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Paternal Age and Preterm Birth in Italy, 1990 to 1998

Astolfi, Paola; De Pasquale, Antonio; Zonta, Laura Attinia

doi: 10.1097/01.ede.0000197053.61176.f4
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Background: Advanced paternal age has been reported to impair pregnancy outcome. Here, we investigated the association of advanced paternal age with preterm birth by using a very large national data set.

Methods: We analyzed data from 1990 to 1998 on Italian firstborn singletons to mothers 20–24 and 25–29 years of age (n = 1,510,823). Odds ratios for overall preterm (<37 weeks’ gestation), very preterm (<32 weeks), and moderate preterm (32–36 weeks) births were evaluated through logistic regression models in paternal age classes (20–24, 25–29, 30–34, 35–39, 40–44, 45–49, 50+ years) after adjustment for confounders. Nonparametric regression models were used to fit the effect of paternal ageing on the incidence of very preterm births.

Results: Odds ratios increased with paternal age more rapidly for very preterm than for moderate preterm births; among 45- to 49-year-old fathers, odds ratios for very preterm births reached 1.91 (95% confidence interval = 1.08–3.38) and 1.72 (1.25–2.36), respectively, in 20- to 24- and 25- to 29-year-old mothers.

Conclusions: This study confirms that paternal age contributes to the risk of preterm birth. The effect is stronger on very preterm births but also influences moderate preterm births.

From the Department of Genetics and Microbiology “A. Buzzati-Traverso,” University of Pavia, Pavia, Italy.

Submitted 1 June 2005; accepted 16 August 2005.

Supported by the University of Pavia (COFIN 2003-04) and Ministero dell’Istruzione, Università e Ricerca (PRIN 2003-04).

Correspondence: Paola Astolfi, Dipartimento di Genetica e Microbiologia “A. Buzzati-Traverso,” Università di Pavia, via Ferrata 1, 27100 Pavia, Italy. E-mail: astolfi@ipvgen.unipv.it.

The tendency to postpone childbearing is a common phenomenon in Western countries. This delay has implications for the outcome of pregnancy, with some reduction in the chance of delivering a healthy child reported even among mothers in their early thirties.1–6 The effects of paternal age have been less extensively studied, although an increase in the risk has been reported for some monogenic diseases, chromosome aberrations, birth defects, complex pathologies (schizophrenia, pre-eclampsia, Alzheimer disease), and adverse pregnancy outcomes (miscarriage, stillbirth, and preterm delivery).7–11

There are contradictory results on the role of paternal age on pregnancy duration.10–14 The present investigation is based on a retrospective study of a very large Italian data set. We evaluated the effect of increasing paternal age on the risk of preterm delivery in young mothers, after adjustment for some possible confounders routinely recorded in the Italian National Vital Statistics.

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METHODS

Data come from the Italian Central Institute of Statistics and comprise all Italian births in 1990–1998 (n = 4,830,742). We analyzed this time period because the incidence of preterm births increased over the course of time, from 3.8% in 1990–1994 to 4.2% in 1995–1998. We excluded records with missing information on parental age and education (1.6%) and infants born to parents younger than 20 years of age (2.4%) because of the peculiar risk factors associated with pregnancy in teenagers.15 From the remaining sample, we excluded 105,944 multiple births (2.3%). A further selection was based on gestational age, which in Italian Vital Statistics is computed on the basis of the last menstrual period. On the basis of Gaussian mixture models fitted to birth weight by gestational age distributions, we excluded 8465 children too heavy for gestational age as likely caused by underestimates of pregnancy duration.16 Of the remaining sample, we selected firstborn children to mothers ages 20–29 years (33%). This procedure avoids distortions caused by the high recurrence risk for preterm deliveries,17 and helps to control for effects associated with advanced maternal age. The final sample size consisted of 1,510,823 birth records.

To minimize the impact of maternal ageing, the study was further stratified by maternal age (20–24 and 25–29 years). The effect of paternal age was evaluated within strata and also adjusted for maternal age in single years. Analyses were conducted using logistic regression models with, as response variables, the overall preterm births, occurring before the completion of the 37th week of gestation, and 2 subtypes of preterm births: very preterm, occurring before the 32nd week of gestation, and moderate preterm, occurring between the 32nd and 36th week.

Odds ratios (ORs, with 95% confidence intervals [CIs]) for paternal age were estimated in 7 age categories (20–24, 25–29, 30–34, 35–39, 40–44, 45–49, and 50+ years) and adjusted for maternal age, sex of the child, couple education, and birth period. Maternal and paternal education was coded as low for the compulsory school diploma and high for the secondary high school or university diploma; 4 classes (high–high, high–low, low–high, low–low) were created based on the levels of the 2 parents. The categories with the lowest crude rate of preterm births were taken as reference for OR estimates: 25–29 years for paternal age, high–high for couple education, female infant sex, and 1990–1994 period.

Interactions between paternal age and covariates were tested by fitting logistic regression models with and without each single interaction. Nonparametric regression models were used to fit the effect of paternal ageing on the incidence of very preterm births.

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RESULTS

Table 1 shows the sample sizes and the crude rates of overall preterm births, and very and moderate preterm births, by classes of paternal age and covariates. In the maternal age groups, paternal age, low education of parents, more recent period, and male sex were potential risk factors. Unadjusted preterm rates are higher among fathers older than the age of 40, with stronger effects in mothers age 20–24 years than in mothers 25–29 years.

TABLE 1

TABLE 1

The adjusted associations are reported in Table 2. ORs generally increased with paternal age, although fluctuations occured in the oldest 2 groups (45–49 and ≥50 years). The impact was stronger on very preterm births (<32 weeks) of younger (20–24 years) mothers than on moderate preterm births (32–36 weeks) or in older (25–29 years) mothers.

TABLE 2

TABLE 2

Adjustment for confounders has only a minor impact on the paternal age effect: parental education, sex of the infant, and time period are slight risk factors, and single year of maternal aging within group increases the risk only in mothers of 25–29 years. Models, including interactions, were tested, but these additional terms did not improve the fitting.

The effect of paternal age on the incidence of very preterm births was fitted using nonparametric regression models. In Figure 1, we report the trend by high–high and low–low educational levels of the couple within maternal age groups. In the low-educated couples, the trends are flat until 35 years and afterward increase roughly linearly; in the high-educated couples the patterns are U-shaped with low values in the 30- to 34-year age group. In both educational levels a more rapid increase with advancing paternal age was observed in younger mothers of 20–24 years.

FIGURE 1.

FIGURE 1.

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DISCUSSION

This study, based on Italian national data, supports a role for advanced paternal age on yet another adverse pregnancy outcome. Our previous analyses of Italian newborns (1990–1996) had suggested paternal age effects on stillbirth and overall preterm birth.8,10 In the present investigation, we found the strongest association with very preterm births (<32 weeks of gestation), in agreement with the results of Zhu and collaborators.11 We also observed a weaker association with moderate preterm births.

A limit of the investigation was the small number of covariates we were able to include in the analyses. Lifestyle, reproductive history, and management of pregnancy influence the risk of preterm delivery18–21 but, unfortunately, such information is not collected routinely in Italian birth records. We also lacked information on maternal pathologic conditions and the etiology of the preterm delivery. We assumed that maternal pathologies would be minimized through the selection of 20- to 29-year-old mothers, who have the lowest incidence of pathologies leading to subfecundity or preterm delivery. Because no information on the reproductive history of the mother was available, we limited the study to firstborn children to control, at least partially, for the genetic and behavioral factors leading the mothers to repeat preterm deliveries in consecutive pregnancies.17

The couple’s education is a surrogate of awareness in pregnancy management and lifestyle and recourse to antenatal care. Among the older (>40 years) fathers, age-dependent alterations in reproductive functions, semen quality, and fertility9 might contribute to the steeper increase in the relative risk (Table 2) and to the raising trend, reported in both the high and the low levels of the couple education (Figure 1).

A particularly high risk of very preterm birth was estimated in couples with fathers of 45–49 years and mothers of 20–24 years (Table 2). An even higher risk was reported by Zhu and collaborators11 for mothers in the same age class and fathers older than 50 years: the shifting of the critical paternal age from 45–49 to 50+ years might be the result of differences in the distributions of paternal age at first childbearing between Italian and Danish population. A wide paternal–maternal age difference might represent a risk factor for several different types of adverse conditions. In these couples, at least 2 social groups might be included: a group of “Hollywood type” mothers and highly educated old fathers and a group of “resourceless” less-educated mothers and less-educated old fathers. However, the effect of paternal age is similar in the 2 groups: in fathers 45 years or older, the ORs were 1.94 (95% CI = 0.86–4.36) for the highly educated fathers and 1.83 (0.98–3.42) for the less-educated fathers.

Although complex and multiple events contribute to a preterm delivery,18–21 advanced paternal age is a risk indicator and may play a causal role. The effect might be, at least partly, of genetic origin.22,23 Studies should be planned to discriminate between the role of new germinal mutations for increasing exposure to mutagens and environmental pollution and the unavoidable accumulation of point mutations for reduced fidelity in base pairing during DNA replication and efficiency in repair mechanisms.

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