A possible limitation of this study is the assumption that maternal height is a good proxy for uterine size.

To minimise confounding, uterine distention was modelled by two natural phenomena: twin pregnancies and singleton fetuses with very rapid growth.

We used uncomplicated pregnancies from a large, healthy, homogeneous population depleted from risk factors associated with gestational age and adult height.

This is the first study to examine the effect of pregnancy-related uterine distention in a medical register data (ie, non-invasively).

Epidemiological studies consistently reported that maternal height (MH) is positively associated with child’s gestational age (GA) at birth, which has been replicated in different populations, ethnic groups and time periods. 5–8 Using Mendelian randomisation methods, we demonstrated that this association is likely causal. 9 Building on the causal association observed in uterine distention experiments in primates, 10 we hypothesised that birth is triggered by an interaction between uterine size and constantly increasing uterine load (UL) (fetal growth). In the current study, we test this hypothesis in humans by modelling the extreme of uterine distention in two natural ‘experiments’: twin versus singleton pregnancy and in singletons with large and small fetuses for their GA.

Preterm birth remains the leading cause of adverse outcomes of pregnancy. Globally preterm delivery (PTD) is the leading cause of childhood mortality (under five). 1 Indeed, the long-term health of the child is dependent to a great extent on the length of time spent in the mother’s womb as a fetus. Worldwide, PTD rates range from about 5% in some Northern European countries to 18% in Malawi. 2 Preterm labour is a complex phenotype thought to be triggered by several causes including microbial-induced inflammation, maternal stress, uterine distention, decidual haemorrhage and vascular diseases. 3 Complexities in the underlying pathophysiology of the PTD process have been an obstacle to identify effective biomarkers and therapeutics. 4

Methods

Study population We investigated pregnancy records in the Swedish Medical Birth Register of mothers who were born in four Nordic countries: Sweden, Norway, Denmark and Finland. Since 1973, it is compulsory for every delivery unit in Sweden to provide the data to this register. Only the first pregnancy of every mother was used, only with spontaneous onset of labour and only with live-born children. Due to the absence of indicators for spontaneous or iatrogenic onset of labour before the year 1990, only births from 1990 to 2013 were included. Deliveries initiated by elective caesarean section or starting with prelabour rupture of membranes were excluded. Further exclusions contained self-reported maternal medical conditions (diabetes, chronic hypertension, chronic kidney disease, inflammatory bowel disease, systemic lupus erythematosus), pregnancy complications reported in hospital records (placental disorders, placenta previa, early separation of placenta, antepartum haemorrhage, polyhydramnios, oligohydramnios) and estimated maternal body mass index <15 or >45 kg/m2, maternal age <18 or >45 years, higher order multiple births than twins.

Variable definitions Pregnancies with MH values <140 cm and >200 cm were removed (0.01%), as well as height values that differed by more than 10 cm from other height values of the same mother in other pregnancies (0.12%). (The latter procedure took place prior to the exclusion of higher-parity pregnancies.) GA at birth (expressed in days) was estimated by midwives or obstetricians using the second-trimester ultrasonography method and supported by estimated GA at birth reported by the delivery unit. In order to ensure the initial assumption that twin pregnancies manifest larger UL than singleton pregnancies, we required that birthweight difference of two twins would be no larger than 2 SD of mean intratwin differences in a particular 7-day window of GA (online supplementary figure 1). As a result of this filter, 174 (5.7%) twin pregnancies were removed. Supplementary file 1 [bmjopen-2018-022929-SP1.pdf] The Medical Birth Register does not collect longitudinal data about the fetal growth (ie, fetal growth curves). However, we used longitudinally derived intrauterine growth curves of healthy Scandinavian pregnancies with term deliveries derived by Marsál et al 11 in order to convert birth weight, fetal sex and GA at birth data into birthweight Z-scores that can be interpreted as being proportional to the fetal growth rate. The newborns with a Z-score larger than 1.5 in the singleton cohort were classified as large for gestational age (LGA), and newborns with a Z-score lower than −1.5 in the singleton cohort were classified as small for gestational age (SGA), online supplementary figure 2.

Data analysis We explored how UL modulates the effect of MH on child’s GA at birth. We used two models of UL: Model 1 with twin versus singleton pregnancies, and Model 2 with LGA versus SGA pregnancies (all singleton). We assumed that at the time of delivery, twins and LGA singletons manifest a larger volumetric UL than singletons and SGA singletons, respectively. In both models, we ran multiple linear regression with child’s GA at birth being dependent on continuous MH, UL categories and their interaction, where large UL was coded as ‘1’ (twins or LGA) and small UL coded as ‘0’ (singletons or SGA): GA = β 0 + β 1 ×MH + β 2 ×UL + β 3 ×MH×UL + ε A simple linear regression was preferred to more complex ones (using polynomial terms and covariates) in order to facilitate interpretability of the interaction patterns. The study population, depleted from risk factors associated with GA and height, further justified this choice. Additionally, we used logistic regression to investigate the same phenomenon in the clinical phenotype—PTD (birth occurring earlier than 259 days of gestation; standard definition). In this analysis, we used extreme dichotomous definitions of maternal stature and UL. Short stature was defined by MH <161 cm (10th percentile, rounded to integers). In Model 1, high volumetric UL was assigned to twin pregnancies, and in Model 2, high volumetric UL was assigned to singleton pregnancies with extreme fetal growth, defined by fetus having a birthweight Z-score larger than 2.75 SD. Statistical significance was reported as an interaction term p value. All statistical analyses were performed with R software for statistical computing (V.3.3.1). The analytical code can be found on github.com/PerinatalLab/MatHeight-GestAge/.