ABSTRACT
Aims
This study investigated the association between maternal age and early and late gestational diabetes mellitus (GDM).
Methods
In total, 72,270 pregnant women were included in this prospective birth cohort study. Associations between maternal age and early GDM (diagnosed at <24 gestational weeks) and late GDM (diagnosed at ≥24 gestational weeks) were evaluated using a multinomial logistic regression model with possible confounding factors. The reference category was maternal age of 30–34.9 years.
Results
Higher maternal age was associated with higher odds of early and late GDM (P‐value for trend <0.0001 and <0.0001, respectively). The adjusted odds ratios (aORs) for early GDM with maternal age of 35–39.9 years and ≥40 were 1.399 (95% confidence interval [CI]: 1.134–1.725) and 2.494 (95% CI: 1.828–3.402), respectively. The aORs for late GDM with maternal age of 35–39 years and ≥40 were 1.603 (95% CI: 1.384–1.857) and 2.276 (95% CI: 1.798–2.881), respectively.
Conclusions
Higher maternal age was associated with an increased risk of GDM regardless of when GDM was diagnosed. The association between maternal age and early GDM was similar to that between maternal age and late GDM.
Keywords: Advanced maternal age, Gestational diabetes, Insulin resistance
Higher maternal age was associated with an increased risk of GDM regardless of when GDM was diagnosed. The association between maternal age and early GDM was similar to that between maternal age and late GDM.
INTRODUCTION
Maternal age has been increasing worldwide due to various factors, such as the rising age of marriage and the development of assisted reproductive technology (ART) 1 , 2 , 3 . In particular, the proportion of women of advanced maternal age (AMA), defined as maternal age >35 years, has been increasing in high‐income countries, including Japan 4 , 5 . AMA is associated with an increased risk of several adverse perinatal complications, including miscarriage, placental abruption, hypertensive disorders of pregnancy, and preterm birth 6 , 7 , 8 .
Gestational diabetes mellitus (GDM) is a common complication of glucose intolerance during pregnancy. GDM is a risk factor for adverse perinatal complications such as preterm birth, macrosomia, large for gestational age (LGA) infants, and shoulder dystocia 9 , 10 . Furthermore, women diagnosed with GDM are at a higher risk of developing type 2 diabetes mellitus (DM) later in life 11 . Children born to mothers with GDM are more likely to develop noncommunicable diseases, including obesity, type 2 DM, impaired fasting glucose, and impaired glucose tolerance after childhood 12 , 13 .
GDM is conventionally defined at ≥24 gestational weeks (late GDM). However, in recent years, research has accumulated on the association between GDM diagnosed at <24 gestational weeks (early GDM) and adverse perinatal outcomes. Early GDM is more strongly associated with increased perinatal mortality and a higher risk of neonatal hypoglycemia than late GDM 14 . Additionally, interventions for early GDM, particularly targeting a high glycemic range, improved perinatal prognosis in a randomized controlled trial 15 .
Physiologically, glucose tolerance differs between early and late pregnancy 16 . However, data on whether the risk factors for early and late GDM are similar is limited. Moreover, no study has investigated the association between maternal age and early or late GDM. This study aimed to investigate the association between maternal age and early (diagnosed at <24 gestational weeks) and late (diagnosed at ≥24 gestational weeks) GDM.
MATERIALS AND METHODS
Study design
This study used datasets from the Japan Environment and Children's Study (JECS). JECS is an ongoing prospective nationwide birth cohort study, and its main objective is to investigate environmental factors that affect children's health and development. Pregnant women and their husbands or partners were recruited from 15 Regional Centres (Hokkaido, Miyagi, Fukushima, Chiba, Kanagawa, Koshin, Toyama, Aichi, Kyoto, Osaka, Hyogo, Tottori, Kochi, Fukuoka, South Kyushu/Okinawa) between January 2011 and March 2014. Maternal information was collected twice during pregnancy using questionnaires (MT1 and MT2) in JECS. The MT1 questionnaire was collected in the first trimester. The MT2 questionnaires were also collected in the second or third trimester. The questionnaire at 6 months after birth was also collected (C6m). In‐T1 and In‐T2, including information on drugs used during pregnancy, were obtained from interviews 17 . The JECS protocol was reviewed and approved by the Ministry of the Environment's Institutional Review Board on Epidemiological Studies and the Ethics Committees of all participating institutions. The study conformed to the provisions of the Declaration of Helsinki of 1995 (revised in Fortaleza, Brazil, October 2013). All study participants provided written informed consent. Previous studies have reported details of the JECS study design 18 , 19 . The “jecs‐ta‐20,190,930” dataset released by the Programme Office in October 2019 was used in this study. The findings and conclusions of this study are solely the responsibility of the authors and do not represent the official views of the above government.
Classification of maternal age
Maternal age, an exposure indicator, was obtained from the MT1 questionnaire. With reference to a previous study, maternal age was classified into five categories: <25, 25–29.9, 30–34.9, 35–39.9, and ≥40 years 20 . The reference category was defined as women aged 30–34.9 years because this age group accounted for the highest proportion of deliveries in Japan and the average maternal age at delivery in the JECS was 31.2 years 5 , 19 .
Definition and classification of GDM
The primary outcome of this study was the diagnosis of GDM. Information on GDM diagnosis and gestational age at diagnosis was obtained from medical records transcription collected by medical doctors, nurses/midwives, and/or Research Co‐ordinators. In Japan, a two‐step screening strategy for GDM in all pregnant women is recommended by the Japan Society of Obstetrics and Gynecology (JSOG) as follows: (i) measure casual blood glucose levels in early pregnancy (cut‐off differs by facility, but generally 95 or 100 mg/dL); (ii) pregnant women are recommended to undergo a 50‐g glucose challenge test (cut‐off is ≥140 mg/dL) or a casual blood glucose level (cut‐off is ≥100 mg/dL) except for those diagnosed with GDM or overt diabetes in pregnancy; (iii) except for those diagnosed with overt diabetes in pregnancy, pregnant women who screened positive should be administered a 75‐g OGTT. With results of the 75‐g OGTT, GDM is diagnosed if one or more of the following criteria are met, regardless of gestational weeks: fasting plasma glucose level of ≥92 mg/dL, 1‐h value of ≥180 mg/dL, and 2‐h value of ≥153 mg/dL 21 . Based on the gestational weeks in a previous study, GDM was divided into two subtypes: early (diagnosed at <24 gestational weeks) and late (diagnosed at ≥24 gestational weeks) 22 . Detailed 75‐g OGTT values were not collected in the JECS.
Data collection of other variables
Descriptions of the other variables collected in this study were shown in Supporting Information.
Statistical analysis
Continuous variables were described as mean (standard deviation [SD]) or median (interquartile range). Categorical variables were described as numbers (percentages). Using the Student's t‐test or chi‐square test, the differences in characteristics between the study participants and those excluded due to missing data were evaluated.
A multinomial logistic regression model investigated the association between maternal age and early and late GDM. In the multinomial logistic regression model, 30–34.9 years of maternal age was the reference category 23 . Model 1 was defined as the unadjusted model. Model 2 was defined as the adjusted model. Model 2 was adjusted for maternal birth weight, maternal height, pre‐pregnancy body mass index (BMI), polycystic ovarian syndrome (PCOS), history of steroid use before 12 weeks of gestation, conception method, smoking status, alcohol drinking status, blood pressure (BP) level at <20 weeks of gestation, highest maternal education level, marital status, systemic lupus erythematosus (SLE) and/or antiphospholipid antibody syndrome (APS), the history of kidney disease, the history of mental disorders, annual household income, and regions where Regional Centres exist 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 . After confirming no strong multicollinearity between the covariates in Model 2, multiple imputations using a Markov chain Monte Carlo simulation were conducted to deal with the missing data of several covariates in Model 2. Ten datasets were created, and each was analyzed using the same model. Finally, the results of these datasets are combined and reported as the results of Model 2. In models 1 and 2, a linear trend test was conducted for the association between maternal age and early and late GDM.
The gtsummary package in R (version 4.1.2) was used to summarize the maternal and neonatal characteristics of the study participants 34 , 35 . The SAS software (version 9.4; SAS Institute Inc., Cary, North Carolina, USA) was used for all statistical analyses.
Furthermore, late GDM was divided into GDM diagnosed between 24 and 32 gestational weeks and GDM diagnosed at ≥33 gestational weeks. The associations between maternal age and early GDM (diagnosed at <24 gestational weeks), GDM diagnosed at 24–32 gestational weeks, and GDM diagnosed at ≥33 gestational weeks were investigated using a multinomial logistic regression model as an additional analysis.
RESULTS
Study population
A flowchart of the subject selection process is shown in Figure 1. A total of 103,060 pregnancies participated in the JECS. Excluded participants were determined as follows: data of multiple participation in the JECS (N = 5,653); Participants who had abortion or stillbirth (N = 1,473); withdrawal of consent (N = 5,440); participants who had been censored in the survey (N = 1,110); maternal nationalities were not Japanese (N = 400); participants diagnosed with type 1 DM (N = 68); participants diagnosed with type 2 DM (N = 111); missing data on type of DM (N = 5); participants who had used insulin before 12 gestational weeks (N = 54); participants who had used oral hypoglycemic agent before 12 gestational weeks (N = 195); missing data on HbA1c (N = 9,667); participants who have had HbA1c measured at ≥24 gestational weeks (N = 1,040); missing data on gestational weeks when HbA1c was measured (N = 235); participants with HbA1c ≥6.5% at <24 gestational weeks (N = 41); missing data on maternal nationalities (N = 4,768); missing gestational week data for GDM diagnosis (N = 261) and missing data on maternal age (N = 269). Finally, 72,270 participants were eligible for the statistical analysis.
Figure 1.
Flowchart of participant selection for the study.
Characteristics of study participants
Table 1 presents the maternal and neonatal characteristics of the study participants. The proportions of women with AMA, early GDM, and late GDM were 18,047 (25.0%), 552 (0.8%), and 1,151 (1.6%), respectively. The proportions of both early GDM and late GDM cases tended to increase with maternal age. Notably, the proportion of early and late GDM in the highest maternal age category was higher than in other maternal age categories (2.1% and 3.6% of participants in the highest maternal age category developed early and late GDM, respectively). Also, Table S1 presents differences in maternal and neonatal characteristics among study participants and those that were excluded.
Table 1.
Maternal and neonatal characteristics of study participants
| Variables | All participants (N = 72,270) | Participants according to maternal age | ||||
|---|---|---|---|---|---|---|
| <25 years (N = 7189) † | 25‐29.9 years (N = 21,268) † | 30‐34.9 years (N = 25,766) † | 35‐39.9 years (N = 15,437) † | ≥40 years (N = 2610) † | ||
| Maternal birth weight, N (%) | ||||||
| <2500 g | 3385 (4.7) | 419 (5.8) | 996 (4.7) | 1150 (4.5) | 699 (4.5) | 121 (4.6) |
| 2500‐2999 g | 20,408 (28.2) | 2247 (31.3) | 6215 (29.2) | 7108 (27.6) | 4101 (26.6) | 737 (28.2) |
| 3000‐3499 g | 33,812 (46.8) | 3149 (43.8) | 9890 (46.5) | 12,290 (47.7) | 7320 (47.4) | 1163 (44.6) |
| 3500‐3999 g | 10,060 (13.9) | 838 (11.7) | 2919 (13.7) | 3634 (14.1) | 2264 (14.7) | 405 (15.5) |
| ≥4000 g | 1568 (2.2) | 119 (1.7) | 415 (2.0) | 584 (2.3) | 385 (2.5) | 65 (2.5) |
| Missing | 3037 (4.2) | 417 (5.8) | 833 (3.9) | 1000 (3.9) | 668 (4.3) | 119 (4.6) |
| Maternal height, cm | 158.1 (5.3) | 157.4 (5.3) | 158.0 (5.3) | 158.3 (5.3) | 158.5 (5.3) | 158.5 (5.4) |
| Pre‐pregnancy body weight, kg | 53.0 (8.6) | 51.6(8.5) | 52.4(8.5) | 53.1(8.5) | 54.0(8.8) | 54.8(8.7) |
| Pre‐pregnancy BMI kg/m2, N (%) | 21.2 (3.2) | 20.8 (3.1) | 21.0 (3.2) | 21.2 (3.2) | 21.5 (3.3) | 21.8 (3.3) |
| Underweight (<18.5 kg/m2) | 11,661 (16.1) | 1552 (21.6) | 3814 (17.9) | 3985 (15.5) | 2023 (13.1) | 287 (11.0) |
| Normal range (18.5‐24.9 kg/m2) | 53,285 (73.7) | 4998 (69.5) | 15,524 (73.0) | 19,152 (74.3) | 11,637 (75.4) | 1974 (75.6) |
| Overweight (25.0‐29.9 kg/m2) | 5686 (7.9) | 506 (7.0) | 1488 (7.0) | 2043 (7.9) | 1370 (8.9) | 279 (10.7) |
| Obese (≥30.0 kg/m2) | 1614 (2.2) | 132 (1.8) | 434 (2.0) | 578 (2.2) | 401 (2.6) | 69 (2.6) |
| Missing | 24 (0.0) | 1 (0.0) | 8 (0.0) | 8 (0.0) | 6 (0.0) | 1 (0.0) |
| Parity, N (%) | ||||||
| Primipara | 30,002 (41.5) | 4728 (65.8) | 10,776 (50.7) | 9023 (35.0) | 4588 (29.7) | 887 (34.0) |
| Multipara | 40,508 (56.1) | 2188 (30.4) | 9854 (46.3) | 16,191 (62.8) | 10,587 (68.6) | 1688 (64.7) |
| Missing | 1760 (2.4) | 273 (3.8) | 638 (3.0) | 552 (2.1) | 262 (1.7) | 35 (1.3) |
| Conception method, N (%) | ||||||
| Spontaneous pregnancy | 66,981 (92.7) | 7116 (99.0) | 20,398 (95.9) | 23,879 (92.7) | 13,497 (87.4) | 2091 (80.1) |
| Non‐ART | 2734 (3.8) | 52 (0.7) | 625 (2.9) | 1101 (4.3) | 815 (5.3) | 141 (5.4) |
| ART | 2250 (3.1) | 3 (0.0) | 161 (0.8) | 665 (2.6) | 1056 (6.8) | 365 (14.0) |
| Missing | 305 (0.4) | 18 (0.3) | 84 (0.4) | 121 (0.5) | 69 (0.4) | 13 (0.5) |
| Multiple pregnancies, N (%) | 669 (0.9) | 45 (0.6) | 186 (0.9) | 236 (0.9) | 164 (1.1) | 38 (1.5) |
| SLE and/or APS, N (%) | 172 (0.2) | 5 (0.1) | 22 (0.1) | 62 (0.2) | 65 (0.4) | 18 (0.7) |
| The history of kidney disease, N (%) | 281 (0.4) | 25 (0.3) | 72 (0.3) | 100 (0.4) | 76 (0.5) | 8 (0.3) |
| The history of mental disorders, N (%) | 5506 (7.6) | 518 (7.2) | 1589 (7.5) | 1994 (7.7) | 1198 (7.8) | 207 (7.9) |
| PCOS, N (%) | 1628 (2.3) | 87 (1.2) | 492 (2.3) | 668 (2.6) | 334 (2.2) | 47 (1.8) |
| History of steroid use before 12 weeks of gestation, N (%) | 2458 (3.4) | 169 (2.4) | 641 (3.0) | 955 (3.7) | 588 (3.8) | 105 (4.0) |
| Smoking status, N (%) | ||||||
| Never | 42,949 (59.4) | 3630 (50.5) | 12,695 (59.7) | 15,617 (60.6) | 9366 (60.7) | 1641 (62.9) |
| Previously did, but quit before realizing current pregnancy | 16,785 (23.2) | 1210 (16.8) | 4455 (20.9) | 6361 (24.7) | 4098 (26.5) | 661 (25.3) |
| Previously did, but quit after realizing current pregnancy | 9177 (12.7) | 1777 (24.7) | 3144 (14.8) | 2720 (10.6) | 1340 (8.7) | 196 (7.5) |
| Currently smoking | 2903 (4.0) | 500 (7.0) | 866 (4.1) | 907 (3.5) | 536 (3.5) | 94 (3.6) |
| Missing | 456 (0.6) | 72 (1.0) | 108 (0.5) | 161 (0.6) | 97 (0.6) | 18 (0.7) |
| Alcohol drinking status, N (%) | ||||||
| Never | 24,876 (34.4) | 2481 (34.5) | 7407 (34.8) | 9013 (35.0) | 5106 (33.1) | 869 (33.3) |
| Quit drinking before | 39,869 (55.2) | 4374 (60.8) | 12,052 (56.7) | 13,863 (53.8) | 8242 (53.4) | 1338 (51.3) |
| Continue drinking | 7245 (10.0) | 298 (4.1) | 1724 (8.1) | 2802 (10.9) | 2037 (13.2) | 384 (14.7) |
| Missing | 280 (0.4) | 36 (0.5) | 85 (0.4) | 88 (0.3) | 52 (0.3) | 19 (0.7) |
| Highest maternal education level, N (%) | ||||||
| Junior high school or high school | 24,568 (34.0) | 4724 (65.7) | 7688 (36.1) | 7081 (27.5) | 4194 (27.2) | 881 (33.8) |
| Technical college | 30,963 (42.8) | 1979 (27.5) | 9001 (42.3) | 11,580 (44.9) | 7241 (46.9) | 1162 (44.5) |
| Graduate degree (Master's/Doctorate) | 16,036 (22.2) | 372 (5.2) | 4377 (20.6) | 6863 (26.6) | 3887 (25.2) | 537 (20.6) |
| Missing | 703 (1.0) | 114 (1.6) | 202 (0.9) | 242 (0.9) | 115 (0.7) | 30 (1.1) |
| Annual household income (million, Japanese Yen), N (%) | ||||||
| <4 | 26,221 (36.3) | 4145 (57.7) | 9116 (42.9) | 8205 (31.8) | 4076 (26.4) | 679 (26.0) |
| 4‐5.99 | 22,568 (31.2) | 1353 (18.8) | 6508 (30.6) | 8815 (34.2) | 5109 (33.1) | 783 (30.0) |
| ≥6 | 18,476 (25.6) | 652 (9.1) | 4222 (19.9) | 7223 (28.0) | 5396 (35.0) | 983 (37.7) |
| Missing | 5005 (6.9) | 1039 (14.5) | 1422 (6.7) | 1523 (5.9) | 856 (5.5) | 165 (6.3) |
| Marital status, N (%) | ||||||
| Married | 68,977 (95.4) | 5836 (81.2) | 20,372 (95.8) | 25,180 (97.7) | 15,089 (97.7) | 2500 (95.8) |
| Unmarried | 2475 (3.4) | 1208 (16.8) | 686 (3.2) | 374 (1.5) | 160 (1.0) | 47 (1.8) |
| Divorced or widowed | 536 (0.7) | 51 (0.7) | 133 (0.6) | 163 (0.6) | 139 (0.9) | 50 (1.9) |
| Missing | 282 (0.4) | 94 (1.3) | 77 (0.4) | 49 (0.2) | 49 (0.3) | 13 (0.5) |
| Blood pressure level at <20 weeks of gestation, N (%) | ||||||
| Normal blood pressure | 55,703 (77.1) | 5547 (77.2) | 16,533 (77.7) | 20,016 (77.7) | 11,756 (76.2) | 1851 (70.9) |
| Prehypertension | 15,813 (21.9) | 1592 (22.1) | 4553 (21.4) | 5460 (21.2) | 3488 (22.6) | 720 (27.6) |
| Hypertension | 754 (1.0) | 50 (0.7) | 182 (0.9) | 290 (1.1) | 193 (1.3) | 39 (1.5) |
| New‐onset HDP, N (%) | ||||||
| Not HDP | 69,880 (96.7) | 6990 (97.2) | 20,727 (97.5) | 25,014 (97.1) | 14,729 (95.4) | 2420 (92.7) |
| New‐onset HDP | 1886 (2.6) | 166 (2.3) | 463 (2.2) | 585 (2.3) | 535 (3.5) | 137 (5.2) |
| Missing | 198 (0.3) | 18 (0.3) | 38 (0.2) | 79 (0.3) | 53 (0.3) | 10 (0.4) |
| GDM, N (%) | ||||||
| Early GDM | 552 (0.8) | 26 (0.4) | 102 (0.5) | 194 (0.8) | 174 (1.1) | 56 (2.1) |
| Late GDM | 1151 (1.6) | 51 (0.7) | 253 (1.2) | 378 (1.5) | 375 (2.4) | 94 (3.6) |
| Gestational weeks at delivery, weeks | 39.2 (1.6) | 39.4 (1.5) | 39.4 (1.5) | 39.2 (1.5) | 39.1 (1.7) | 38.9 (1.8) |
| Preterm birth, N (%) | 3506 (4.9) | 273 (3.8) | 909 (4.3) | 1220 (4.7) | 926 (6.0) | 178 (6.8) |
| Infant birth weight in grams | 3025 (412) | 3026 (394) | 3028 (398) | 3028 (412) | 3022 (433) | 2989 (452) |
| Regions where regional centres exist, N (%) | ||||||
| Hokkaido | 5861 (8.1) | 512 (7.1) | 1766 (8.3) | 2149 (8.3) | 1237 (8.0) | 197 (7.5) |
| Tohoku | 15,746 (21.8) | 2086 (29.0) | 5129 (24.1) | 5319 (20.6) | 2773 (18.0) | 439 (16.8) |
| Kanto | 7907 (10.9) | 640 (8.9) | 2209 (10.4) | 2908 (11.3) | 1839 (11.9) | 311 (11.9) |
| Chubu | 13,250 (18.3) | 1030 (14.3) | 3754 (17.7) | 4790 (18.6) | 3117 (20.2) | 559 (21.4) |
| Kinki | 12,414 (17.2) | 1263 (17.6) | 3371 (15.9) | 4399 (17.1) | 2891 (18.7) | 490 (18.8) |
| Chugoku | 2193 (3.0) | 185 (2.6) | 645 (3.0) | 802 (3.1) | 495 (3.2) | 66 (2.5) |
| Shikoku | 4826 (6.7) | 408 (5.7) | 1452 (6.8) | 1766 (6.9) | 1027 (6.7) | 173 (6.6) |
| Kyushu‐Okinawa | 10,073 (13.9) | 1065 (14.8) | 2942 (13.8) | 3633 (14.1) | 2058 (13.3) | 375 (14.4) |
APS, antiphospholipid antibody syndrome; ART, assisted reproductive technology; BMI, body mass index; GDM, gestational diabetes mellitus; HDP, hypertensive disorders of pregnancy; PCOS, polycystic ovarian syndrome; SD, standard deviation; SLE, systemic lupus erythematosus.
Continuous variables are expressed as means (SD). Categorical variables are expressed as n (%).
Associations of maternal age with early or late GDM
Figure 2 shows the association of maternal age with early‐ and late GDM. A higher maternal age was associated with increasing odds of early GDM in both models 1 and 2 (P‐values for the trend were <0.0001 for both models). Lower maternal age categories (<25 years and 25–29.9 years) had significantly lower odds of developing early GDM than the maternal age of 30–34.9 years. The adjusted odds ratios (ORs) were 0.535 (95% confidence interval [CI]: 0.346–0.826) for maternal age <25 years and 0.665 (95% CI: 0.520–0.851) for maternal age 25–29.9 years. Advanced maternal age (35–39.9 years and ≥40 years) had significantly higher odds of developing early GDM than maternal age of 30–34.9 years. The adjusted ORs of early GDM were 1.399 (95% CI: 1.134–1.725) for maternal age of 35–39.9 years and 2.494 (95% CI: 1.828–3.402) for maternal age of ≥40 years. The adjusted OR of early GDM for maternal age per 5 years increase was 1.549 (95% CI: 1.410–1.703).
Figure 2.
Associations between maternal age with early and late GDM. (a) Early GDM. (b) Late GDM. Model 1: Crude model. Model 2: Adjusted for maternal birth weight, maternal height, pre‐pregnancy BMI, PCOS, history of steroid use before 12 weeks of gestation, conception method, smoking history, alcohol drinking status, blood pressure level at <20 weeks of gestation, highest maternal education level, marital status, SLE and/or APS, history of kidney disease, history of mental disorders, annual income, and locations where Regional Centres exist. APS, antiphospholipid antibody syndrome ; BMI, body mass index; CI, confidence interval; GDM, gestational diabetes mellitus; MBW, maternal birth weight; NA, not applicable; OR, odds ratio; PCOS, polycystic ovarian syndrome; SLE, systemic lupus erythematosus.
The association between maternal age and late GDM was similar to that of early GDM; a linear graded association between maternal age and late GDM was found in Models 1 and 2 (P‐values for the trend were <0.0001 for both Models). Compared with the maternal age of 30–34.9 years, the adjusted ORs of late GDM were 0.453 (95% Cl: 0.332–0.617) for those aged <25 years and 0.811 (95% Cl: 0.688–0.955) for those aged 25–29.9 years. Advanced maternal age was associated with significantly higher odds of late GDM than maternal age of 30–34.9 years. The adjusted ORs of late GDM were 1.603 (95% Cl: 1.384–1.857) for maternal age of 35–39.9 years and 2.276 (95% Cl: 1.798–2.881) for those of ≥40 years. The adjusted OR of late GDM for maternal age per 5 years increase was 1.519 (95% CI: 1.423–1.621).
Associations of maternal age with early GDM (diagnosed at <24 gestational weeks), GDM diagnosed at 24–32 gestational weeks, and GDM diagnosed at ≥33 gestational weeks.
Details of the associations between maternal age and early GDM (diagnosed at <24 gestational weeks), GDM diagnosed at 24–32 gestational weeks, and GDM diagnosed at ≥33 gestational weeks are shown in Figure S1. Briefly, higher maternal age was associated with higher odds of early GDM, GDM diagnosed at 24–32 gestational weeks, and GDM diagnosed at ≥33 gestational weeks (P‐values for trend were <0.0001, <0.0001, and 0.0005 in model 2).
Associations of maternal age with early GDM (diagnosed at <24 gestational weeks), GDM diagnosed at 24–32 gestational weeks, and GDM diagnosed at ≥33 gestational weeks.
DISCUSSION
This study is the first report to indicate the association between maternal age and GDM, classified into early and late GDM, based on the gestational age at GDM diagnosis. Higher maternal age was associated with an increased risk of developing both early and late GDM. In addition, the association between maternal age and early GDM was similar to those with late GDM.
The association between maternal age and GDM in this study was consistent with previous studies, which showed that GDM diagnosed at 24–28 gestational weeks increased as maternal age increased 20 .
Because our study was an epidemiological study, the detailed mechanism of the association of maternal age with early and late GDM could not be indicated. Several etiologies might have been involved between the maternal age and GDM. The first is beta‐cell dysfunction due to aging. The proliferation and regeneration of beta cells are decreased with aging 36 . Also, the other study attributed the primary cause of beta‐cell dysfunction with age to the loss of functional cell mass 37 . These changes lead to increasing the risk of glucose intolerance in aging people. The second is hormone changes during pregnancy. Human placental lactogen (hPL) is a placental hormone associated with glucose tolerance. Although hPL elevates maternal blood glucose levels to support fetal growth, it can potentially lead to GDM development 38 . In the animal study, placental lactogen gene expression of old was more enhanced than that of young 39 . Changes in placental lactogen gene expression affect glucose tolerance during pregnancy 40 . Hence, aging pregnant women may result in changes in hPL and potentially increase the risk of developing GDM. Third, adiponectin, an adipocytokine related to glucose metabolism secreted from adipose tissue, may explain the association between maternal age and GDM development. Adiponectin levels are known to decrease in pregnant women with GDM and also decrease with aging 41 . Additionally, adiponectin has been reported to decrease from mid‐to‐late pregnancy in pregnant women delivering LGA infants compared to those delivering AGA infants 42 . Animal studies have shown that supplementing to mothers whose adiponectin gene knockout results in restraining excessive fetal growth 43 , 44 .
Several studies have reported differences in insulin resistance between early and late gestation. As pregnancy progresses, insulin resistance increases 45 , 46 . However, the association between maternal age and early GDM was similar to that between maternal age and late GDM. Also, additional analysis showed a higher maternal age was associated with GDM diagnosed at ≥33 gestational weeks. Therefore, a higher maternal age has been suggested to be associated with GDM, regardless of gestational weeks. The finding that DNA methylation in cord blood samples did not differ between early and late GDM may explain the similar associations between maternal age and early and late GDM 47 .
The findings of this study highlight potential future public health issues. As maternal age increases in Japan, the prevalence of GDM, regardless of gestational weeks, may increase in the future. Although immediate treatment for early GDM reduced the risk of an adverse neonatal outcome event, the risk of small for gestational age infants increased in the lower glycemic range group (The fasting plasma glucose [PG] level ranged from 92 to 94 mg/dL the 1‐h PG level ranged from 180 to 190 mg/dL. The 2‐h PG level ranged from 153 to 161 mg/dL in the 75 g OGTT) 15 , 48 . In addition, a large proportion of patients with early GDM without treatment are not diagnosed with late GDM 48 , 49 . Therefore, studies on the diagnostic and interventional criteria of early GDM are required.
The strength of our study is its high external validity because pregnant women were recruited from multiple regions in Japan. Indeed, baseline characteristics, including maternal age, maternal height, parity, gestational weeks at delivery, and infant birth weight in grams, were similar to other birth cohort studies conducted in Japan 19 , 50 , 51 . Furthermore, the large sample size allowed us to adjust numerous variables in the statistical analysis. However, this study has several limitations. Because this study was limited to Japanese individuals, it is unclear whether the findings are generalizable to other ethnic groups. A family history of diabetes and 75 g OGTT values were not investigated in the JECS 32 . Consequently, this study may have had residual confounding factors in pregnant women with undiagnosed GDM. Additionally, not all pregnant women underwent the 75 g OGTT in the JECS. Therefore, the prevalence of GDM reported in the JECS was considerably lower than the prevalence reported in the Japanese population. A previous study indicated that the proportion of GDM was 10.1% when 75 g OGTT was conducted in all pregnant women in Japan 52 .
In conclusion, higher maternal age was associated with an increased risk of GDM regardless of the gestational age at GDM diagnosis. The association between maternal age and early GDM was similar to that of late GDM.
DISCLOSURE
The authors declare no conflict of interest.
Approval of the research protocol: The JECS protocol was reviewed and approved by the Ministry of the Environment's Institutional Review Board on Epidemiological Studies and the Ethics Committees of all participating institutions (Ethical Approval Number: 100910001).
Informed consent: Written informed consent was obtained from all study participants.
Registry and the registration no. of the study/trial: The JECS protocol was reviewed and approved by the Ministry of the Environment's Institutional Review Board on Epidemiological Studies and the Ethics Committees of all participating institutions (No. 2024‐006, approved on 23 August 2024).
Animal studies: N/A.
Supporting information
Figure S1 | Association of MBW with early GDM (diagnosed at <24 gestational weeks), late GDM (diagnosed from 24 to 32 gestational weeks), and late GDM (diagnosed at ≥33 gestational weeks).
Table S1 | Differences in maternal and neonatal characteristics among study participants and those that were excluded.
ACKNOWLEDGMENTS
We would like to express our sincere gratitude to all the participants and staff of JECS. We thank Editage (https://www.editage.com/) for the English language editing.
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Associated Data
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Supplementary Materials
Figure S1 | Association of MBW with early GDM (diagnosed at <24 gestational weeks), late GDM (diagnosed from 24 to 32 gestational weeks), and late GDM (diagnosed at ≥33 gestational weeks).
Table S1 | Differences in maternal and neonatal characteristics among study participants and those that were excluded.