Placental Vascular Dysfunction, Fetal and Childhood Growth, and Cardiovascular Development: The Generation R Study Romy Gaillard, Eric A.P. Steegers, Henning Tiemeier, Albert Hofman and Vincent W.V. Jaddoe Circulation. 2013;128:2202-2210; originally published online October 17, 2013; doi: 10.1161/CIRCULATIONAHA.113.003881 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2013 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/content/128/20/2202
Data Supplement (unedited) at: http://circ.ahajournals.org/content/suppl/2013/10/17/CIRCULATIONAHA.113.003881.DC1.html
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation is online at: http://circ.ahajournals.org//subscriptions/
Downloaded from http://circ.ahajournals.org/ at Universitaet Duesseldorf on January 17, 2014
Epidemiology and Prevention Placental Vascular Dysfunction, Fetal and Childhood Growth, and Cardiovascular Development The Generation R Study Romy Gaillard, MSc; Eric A.P. Steegers, MD, PhD; Henning Tiemeier, MD, PhD; Albert Hofman, MD, PhD; Vincent W.V. Jaddoe, MD, PhD Background—Suboptimal fetal nutrition may influence early growth and cardiovascular development. We examined whether umbilical and uterine artery resistance indices, as measures of feto-placental and utero-placental vascular function, respectively, are associated with fetal and childhood growth and cardiovascular development. Methods and Results—This study was embedded in a population-based prospective cohort study among 6716 mothers and their children. Umbilical artery pulsatility index and uterine artery resistance index and fetal growth were measured in third trimester. Childhood growth was repeatedly assessed from birth to the age of 6 years. We measured body fat distribution, left ventricular mass, and blood pressure at the age of 6 years. Higher third trimester umbilical and uterine artery vascular resistance were associated with lower fetal length and weight growth in third trimester resulting in a smaller size at birth among boys and girls (P values < 0.05). These differences in length and weight growth became smaller from the age of 6 months onwards, but were still present at the age of 6 years. Higher third trimester umbilical artery vascular resistance, but not uterine artery vascular resistance, was associated with higher childhood body mass index, total fat mass, android/gynoid fat mass ratio, and systolic blood pressure, and with a lower left ventricular mass (P values0.80) with corresponding low coefficient of variation values (10%. Tables I–III in the online-only Data Supplement show the associations of each covariate with the outcomes of interest. All body fat distribution outcomes were additionally adjusted for child’s height, and all cardiovascular outcomes were additionally adjusted for child’s body mass index. To explore whether birth weight explained these associations, analyses were additionally adjusted for gestational-age-adjusted birth weight. We tested potential interactions between placental vascular function and sex, and between placental vascular function and birth weight for the analyses focused on childhood outcomes. Because significant interactions with sex, but not with birth weight, were present, all analyses were performed for the total group and for boys and girls separately. Missing data of covariates were imputed using multiple imputations (details given in the online-only Data Supplement). The repeated measurement analysis was performed using the Statistical Analysis System version 9.2 (SAS, Institute Inc. Cary NC), including the Proc Mixed module for unbalanced repeated measurements. All other analyses were performed using the Statistical Package of Social Sciences version 17.0 for Windows (SPSS Inc, Chicago, IL).
Results Subject Characteristics Characteristics of the participants are shown in Table 1. Table IV in the online-only Data Supplement shows fetal and childhood growth characteristics. Table V in the online-only Data Supplement shows that mothers whose children participated in follow-up measurements were more often higher educated and from European descent as compared with mothers whose children did not participate.
Placental Vascular Function and Fetal and Childhood Growth Characteristics Higher third trimester umbilical artery pulsatility index and uterine artery resistance index were associated with lower third trimester fetal length and weight growth, resulting in a smaller size at birth among boys and girls (difference in birth length and birth weight for the total group: −0.12 SDS (95% CI, −0.16 to −0.08), −0.17 SDS (95% CI, −0.20 to −0.14) per SD change in umbilical artery pulsatility index, and −0.09 SDS (95% CI, −0.14 to −0.04), −0.16 SDS (95% CI, −0.20 to −0.12) per SD change in uterine artery resistance index, respectively; Figure 2A–2D). The effect estimates for the associations of third trimester umbilical artery pulsatility index and uterine artery resistance index with childhood length and weight growth became smaller from the age of 6 months onwards among boys and girls. At the age of 6 years, higher third trimester umbilical artery pulsatility index and uterine artery resistance index were still associated with a shorter stature and lower weight among all children (difference in length and weight at the age of 6 years for the total group: −0.03 SDS (95% CI, −0.06 to 0), −0.03 SDS (95% CI, −0.06 to 0) per SD change in umbilical artery pulsatility index, and −0.06 SDS (95% CI, −0.10 to −0.02), −0.07 SDS (95% CI, −0.10 to −0.03) per SD change in uterine artery resistance index, respectively). The interaction term of third trimester umbilical artery pulsatility index with sex for weight growth was significant in the repeated measurement regression model. Among boys, higher third trimester umbilical artery pulsatility index was associated with lower childhood weight growth until the age of 6 years, whereas among girls these associations were no longer significant from the age of 3 years onwards.
Placental Vascular Function and Childhood Cardiovascular Risk Factors Table 2 shows the associations of third trimester umbilical artery vascular resistance with childhood cardiovascular outcomes at the age of 6 years, unadjusted and adjusted for gestational-age-adjusted birth weight, respectively. In the total group, we observed that, in the model unadjusted for birth weight, higher third trimester umbilical artery pulsatility index was associated with a lower childhood height and weight, but a higher total fat mass percentage and android/ gynoid fat mass ratio (differences −0.33 cm [95% CI, −0.48 to −0.18]; −0.14 kg [95% CI, −0.25 to −0.04]; 0.17% [95% CI, 0.02 to 0.31] and 0.26% [95% CI, 0.08 to 0.45] per SD change in third trimester umbilical artery pulsatility index, respectively). The associations of third trimester umbilical artery pulsatility index with childhood growth outcomes, but not body fat distribution outcomes, were largely explained by birth weight. Analysis stratified by sex, showed that a higher third trimester umbilical artery pulsatility index was associated with a higher childhood body mass index, total fat mass and android/gynoid fat mass ratio among girls (difference in body mass index, total fat mass percentage, and android/gynoid fat mass ratio: 0.08 kg/m2 (95% CI, 0.01 to 0.16), 0.25% (95% CI, 0.05 to 0.46), and 0.43% (95% CI, 0.15 to 0.71) per SD change in third trimester umbilical artery pulsatility index in the fully adjusted model, respectively).
Downloaded from http://circ.ahajournals.org/ at Universitaet Duesseldorf on January 17, 2014
Gaillard et al Placental Function and Childhood Outcomes 2205 Table 1. Maternal and Childhood Characteristics (n=6716)* Total Group
Boys
Girls
n=6716
n=3424
n=3292
Maternal Characteristics Age, mean (SD), y Height, mean (SD), cm
29.7 (5.3)
29.7 (5.3)
29.8 (5.3)
167.3 (7.4)
167.3 (7.3)
167.3 (7.5)
Prepregnancy weight, mean (SD), kg
66.1 (12.5)
66.0 (12.6)
66.2 (12.4)
Prepregnancy body mass index, mean (SD), kg/m2
23.5 (4.2)
23.5 (4.3)
23.6 (4.2)
Gestational age at intake, median (95% range), weeks
13.8 (9.8–25.5)
13.8 (9.6, 24.9)
13.7 (9.8, 26.5)
Education, n (%) Primary
676 (10.9)
341 (10.8)
335 (11.0)
Secondary
2833 (45.6)
1455 (45.8)
1378 (45.3)
Higher
2707 (43.5)
1375 (43.4)
1332 (43.7)
Dutch or European
3768 (58.6)
1904 (58.0)
1864 (59.2)
Non – European
2666 (41.4)
1381 (42.0)
1285 (40.8)
Nulliparous
3767 (56.7)
1912 (56.4)
1855 (57.0)
Multiparous
2882 (43.3)
1480 (43.6)
1402 (43.0)
Yes
3651 (72.3)
1819 (71.2)
1832 (73.5)
No
1397 (27.7)
736 (28.8)
661 (26.5)
Yes
1621 (27.3)
864 (28.6)
757 (26.0)
No
4316 (72.7)
2157 (71.4)
2159 (74.0)
Umbilical artery pulsatility index, mean (SD)
0.98 (0.17)
0.97 (0.17)
1.00 (0.17)
Uterine artery resistance index, mean (SD)
0.49 (0.08)
0.49 (0.08)
0.48 (0.08)
Gestational hypertension, n (%), Yes
228 (3.6)
123 (3.8)
105 (3.4)
Pre-eclampsia, n (%), Yes
130 (2.1)
63 (2.0)
67 (2.2)
58 (0.9)
32 (1.0)
26 (0.8)
Ethnicity, n (%)
Parity, n (%)
Folic acid supplement use, n (%)
Smoking, n (%)
Third trimester placental resistance indices
Pregnancy complications
Diabetes gravidarum, n (%), Yes Birth and Infant Characteristics Gestational age, median (95% range), weeks
40.1 (36.0–42.3)
40.1 (36.0–42.4)
40.1 (36.1–42.2)
Birth Weight, mean (SD), grams
3430 (536)
3487 (547)
3370 (518)
Breastfeeding, n (%), Yes
4670 (91.9)
2358 (91.7)
2312 (92.2)
Childhood Characteristics Age at follow up, median (95% range), y Length, mean (SD), cm
6.0 (5.6, 7.7)
6.0 (5.6, 7.8)
6.0 (5.6, 7.7)
119.1 (5.8)
119.6 (5.8)
118.7 (5.8)
23.1 (4.1)
23.3 (3.9)
23.0 (4.2)
Body mass index, mean (SD), kg/m
16.2 (1.8)
16.2 (1.7)
16.2 (1.9)
Total fat mass, mean (SD), %
24.8 (5.6)
22.6 (4.9)
27.1 (5.3)
Android/Gynoid fat mass ratio, mean (SD),%
25.1 (6.3)
24.8 (5.8)
25.4 (6.8)
Left ventricular mass, mean (SD), grams
53.4 (11.6)
55.9 (11.7)
50.7 (10.6)
Weight, mean (SD), kg 2
Systolic blood pressure, mean (SD), mm Hg
102.6 (8.1)
102.2 (7.9)
103.1 (8.4)
Diastolic blood pressure, mean (SD), mm Hg
60.6 (6.8)
60.0 (6.8)
61.3 (6.8)
*Values are means (standard deviations) or medians (95% range) or observed numbers (valid percentages). Valid percentages represent the percentage of only nonmissing cases in each category of categorical variables.
A higher third trimester umbilical artery pulsatility index was associated with a lower childhood left ventricular mass and higher systolic blood pressure among all children
(difference: -0.57 g (95% CI, −0.88 to −0.25), 0.31 mm Hg (95% CI, 0.07 to 0.55) per SD change in third trimester umbilical artery pulsatility index, respectively). These associations
Downloaded from http://circ.ahajournals.org/ at Universitaet Duesseldorf on January 17, 2014
2206 Circulation November 12, 2013
Figure 2. Associations of third trimester feto-placental vascular function and utero-placental vascular function with fetal and childhood growth characteristics. A, Umbilical artery pulsatility index and length growth.* B, Umbilical artery pulsatility index and weight growth.* C, Uterine artery resistance index and length growth.* D, Uterine artery resistance index and weight growth.* *Fetal and childhood length and weight growth in SDS per SD change in third trimester umbilical artery pulsatility index and uterine artery resistance index. Results are based on repeated measurement regression models and reflect the differences in (gestational) age-adjusted standard deviation scores (SDS) of length and weight growth per SD change in third trimester umbilical artery vascular resistance and uterine artery vascular resistance at 30 weeks and 40 weeks of gestation prenatal and at 6 months, 12 months, 24 months, 36 months, 48 months, and 72 months postnatal. All models are adjusted for gestational age at enrollment and at placental resistance index measurement, maternal age, parity, ethnicity, education, body mass index, smoking, folic acid supplementation use, and pregnancy complications. Total group analyses are additionally adjusted for child’s sex. P value for sex interaction
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/content/128/20/2202
Data Supplement (unedited) at: http://circ.ahajournals.org/content/suppl/2013/10/17/CIRCULATIONAHA.113.003881.DC1.html
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation is online at: http://circ.ahajournals.org//subscriptions/
Downloaded from http://circ.ahajournals.org/ at Universitaet Duesseldorf on January 17, 2014
Epidemiology and Prevention Placental Vascular Dysfunction, Fetal and Childhood Growth, and Cardiovascular Development The Generation R Study Romy Gaillard, MSc; Eric A.P. Steegers, MD, PhD; Henning Tiemeier, MD, PhD; Albert Hofman, MD, PhD; Vincent W.V. Jaddoe, MD, PhD Background—Suboptimal fetal nutrition may influence early growth and cardiovascular development. We examined whether umbilical and uterine artery resistance indices, as measures of feto-placental and utero-placental vascular function, respectively, are associated with fetal and childhood growth and cardiovascular development. Methods and Results—This study was embedded in a population-based prospective cohort study among 6716 mothers and their children. Umbilical artery pulsatility index and uterine artery resistance index and fetal growth were measured in third trimester. Childhood growth was repeatedly assessed from birth to the age of 6 years. We measured body fat distribution, left ventricular mass, and blood pressure at the age of 6 years. Higher third trimester umbilical and uterine artery vascular resistance were associated with lower fetal length and weight growth in third trimester resulting in a smaller size at birth among boys and girls (P values < 0.05). These differences in length and weight growth became smaller from the age of 6 months onwards, but were still present at the age of 6 years. Higher third trimester umbilical artery vascular resistance, but not uterine artery vascular resistance, was associated with higher childhood body mass index, total fat mass, android/gynoid fat mass ratio, and systolic blood pressure, and with a lower left ventricular mass (P values0.80) with corresponding low coefficient of variation values (10%. Tables I–III in the online-only Data Supplement show the associations of each covariate with the outcomes of interest. All body fat distribution outcomes were additionally adjusted for child’s height, and all cardiovascular outcomes were additionally adjusted for child’s body mass index. To explore whether birth weight explained these associations, analyses were additionally adjusted for gestational-age-adjusted birth weight. We tested potential interactions between placental vascular function and sex, and between placental vascular function and birth weight for the analyses focused on childhood outcomes. Because significant interactions with sex, but not with birth weight, were present, all analyses were performed for the total group and for boys and girls separately. Missing data of covariates were imputed using multiple imputations (details given in the online-only Data Supplement). The repeated measurement analysis was performed using the Statistical Analysis System version 9.2 (SAS, Institute Inc. Cary NC), including the Proc Mixed module for unbalanced repeated measurements. All other analyses were performed using the Statistical Package of Social Sciences version 17.0 for Windows (SPSS Inc, Chicago, IL).
Results Subject Characteristics Characteristics of the participants are shown in Table 1. Table IV in the online-only Data Supplement shows fetal and childhood growth characteristics. Table V in the online-only Data Supplement shows that mothers whose children participated in follow-up measurements were more often higher educated and from European descent as compared with mothers whose children did not participate.
Placental Vascular Function and Fetal and Childhood Growth Characteristics Higher third trimester umbilical artery pulsatility index and uterine artery resistance index were associated with lower third trimester fetal length and weight growth, resulting in a smaller size at birth among boys and girls (difference in birth length and birth weight for the total group: −0.12 SDS (95% CI, −0.16 to −0.08), −0.17 SDS (95% CI, −0.20 to −0.14) per SD change in umbilical artery pulsatility index, and −0.09 SDS (95% CI, −0.14 to −0.04), −0.16 SDS (95% CI, −0.20 to −0.12) per SD change in uterine artery resistance index, respectively; Figure 2A–2D). The effect estimates for the associations of third trimester umbilical artery pulsatility index and uterine artery resistance index with childhood length and weight growth became smaller from the age of 6 months onwards among boys and girls. At the age of 6 years, higher third trimester umbilical artery pulsatility index and uterine artery resistance index were still associated with a shorter stature and lower weight among all children (difference in length and weight at the age of 6 years for the total group: −0.03 SDS (95% CI, −0.06 to 0), −0.03 SDS (95% CI, −0.06 to 0) per SD change in umbilical artery pulsatility index, and −0.06 SDS (95% CI, −0.10 to −0.02), −0.07 SDS (95% CI, −0.10 to −0.03) per SD change in uterine artery resistance index, respectively). The interaction term of third trimester umbilical artery pulsatility index with sex for weight growth was significant in the repeated measurement regression model. Among boys, higher third trimester umbilical artery pulsatility index was associated with lower childhood weight growth until the age of 6 years, whereas among girls these associations were no longer significant from the age of 3 years onwards.
Placental Vascular Function and Childhood Cardiovascular Risk Factors Table 2 shows the associations of third trimester umbilical artery vascular resistance with childhood cardiovascular outcomes at the age of 6 years, unadjusted and adjusted for gestational-age-adjusted birth weight, respectively. In the total group, we observed that, in the model unadjusted for birth weight, higher third trimester umbilical artery pulsatility index was associated with a lower childhood height and weight, but a higher total fat mass percentage and android/ gynoid fat mass ratio (differences −0.33 cm [95% CI, −0.48 to −0.18]; −0.14 kg [95% CI, −0.25 to −0.04]; 0.17% [95% CI, 0.02 to 0.31] and 0.26% [95% CI, 0.08 to 0.45] per SD change in third trimester umbilical artery pulsatility index, respectively). The associations of third trimester umbilical artery pulsatility index with childhood growth outcomes, but not body fat distribution outcomes, were largely explained by birth weight. Analysis stratified by sex, showed that a higher third trimester umbilical artery pulsatility index was associated with a higher childhood body mass index, total fat mass and android/gynoid fat mass ratio among girls (difference in body mass index, total fat mass percentage, and android/gynoid fat mass ratio: 0.08 kg/m2 (95% CI, 0.01 to 0.16), 0.25% (95% CI, 0.05 to 0.46), and 0.43% (95% CI, 0.15 to 0.71) per SD change in third trimester umbilical artery pulsatility index in the fully adjusted model, respectively).
Downloaded from http://circ.ahajournals.org/ at Universitaet Duesseldorf on January 17, 2014
Gaillard et al Placental Function and Childhood Outcomes 2205 Table 1. Maternal and Childhood Characteristics (n=6716)* Total Group
Boys
Girls
n=6716
n=3424
n=3292
Maternal Characteristics Age, mean (SD), y Height, mean (SD), cm
29.7 (5.3)
29.7 (5.3)
29.8 (5.3)
167.3 (7.4)
167.3 (7.3)
167.3 (7.5)
Prepregnancy weight, mean (SD), kg
66.1 (12.5)
66.0 (12.6)
66.2 (12.4)
Prepregnancy body mass index, mean (SD), kg/m2
23.5 (4.2)
23.5 (4.3)
23.6 (4.2)
Gestational age at intake, median (95% range), weeks
13.8 (9.8–25.5)
13.8 (9.6, 24.9)
13.7 (9.8, 26.5)
Education, n (%) Primary
676 (10.9)
341 (10.8)
335 (11.0)
Secondary
2833 (45.6)
1455 (45.8)
1378 (45.3)
Higher
2707 (43.5)
1375 (43.4)
1332 (43.7)
Dutch or European
3768 (58.6)
1904 (58.0)
1864 (59.2)
Non – European
2666 (41.4)
1381 (42.0)
1285 (40.8)
Nulliparous
3767 (56.7)
1912 (56.4)
1855 (57.0)
Multiparous
2882 (43.3)
1480 (43.6)
1402 (43.0)
Yes
3651 (72.3)
1819 (71.2)
1832 (73.5)
No
1397 (27.7)
736 (28.8)
661 (26.5)
Yes
1621 (27.3)
864 (28.6)
757 (26.0)
No
4316 (72.7)
2157 (71.4)
2159 (74.0)
Umbilical artery pulsatility index, mean (SD)
0.98 (0.17)
0.97 (0.17)
1.00 (0.17)
Uterine artery resistance index, mean (SD)
0.49 (0.08)
0.49 (0.08)
0.48 (0.08)
Gestational hypertension, n (%), Yes
228 (3.6)
123 (3.8)
105 (3.4)
Pre-eclampsia, n (%), Yes
130 (2.1)
63 (2.0)
67 (2.2)
58 (0.9)
32 (1.0)
26 (0.8)
Ethnicity, n (%)
Parity, n (%)
Folic acid supplement use, n (%)
Smoking, n (%)
Third trimester placental resistance indices
Pregnancy complications
Diabetes gravidarum, n (%), Yes Birth and Infant Characteristics Gestational age, median (95% range), weeks
40.1 (36.0–42.3)
40.1 (36.0–42.4)
40.1 (36.1–42.2)
Birth Weight, mean (SD), grams
3430 (536)
3487 (547)
3370 (518)
Breastfeeding, n (%), Yes
4670 (91.9)
2358 (91.7)
2312 (92.2)
Childhood Characteristics Age at follow up, median (95% range), y Length, mean (SD), cm
6.0 (5.6, 7.7)
6.0 (5.6, 7.8)
6.0 (5.6, 7.7)
119.1 (5.8)
119.6 (5.8)
118.7 (5.8)
23.1 (4.1)
23.3 (3.9)
23.0 (4.2)
Body mass index, mean (SD), kg/m
16.2 (1.8)
16.2 (1.7)
16.2 (1.9)
Total fat mass, mean (SD), %
24.8 (5.6)
22.6 (4.9)
27.1 (5.3)
Android/Gynoid fat mass ratio, mean (SD),%
25.1 (6.3)
24.8 (5.8)
25.4 (6.8)
Left ventricular mass, mean (SD), grams
53.4 (11.6)
55.9 (11.7)
50.7 (10.6)
Weight, mean (SD), kg 2
Systolic blood pressure, mean (SD), mm Hg
102.6 (8.1)
102.2 (7.9)
103.1 (8.4)
Diastolic blood pressure, mean (SD), mm Hg
60.6 (6.8)
60.0 (6.8)
61.3 (6.8)
*Values are means (standard deviations) or medians (95% range) or observed numbers (valid percentages). Valid percentages represent the percentage of only nonmissing cases in each category of categorical variables.
A higher third trimester umbilical artery pulsatility index was associated with a lower childhood left ventricular mass and higher systolic blood pressure among all children
(difference: -0.57 g (95% CI, −0.88 to −0.25), 0.31 mm Hg (95% CI, 0.07 to 0.55) per SD change in third trimester umbilical artery pulsatility index, respectively). These associations
Downloaded from http://circ.ahajournals.org/ at Universitaet Duesseldorf on January 17, 2014
2206 Circulation November 12, 2013
Figure 2. Associations of third trimester feto-placental vascular function and utero-placental vascular function with fetal and childhood growth characteristics. A, Umbilical artery pulsatility index and length growth.* B, Umbilical artery pulsatility index and weight growth.* C, Uterine artery resistance index and length growth.* D, Uterine artery resistance index and weight growth.* *Fetal and childhood length and weight growth in SDS per SD change in third trimester umbilical artery pulsatility index and uterine artery resistance index. Results are based on repeated measurement regression models and reflect the differences in (gestational) age-adjusted standard deviation scores (SDS) of length and weight growth per SD change in third trimester umbilical artery vascular resistance and uterine artery vascular resistance at 30 weeks and 40 weeks of gestation prenatal and at 6 months, 12 months, 24 months, 36 months, 48 months, and 72 months postnatal. All models are adjusted for gestational age at enrollment and at placental resistance index measurement, maternal age, parity, ethnicity, education, body mass index, smoking, folic acid supplementation use, and pregnancy complications. Total group analyses are additionally adjusted for child’s sex. P value for sex interaction
