European Journal of Obstetrics & Gynecology and Reproductive Biology 242 (2019) 178–181

European Journal of Obstetrics & Gynecology and Reproductive Biology 242 (2019) 178–181

Full length article

Impact of advanced maternal age on adverse infant outcomes: A Japanese population-based study

Shigeki Koshidaa,*, Hisatomi Arimab, Takako Fujiic, Yoshiya Itod, Takashi Murakamie, Kentaro Takahashia

a Perinatal Center, Shiga University of Medical Science, Japan b Department of Preventive Medicine & Public Health, Fukuoka University, Japan c Department of Neurosurgery, Shiga University of Medical Science, Japan d Department of Clinical Medicine, Japanese Red Cross Hokkaido College of Nursing, Japan e Department of Obstetrics and Gynecology, Shiga University of Medical Science, Japan

A R T I C L E I N F O

Article history: Received 6 June 2019 Received in revised form 12 August 2019 Accepted 21 August 2019

Keywords: Maternal age Infant outcome Small for gestational age Low birth weight Preterm births

A B S T R A C T

Objective: The number of births among women of higher age has been rapidly increasing in many countries for several decades. While recent epidemiological studies on the impact of maternal age on infant outcomes in developed countries have evaluated the outcomes of singleton infants, few population-based studies have investigated all deliveries including multiple births. Thus, we aimed to assess the impact of maternal age on adverse infant outcomes using data from all birth certificates, including multiple births, in Shiga prefecture, Japan. Study design: The data from all birth certificates in Shiga Prefecture from 2013 to 2014 (23,294 births from 23,048 mothers) were obtained. We evaluated the impact of maternal age on adverse infant outcomes, including small for gestational age (SGA), low birth weight (LBW), and preterm birth (PTB). A multivariable logistic regression analysis was performed to determine adjusted odds ratios (aORs) for infant outcomes with various maternal factors, including multiple pregnancies. Statistical analysis for trend was performed using the Jonckheere-Terpstra test. Results: The incidence rates of adverse infant outcomes began to increase at a maternal age of 30 years. A maternal age of �35 years was associated with significantly increased risks of adverse infant outcomes, including SGA (adjusted odds ratio [aOR]: 1.15, 95% confidence interval [95% CI]: 1.03–1.29), LBW (aOR: 1.29, 95% CI: 1.16–1.43), and PTB (aOR: 1.17, 95%CI: 1.04–1.33). Conclusions: The risk of adverse infant outcomes was significantly increased in women older than 35 years of age. These data would be useful for younger women to decide family-planning in advance.

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Introduction

Over the past four decades, there has been an increasing trend for women in high-income countries to delay childbearing [1–3]. This trend is due to several changes, including the pursuit-by women-of higher education and career advancement, fertility control through contraception methods, and financial problems [4,5]. There rate of delayed childbearing is remarkably high in Japan, where the average of maternal age at first birth is the 5th highest among OECD countries, after South Korea, Italy, Spain, and Switzerland [6]. While the total number of births in Japan has decreased by approximately 20% over the past 20 years, both the

* Corresponding author. E-mail address: koshida@belle.shiga-med.ac.jp (S. Koshida).

https://doi.org/10.1016/j.ejogrb.2019.08.011 0301-2115/© 2019 Elsevier B.V. All rights reserved.

number and proportion of the births from women of advanced maternal age (AMA), defined as �35 years of age, have rapidly increased for several decades; there were 118,553 (9.8%) births to women of AMA in 1996 and 278,162 (28.5%) in 2016 [7]. Thus, the evaluation of Japanese data may be useful to study the impact of AMA on perinatal issues.

AMA has been reported to be associated with various adverse perinatal outcomes, including fetal growth restriction, preterm birth (PTB), placental abruption, and preeclampsia [8]. As small for gestational age (SGA) infants, low birth weight (LBW), and PTB, are considered to be associated with a high risk of neonatal mortality and morbidity [9–11], it is important to study the impact of maternal age on infant outcomes. Recent epidemiological studies on the impact of maternal age on infant outcomes have evaluated the outcomes of singleton infants [4,12–14]; however, few population-based studies in developed countries have investigated

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Fig. 1. Outline of this survey GA, gestational age.

Table 1 Profile of the perinatal factors analyzed in this study.

Characteristics of this study n (%)

Mother n = 23,048 Maternal age at delivery (years) 31.0 � 0.03 Advanced maternal age (� 35years) 5887 [25] Gestational age at birth (weeks) 38.7 � 0.01 Parity (Multiparous/Primiparous) 12,859 (56)/10,189 (44) Plurality (Singleton/Multiple) 22,791 (99)/257 (1)

Infants (n = 23,294) Birth weight (g) 2999 � 432 Gender (male/female) 12,022 (52)/11,272 (48) Preterm birth (<37 weeks) 1451 (6.2) Low birth weight infants (<2500 g) 2217 (9.5) Multiple births 503 (2.2) Small for gestational age (BW < 10 percentile) 1725 (7.4) Data represent the mean � standard deviation or n (%). S. Koshida et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 242 (2019) 178–181 179 all deliveries, including multiple births. Accounting for approxi- mately 3% of total births in developed countries [15,16], multiple birth is associated with a higher risk of adverse infant outcomes, including PTB, LBW, and SGA, in comparison to singleton birth [17]. Enrolling all deliveries in a target region, including multiple births, is essential for the accurate assessment of the impact of maternal age. Thus, we studied the impact of maternal age, investigating all birth certificates in one prefecture of Japan, Shiga. In Shiga, there are approximately 13,000 annual births and no specific of obstetric issues. The results of a population-based study in Shiga may represent the general data of Japan, and reflect the problems associated with AMA birth throughout the world. Materials and methods Study design This population-based cross-sectional study was performed in Shiga Prefecture, Japan from 2013 to 2014. Data collection There are approximately 13,000 annual births in 30 primary obstetric clinics and 11 hospitals in Shiga Prefecture. Information from all birth certificates in Shiga prefecture between January 2013 and December 2014 was obtained with permission from the Ministry of Health, Labor and Welfare, Japan. We obtained maternal data (maternal age and gestational age [GA] at delivery, parity, and plurality), and infant data (weight and height at birth, and sex). Infant outcomes Low birth weight (LBW) was defined as a birth weight of <2500 g. Preterm birth (PTB) was defined as GA < 37 weeks. SGA was defined as birth weight below the 10th percentile of the Japanese neonatal anthropometric chart for GA at birth [18]. Population This study included 26,524 births during the 2-year study period. We excluded 3230 births from the analyses for the following reasons: birth took place outside of Shiga (n = 3009), insufficient data (n = 190), and GA � 42 weeks (n = 31). Previous studies in Japan only included singleton births [19,20]. In contrast, the present population-based study included both multiple births and singleton births. Thus, a total of 23,294 births from 23,048 mothers were included in the present study. Statistical analyses The incidence rates of the abovementioned infant outcomes were estimated by the number of outcomes divided by the total number of births in each age group. The P value for trend was estimated using the Jonckheere-Terpstra test. We also estimated impact of AMA on the incidence of adverse infant outcomes using multivariable logistic regression models, the results of which were presented as adjusted odds ratios (aOR) with 95% confidence intervals (CIs). The multivariable models included maternal age, plurality, and parity as covariates. P values of <0.05 were considered to indicate statistical significance. All statistical analyses were performed using the IBM SPSS software program, (ver.22 IBM Japan, Tokyo, Japan) (Fig. 1). Results Characteristics The characteristics of the study population are shown in Table 1. Among 23,048 mothers, the average maternal age was 31 years and the average gestational age at delivery was 38 weeks. Five thousand eight hundred eighty-seven (26%) women were classi- fied as AMA (�35 years of age at delivery). Forty-four percent of the women were primiparous and 1% of the women had multiple pregnancies. Among 23,294 infants, the average birth weight was 2999 g. The incidence rates of PTB (GA < 37 weeks) and LBW (<2500 g) were 6.2% and 9.5%, respectively. There were 503 multiple-birth infants (2.2%) and 1725 (7.4%) SGA infants. Incidence of adverse infant outcomes according to maternal age Fig.2 shows the incidence of adverse infant outcomes, including SGA, LBW, and PTB, according to the maternal age. The incidence of these outcomes gradually increased according to the maternal age with a rapid increase from 30 to 35 years. The incidence rates of each outcome in women of 30–34 years of age, 35–39 years of age, and �40 years of age, were as follows: SGA, 7.2%, 8.0%, and 9.0%, respectively; LBW, 9.1%, 10.9%, and 13.3%; and PTB, 6.0%, 7.1%, and 8.5%. The P values for trend for SGA, LBW, and PTB were 0.01, <0.001 and <0.001, respectively. Maternal factors associated with adverse infant outcomes In comparison to women of <35 years of age, those of �35 years of age hernal age. The incidence of these outcomes gradually increased according to the maternal age with a rapid increase from 30 to 35 years. The incidence rates of each outcome in women of 30–34 years of age, 35–39 years of age, and �40 years of age, were as follows: SGA, 7.2%, 8.0%, and 9.0%, respectively; LBW, 9.1%, 10.9%, Fig. 2. Incidence of adverse infant outcomes according to maternal age Bold line, incidence of LBW; gray line, SGA; dotted line, PTB;LBW, low birth weight; SGA, small for gestational age; PTB, preterm birth. 180 S. Koshida et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 242 (2019) 178–181 and 13.3%; and PTB, 6.0%, 7.1%, and 8.5%. The P values for trend for SGA, LBW, and PTB were 0.01, <0.001 and <0.001, respectively. Maternal factors associated with adverse infant outcomes In comparison to women of <35 years of age, those of �35 years of age hernal age. The incidence of these outcomes gradually increased according to the maternal age with a rapid increase from 30 to 35 years. The incidence rates of each outcome in women of 30–34 years of age, 35–39 years of age, and �40 years of age, were as follows: SGA, 7.2%, 8.0%, and 9.0%, respectively; LBW, 9.1%, 10.9%, and 13.3%; and PTB, 6.0%, 7.1%, and 8.5%. The P values for trend for SGA, LBW, and PTB were 0.01, <0.001 and <0.001, respectively. Maternal factors associated with adverse infant outcomes In comparison to women of <35 years of age, those of �35 years of age had significantly higher risks of adverse infant outcomes, even after adjustment for plurality and parity (SGA: aOR, 1.15; 95% CI, 1.03–1.29; p = 0.013, LBW: aOR, 1.29; 95% CI, 1.16–1.43; p < 0.001, and PTB: aOR, 1.17; 95% CI, 1.04–1.33; p = 0.012) (Table 2). Comment Our analysis of all birth certificate data from a two-year period in Shiga Prefecture, Japan revealed that women of AMA had a significantly higher incidence of adverse infant outcomes, includ- ing SGA, LBW, and PTB. Additionally, we showed that a maternal age of >30 years was associated with an increased risk of adverse infant outcomes.

Table 2 Maternal factors associated with adverse infant outcomes.

Small for gestational age Low birth w

n (%) aOR (95% CI) p n (%)

Maternal age <35 1236 (72) Reference 1541 (70) �35 489 (28) 1.15 (1.03–1.29) 0.013 676 (30) Plurality Singleton 1593 (92) Reference 1851 (84) Multiple births 132 (8) 4.62 (3.77–5.68) <0.001 366 (17) Parity Primiparous 813 (47) 1.13 (1.02–1.25) 0.015 1109 (50) Multiparous 912 (53) Reference 1108 (50) The multivariable logistic regression analysis of maternal factors associated with adve aOR, adjusted odds ratio; CI, confidential interval. First, women of AMA had a significantly higher incidence of adverse neonatal outcomes. The finding that AMA was associated with adverse infant outcomes such as SGA, LBW, and PTB, was consistent with a recent meta-analysis of AMA births in many countries [8]. While previous epidemiological studies in developed countries targeted only singleton infants [4,12–14], we enrolled all deliveries, including multiple births, and evaluated the impact of maternal age by a multivariable logistic regression analysis of maternal factors, including multiple pregnancies. To our knowl- edge, this is the first current population-based study in a developed country to evaluate the impact of AMA on adverse infant outcomes, including SGA, LBW, and PTB, and include all regional deliveries including multiple births based on birth certificates. In addition, our finding was also consistent with recent Japanese population-based studies [19,20], which had limitations with respect to the target population. The study by Ogawa et al. only included data from deliveries in tertiary perinatal centers in Japan and did not include data from non-tertiary centers, such as general hospitals and primary obstetric clinics [19]. As approximately 40% of Japanese deliveries take place in primary obstetric clinics, the study potentially included a target population bias. In contrast, our study covered deliveries in all obstetric institutions in our region, primary obstetric clinics, general hospitals, and tertiary centers in our region. Another recent population-based study by Kyozuka et al. in Japan showed that higher maternal age (�30 years) at the first childbirth was associated with adverse infant outcomes, including LBW, PTB, and SGA [20]; however, the study population was limited to primiparous women whereas our study included both multiparous and primiparous women. In the present study the combination of primiparous delivery and AMA was not identified as an independent risk factor for adverse infant outcomes (data not shown). Our results indicated that, in comparison to pregnancies in younger women, AMA birth was associated with a high risk of adverse infant outcomes in both multiparous and primiparous women. Next, our finding that a maternal age of �30 years was associated with an increased risk of adverse infant outcomes, including SGA, is consistent with a previous study [20]. Although placental dysfunction is a major cause of fetal growth restriction (FGR), which is used as a proxy for SGA, the relationship between maternal aging and the placental function is not completely understood [21]. Another cause of FGR is the compromised oocyte quality in older women [22]. In addition to compromised genetic quality, some studies using mouse models have indicated that oocyte aging is associated with epigenetic changes [23,24]. One possible explanation for the increased risks of PTB and LBW at higher maternal age is a significant increase in the rate of both eight Preterm birth aOR (95% CI) p n (%) aOR (95% CI) p Reference 1014 (70) Reference 1.29 (1.16–1.43) <0.001 437 (30) 1.17 (1.04–1.33) 0.012 Reference 1180 (81) Reference 29.3 (24.0-35.9) <0.001 271 (19) 21.2 (17.6–25.5) <0.001 1.30 (1.18–1.42) <0.001 648 (45) 0.97 (0.87–1.09) 0.654 Reference 803 (55) Reference rse infant outcomes. S. Koshida et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 242 (2019) 178–181 181 elective and emergency caesarean delivery in women of >30 years of age [12]. As births certificates in Japan do not include data on the mode of delivery, we could not evaluate the association between the rate of caesarean delivery and maternal age.

We have several limitations in this study. First, we were unable to assess maternal perinatal information, such as the method of conception,which couldsignificantlyaffect infantoutcomesbecause we used data from birth certificates, which contain limited information. Some reports have indicated that conception using assisted reproductive technology (ART) is associated with a higher rate of adverse infant outcomes in comparison to pregnancies achieved without ART [5,19,25]. As older women can be expected to undergo fertility treatment (including ART) more frequently than younger women, the analysis of maternal age in our study possibly includes the influence of fertility treatments. Second, we could not evaluate neonatal medical data, such as the pH of the umbilical cord artery or Apgar score, which have a significant impact on the neuro- developmental outcomes of infants, because birth certificates lack these data. As almost all Japanese deliveries occur in obstetric clinics or hospitals in which obstetricians/pediatricians/midwives attend and routinely check their Apgar scores, it would be possible to include the Apgar score on birth certificates.

In conclusion, women of advanced maternal age have a significantly higher incidence of adverse infant outcomes, includ- ing SGA, LBW, and PTB. Our data would be useful for helping younger women determine the optimal time for child-bearing.

Funding

This study was supported by Grant-in-Aid for Scientific Research of Japan, Grant Number JP15K08803.

Author’s contribution

SK, TM, and KT conceived the idea for the study. SK, and TF performed the data collection for the original studies. HA and YI performed statistical analyses. SK wrote the first draft. All authors revised the article, and approved the final version.

Declaration of Competing Interest

The authors declare no conflicts of interest in association with the present study.

Acknowledgements

The authors thank all of the members who collected the birth certificate data: Ayako Okuda, Masae Torii, Yumiko Nakamura, Asuka Yoshioka, Keiko Isojima, Yukiko Samejima and Youko Hosomi.

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Impact of advanced maternal age on adverse infant outcomes: A Japanese population-based study
Introduction
Materials and methods
Study design
Data collection
Infant outcomes
Population
Statistical analyses
Results
Characteristics
Incidence of adverse infant outcomes according to maternal age
Maternal factors associated with adverse infant outcomes
Maternal factors associated with adverse infant outcomes
Maternal factors associated with adverse infant outcomes
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