Journal Club Papers
Gestational age at birth and cognitive outcomes in adolescence: population based full sibling cohort study. Husby et al. BMJ. 18 January 2023. DOI: 10.1136/bmj-2022-072779
Preterm birth has long been associated with poor long-term cognitive outcomes. However, these findings have been based on observational data and are often limited by the presence of confounding factors, especially parental educational level or household socioeconomic status. In a bid to overcome this, the authors performed a sibling analysis, where outcomes were compared between full siblings (same mother and father) born at different gestational ages. Most siblings with the same parents will be likely be raised in the same household, which corrects for other possible confounders in environmental factors growing up, and particularly socioeconomic status.
- This nationwide Danish cohort study included 792,724 sibling pairs. Of these 44,322 (5.6%) had a sibling born <37 weeks’ gestation.
- The main outcomes were mean differences in year 9 grades (ages 15 – 16) of written Danish and mathematics. Results were adjusted for sex, birthweight percentile, malformations, maternal/paternal age at delivery, maternal/paternal education level, and number of older siblings.
- Early preterm birth: Compared to children born at 40 weeks’, those born at <34 weeks’ had significantly lower mean grades in mathematics. As expected, grades decreased with increasing prematurity:
Compared to those born at 40 weeks:
- 32-33 weeks’ gestation (z score difference -0.05 [95% CI -0.08, -0.01]).
- 28-31 weeks’ gestation (z score difference -0.13 [95% CI -0.17, -0.09]).
- ≤ 27 weeks’ gestation: z score difference -0.23 [95% CI -0.32, -0.15]. Children born ≤ 27 weeks’ also had significantly lower mean grades in written language (z score difference -0.10 [95% CI -0.20, -0.01]).
However, in this analysis these findings were surprising:
- Late preterm birth (34 – 36 weeks): Compared to those children born at 40 weeks’, those born 34 – 36 weeks’ had no significant difference in written or mathematics grades.
- Term births (>37 weeks): Compared to children born at 40 weeks’, children born >41 weeks had significantly lower z scores for mathematics. No other term gestations (37, 38, 39 or >42 weeks) had significantly different cognitive outcomes compared with births at 40 weeks.
- When not accounting for shared family factors, but adjusting for all other covariates, a significant difference in both written language and mathematics grades were seen for every gestation prior to 40 weeks. This suggests that the differences in cognitive outcomes observed among children born 34-39 weeks (and reported in many prior studies) may be explained primarily by confounders removed in this sibling analysis.
An additional nested study was performed that examined results among brothers that had further intelligence testing performed at military conscription (mandated for all physically fit men in Denmark). Results were similar in this analysis with only those born <34 weeks’ having a significantly reduced IQ compared to term born siblings:
- 32-33 weeks’ gestation: 2.4 IQ point reduction (95% CI 1.1, 3.6).
- 28-31 weeks’ gestation: 3.8 IQ point reduction (95% CI 2.3, 5.3).
- ≤ 27 weeks’ gestation: 4.2 IQ point reduction (95% CI 0.8, 7.5).
In both analyses, cognitive outcomes in adolescence and early adulthood did not differ between children born ≥ 34 weeks’ gestation compared with 40 weeks’ gestation, whilst children born < 34 weeks’ gestation had significantly reduced cognitive outcomes.
This sibling analysis is the first to suggest that the deficits in cognitive outcomes observed among children born 34-39 weeks may be explained primarily by shared family factors, and not gestational age.
Maternal hypertensive disorder of pregnancy and mortality in offspring from birth to young adulthood: National population-based cohort study. Huang et al. BMJ. 19 October 2022. DOI: 10.1136/bmj-2022-072157
Hypertensive disorders of pregnancy are associated with adverse long-term health outcomes including risk of adulthood mortality in both mothers and offspring. However, there is lacking evidence examining the association of hypertensive disorders of pregnancy and earlier offspring mortality. This paper utilised a nation-wide, population-based cohort to examine the association between hypertensive disorders of pregnancy and mortality in offspring, from birth to young adulthood.
- Data were obtained from Danish national health registries. All livebirths in Denmark between 1978-2018 who survived at least one day post-birth were included (N=2,437,718). Follow-up began from the date of birth and ended with death, emigration, or on 31 December 2018, whichever came first.
- The primary outcome was all-cause mortality. Secondary outcomes were 13 specific causes of death.
During the follow-up of up to 41 years, maternal hypertensive disorders of pregnancy were associated with a 26% increased risk of all-cause mortality in offspring (HR 1.26, 95% CI 1.18-1.34).
- Assessing type of hypertensive disorder, children born to mothers with preeclampsia had a 29% increased risk of all-cause mortality [HR 1.29, 95% CI 1.20-1.38]), and for eclampsia this was 2.88-fold increased [HR 2.88, 95% CI 1.79-4.63]). The association was not as strong for hypertension alone (HR 1.12, 95% CI 0.98-1.28).
- A dose response between all-cause mortality and severity of hypertensive disorders was found: 1) Moderate preeclampsia (HR 0.90, 95% CI 0.82-0.99), 2) Severe preeclampsia (HR 2.99, 95% CI 2.66-3.37) and 3) HELLP syndrome (HR 4.79, 95% CI 3.34-6.86). Early-onset preeclampsia was also associated with a greater risk of all-cause mortality (HR 2.71, 95% CI 2.45-3.00) than late-onset preeclampsia (HR 0.80, 95% CI 0.72-0.89).
- Diabetes in addition to hypertensive disorders of pregnancy further increased the risk of all-cause mortality (HR 1.57, 95% CI 1.16-2.14).
A significant limitation of this study is that gestational age at birth was not controlled for. Although the previous study has suggested that late-preterm birth may not impact childhood outcomes, early preterm birth (<34 weeks) remains a significant risk factor for poor cognitive outcomes and lifelong mortality. It is plausible that the increased risk of mortality for children born following a pregnancy affected by hypertensive disorders may be at least partially explained by early preterm birth, specifically for those born following severe forms of disease needing early birth.
Although the impact of gestational age at birth on these findings is unclear, these findings do still highlight the need for increased surveillance among families affected by hypertensive disorders of pregnancy and the potential for targeted early intervention with surveillance and risk factor modification for both mother and child
Childhood developmental outcomes: are infants born <25th percentile an at-risk group?
Association of birthweight percentiles and early childhood development of singleton infants born from 37 weeks of gestation in Scotland: A population-based cohort study. Adanikin et al. PLOS Medicine. 11 October 2022. DOI: 10.1371/journal.pmed.1004108
Perinatal complications are more common among infants born small for gestational age. However, it is unclear whether these infants are also at risk of longer-term developmental delays as they enter childhood.
- This retrospective Scottish population-based cohort study included 295,200 singleton term born children with data of routine child health assessment at 2 – 3.5-years old.
- The primary outcomes were developmental concerns (concern vs no concern) in the domains of fine motor, gross motor, communication, and social skills.
- Results were adjusted for maternal age, BMI, year of birth, gestation at birth, sex, smoking, substance or alcohol use in pregnancy, socioeconomic status, ethnicity, pre-existing maternal disease and a history of pregnancy complications.
Term born children with a birthweight <25th percentile had an increased risk of developmental concern in early childhood compared with children with a birthweight between the 25th – 74th percentile.
- A dose response between risk of developmental concern and decreasing birthweight percentile was found:
- Children born <3rd percentile had a 37% increased risk of developmental concern (aRR 1.37, 95% CI: 1.24-1.50) compared with infants born between 25-74th percentiles. This was followed by children born between 3-9th percentiles (aRR 1.18, 95% CI: 1.13-1.25) and lastly, the 10 - 24th percentiles (aRR 1.07, 95% CI: 1.03-1.12).
- Infants born ≥75th percentile were no more likely to demonstrate developmental concern compared to those born between 25-74th percentiles.
- The authors also reported the percentage of developmental concern attributable to low birthweight and found that although children born <3rd percentile were at greater risk of developmental concern, the group with the larger attributable percentage of developmental concern were those born between 10 – 24th percentiles (0.81% vs 1.05%).
Although the authors adjusted for important maternal and pregnancy factors there was no adjustment for postpartum factors that may influence developmental outcomes such as childhood illness. Nonetheless, this paper provides new insights into childhood developmental outcomes for infants born at term below the 25th percentile. This provides an opportunity for early surveillance and intervention in this previously unrecognised at-risk group who account for a larger proportion of the at-risk population.