Abstract
We aimed to examine the clinical factors associated with the birth weight of infants born to Japanese pregnant women with diabetes. This retrospective observational study enrolled 204 Japanese women with singleton pregnancies with type 1 diabetes (n = 135) or type 2 diabetes (n = 69). We used multiple regression analyses to examine factors associated with birth weight standard deviation (SD) scores. In addition, we compared the clinical findings among the groups of mothers who gave birth to appropriate for gestational age infants (AGA group), large for gestational age infants (LGA group), and small for gestational age infants (SGA group). Multiple regression analyses showed that the birth weight SD score was positively associated with type 2 diabetes. In women with type 1 diabetes, the birth weight SD score was positively associated with glycated albumin levels and gestational weight gain and negatively associated with pre-pregnancy underweight. Only gestational weight gain was positively associated with birth weight SD scores in women with type 2 diabetes. Glycated hemoglobin levels, gestational weight gain, and triglyceride levels were significantly higher in the LGA group than in the AGA group. The SGA group showed significantly lower gestational weight gain and triglyceride levels than the AGA group. These results suggest that it is important to manage not only blood glucose levels but also pre-pregnancy body weight and gestational weight gain for appropriate fetal growth. The effects of clinical factors on infant birth weight may differ between patients with type 1 and those with type 2 diabetes.
Keywords: Gestational weight gain, Infant’s birth weight, Birth weight SD score, Glycated albumin, Pre-pregnancy BMI
Introduction
Maternal hyperglycemia increases the risk of maternal and fetal complications. Poor glycemic control during the second and third trimesters of pregnancy is associated with infants being large for gestational age (LGA) [1]. The placental transfer of elevated maternal glucose causes fetal hyperinsulinemia, leading to fetal overgrowth [2]. Fetal overgrowth induces perinatal complications, such as cesarean section, injury to the birth canal and baby, and neonatal hypoglycemia. Glycemic management during pregnancy has advanced in recent decades with the widespread use of insulin analogs and the development of advanced devices, such as continuous glucose monitoring (CGM) systems and insulin pumps. However, the incidence of fetal macrosomia and LGA infants remains high in diabetic pregnancies [3]. In contrast, birth weight has rapidly declined in Japan. The rate of low birth weight (< 2500 g) was 5% in 1975, which increased to approximately 10% since 2007 [4]. This issue is unique to Japan and may be associated with a decreased maternal body mass index (BMI) and aggressive management of gestational weight gain.
Exposure to environmental factors, such as undernutrition, in utero and in early life leads to the development of non-communicable diseases, including obesity, type 2 diabetes, hypertension, metabolic syndrome, cardiovascular diseases, and osteoporosis, in adulthood [5–7]. A meta-analysis showed that both low birth weight (< 2500 g) and high birth weight (> 4000 g) were associated with the risk of developing type 2 diabetes [8]. A survey of childhood-onset type 2 diabetes in Japan also showed a U-shaped relationship between birth weight and the development of type 2 diabetes [9]. Thus, appropriate fetal growth is important to prevent perinatal complications and non-communicable diseases in the future, especially in diabetic pregnancies.
The birth weight of an infant is also influenced by maternal weight and weight gain during pregnancy [10, 11]. Standard BMI and height differ according to ethnicity and race; however, few studies have investigated the risk factors for abnormal fetal birth weight in Japanese women with pregestational diabetes. Therefore, we conducted this study to examine the birth weight of infants and associated clinical factors in pregnant Japanese women with type 1 and type 2 diabetes to help establish the proper management of pregnant women with diabetes.
Research design and methods
Patients
Between April 2014 and December 2020, 258 pregnant women with diabetes delivered at Tokyo Women’s Medical University Hospital. Among them, the eligible women for this study were those with singleton pregnancies. Fifty-four patients were excluded for the following reasons: multiple pregnancies (type 1 and type 2 diabetes, n = 7 and n = 2), delivery before 36 weeks of gestation (n = 13 and n = 12, respectively), diabetic nephropathy stage 3–5 [12] (n = 0 and n = 3, respectively), non-Japanese (n = 2 and n = 0, respectively), and hypertensive disorder of pregnancy (n = 13 and n = 2, respectively). Finally, 135 and 69 women with type 1 and type 2 diabetes were included in this study. Type 1 and type 2 diabetes were diagnosed according to the Japan Diabetes Society criteria [13].
Monitoring of glycemic status and managing body weight during pregnancy
Patients’ glucose levels were recorded using self-monitoring blood glucose (SMBG) and/or the CGM system. Insulin doses were adjusted at each patient’s visit every 2 weeks, according to the SMBG/CGM profiles, glycated hemoglobin (HbA1c), and glycated albumin (GA) levels, targeting blood glucose below 100 mg/dL for preprandial levels until 2019 or 95 mg/dL for preprandial levels since 2020 [14] and below 120 mg/dL at 2-h postprandial levels.
Body weights were measured at each visit. The patients were advised to control their body weight according to the recommendations of the Ministry of Health, Labour and Welfare in 2001: weight gain of 9 to 12 kg at the 40th gestational week in underweight women, 7 to 12 kg in normal-weight women, and approximately 5 kg in obese women [15].
Study methods
We extracted maternal clinical information, including maternal age; duration of diabetes; height; pre-pregnancy body weight; mean HbA1c and GA levels during the first, second, and third trimesters; total cholesterol and triglyceride levels in the first and third trimesters; maximum daily insulin dose; parity; the presence of retinopathy and microalbuminuria; and smoking habit, from the medical records. Information on pregnancy outcomes, including gestational age at delivery, maximum body weight at the end of the gestation period, sex of the infant, birth weight of the infant, Apgar scores at 1 and 5 min, placental weight, neonatal complications, and admission to the neonatal intensive care unit (NICU) were collected. Neonatal complications included respiratory problems, hypoglycemia, hyperbilirubinemia, polycythemia, hypocalcemia, and congenital malformations.
First, we investigated the associations between infant birth weight standard deviation (SD) scores and maternal clinical characteristics and pregnancy outcomes. Then, we divided patients into the following three groups: those who gave birth to appropriate for gestational age (AGA) infants comprised the AGA group, those who gave birth to LGA infants comprised the LGA group, and those who gave birth to small for gestational age (SGA) infants comprised the SGA group; we compared the clinical findings among the three groups.
Obesity was defined as a BMI ≥ 25 kg/m2, and underweight was defined as a BMI < 18.5 kg/m2 [16].
Infant birth weight SD scores were calculated using software provided by the Japanese Society for Pediatric Endocrinology [17]. Infants with birth weights between the 10th and 90th percentiles were defined as AGA, those with > 90th percentile as LGA, and those with < 10th percentile as SGA. Respiratory disorders included transient tachypnea in newborns, apnea, respiratory distress syndrome, and other respiratory problems that require respiratory care. Neonatal hypoglycemia was defined as a blood glucose level < 50 mg/dL. Hypocalcemia was defined as a Ca2+ level of < 0.75 mmol/L. Hyperbilirubinemia was defined as the requirement for phototherapy. Polycythemia was defined as a hematocrit > 65%. Congenital malformations included abnormalities of a body part that may or may not be perceived as problematic.
HbA1c levels were determined using high-performance liquid chromatography (ADAMS A1c HA-8190V; Arkray Corp., Tokyo, Japan). Serum GA levels were analyzed using an enzymatic method with albumin-specific proteinase, ketoamine oxidase, and an albumin assay reagent (Lucica GA-L; Asahi Kasei Pharma Corp., Tokyo, Japan). Triglyceride levels were measured using the enzyme colorimetric method (LABOSPECT 008; Hitachi, Ltd., Tokyo, Japan), and total cholesterol levels were measured using the enzyme method (LABOSPECT 008; Hitachi, Ltd., Tokyo, Japan).
Statistical analysis
We used the Shapiro–Wilk test to investigate the normal distribution. The Student’s t-test was used to compare normally distributed continuous variables, the Mann–Whitney U test was used to compare non-normally distributed continuous variables, and the chi-square test was used to compare categorical variables. We performed univariate linear regression analysis to evaluate the correlation between birth weight SD scores and clinical factors and multiple regression analysis to identify the variables that were independently related to birth weight SD scores of infants. Furthermore, we compared the clinical findings among the three groups of mothers who delivered AGA, LGA, and SGA infants using Dunnett’s method. Statistical significance was set at p < 0.05. All statistical analyses were performed using the SPSS version 21 for Windows (IBM Corp., Armonk, NY, USA).
Results
Characteristics of patients and pregnancy outcome
The maternal age was 32.7 ± 4.0 and 34.8 ± 4.5 in women with type 1 and type 2 diabetes, respectively (Table 1). The pre-pregnancy BMI was 22.3 ± 3.1 and 24.3 ± 4.6 in women with type 1 and type 2 diabetes, respectively. Forty-one women of all patients were smokers, and all but one with type 2 diabetes had quit smoking after pregnancy. Mean GA levels decreased over the course of pregnancy in women with type 1 and type 2 diabetes.
Table 1.
Clinical characteristics of patients and pregnancy outcomes
| All (n = 204) | Women with T1DM (n = 135) |
Women with T2DM (n = 69) |
|
|---|---|---|---|
| Maternal age (years) | 33.4 ± 4.3 | 32.7 ± 4.0 | 34.8 ± 4.5 |
| Duration of diabetes (years) | 12.3 ± 7.7 | 14.4 ± 7.3 | 7.9 ± 6.7 |
| Height (cm) | 159.0 ± 5.5 | 159.3 ± 5.3 | 158.2 ± 5.9 |
| Pre-pregnancy body weight (kg) | 58.0 ± 10.2 | 56.6 ± 8.7 | 60.9 ± 12.3 |
| Pre-pregnancy BMI (kg/m2) | 22.9 ± 3.9 | 22.3 ± 3.1 | 24.3 ± 4.6 |
| Primipara (%) | 61.3 | 62.2 | 59.4 |
| Retinopathy NDR/SDR/pre PDR/PDR (%) | 74.0/22.5/1.5/2.0 | 75.6/23.0/0/1.5 | 71.0/21.7/4.3/2.9 |
| Nephropathy, stage 1/stage 2 (%) | 98.0/2.0 | 100/0 | 94.2/5.8 |
| Ex-smokers (%) | 20.1 | 17.8 | 24.6 |
| Glycemic control | |||
| Mean HbA1c in first trimester (%) | 6.6 ± 0.8 | 6.6 ± 0.6 | 6.7 ± 1.0 |
| Mean HbA1c in second trimester (%) | 5.9 ± 0.5 | 6.0 ± 0.7 | 5.8 ± 0.5 |
| Mean HbA1c in third trimester (%) | 6.2 ± 0.5 | 6.2 ± 0.5 | 6.1 ± 0.5 |
| Mean GA in first trimester (%) | 17.8 ± 2.6 | 18.3 ± 2.5 | 16.8 ± 2.6 |
| Mean GA in second trimester (%) | 16.0 ± 2.3 | 16.7 ± 2.2 | 14.6 ± 1.8 |
| Mean GA in third trimester (%) | 14.8 ± 1.6 | 15.1 ± 1.6 | 14.1 ± 1.5 |
| Lipid profiles | |||
| Total cholesterol in first trimester (mg/dL) | 170 ± 28 | 171 ± 26 | 169 ± 34 |
| Total cholesterol in third trimester (mg/dL) | 260 ± 42 | 265 ± 39 | 249 ± 46 |
| Triglycerides in first trimester (mg/dL) | 86 ± 45 | 79 ± 340 | 101 ± 53 |
| Triglycerides in third trimester (mg/dL) | 233 ± 105 | 221 ± 90 | 259 ± 130 |
| Gestational age at delivery (weeks) | 38.7 ± 0.6 | 38.7 ± 0.6 | 38.7 ± 0.6 |
| Caesarean section (%) | 33.3 | 31.9 | 34.1 |
| Gestational weight gain (kg) | 10.4 ± 3.4 | 10.9 ± 3.2 | 9.6 ± 3.7 |
| Maximum insulin dose (units/day) | 67.0 ± 30.3 | 70.1 ± 25.7 | 60.7 ± 37.1 |
| Sex of the infant male/female (%) | 48.5/51.5 | 44.4/55.6 | 56.5/43.5 |
| Birth weight of infant (g) | 3066 ± 404 | 3035 ± 412 | 3127 ± 385 |
| Birth weight SD score | 0.5 ± 1.1 | 0.4 ± 1.2 | 0.6 ± 1.0 |
| SGA/AGA/LGA (%) | 5.9/70.1/24.0 | 7.4/69.6/23.0 | 2.9/71.0/26.1 |
| Apgar score at 1 min 0–3/4–7/8–10 points (%) | 2.5/8.8/88.8 | 1.4/9.7/88.9 | 4.3/7.2/88.4 |
| Apgar score at 5 min 0–3/4–7/8–10 points (%) | 0/3.0/97.0 | 0/3.7/96.2 | 0/1.4/98.5 |
| Placental weight (g) | 589±112 | 588±111 | 591±115 |
| Neonatal complications | |||
| Respiratory disorder (%) | 22.5 | 23.0 | 21.7 |
| Hypoglycemia (%) | 41.7 | 46.7 | 31.9 |
| Hypocalcemia (%) | 0.5 | 0 | 1.4 |
| Hyperbilirubinemia (%) | 17.6 | 18.5 | 15.9 |
| Polycythemia (%) | 2.0 | 2.2 | 1.4 |
| Malformation (%) | 3.9 | 4.4 | 2.9 |
| Admission to NICU (%) | 17.6 | 20.0 | 13.0 |
T1DM type 1 diabetes mellitus, T2DM type 2 diabetes mellitus, BMI body mass index, NDR no diabetic retinopathy, SDR simple diabetic retinopathy, pre PDR preproliferative diabetic retinopathy, PDR proliferative diabetic retinopathy, HbA1c glycated hemoglobin, GA glycated albumin, SD standard deviation, SGA small for gestational age, AGA appropriate for gestational age, LGA large for gestational age, NICU neonatal intensive care unit
The gestational age at delivery was 38.7 ± 0.6 and 38.7 ± 0.6 in women with type 1 and type 2 diabetes, respectively. And the gestational weight gain was 10.9 ± 3.2 and 9.6 ± 3.7 in women with type 1 and type 2 diabetes, respectively.
The infant’s average birth weight was 3066 ± 404 g (SD score, 0.5 ± 1.1). The frequencies of SGA, AGA, and LGA infants were 7.4, 69.6, and 23.0%, respectively in women with type 1 diabetes and 2.9, 71.0, and 26.1%, respectively in women with type 2 diabetes. Neonatal hypoglycemia was the most frequent neonatal complication and the frequencies were 46.7% and 31.9%, respectively in infants born to women with type 1 diabetes than in those born to women with type 2 diabetes.
Clinical factors associated with birth weight SD scores
In all patients, pre-pregnancy body weight, height, gestational weight gain, mean HbA1c levels in the third trimester, and log triglycerides in the third trimester were positively correlated with birth weight SD scores in the correlation analysis (Table 2). In the multiple regression analyses, the birth weight SD score was positively associated with type 2 diabetes, mean GA levels in the third trimester, log triglycerides in the third trimester, and gestational weight gain and negatively associated with pre-pregnancy underweight (Table 3).
Table 2.
Correlation between birth weight SD scores and clinical parameters using correlation analysis (Pearson correlation)
| All n = 204 |
Women with T1DM n = 135 |
Women with T2DM n = 69 |
||||
|---|---|---|---|---|---|---|
| Correlation coefficient | p value | Correlation coefficient | p value | Correlation coefficient | p value | |
| Maternal age | 0.111 | 0.116 | 0.062 | 0.478 | 0.152 | 0.214 |
| Duration of diabetes | − 0.051a | 0.468a | − 0.054 | 0.535 | 0.102a | 0.403a |
| Height | 0.224 | 0.001 | 0.257 | 0.003 | 0.194 | 0.111 |
| Pre-pregnancy body weight | 0.190a | 0.007a | 0.197a | 0.022a | 0.142 | 0.246 |
| Pre-pregnancy BMI | 0.109a | 0.119a | 0.087a | 0.316a | 0.085 | 0.487 |
| Pre-pregnancy underweight | 0.071b | 0.371b | 0.048b | |||
| Pre-pregnancy obesity | 0.745b | 0.957b | 0.902b | |||
| Primipara | 0.967b | 0.521b | 0.317b | |||
| Retinopathy | 0.595b | 0.690b | 0.152b | |||
| Nephropathy | 0.766b | – | 0.965b | |||
| Ex-smokers | 0.888b | 0.084b | 0.018b | |||
| Glycemic control | ||||||
| Mean HbA1c in first trimester | 0.017a | 0.819a | 0.048a | 0.592a | − 0.059a | 0.655a |
| Mean HbA1c in second trimester | 0.120a | 0.091a | 0.178 | 0.041 | 0.075a | 0.549a |
| Mean HbA1c in third trimester | 0.264a | < 0.001a | 0.231a | 0.007a | 0.351a | 0.003a |
| Mean GA in first trimester | 0.053a | 0.496a | 0.149a | 0.107a | − 0.074a | 0.600a |
| Mean GA in second trimester | 0.084a | 0.238a | 0.127 | 0.147 | 0.109 | 0.379 |
| Mean GA in third trimester | 0.130a | 0.065a | 0.096a | 0.268a | 0.226a | 0.061a |
| Lipid profiles | ||||||
| Total cholesterol in first trimester | − 0.011a | 0.901a | 0.082 | 0.446 | − 0.229a | 0.149a |
| Total cholesterol in third trimester | − 0.015a | 0.849a | 0.069a | 0.468a | − 0.106a | 0.435a |
| Log triglycerides in first trimester | 0.125 | 0.105 | 0.173a | 0.063a | − 0.110 | 0.436 |
| Log triglycerides in third trimester | 0.325 | < 0.001 | 0.294 | 0.001 | 0.365 | 0.005 |
| Gestational age at delivery | 0.037a | 0.597a | 0.053 | 0.542 | 0.008 | 0.951 |
| Gestational weight gain | 0.270 | < 0.001 | 0.215 | 0.012 | 0.440 | < 0.001 |
| Maximum insulin dose | 0.028a | 0.687a | − 0.012a | 0.887a | 0.190a | 0.117a |
SD standard deviation, T1DM type 1 diabetes mellitus, T2DM type 2 diabetes mellitus, BMI body mass index, HbA1c glycated hemoglobin, GA glycated albumin
aSpearman correlation, bStudent’s t test
Table 3.
Association between birth weight SD scores and maternal clinical factors in all patients using the multiple regression analysis (forced entry method)
| Independent | B | Standard error | β | P | 95% CI | Adjusted R2 |
|---|---|---|---|---|---|---|
| DM type (type 2 DM) | 0.449 | 0.220 | 0.185 | 0.043 | 0.015 to 0.882 | 0.178 |
| Maternal age | − 0.006 | 0.021 | − 0.021 | 0.789 | − 0.048 to 0.037 | |
| Duration | − 0.014 | 0.013 | − 0.097 | 0.257 | − 0.039 to 0.011 | |
| Pre-pregnancy underweight | − 0.688 | 0.301 | − 0.176 | 0.024 | − 1.282 to − 0.094 | |
| Pre-pregnancy obesity | 0.164 | 0.264 | 0.062 | 0.535 | − 0.358 to 0.687 | |
| Retinopathy | − 0.069 | 0.201 | − 0.026 | 0.732 | − 0.465 to 0.327 | |
| Microalbuminuria | − 0.033 | 0.663 | − 0.004 | 0.961 | − 1.342 to 1.277 | |
| EX-smoker | 0.082 | 0.216 | 0.029 | 0.704 | − 0.344 to 0.509 | |
| Mean GA in third trimester | 0.160 | 0.056 | 0.234 | 0.005 | 0.049 to 0.272 | |
| Total cholesterol in third trimester | 0.003 | 0.002 | 0.093 | 0.262 | − 0.002 to 0.007 | |
| Log triglycerides in third trimester | 1.319 | 0.540 | 0.203 | 0.016 | 0.252 to 2.386 | |
| Gestational weight gain | 0.108 | 0.026 | 0.335 | < 0.001 | 0.057 to 0.158 | |
| Maximum insulin dose | − 0.002 | 0.003 | − 0.058 | 0.515 | − 0.009 to 0.004 |
SD standard deviation, 95% CI 95% confidence interval, DM diabetes mellitus, GA glycated albumin
In women with type 1 diabetes, pre-pregnancy body weight, height, gestational weight gain, mean HbA1c levels in the second and third trimesters, and log triglyceride levels in the third trimester were positively correlated with birth weight SD scores in the correlation analysis (Table 2). In multiple regression analyses, the birth weight SD score was positively associated with mean GA levels in the third trimester, log triglycerides in the third trimester, and weight gain and negatively associated with pre-pregnancy underweight (Table 4).
Table 4.
Association between birth weight SD scores and maternal clinical factors in women with type 1 diabetes using the multiple regression analysis (forced entry method)
| Independent | B | Standard error | β | P | 95% CI | Adjusted R2 |
|---|---|---|---|---|---|---|
| Maternal age | − 0.033 | 0.030 | − 0.115 | 0.278 | − 0.092 to 0.027 | 0.160 |
| Duration | − 0.011 | 0.017 | − 0.064 | 0.539 | − 0.044 to 0.023 | |
| Pre-pregnancy underweight | − 0.825 | 0.400 | − 0.190 | 0.042 | − 1.620 to 0.031 | |
| Pre-pregnancy obesity | 0.246 | 0.374 | 0.073 | 0.513 | − 0.497 to 0.988 | |
| Retinopathy | − 0.383 | 0.268 | − 0.143 | 0.156 | − 0.915 to 0.149 | |
| EX-smoker | 0.419 | 0.281 | 0.139 | 0.139 | − 0.139 to 0.976 | |
| Mean GA in third trimester | 0.212 | 0.072 | 0.286 | 0.004 | 0.069 to 0.355 | |
| Total cholesterol in third trimester | 0.004 | 0.003 | 0.137 | 0.178 | − 0.002 to 0.010 | |
| Log triglycerides in third trimester | 1.911 | 0.810 | 0.257 | 0.020 | 0.304 to 3.518 | |
| Gestational weight gain | 0.098 | 0.035 | 0.268 | 0.006 | 0.029 to 0.167 | |
| Maximum insulin dose | − 0.008 | 0.005 | − 0.174 | 0.107 | − 0.018 to 0.002 |
95% CI 95% confidence interval, DM diabetes mellitus, GA glycated albumin
In normal weight women (18.5 ≤ BMI < 25 kg/m2) with type 1 diabetes (n = 107), pre-pregnancy body weight, height, gestational weight gain, mean HbA1c levels in the second and third trimesters, mean GA levels in the all trimesters and log triglycerides in the third trimester were positively correlated with birth weight SD scores in the correlation analysis, and multiple regression analyses showed that mean GA levels in the third trimester and gestational weight gain were positively associated with birth weight SD scores (B = 0.255, p = 0.002, B = 0.088, p = 0.039, respectively).
In obesity women (BMI ≥ 25 kg/m2) with type 1 diabetes (n = 18), gestational weight gain and log triglycerides in the third trimester were positively associated with the birth weight SD score in the correlation analysis, and multiple regression analyses showed that only gestational weight gain was positively associated with birth weight SD scores (B = 0.190, p = 0.039).
In women with type 2 diabetes, gestational weight gain, mean HbA1c levels in the third trimester and log triglycerides in the third trimester were positively associated with the birth weight SD score, while pre-pregnancy underweight and smoking history were negatively correlated with the birth weight SD score in the correlation analysis (Table 2). Only gestational weight gain was positively associated with birth weight SD scores in multiple regression analyses (Table 5).
Table 5.
Association between birth weight SD scores and maternal clinical factors in women with type 2 diabetes using the multiple regression analysis (forced entry method)
| Independent | B | Standard error | β | P | 95% CI | Adjusted R2 |
|---|---|---|---|---|---|---|
| Maternal age | 0.006 | 0.034 | 0.025 | 0.852 | − 0.063 to 0.076 | 0.227 |
| Duration | − 0.005 | 0.020 | − 0.033 | 0.810 | − 0.046 to 0.036 | |
| Pre-pregnancy underweight | − 0.465 | 0.476 | − 0.147 | 0.334 | − 1.424 to 0.495 | |
| Pre-pregnancy obesity | 0.104 | 0.381 | 0.049 | 0.786 | − 0.663 to 0.872 | |
| Retinopathy | 0.431 | 0.331 | 0.178 | 0.200 | − 0.236 to 1.098 | |
| Microalbuminuria | − 0.116 | 0.660 | − 0.025 | 0.862 | − 1.448 to 1.216 | |
| EX-smoker | − 0.457 | 0.364 | − 0.179 | 0.216 | − 1.190 to 0.277 | |
| Mean GA in third trimester | 0.099 | 0.093 | 0.151 | 0.290 | − 0.087 to 0.286 | |
| Total cholesterol in third trimester | 0.002 | 0.004 | 0.106 | 0.502 | − 0.005 to 0.010 | |
| Log triglycerides in third trimester | 0.904 | 0.757 | 0.173 | 0.239 | − 0.623 to 2.431 | |
| Gestational weight gain | 0.094 | 0.040 | 0.356 | 0.024 | 0.013 to 0.175 | |
| Maximum insulin dose | 0.002 | 0.004 | 0.067 | 0.671 | − 0.007 to 0.011 |
95% CI 95% confidence interval, DM diabetes mellitus, GA glycated albumin
In normal weight women (18.5 ≤ BMI < 25 kg/m2) with type 2 diabetes (n = 32), gestational weight gain was positively correlated with birth weight SD scores, while total cholesterol in the first trimester was negatively correlated with birth weight SD scores in the correlation analysis, and multiple regression analyses showed that only gestational weight gain was positively associated with birth weight SD scores (B = 0.156, p = 0.028).
In obesity women (BMI ≥ 25 kg/m2) with type 2 diabetes (n = 30), gestational weight gain, mean HbA1c levels in the third trimester and log triglycerides in the third trimester were positively associated with the birth weight SD score in the correlation analysis, and none of the factors was associated with birth weight SD scores in multiple regression analyses.
Comparison among three groups of mothers who gave birth to AGA, LGA, and SGA infants
AGA, LGA, and SGA infants accounted for 70.1, 24.0, and 5.9%, respectively (Table 1). Mean HbA1c levels in the second and third trimesters of pregnancy (5.9% vs. 6.1%, p = 0.012, 6.1% vs. 6.4%, p = 0.006, respectively), gestational weight gain (10.3 ± 3.3 kg vs. 12.0 ± 2.9 kg, p = 0.005), and log triglycerides in the third trimester (2.3 ± 0.2 vs. 2.4 ± 0.2, p = 0.025) were significantly higher in the LGA group than in the AGA group (Table 6). The SGA group had significantly lower weight gain (10.3 ± 3.3 kg vs. 7.1 ± 3.6 kg, p = 0.005) and log triglyceride levels in the third trimester of pregnancy (2.3 ± 0.2 vs. 2.2 ± 0.1, p = 0.023) than the AGA group.
Table 6.
Comparison among the three groups of mothers who gave to AGA, LGA, and SGA infants
| SGA group (n = 11) | AGA group (n = 151) | LGA group (n = 42) | AGA group vs LGA group P |
AGA group vs SGA group P |
|
|---|---|---|---|---|---|
| Women with T1DM (n)/women with T2DM (n) | 9/2 | 98/53 | 28/14 | ||
| Maternal age (years) | 30.7 ± 4.4 | 33.5 ± 4.4 | 33.4 ± 3.8 | 0.990a | 0.073a |
| Duration of diabetes (years) | 12.9 ± 7.6 | 12.0 ± 7.9 | 12.8 ± 7.1 | 0.813a | 0.916a |
| Height (cm) | 155.4 ± 5.2 | 158.7 ± 5.7 | 160.7 ± 4.4 | 0.085a | 0.095a |
| Pre-pregnancy BMI (kg/m2) | 23.0 ± 6.1 | 22.8 ± 3.6 | 23.5 ± 3.9 | 0.505a | 0.984a |
| Ex-smokers (%) | 18.2 | 22.5 | 11.9 | 0.312b | |
| Retinopathy (%) | 18.2 | 27.2 | 23.8 | 0.756b | |
| Nephropathy stage 2 (%) | 0 | 2.0 | 2.4 | 0.878b | |
| Glycemic control | |||||
| Mean HbA1c in first trimester (%) | 6.3 ± 0.6 | 6.6 ± 0.7 | 6.8 ± 0.9 | 0.167a | 0.345a |
| Mean HbA1c in second trimester (%) | 5.9 ± 0.5 | 5.9 ± 0.5 | 6.1 ± 0.5 | 0.012a | 0.979a |
| Mean HbA1c in third trimester (%) | 6.0 ± 0.4 | 6.1 ± 0.5 | 6.4 ± 0.6 | 0.006a | 0.725a |
| Mean GA in first trimester (%) | 16.7 ± 2.6 | 17.9 ± 2.6 | 17.8 ± 2.6 | 0.994a | 0.373a |
| Mean GA in second trimester (%) | 14.9 ± 1.7 | 16.0 ± 2.2 | 16.2 ± 2.5 | 0.816a | 0.240a |
| Mean GA in third trimester (%) | 14.0 ± 1.0 | 14.8 ± 1.6 | 14.9 ± 1.9 | 0.855a | 0.216a |
| Maximum insulin dose (units/day) | 63.2 ± 25.1 | 67.1 ± 32.1 | 67.1 ± 24.9 | 1.000a | 0.896a |
| Lipid profiles | |||||
| Total cholesterol in first trimester (mg/dL) | 158.3 ± 9.8 | 172.1 ± 29.9 | 168.2 ± 24.4 | 0.788a | 0.380a |
| Total cholesterol in third trimester (mg/dL) | 244.8 ± 38.5 | 260.0 ± 40.0 | 262.6 ± 49.3 | 0.932a | 0.440a |
| Log triglycerides in first trimester (mg/dL) | 1.8 ± 0.1 | 1.9 ± 0.2 | 1.9 ± 0.2 | 0.519a | 0.543a |
| Log triglycerides in third trimester (mg/dL) | 2.2 ± 0.1 | 2.3 ± 0.2 | 2.4 ± 0.2 | 0.025a | 0.023a |
| Pregnancy outcome | |||||
| Gestational age at delivery (weeks) | 38.5 ± 0.8 | 38.7 ± 7.1 | 38.7 ± 0.5 | 0.983a | 0.645a |
| Caesarean section (%) | 18.2 | 31.1 | 45.2 | 0.126b | |
| Gestational weight gain (kg) | 7.1 ± 3.6 | 10.3 ± 3.3 | 12.0 ± 2.9 | 0.005a | 0.005a |
| Birth weight of infant (g) | 2273 ± 129 | 2977 ± 276 | 3594 ± 207 | < 0.001a | < 0.001a |
| Placental weight (g) | 430 ± 51 | 572 ± 88 | 692 ± 123 | < 0.001a | < 0.001a |
SGA small for gestational age, AGA appropriate for gestational age, LGA large for gestational age, T1DM type 1 diabetes mellitus, T2DM type 2 diabetes mellitus, BMI body mass index, HbA1c glycated hemoglobin, GA glycated albumin
aDunnett’s test, bChi-square test
Discussion
This study showed that the frequency of LGA infants in Japan has remained high in women with type 1 and type 2 diabetes in recent years. Birth weight SD score was positively associated with type 2 diabetes in all patients; it was associated with mean GA levels, triglyceride levels and gestational weight gain in patients with type 1 diabetes, and it was associated with gestational weight gain in patients with type 2 diabetes. The birth weight SD score was negatively associated with pre-pregnancy underweight status in patients with type 1 diabetes. The LGA group had higher HbA1c levels in the second and third trimesters of pregnancy, gestational weight gain, and triglyceride levels in the third trimester, whereas the SGA group had lower gestational weight gain and triglyceride levels in the third trimester than the AGA group.
Several factors affect the birth weight of infants in the general population. Maternal short stature [18, 19], pre-pregnancy underweight [11, 20, 21], Indian or Asian ethnicity [19, 22], nulliparity [18, 19], insufficient gestational weight gain [10, 23, 24], low birth weight of parents [25, 26], cigarette smoking [18, 19, 27], cocaine use [28], maternal medical history of chronic hypertension [29–31], and renal disease [32, 33] were associated with smaller infants. In contrast, pre-pregnancy overweight or obesity [11, 20, 21], excessive gestational weight gain [10, 23, 24], pregestational diabetes [34, 35], and gestational diabetes mellitus [36] were associated with larger infants.
Poor glycemic control is believed to be a risk factor for increased birth weight in women with diabetes. Therefore, glycemic control should be as close as possible to normal during pregnancy to prevent perinatal complications [14]. In this study, the birth weight SD score was positively associated with mean GA levels in the third trimester in women with type 1 diabetes, whereas the same relationship was not found in women with type 2 diabetes. One reason for this may be that glycemic control in women with type 2 diabetes was better than that in women with type 1 diabetes.
Important factors associated with the birth weight of infants were maternal weight and gestational weight gain in women with diabetes. Several reports have examined the relationship between the birth weight of infants and maternal weight and gestational weight gain in women with diabetes. Maternal pre-pregnancy BMI was associated with macrosomia [37] and neonatal overweight [38] in type 1 diabetes. Excessive gestational weight gain was also reported to be associated with LGA infants [39, 40] and high birth weight SD scores [41] in women with type 1 diabetes and LGA infants and macrosomia [42] in women with type 2 diabetes. Furthermore, a study of the general Japanese population indicated that high pre-pregnancy BMI and excess weight gain during pregnancy were risk factors for LGA infants and macrosomia, and poor weight gain was a risk factor for SGA infants [20]. In the present study, we found that birth weight SD scores were positively associated with gestational weight gain in Japanese women with type 1 and type 2 diabetes, and the LGA group had higher gestational weight gain than the AGA group. No relationship between the birth weight of infants and maternal pre-pregnancy overweight was found, whereas the birth weight SD score was negatively associated with pre-pregnancy underweight in women with type 1 diabetes in this study. The BMI of our Japanese patients was lower than that reported in previous studies in Finland [37] and Sweden [38]. Nutritional therapy was recommended before pregnancy to control body weight. The discrepancy between the results of the present study and those of previous studies may be related to racial differences and small meals.
Moreover, fetal growth was associated with type 2 diabetes rather than with type 1 diabetes, and glycemic control and maternal weight had different effects on the birth weight of infants born to women with type 1 diabetes and women with type 2 diabetes. Similar results have been reported in Sweden [38], in which gestational weight gain and HbA1c in the second trimester were associated with LGA infants in type 1 diabetes, and gestational weight gain was associated with LGA infants in type 2 diabetes. The presence of insulin resistance in women with gestational glucose intolerance has been reported to increase the risk of LGA infants, independent of pregestational BMI [43]. These results suggest that a diabetes-type-specific approach, including different targets for weight and glycemic control, is needed to prevent abnormal fetal growth.
With regard to other factors associated with fetal growth, we found a relationship between the birth weight of infants and triglyceride levels during the third trimester of women with type 1 diabetes. This result is consistent with that of a previous study [44].
Analyses that divided the women by BMI showed that the factors associated with the birth weight SD scores in normal weight women were almost similar to those in all women with type 1 and type 2 diabetes. Further investigations are needed in large numbers of obese and lean women with diabetes.
The present study had several limitations. The sample size of this study was small. This study was conducted at a single center; therefore, the generalizability of the results may be limited. There is a possibility of selection bias because the proportion of patients with type 1 and type 2 diabetes in our study was not consistent with that in the general Japanese population. Further studies with larger sample sizes, particularly for type 2 diabetes, are required.
Conclusion
Infant birth weight was more associated with type 2 diabetes than with type 1 diabetes. The factors associated with birth weight were different for type 1 and type 2 diabetes; the birth weight was associated with glycemic control, pregestational underweight, and gestational weight gain in women with type 1 diabetes, whereas it was associated with only gestational weight gain in women with type 2 diabetes. These results suggest that in women with diabetes, especially those with type 2 diabetes, it is important to manage not only blood glucose levels but also weight gain during pregnancy.
Data availability
The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request.
Declarations
Conflict of interest
Authors declare that they have no conflict of interest.
Ethical standards
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. Informed consent or substitute for it was obtained from all patients for being included in the study. This study was approved by the Ethical Committee of Tokyo Women’s Medical University School of Medicine (Approval No. 2021-0001, approval date: 1 April 2021).
Footnotes
Publisher's Note
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request.