Association between antenatal diagnosis of late fetal growth restriction and educational outcomes in mid-childhood: A UK prospective cohort study with long-term data linkage study

Authors:
Laurentya Olga, et al.

S1 Table. Childhood medical conditions for model adjustment.

These conditions are not linked to intrauterine development but could impact childhood educational performance and therefore were adjusted in primary analyses. This prespecified morbidity list was defined in consultation with a paediatric consultant (HW). A full year of hospital episode statistics (HES) was obtained for each child, as it is highly likely that any child with a significant excludable health condition would have at least one HES-recorded appointment within a year. Children without any HES data recorded during the time frame (1 year) are assumed to not have any of the prespecified morbidities. There may be a small number of children who were being managed entirely via the private healthcare system or not have required any hospital management at all over the course of a year; however, given the medical complexity of the prespecified conditions, this is unlikely and would only apply to a very small number of children.

https://doi.org/10.1371/journal.pmed.1004225.s004

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S3 Table. Baseline characteristics among exposure groups.

Values are median (IQR) or N (%) as appropriate. Maternal age was defined as age at recruitment. Maternal BMI was derived from weight measured at recruitment divided by the square of height (kg/m2). All other maternal characteristics were either self-reported at the 20-week gestational age visit, from examination of the clinical record, or linkage to the hospital’s electronic databases. Deprivation was quantified using the IMD 2007 based on census data from the area of the mother’s postcode. Birth weight percentiles and z scores were calculated using UK 1990 growth reference. Abbreviations: AGA, appropriate-for-gestational age; BMI, body mass index; FGR, fetal growth restriction; GA, gestational age; IMD, index of multiple deprivation; IQR, interquartile range; SGA, small-for-gestational age.

https://doi.org/10.1371/journal.pmed.1004225.s006

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S4 Table. Educational attainment aged 5–7 years by fetal growth status.

Table A. Rate of passing educational standard aged 5–7 years in all exposure groups. No/total (%) of participants of each group who failed corresponding educational assessment are displayed. *p < 0.05 and **p < 0.01 versus healthy AGA (referent) based on chi-squared test. Abbreviations: AGA, appropriate-for-gestational age; FGR, fetal growth restriction; GA, gestational age. Table B. Association between educational attainment aged 5–7 years and presence of any markers of placental dysfunction by fetal growth status. Outcome: Not achieving expected educational standard at each age/domain (as appropriate). Odds ratios (OR; for unadjusted models) or adjusted odds ratios (aOR; for adjusted models) with 95% confidence intervals are displayed with antenatal healthy AGA (Total N = 1,429) as the referent group. Markers of placental dysfunction are defined as one or more of the following: low AC growth between 20–36 weeks, high uterine artery pulsatility index at 20 weeks, high umbilical artery pulsatility index at 36 weeks, EFW <third centile, low PAPPA, sFlt-1:PlGF ratio, and high AFP. For adjusted models, covariates included in all models: maternal factors (age at pregnancy, BMI at recruitment, ethnicity, occupation, partner status, smoking history), infant factors (gestational age, sex, birth seasonality, childhood physical health), socioeconomic factors (IMD, school funding type, academic year). Abbreviations: AC, abdominal circumference; AFP, alpha-feto protein; AGA, appropriate-for-gestational age; aOR, adjusted odds ratio; CI, confidence interval; EFW, estimated fetal weight; FGR, fetal growth restriction; OR, odds ratio; PAPP-A, pregnancy-associated plasma protein-A; sFlt1:PlGF, soluble fms-like tyrosine kinase 1:placental growth factor ratio; SGA, small-for-gestational age; UMB-PI, umbilical artery pulsatility index; UT-PI, uterine artery pulsatility index.

https://doi.org/10.1371/journal.pmed.1004225.s007

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S5 Table. Associations between educational attainment aged 5–7 and markers of placental dysfunction by fetal growth status.

Table A. Association between educational attainment aged 5 and markers of placental dysfunction by fetal growth status. Outcome: Not achieving expected educational standard aged 5. Odds ratios (OR) with 95% confidence intervals are displayed with antenatal healthy AGA (N = 1,418) as the referent group. aLow AC velocity, High UT-PI, High UMB-PI, EFW <third centile, Low PAPP-A, sFlt-1:PlGF >38, High AFP; bLow AC velocity, High UT-PI, High UMB-PI, EFW <third centile; cLow PAPP-A, sFlt-1:PlGF >38, High AFP. Covariates included in fully adjusted models: maternal factors (age at pregnancy, BMI at recruitment, ethnicity, occupation, partner status, smoking history), infant factors (gestational age, sex, birth seasonality, childhood physical health), socioeconomic factors (IMD, school funding type, academic year). Abbreviations: AC, abdominal circumference; AFP, alpha-feto protein; AGA, appropriate-for-gestational-age; aOR, adjusted odds ratio; CI, confidence interval; EFW, estimated fetal weight; FGR, fetal growth restriction; NA, not applicable; PAPP-A, pregnancy-associated plasma protein-A; sFlt1:PlGF, soluble fms-like tyrosine kinase 1:placental growth factor ratio; SGA, small-for-gestational-age; UMB-PI, umbilical artery pulsatility index; UT-PI, uterine artery pulsatility index. Table B. Association between educational attainment aged 6 and markers of placental dysfunction by fetal growth status. Outcome: Not achieving expected educational standard aged 6. Odds ratios (OR) with 95% confidence intervals are displayed with antenatal healthy AGA (N = 1,399) as the referent group. aLow AC velocity, High UT-PI, High UMB-PI, EFW <third centile, Low PAPP-A, sFlt-1:PlGF >38, High AFP; bLow AC velocity, High UT-PI, High UMB-PI, EFW <third centile; cLow PAPP-A, sFlt-1:PlGF >38, High AFP. Covariates included in fully adjusted models: maternal factors (age at pregnancy, BMI at recruitment, ethnicity, occupation, partner status, smoking history), infant factors (gestational age, sex, birth seasonality, childhood physical health), socioeconomic factors (IMD, school funding type, academic year). Abbreviations: AC, abdominal circumference; AFP, alpha-feto protein; AGA, appropriate-for-gestational age; aOR, adjusted odds ratio; CI, confidence interval; EFW, estimated fetal weight; FGR, fetal growth restriction; NA, not applicable; PAPP-A, pregnancy-associated plasma protein-A; sFlt1:PlGF, soluble fms-like tyrosine kinase 1:placental growth factor ratio; SGA, small-for-gestational age; UMB-PI, umbilical artery pulsatility index; UT-PI, uterine artery pulsatility index. Table C. Association between educational attainment aged 7 (Reading domain) and markers of placental dysfunction by fetal growth status. Outcome: Not achieving expected educational standard aged 7 in Reading domain. Odds ratios (OR) with 95% confidence intervals are displayed with antenatal healthy AGA (N = 1,214) as the referent group. aLow AC velocity, High UT-PI, High UMB-PI, EFW <third centile, Low PAPP-A, sFlt-1:PlGF >38, High AFP; bLow AC velocity, High UT-PI, High UMB-PI, EFW <third centile; cLow PAPP-A, sFlt-1:PlGF >38, High AFP. Covariates included in all models: maternal factors (age at pregnancy, BMI at recruitment, ethnicity, occupation, partner status, smoking history), infant factors (GA, sex, birth seasonality, childhood physical health), socioeconomic factors (IMD, school funding type, academic year). Abbreviations: AC, abdominal circumference; AFP, alpha-feto protein; AGA, appropriate-for-gestational age; aOR, adjusted odds ratio; CI, confidence interval; EFW, estimated fetal weight; FGR, fetal growth restriction; NA, not applicable; PAPP-A, pregnancy-associated plasma protein-A; sFlt1:PlGF, soluble fms-like tyrosine kinase 1:placental growth factor ratio; SGA, small-for-gestational age; UMB-PI, umbilical artery pulsatility index; UT-PI, uterine artery pulsatility index. Table D. Association between educational attainment aged 7 (Writing domain) and markers of placental dysfunction by fetal growth status. Outcome: Not achieving expected educational standard aged 7 in Writing domain. Odds ratios (OR) with 95% confidence intervals are displayed with antenatal healthy AGA (N = 1,216) as the referent group. aLow AC velocity, High UT-PI, High UMB-PI, EFW <third centile, Low PAPP-A, sFlt-1:PlGF >38, High AFP; bLow AC velocity, High UT-PI, High UMB-PI, EFW <third centile; cLow PAPP-A, sFlt-1:PlGF >38, High AFP. Covariates included in all models: maternal factors (age at pregnancy, BMI at recruitment, ethnicity, occupation, partner status, smoking history), infant factors (GA, sex, birth seasonality, childhood physical health), socioeconomic factors (IMD, school funding type, academic year). Abbreviations: AC, abdominal circumference; AFP, alpha-feto protein; AGA, appropriate-for-gestational age; aOR, adjusted odds ratio; CI, confidence interval; EFW, estimated fetal weight; FGR, fetal growth restriction; NA, not applicable; PAPP-A, pregnancy-associated plasma protein-A; sFlt1:PlGF, soluble fms-like tyrosine kinase 1:placental growth factor ratio; SGA, small-for-gestational age; UMB-PI, umbilical artery pulsatility index; UT-PI, uterine artery pulsatility index. Table E. Association between educational attainment aged 7 (Mathematics domain) and markers of placental dysfunction by fetal growth status. Outcome: Not achieving expected educational standard aged 7 in Mathematics domain. Odds ratios (OR) with 95% confidence intervals are displayed with antenatal healthy AGA (N = 1,216) as the referent group. aLow AC velocity, High UT-PI, High UMB-PI, EFW <third centile, Low PAPP-A, sFlt-1:PlGF >38, High AFP; bLow AC velocity, High UT-PI, High UMB-PI, EFW <third centile; cLow PAPP-A, sFlt-1:PlGF >38, High AFP. Covariates included in all models: maternal factors (age at pregnancy, BMI at recruitment, ethnicity, occupation, partner status, smoking history), infant factors (GA, sex, birth seasonality, childhood physical health), socioeconomic factors (IMD, school funding type, academic year). Abbreviations: AC, abdominal circumference; AFP, alpha-feto protein; AGA, appropriate-for-gestational age; aOR, adjusted odds ratio; CI, confidence interval; EFW, estimated fetal weight; FGR, fetal growth restriction; NA, not applicable; PAPP-A, pregnancy-associated plasma protein-A; sFlt1:PlGF, soluble fms-like tyrosine kinase 1:placental growth factor ratio; SGA, small-for-gestational age; UMB-PI, umbilical artery pulsatility index; UT-PI, uterine artery pulsatility index. Table F. Association between educational attainment aged 7 (Science domain) and markers of placental dysfunction by fetal growth status. Outcome: Not achieving expected educational standard aged 7 in Science domain. Odds ratios (OR) with 95% confidence intervals are displayed with antenatal healthy AGA (N = 1,216) as the referent group. aLow AC velocity, High UT-PI, High UMB-PI, EFW <third centile, Low PAPP-A, sFlt-1:PlGF >38, High AFP; bLow AC velocity, High UT-PI, High UMB-PI, EFW <third centile; cLow PAPP-A, sFlt-1:PlGF >38, High AFP. Covariates included in all models: maternal factors (age at pregnancy, BMI at recruitment, ethnicity, occupation, partner status, smoking history), infant factors (GA, sex, birth seasonality, childhood physical health), socioeconomic factors (IMD, school funding type, academic year). Abbreviations: AC, abdominal circumference; AFP, alpha-feto protein; AGA, appropriate-for-gestational age; aOR, adjusted odds ratio; CI, confidence interval; EFW, estimated fetal weight; FGR, fetal growth restriction; NA, not applicable; PAPP-A, pregnancy-associated plasma protein-A; sFlt1:PlGF, soluble fms-like tyrosine kinase 1:placental growth factor ratio; SGA, small-for-gestational age; UMB-PI, umbilical artery pulsatility index; UT-PI, uterine artery pulsatility index.

https://doi.org/10.1371/journal.pmed.1004225.s008

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