 11 psychopathological syndrome scales evaluated in the CBCL/6–18. Moreover, the mean total CBCL score was not significantly different between the vaginal progesterone groups (31.08 ± 22.58 for the 200 mg/d group, 37.48 ± 28.59 for the 400 mg/d group, and 34.00 ± 25.60 for the 200 & 400 mg/d group) and the placebo group (34.60 ± 25.55). (P = 0.38, 0.54, and 0.87, respectively). There were no significant differences between the placebo group and the vaginal progesterone 200 mg/d and 400 mg/d groups in the proportion of children with T-scores ≥64: 11/68 (16.2%), 11/75 (14.7%), and 15/63 (23.8%), respectively (P = 0.80 and 0.28 for the comparison between the placebo group and the vaginal progesterone 200 mg/day and 400 mg/d groups, respectively). The mean percentiles of the Raven’s test were slightly higher among children exposed to vaginal progesterone (63.11 ± 27.03 and 60.40 ± 31.51 for vaginal progesterone 200 mg/d and 400 mg/d, respectively) than among those exposed to placebo (59.40 ± 30.64) although these differences were not statistically significant. (P = 0.44 and 0.85, respectively).
TABLE 3.
Psychopathological and cognitive profiles in children exposed prenatally to vaginal progesterone or placebo.
| Vaginal progesterone |
|||||||
|---|---|---|---|---|---|---|---|
| Outcome | 200 mg/d (n=75) | 400 mg/d (n=63) | 200 & 400 mg/d (n=138) | Placebo (n=68) | P valuea | P valueb | P valuec |
|
| |||||||
| Child Behavior Checklist | |||||||
|
| |||||||
| Anxiety/Depression | 4.20 ± 3.79 | 5.32 ± 4.67 | 4.71 ± 4.23 | 5.16 ± 5.35 | 0.23 | 0.85 | 0.54 |
|
| |||||||
| Isolation | 1.85 ± 3.24 | 1.94 ± 2.19 | 1.89 ± 2.80 | 2.71 ± 3.32 | 0.12 | 0.10 | 0.08 |
|
| |||||||
| Somatic complaints | 3.12 ± 3.79 | 3.51 ± 3.99 | 3.30 ± 3.87 | 4.38 ± 5.00 | 0.10 | 0.27 | 0.12 |
|
| |||||||
| Social problems | 2.05 ± 1.93 | 2.81 ± 2.65 | 2.40 ± 2.31 | 2.47 ± 2.69 | 0.29 | 0.46 | 0.85 |
|
| |||||||
| Thought problems | 1.87 ± 2.38 | 2.14 ± 2.78 | 1.99 ± 2.56 | 2.31 ± 2.40 | 0.29 | 0.65 | 0.38 |
| Attention problems | 5.80 ± 5.26 | 5.79 ± 5.06 | 5.80 ± 5.15 | 5.56 ± 4.90 | 0.78 | 0.79 | 0.74 |
|
| |||||||
| Rule breaking behavior | 3.16 ± 4.04 | 4.40 ± 5.83 | 3.72 ± 4.96 | 3.09 ± 4.24 | 0.92 | 0.14 | 0.34 |
|
| |||||||
| Aggressive behavior | 5.08 ± 5.25 | 7.00 ± 7.51 | 5.96 ± 6.43 | 5.00 ± 5.14 | 0.93 | 0.08 | 0.25 |
|
| |||||||
| Sexual problems | 1.62 ± 2.35 | 2.51 ± 2.64 | 2.02 ± 2.52 | 1.69 ± 2.31 | 0.86 | 0.06 | 0.35 |
|
| |||||||
| Internalizing problems | 9.17 ± 9.56 | 10.76 ± 9.90 | 9.90 ± 9.71 | 12.25 ± 12.44 | 0.10 | 0.42 | 0.17 |
|
| |||||||
| Externalizing problems | 8.24 ± 9.02 | 11.43 ± 12.86 | 9.70 ± 11.01 | 7.79 ± 8.22 | 0.75 | 0.05 | 0.16 |
|
| |||||||
| Total CBCL score | 31.08 ± 22.58 | 37.48 ± 28.59 | 34.00 ± 25.60 | 34.60 ± 25.55 | 0.38 | 0.54 | 0.87 |
|
| |||||||
| Raven, percentile | 63.11 ± 27.03 | 60.40 ± 31.51 | 61.86 ± 29.10 | 59.40 ± 30.64 | 0.44 | 0.85 | 0.58 |
Data presented as mean ± SD.
CBCL, child behavior checklist.
Comparison between vaginal progesterone 200 mg/day and placebo groups.
Comparison between vaginal progesterone 400 mg/day and placebo groups.
Comparison between vaginal progesterone (200 & 400 mg/d) and placebo groups.
The mean scores for the 11 psychopathological syndrome scales, mean total CBCL score, and the mean percentile of the Raven’s test did not significantly differ between the vaginal progesterone (200 & 400 mg/d) and the placebo groups in both males and females (Table 4)
TABLE 4.
Psychopathological and cognitive profiles in children exposed prenatally to vaginal progesterone or placebo according to gender.
| Male |
Female |
|||||
|---|---|---|---|---|---|---|
| Outcome | Vaginal progesterone 200 & 400 mg/d (n=71) | Placebo (n=25) | P value | Vaginal progesterone 200 & 400 mg/d (n=67) | Placebo (n=43) | P value |
|
| ||||||
| Child Behavior Checklist | ||||||
|
| ||||||
| Anxiety/Depression | 4.59 ± 3.72 | 3.24 ± 3.13 | 0.08 | 4.84 ± 4.74 | 6.28 ± 6.05 | 0.19 |
|
| ||||||
| Isolation | 1.63 ± 1.95 | 1.92 ± 2.02 | 0.53 | 2.16 ± 3.48 | 3.16 ± 3.84 | 0.17 |
|
| ||||||
| Somatic complaints | 2.93 ± 3.35 | 3.56 ± 4.10 | 0.49 | 3.69 ± 4.35 | 4.86 ± 5.45 | 0.24 |
|
| ||||||
| Social problems | 2.48 ± 2.14 | 1.96 ± 2.15 | 0.30 | 2.31 ± 2.49 | 2.77 ± 2.94 | 0.40 |
|
| ||||||
| Thought problems | 2.01 ± 2.13 | 1.72 ± 1.72 | 0.50 | 1.97 ± 2.97 | 2.65 ± 2.67 | 0.21 |
|
| ||||||
| Attention problems | 6.30 ± 5.34 | 5.76 ± 4.24 | 0.61 | 5.27 ± 4.94 | 5.44 ± 5.29 | 0.87 |
|
| ||||||
| Rule breaking behavior | 5.00 ± 6.01 | 5.52 ± 5.97 | 0.71 | 2.37 ± 3.01 | 1.67 ± 1.64 | 0.12 |
|
| ||||||
| Aggressive behavior | 7.93 ± 7.53 | 7.4 ± 6.76 | 0.74 | 3.87 ± 4.12 | 3.60 ± 2.67 | 0.68 |
|
| ||||||
| Sexual problems | 2.39 ± 2.78 | 2.29 ± 2.60 | 0.87 | 1.64 ± 1.17 | 1.34 ± 2.08 | 0.39 |
|
| ||||||
| Internalizing problems | 9.15 ± 7.57 | 8.72 ± 8.31 | 0.82 | 10.69 ± 11.57 | 14.30 ± 13.98 | 0.16 |
|
| ||||||
| Externalizing problems | 12.93 ± 13.11 | 12.12 ± 11.23 | 0.77 | 6.27 ± 6.80 | 5.28 ± 4.27 | 0.35 |
|
| ||||||
| Total CBCL score | 37.13 ± 26.29 | 35.32 ± 26.96 | 0.77 | 30.69 ± 24.62 | 34.19 ± 25.01 | 0.47 |
|
| ||||||
| Raven, percentile | 59.30 ± 29.86 | 62.29 ± 31.96 | 0.68 | 64.62 ± 28.22 | 57.79 ± 30.14 | 0.23 |
Data presented as mean ± SD.
CBCL, child behavior checklist
A dose-response relationship could not be established using the coefficient of correlation rs after classifying the 11 psychopathological syndrome scales evaluated according to the daily dose of vaginal progesterone received (0 mg, 200 mg, and 400 mg) (P >0.05 for all psychopathological syndrome scales evaluated). A similar result was obtained when analyzing the Raven’s test according to the daily dose of vaginal progesterone received (rs = 0.026, P >0.05). Finally, no significant differences were found between the study groups in the proportion of children with high or low Raven scores (≥90th percentile, which corresponds to scores ≥20, ≥20, and ≥23 for the placebo and vaginal progesterone 200 mg/d and 400 mg/d groups, respectively; and ≤10th percentile, which corresponds to scores ≤9, ≤6 and ≤9 for the placebo and vaginal progesterone 200 mg/d and 400 mg/d groups, respectively).
COMMENT
Principal findings
The most important finding of this follow-up study was that prenatal exposure to vaginal progesterone (200 or 400 mg/day) for preventing preterm birth was not associated to any harmful psychopathological effect or alteration of the cognitive development in dichorionic twins at 6–9 years of age. The effects of the prenatal exposure to vaginal progesterone on psychopathological and cognitive profiles did not differ between male and female children. This finding reassures the safety of vaginal progesterone administration to prevent preterm birth on the neurodevelopment of dichorionic twins at least until 9 years of age.
Results in the context of what is known
Information regarding the effects of in utero vaginal progesterone exposure on long-term neurodevelopment outcomes in twins is limited.29,36 McNamara et al25 evaluated the health and developmental outcomes of all surviving children (at 3–6 years of age) born to mothers who participated in the STOPPIT study, a double-blind, placebo-controlled trial of vaginal progesterone administered for the prevention of preterm birth in twin gestations.27 Follow-up was performed via record linkage and two parent-completed validated questionnaires, the Child Development Inventory (CDI) and the Health Utilities Index (HUI) at a mean age of 55.5 months. There were no significant differences between the vaginal progesterone and placebo groups with respect to social development (reported on the CDI), emotion and cognition (reported on the HUI). The authors concluded that exposure in utero to vaginal progesterone, given in twin gestations for the prevention of preterm birth, had no significant impact on developmental outcomes at 3–6 years of age.
Vedel et al26 assessed the neurophysiological development of twins exposed prenatally to vaginal progesterone in the PREDICT study22 by using the parent completed Ages and Stages Questionnaire (ASQ) at either 48 or 60 months of corrected age. Mean total ASQ score and gross motor skills mean score were significantly higher in the vaginal progesterone-exposed group than in the placebo-exposed group (both, P = 0.03). Overall, there was no significant difference in the proportion of children with a low ASQ score (defined as <10th percentile for the population) between the two study groups. Subgroup analyses showed that dichorionic twins that were exposed to vaginal progesterone had a higher total mean score (P = 0.01), and higher mean scores in communication (P = 0.04), gross motor skills (P = 0.02) and personal/social skills (P = 0.04) than those that were exposed to placebo. Moreover, dichorionic twins of the vaginal progesterone group had a significantly decreased risk for a low total ASQ score (odds ratio, 0.34; 95% CI, 0.14–0.86) and a low gross motor skills score (odds ratio, 0.43; 95% CI, 0.21–0.90). The findings of this study suggest that dichorionic twins exposed to vaginal progesterone in the second and third trimester of pregnancy could have a better neurophysiological outcome in preschool age and a decreased risk for a low ASQ score.
Finally, Tran et al37 performed a follow-up study in 2-year age children who were born to women with twin gestations and a cervical length <38 mm who were randomized to receive vaginal progesterone 400 mg/d or pessary.38 The mean ASQ-3 scores and the composite outcome of perinatal death or survival with any abnormal ASQ-3 did not significantly differ between the two study groups.
Clinical implications
The results of this follow-up study provide reassurance that prenatal exposure to vaginal progesterone for preventing preterm birth has no demonstrable detrimental effects on the psychopathological and cognitive profiles of dichorionic twins at 6–9 years of age. As there is some evidence that maternal vaginal progesterone administration reduces maternal inflammation-induced fetal brain injury by inhibiting specific inflammatory and oxidative pathways in both brain and placenta in a mouse model of preterm birth,39,40 a direct beneficial effect of vaginal progesterone on childhood neurodevelopment would be plausible, as reported in the follow-up study by Vedel et al.26 However, we did not find such potential beneficial effects in our study.
Research implications
Researchers who have conducted randomized controlled trials assessing vaginal progesterone to prevent preterm birth in twin gestations could perform follow-up studies to evaluate neurodevelopmental outcomes at later ages with appropriate outcome measures and a larger sample size.
Strengths and limitations
The major strengths of this study are the following: (1) for the best of our knowledge, this is the first follow-up study evaluating the psychopathological profiles of dichorionic twins exposed to prenatal administration of vaginal progesterone for preventing preterm birth, and the first one assessing their cognitive profiles beyond 6 years of age; (2) data were derived from a rigorously conducted randomized controlled trial;30 (3) this follow-up study was double-blinded in which neither the parents nor the investigator responsible for the questionnaires knew about the intervention allocation; (4) this is the only study that has evaluated the potential effects of different doses of prenatal vaginal progesterone (200 and 400 mg/day) on the psychopathological and cognitive profiles of twins;(5) the used questionnaires are widely accepted tools to investigate the children’s psychopathological and cognitive profiles and have been adequately validated, even in the Spanish population, where this study was carried out; (6) the performance of the subgroup analysis according to gender; and finally, although vaginal progesterone was administered in the second half of pregnancy for preterm birth prevention, 97% of the dichorionic twin pregnancies that were included in the original trial were conceived using assisted reproductive techniques or ovarian stimulation and most of them also received vaginal progesterone in the first trimester at higher doses. This extended period of in utero exposure to vaginal progesterone reinforces the safety of this intervention on the long-term psychopathological and cognitive profiles of dichorionic twins.
Our study has some potential limitations: First, it included only 35.4% of pregnancies included in the original randomized controlled trials. However, participants of this follow-up study were representative of the whole population included in the original randomized controlled trial as shown in Supplemental Tables 1 and 2. Second, the statistical power of our follow-up study may have been inadequate for the examined outcomes, for which a larger sample size may have yielded more robust results. Third, the CBCL/6–18 test is a parent-reported questionnaire and, although fully validated, it may be susceptible to the parental opinion of their children and might be less useful in detecting mild psychopathological problems. Finally, the potential confounding effects of the paternal age, the psychopathological profile of the parents, and their socioeconomic status on the outcome measures could not be evaluated.
Conclusion
In conclusion, exposure to 200 or 400 mg/day of vaginal progesterone during the second half of pregnancy to prevent preterm birth had no effect on the psychopathological and cognitive profiles of dichorionic twins at 6–9 years of age.
Supplementary Material
Tweetable statement:
Prenatal exposure to vaginal progesterone for the prevention of preterm birth is not associated with abnormal psychopathological and cognitive profiles in dichorionic twins at 6 to 9 years of age.
AJOG at a Glance.
Why was this study conducted?
This study was conducted to explore the effects of vaginal progesterone administration to prevent preterm birth in dichorionic twin gestations on psychopathological and cognitive profiles at 6 to 9 years of age.
Key findings
Exposure to vaginal progesterone (200 or 400 mg/day) in the second half of pregnancy for preterm birth prevention had no effect on the psychopathological and cognitive profiles of dichorionic twins at 6 to 9 years of age.
What does this study add to what is known?
This is the first study assessing the effects of prenatal exposure to vaginal progesterone for preterm birth prevention on the psychopathological and cognitive profiles of dichorionic twins beyond 6 years of age. These findings provide reassurance about the safety of vaginal progesterone administration to prevent preterm birth.
ACKNOWLEDGMENTS
We are very grateful to all the participating parents who agreed to take part in the study.
Financial support:
No external funding was provided for this study. Authors were supported by their respective institutions. Dr. Romero has contributed to this work as part of his official duties as an employee of the United States Federal Government.
GLOSSARY
- Denver II Developmental Screening Test
it is a screening instrument designed to identify developmental deficits in children ages 0–6 years. The instrument evaluates personal–social, fine motor-adaptive, language, and gross motor abilities
- Bayley Scales of Infant and Toddler Development
It is a standard series of measurements used primarily to assess the development of infants and toddlers, ages 1–42 months. The Bayley-III has three main subtests: the Cognitive Scale, the Language Scale, and the Motor Scale
- Child Behavior Checklist for ages 6–18 (CBCL/6–18)
It is a questionnaire with 112 items, filled by the parents, designed to assess behavioral and emotional problems in children and young people aged 6–18 years
- Raven’s colored progressive matrices test (RCPM)
It is a non-verbal assessment tool designed to measure analogical perception, reasoning and abstraction ability in children aged 5–11 years. This test is performed directly by the children
Footnotes
Trial registration: This trial was registered with the European Union Clinical Trials Register (EudraCT 2004–004136-31) on July 8, 2005 and the date of initial participant enrollment was on January 27, 2006.
Disclosure: The authors declare no conflicts of interest.
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Data sharing statement:
After publication, trial data will be made available on reasonable request to the corresponding author. A proposal with a detailed description of study objectives and a statistical analysis plan will be needed for assessment of requests. To gain access, requesters will need to sign an agreement form and confirm that data will be used for the purpose for which access was granted. Additional materials might also be required during the process of assessment. Deidentified participant data will be provided after approval by the chief investigator and trial management group.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
After publication, trial data will be made available on reasonable request to the corresponding author. A proposal with a detailed description of study objectives and a statistical analysis plan will be needed for assessment of requests. To gain access, requesters will need to sign an agreement form and confirm that data will be used for the purpose for which access was granted. Additional materials might also be required during the process of assessment. Deidentified participant data will be provided after approval by the chief investigator and trial management group.