Parental age and stillbirth: a population-based cohort of nearly 10 million California deliveries from 1991 to 2011

Purpose: Parental age at delivery in the United States has been rising. Advanced maternal and paternal ages have been associated with adverse pregnancy outcomes including stillbirth. However, these relationships come from studies that often do not present results for both mother and father concurrently. The purpose of this study was to estimate the risk of stillbirth for maternal and paternal age in the same cohort of deliveries.

Methods: This is a population-based cohort study of all live birth and stillbirth deliveries in California from 1991 to 2011. The individual associations between maternal and paternal ages and stillbirth were estimated with hazard ratios from Cox proportional hazard models. Age was modeled continuously with restricted cubic splines to account for nonlinear relationships. Mean parental age was used as the referent group.

Results: J-shaped associations between maternal and paternal ages were observed in crude models where older mothers and fathers had the highest hazard ratios for stillbirth. In maternal models, after adjusting for maternal and paternal covariates, young maternal age no longer showed increased hazard ratio for stillbirth, whereas the association with older mothers remained. In adjusted paternal models, the relationship between young paternal age and stillbirth was unchanged while the hazard ratio for older fathers was slightly smaller.

Conclusions: After adjusting for both parents’ age, education, race/ethnicity, along with parity, older mothers and fathers were independently associated with elevated hazard ratios for stillbirth.

## Introduction

Average parental ages at delivery in the United States have been rising. From 1960 to 2018, mean maternal age increased from 23.6 to 33.7 years [1,2]. Mean age at delivery for fathers has also increased from 32.4 to 35.9 years over the last four decades [3]. Both maternal and paternal ages have been associated with adverse pregnancy outcomes [4,5]. Advanced maternal age, usually defined as 40 years and older, has been associated with preterm birth (PTB), stillbirth, preeclampsia, and selected birth defects, including chromosomal anomalies [6e10]. Advanced paternal age, although less studied, has shown some association with stillbirth, low birth weight, PTB, and certain birth defects [9,11e16]. Advanced paternal age has received recent attention owing to its role in the increased occurrence of fetal de novo mutations and their potential contribution to disease risk, including PTB [17,18].

Two recent population-based cohort studies observed J-shaped associations between age and stillbirth, with one study investigating maternal age and the other paternal age [10,13]. Each study modeled age as a continuous variable and allowed for nonlinearities in the relationship with stillbirth by use of restricted cubic splines. Such analytic approaches allow the relation between outcome and exposure to possess a flexible curve [19] and remove the reliance on categorizing age into groups, for example, 5-year increments. The two studies, however, involve differing populations, British Columbia and Denmark, and neither simultaneously presented age-related risks for both mothers and fathers.

To extend the limited data in this area of potential reproductive effects of advanced age, our objective of the present study was to estimate the risk of stillbirth for maternal and paternal age, simultaneously, in a population-based cohort of approximately 10 million California births from 1991 to 2011.

## Methods

### Data

Data for this study come from the 1991-2011 California linked Birth Cohort Files. These files contain merged birth, fetal death, and infant death certificates for all vital records in California with Office of Statewide Health Planning and Development (OSHPD) maternal and infant hospital discharge data 9 months before delivery, at delivery, and up to 1 year after delivery. The linkage used to assemble the birth cohort is accurate and has been previously described [20]. This linked dataset includes information on a variety of demographics and pregnancy characteristics found on the birth certificate paired with clinical detail from the delivery hospitalization for practically all inpatient deliveries and has been described in detail elsewhere [21]. For California vital records, the definition of stillbirth is a fetal death delivered at 20 weeks or more gestation. Stanford University Institutional Review Board and the California State Committee for the Protec

### Study population

From 1991 to 2011, there were 11,559,616 deliveries in California. Inclusion criterion for the study was singleton live birth or stillbirth delivery (n ¼ 11,234,886). Included were deliveries between 20 and 45 weeks gestational age based on last menstrual period (n ¼ 10,674,900). Exclusion criteria were maternal age less than 13 or greater than 55 years or missing (0.01%) and paternal age less than 13 or greater than 70 years (0.01%) or missing (7%). After applying exclusion criteria, there were 9,931,407 deliveries included for analyses with 48,534 stillbirths (0.49%), where stillbirths are defined as in utero fetal deaths delivered at 20 or more weeks’ gestation. All variables for study were extracted from the birth or fetal death certificate. Gestational age at delivery in weeks was assessed continuously in 1-week intervals. Maternal and paternal education were categorized as some high school or less, high school diploma or equivalent, some college, college graduate or more, or missing. Maternal and paternal race/ethnicity were categorized as non-Hispanic white, non-Hispanic black, Asian, Pacific Islander, Hispanic, American Indian/Alaskan Native, Other, or missing. Parity was categorized as nulliparous, multiparous, or missing. Maternal and paternal demographics are presented in Table 1.

### Statistical analysis

A Cox proportional hazard model with gestational age in completed weeks as the underlying time was used to estimate the relative rate of stillbirth defined as the hazard ratio (HR) and 95% confidence interval (CI) for maternal and paternal age in separate models. Given the shortest gestation recognized by California was 20 weeks for a live birth and stillbirth alike, time zero is set as 19 weeks. Live birth is considered as a competing event with the chance of being born dependent on parental age. As such, the results present the cause-specific hazard for stillbirth conditional on not being born before a given gestational age. Accordingly, HRs generated by the Cox model should be interpreted as risk ratios. HRs for stillbirth, according to maternal age, were compared with the population mean maternal age, 33 years, as the referent group. Maternal age was modeled as crude, maternally adjusted (education, race/ethnicity, and parity), and maternally and paternally (age, education, and race/ethnicity) adjusted. Education, race/ethnicity, and parity were identified as potential confounders of the relationship between parental age and stillbirth. Alternatively, HRs estimated for paternal age were compared with mean paternal age, 40 years, and were modeled as crude, paternally (education and race/ethnicity) adjusted, and paternally and maternally (age, education, race/ ethnicity, and parity) adjusted. The proportional hazards assumption was evaluated using the Schoenfeld residuals, which revealed generally flat lines centered around 0 for all variables indicating their coefficients did not change appreciably over time. The cumulative incidence of stillbirth was also calculated conditional on reaching a given gestational week without being born.

Maternal and paternal ages were modeled separately using restricted cubic splines to allow for the nonlinear relationship with stillbirth. Knots were placed at the default percentiles as recommended by Harrell [22], between three and seven knots, and compared using model Akaike Information Criterion. Akaike Information Criterion values produced by each default knot placement were not substantially different. A 5-knot structure was ultimately chosen based on actual stillbirth rates by age that depicted similar inflection points (data not shown). Knots for maternal and paternal were placed at the 5th, 27.5th, 50th, 72.5th, and 95th percentiles of their distributions. For maternal age, this generated knots at ages 27, 31, 35, 39, 43, 47, 51, 55 and 58 years. Knots for paternal age were placed at 35, 41, 45, 50, 55, 59 and 63 years. In the United States, mean maternal age has risen for all birth orders, but this increase has been more pronounced for age at first birth [1]. Analysis stratified on parity was performed to determine whether the overall association between parental age and stillbirth rate was considerably altered by a previous live birth to the mother.

### Sensitivity analysis

The time variable gestational age at delivery in weeks on the California birth/fetal death certificate was updated from a last menstrual period estimate to the more accurate obstetric estimate in 2007. Three sensitivity analyses were conducted limiting to the period 2007-2011. The first sensitivity analysis, containing 2,381,183 deliveries, was a replication of the main results based on the aforementioned methods. This analysis contained two additional variables: maternal smoking during pregnancy (yes, no, and missing) and maternal prepregnancy body mass index (underweight, normal, overweight, obese I, obese II, obese III, and missing). Knot placement and referent group were based on the new age distributions, which did not vary substantially compared with 1991-2011. Next, a complete case analysis was performed where records with any missing covariate information were excluded. Lastly, a sensitivity analysis was performed on 2007-2011 data where multiple imputation was used to impute missing data for parity and parental age, education, and race/ethnicity. All dependent and independent variables used in adjusted analyses were used to impute missing values across five imputations.

All analyses were performed using SAS 9.4 (Cary, NC).

### Results

In California, the average maternal and paternal ages were 33.1 and 36.8 years, respectively, in 2011. The increase in mean age for mothers and fathers from 1991 to 2011 was roughly the same, about 1.8 years. The correlation between maternal and paternal age was 0.74. Teenage mothers were more frequent than teenage fathers (9.3% vs. 4.2%), but the frequency of fathers ages 40 years and older was greater (10.5% vs. 3%; Table 2) than that of mothers. Most deliveries were to mothers aged 25-29 years (27.4%) and fathers aged 30-34 years (25.8%). The proportion of all deliveries that were stillbirth was 0.5% (Table 1). The distribution of gestational age