Our analyses found associations with adverse neonatal outcomes for some reproductive characteristics previously considered high risk, while not for others. Nulliparous women had significant associations with adverse outcomes, but particularly when mothers were also of young age; women who were both nulliparous and age <18 consistently experienced the highest risk. Young age appeared to drive preterm risk, as seen in the statistically significantly different preterm associations comparing nulliparous women age <18 to age 18-<35. When we conducted sensitivity analyses using a lower age cut-off of 16, the associations increased in magnitude, particularly for preterm outcomes. Although the change in associations were not statistically significant, this may be driven by sample size, as we had a very low prevalence of women under age 16. Several studies have reported increased rates of preterm delivery and/or neonatal mortality among young mothers [3, 5, 39, 40]. A plausible biological explanation may be incomplete maternal physical growth and relative malnutrition, which is related to the mother’s gynecological age rather than chronological age . In a U.S. study, growing adolescents accrued more fat and more weight during their pregnancy, but their infants weighed less at birth and their mothers retained more weight postpartum . In resource-constrained settings, adolescent mothers may have an even larger nutritional burden; a study in rural Nepal observed lighter newborns and a larger loss of mid-upper arm circumference in pregnancy among adolescent mothers than their older counterparts . The association with young age may also be related to women taking two years post-menarche or longer to reach their adult stature and pelvic dimensions . We did not have data on gynecological age to explore this issue.
For age ≥35, we witnessed an increase in risk of preterm birth, but no association with SGA. The preterm association may be attributed to greater incidence of chromosomal or congenital abnormalities, or confounding by maternal morbidities such as gestational diabetes, pre-eclampsia, and hypertension, as well as chronic disease, which may be more common among older mothers [9, 44]. Previous studies link advanced maternal age to increased risk of preterm delivery and poor perinatal outcomes, with age having a dose response relationship to risk [9, 45]. There were not enough women in our data with advanced age to explore a possible dose response relationship of age beyond 35.
Our analysis yielded mixed results on the association between parity ≥3 and adverse outcomes. We saw no adverse association with SGA, and a weak association with preterm. WWhen we conducted sensitivity analyses by raising the parity cut-off to ≥5, we saw no dose response relationship, which puts into question an actual biological association between high parity and adverse newborn outcomes. This hypothesis is supported by some previous literature. A separate analysis in this supplement using DHS datasets  noted that the increased mortality risk among high parity infants was attributable mostly, if not entirely, to confounders strongly correlated with the mother having high fertility at the end of her reproductive period. A series of studies from Israel also attributed higher rates of negative outcomes to socioeconomic and environmental factors highly correlated with high parity [10, 47, 48]. Finally, several studies have reported that grand multiparous women had no increased risk in contexts where women were economically stable or had proper access to care [49–51]. In light of these findings, we believe that residual confounding, and not biological mechanisms, may fully account for the association between high parity and adverse outcomes. It is unclear why we see a slight, but significant protective association between parity ≥3 and SGA. With the parity ≥5 cut-off, the magnitude of the associations remained almost identical, although the associations lost statistical significance. The lack of change in risk with increasing parity may again hint that confounders not captured by the covariates in our data are at play.
All risk categories had a statistically significant association with neonatal mortality, with age <18 and age ≥35 appearing to be the largest drivers of mortality. Only nulliparous/age <18 and parity≥3/age 18-<35 retained statistically significant associations with infant mortality. The parity and age risks may be operating on mortality through SGA/preterm and/or confounders like socioeconomic characteristics or access to care that may not have been fully captured by the available control variables.
An increase in contraceptive prevalence has been effective in reducing high parity and advanced age births, but not in delaying maternal age at first birth. Stover and Ross report an extremely low correlation of R2=0.05 between contraceptive prevalence rate and percentage of births with mothers age <18 years . This implies the need to focus on addressing adolescent pregnancies and for innovative strategies that may be more successful in delaying age at first birth. This may mean expanding the scope of interventions beyond the health sector; for instance, some literature suggests that educational attainment delays age to first birth [53–55]. In finding effective interventions, it is also important to understand factors beyond knowledge and access that motivate reproductive decisions. For instance, survival of previous children and desired family size could be driving higher age and parity births, and depending on the circumstances, ensuring child survival may be more effective in addressing reproductive risk than family planning. Finally, there is a need to address the equity issues surrounding access to family planning. There are substantial gaps in contraceptive prevalence between women belonging to high wealth quintiles and to low wealth quintiles [56, 57]. Those who have the least access are most likely the ones who need it the most, as suggested by our concerns with residual confounding.
The strength of our analyses is the use of high quality, population-based cohort data that allows us to make better inferences of causation. We have examined how parity and maternal age together may impact outcome, rather than simply using one or the other as a control variable. We were also able to use standardized definitions for both exposures and outcomes, enhancing comparability across studies. Previous studies have used a variety of cut-offs and definitions for parity and age [3, 4, 15, 16]. Taking SGA as an example, even using the most widely accepted definition (under 10th percentile of a reference distribution), the prevalence of SGA can vary depending on which reference distribution is being used. SGA prevalence ranged from 5-72% when applying existing reference distributions to a single population sample (Joanne Katz, personal communication).
A weakness of our study is the limit of confounders available in each primary study. We controlled for the available confounders, but there still remains the possibility of residual confounding. In addition to our aforementioned discussion on high parity and residual confounding, there is also literature suggesting that controlling for socioeconomic characteristics largely attenuates the risk of adverse outcomes with young maternal age [58, 59]. Although there is strong evidence for biological mechanisms linking nulliparity to adverse outcomes, those associations may also still be partially confounded by factors like quality and/or access to health care. Birth interval is another reproductive factor that could be a confounder, but was not included in this analysis, as a majority of the studies did not have that information. A separate study in this supplement evaluates the associations between birth intervals and poor outcomes, controlling for parity and maternal age in a subset of our datasets with relevant information . Variables like survival of previous children may reflect underlying maternal health and socioeconomic conditions that are not well captured in the available variables.
Due to limitations of the data, we were not able to explore gravidity (all pregnancies), instead of parity (all live births), as the exposure. Using gravidity instead may have given us additional insight into the mechanisms linking parity and birth outcome; particularly with stillbirths and less so with miscarriages, we would expect mothers to endure similar nutritional demand during pregnancy as a live birth. Furthermore, by not taking into account miscarriages and stillbirths as outcomes, we may be underestimating the negative impact of some of the risk factors. There is existing literature that links nulliparity with stillbirth and intrapartum-related neonatal mortality [6, 61, 62]. A systematic review showed increased risk of stillbirth and perinatal death with older maternal age . In contrast, publications have produced mixed findings pertaining to the associations between high parity and stillbirth [6, 64] as well as young maternal age and stillbirth . Collecting more detailed information may help us better understand the mechanisms linking reproductive health risk factors to adverse fetal and perinatal outcomes, and support better-designed and better-timed interventions for at-risk mothers and newborns.
Although the studies included in our analyses are all population-based studies, we acknowledge that the data are not nationally representative. However, we believe that the risk associations we present here are less likely to be influenced by this, as prevalence estimates may be. Finally, we were only able to conduct sensitivity analyses of the parity ≥5 and age <16 years cut-offs on the datasets available to the primary author and with high enough prevalence in the respective categories.