The Journal of Maternal-Fetal & Neonatal Medicine
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Pregnancy outcomes in women aged 35 years or older with gestational diabetes – a registry-based study in Finland Reeta Lamminpää, Katri Vehviläinen-Julkunen, Mika Gissler, Tuomas Selander & Seppo Heinonen To cite this article: Reeta Lamminpää, Katri Vehviläinen-Julkunen, Mika Gissler, Tuomas Selander & Seppo Heinonen (2014): Pregnancy outcomes in women aged 35 years or older with gestational diabetes – a registry-based study in Finland, The Journal of Maternal-Fetal & Neonatal Medicine To link to this article: http://dx.doi.org/10.3109/14767058.2014.986450
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Date: 05 November 2015, At: 13:44
http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, Early Online: 1–5 ! 2014 Informa UK Ltd. DOI: 10.3109/14767058.2014.986450
ORIGINAL ARTICLE
Pregnancy outcomes in women aged 35 years or older with gestational diabetes – a registry-based study in Finland Reeta Lamminpa¨a¨1, Katri Vehvila¨inen-Julkunen2, Mika Gissler3,4, Tuomas Selander2, and Seppo Heinonen5,6
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1
Department of Nursing Science, University of Eastern Finland, Kuopio, Finland, 2Kuopio University Hospital, University of Eastern Finland, Kuopio, Finland, 3National Institute for Health and Welfare (THL), Helsinki, Finland, 4Nordic School for Public Health, Gothenburg, Sweden, 5Department of Obstetrics and Gynaecology, Kuopio University Hospital, University of Eastern Finland, Kuopio, Finland, and 6Helsinki University Central Hospital, Helsinki, Finland Abstract
Keywords
Objective: To compare pregnancy outcomes of women 35 years to women535 years with and without gestational diabetes. Methods: The data include 230 003 women 535 years and 53 321 women 35 years and their newborns from 2004 to 2008. In multivariate modeling, the main outcome measures were preterm delivery (528, 28–31 and 32–36 weeks’ gestation), Apgar scores 57 at 5 min, small for gestational age (SGA), fetal death, asphyxia, preeclampsia, admission to neonatal intensive care unit (NICU), shoulder dystocia and large for gestational age (LGA). Results: In comparison to women 535 with normal glucose tolerance, preeclampsia (OR 1.57, CI 1.30–1.88), admission to the NICU (OR 3.30, CI 2.94–3.69) and shoulder dystocia (OR 2.12, CI 1.05–4.30) were highest in insulin-treated women 35 years. In women 35, diet- and insulin-treated gestational diabetes mellitus (GDM) increased the rates of preeclampsia, shoulder dystocia and admission to NICU (OR 3.07 CI 2.73–3.45). The effect of advanced maternal age was observed in very preterm delivery (528 weeks), fetal death, preeclampsia and NICU. The increase in preeclampsia was statistically significant. Conclusions: GDM at advanced age is a high risk state and, more specifically, the risk caused by age and GDM appear to be increasing in preeclampsia.
Advanced maternal age, birth outcomes, diettreated GDM, insulin-treated GDM, normal glucose tolerance, register-based study
Introduction Gestational diabetes mellitus (GDM) is defined as abnormal glucose tolerance that develops or is recognized in pregnancy. The definition includes those women with previously undiagnosed diabetes, as well as those with pregnancy-induced high glucose levels. The diagnosis is based on glucose levels on a 75 g oral glucose tolerance test (OGTT). In Finland, the diagnostic criteria are defined as 5.3 mmol/l for fasting plasma glucose, 10.0 mmol/l after 1 h and 8.6 mmol/l after 2 h. The screening for GDM is performed for nearly all pregnant women with OGTT during gestational weeks 24–28. [1]. In Finland, the proportion of women with GDM has increased in recent years and was 13% in 2012 [2]. Risks factors associated with developing GDM are high maternal body mass index (BMI), advanced maternal age (AMA), polycystic ovarian syndrome, increasing maternal parity, previous GDM, family history of diabetes and twin pregnancy [3]. Women with GDM are at an increased risk
Address for correspondence: Reeta Lamminpa¨a¨, Department of Nursing Science, University of Eastern Finland, P.O Box 1627, Kuopio 70211, Finland. E-mail: [email protected]
History Received 22 September 2014 Revised 5 November 2014 Accepted 7 November 2014 Published online 8 December 2014
for cesarean delivery, macrosomia, fetal congenital malformations, preterm delivery and shoulder dystocia [4]. GDM also increases the likelihood of developing type 2 diabetes; therefore, screening for GDM enables the identification of women at increased risk of diabetes before disease onset and permits practitioners to begin preventive measures [3]. The phenomena of childbearing at an advanced age are a growing trend in developed countries. Usually AMA is defined as maternal age of 35 and older at the time of pregnancy [5]. AMA has been associated with poorer pregnancy outcomes and complications in pregnancy and labor and is an independent risk factor for adverse pregnancy outcomes [5–7]. In 2012, the proportion of women over 35 years old giving birth in Finland was 18% [2]. Women with GDM have been widely studied, but less is known about the effects of AMA on GDM. In previous studies, GDM has been related to obesity and preeclampsia, with a significant association between these conditions, as well as poorer pregnancy outcomes [8–12]. The aim of this study was to compare pregnancy outcomes of women over 35 years old to women less than 35 years old with and without GDM (categorized in normal glucose tolerance, diet-treated GDM and insulin-treated GDM).
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Methods The data for this study consist of information from the Medical Birth Register (MBR), the Hospital Discharge Register (HDR) and the Register of Congenital Malformations. Permission to use the data in this study was granted by the National Institute for Health and Welfare in September 2009 (THL/906/5.05.00/2009), as required by the national data protection legislation. Ethical considerations were performed by the register authorities. An ethical review board statement is not required for register-based studies in Finland. The MBR is a population-based registry established in 1987 and is currently maintained by the National Institute for Health and Welfare (THL). The MBR includes information on maternal and neonatal birth characteristics and perinatal outcomes of all women who have given birth in Finland and all newborns up to seven days of age. The form is filled out at hospitals and sent, mostly electronically, to THL [13]. The HDR was established in 1969 and it contains information on all aspects of inpatient care in public and private hospital visits and outpatient visits to public hospitals (since 1998). Hospitals send data electronically to THL [14]. The Register of Congenital Malformations is run by THL and contains nationwide data on congenital chromosomal and structural anomalies detected in stillborn and live-born infants and fetuses in pregnancies terminated due to fetal indication. The registration of anomalies began in 1963 [15]. The study data contains information on 292 667 women and their newborns from 2004 to 2008. Live births and stillbirths with major congenital anomalies were excluded (N ¼ 9343). The study population of the current study included women who were diagnosed with GDM. We compared women aged 35 years or older to women less than 35 years old. GDM was classified into diet- and insulintreated disease, which were compared to the normal glucose tolerance condition. Participants with gestational diabetes were identified in two ways. First, we included eligible women based on diagnoses recorded using International Statistical Classification of Diseases and Related Health Problems (10th revision) (ICD-10 codes; GDM: ICD-10 codes O24.4 and O24.9). Second, we identified participants in the data who were recorded as having a ‘‘pathological glucose tolerance test’’. Afterwards, we combined groups mentioned characterized as having ‘‘GDM’’ and separated those who were recorded as receiving ‘‘insulin treatment for GDM’’. The remainder was classified as undergoing ‘‘diet treatment’’. Statistical analyses were performed using the R-program version 2.15.2. Variables used in the binary logistic regression analysis were dichotomous and observations that had missing data values were excluded. The following definitions were used to record pregnancy outcomes: low Apgar scores at 5 min (0–6); preterm delivery, before 28, 28–31 and 32–36 weeks of gestation; small for gestational age (SGA), infants were considered small when the sex- and age-adjusted birth weight was below the 5th percentile according to the standard tables for the Finnish population data for all births [16]; large for gestational age (LGA), infants were considered large when the sex- and ageadjusted birth weight was above the 95th percentile [16].
J Matern Fetal Neonatal Med, Early Online: 1–5
Binary logistic regression adjusted for potential confounding factors, including smoking, anemia, placenta previa, In vitro fertilisation (IVF), fertility treatment other than IVF, previous caesarean section, and hospitalization because of bleeding, pre-pregnancy BMI 25 and preeclampsia. Odds ratios with 95% confidence intervals were estimated to compare the pregnancy outcomes with interaction of women aged less than 35 years old to women aged 35 years or older categorized with insulin- or diet-treated GDM and normal glucose tolerance. p values for interactions between grouped variables, maternal age and GDM were calculated and they were not statistically significant. Women younger than 35 with normal glucose tolerance were used as the reference group. In subgroup analyses, women aged 35 years or older with GDM were first compared to the group of women with normal glucose tolerance aged 35 years or older, then these women were compared to women less than 35 years old separately in each category (normal glucose tolerance, diet-treated GDM, and insulintreated GDM).
Results After excluding cases with major congenital anomalies, there were 230 003 women less than 35 years old and 53 321 women aged 35 years or older. Of those aged less than 35 years, 19 422 (8.4%) had GDM, and 2845 (14.6%) of them had insulin-treated GDM. In the group of women aged 35 years or older, there were 7732 (14.5%) women with GDM, of which 1460 (18.9%) were insulin treated. Women of AMA had higher rates of preeclampsia, IVF and other fertility treatments, previous cesarean and prepregnancy BMI 425, than younger women aged less than 35. The background information of older and younger women with normal glucose tolerance, diet-treated and insulin-treated GDM is shown in Table 1. When compared to younger women with normal glucose tolerance aged less than 35 years old, the rates of preeclampsia, admission to NICU and shoulder dystocia were the highest in insulin-treated women aged 35 years or older, with over a threefold risk in admission to NICU and over a doubled risk for shoulder dystocia. The risk for LGA infants was increased in both older and younger women, with similar results in both groups (Table 2). In a subgroup analysis, diet- and insulin-treated GDM seemed to increase the incidence of the outcomes mentioned above in women 35 years or older; admission to NICU was still the highest (OR 3.07, CI 2.73–3.45) in women with insulin-treated GDM. The risk increases in the other outcomes (preeclampsia, shoulder dystocia and LGA) were approximately 40–90% compared to women with normal glucose tolerance of the same age (Table 3a). In another subgroup analysis, women of AMA with normal glucose tolerance and diet- or insulin-treated GDM were compared to younger women of the same categories. The effect of AMA was observed in very preterm delivery (528 weeks of gestation), fetal death, preeclampsia and admission to NICU. Of these variables, the increase in preeclampsia was statistically significant. However, the risks of preeclampsia
Pregnancy outcomes of AMA women with GDM
DOI: 10.3109/14767058.2014.986450
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Table 1. Background information of women aged less than 35 years and 35 years or older categorized with normal glucose tolerance, diet-treated GDM and insulin-treated GDM. 35 y
535 y Normal glucose tol.
Diet-treated
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Smoking % 24 333 (11.9) 2241 Preeclampsia % 8880 (4.2) 1161 Anemia % 3640 (1.7) 264 Placenta previa % 454 (0.2) 36 Late pregnancy bleeding % 2195 (1.0) 207 Single % 88 448 (42.0) 7033 Fertility treatment other than IVF % 2964 (1.4) 296 IVFv % 3228 (1.5) 328 Pre-pregnancy BMI 25 50 547 (26.6) 12 117 Previous cesarean % 13 913 (6.6) 1721 Primiparous women % 9488 (47.3) 6887
(13.3) (6.7) (1.6) (0.2) (1.2) (42.4) (1.7) (1.9) (71.9) (10.4) (41.5)
Insulin-treated 420 236 84 6 50 1164 38 83 2336 374 1147
(14.1) (7.7) (3.0) (0.2) (1.8) (40.9) (1.2) (2.7) (77.3) (13.1) (40.3)
p
Normal glucose tol.
Diet-treated Insulin-treated
50.001 3375 (7.68) 609 50.001 2318 (5.1) 536 50.001 812 (1.8) 99 0.998 183 (0.4) 33 50.001 613 (1.3) 82 0.288 14 962 (32.8) 2228 0.005 1297 (2.9) 171 50.001 1944 (4.3) 255 50.001 12 540 (31.7) 4470 50.001 6019 (13.2) 1056 50.001 10 524 (23.1) 1264
(9.6) (8.2) (1.6) (0.5) (1.3) (35.5) (2.6) (3.9) (70.3) (16.8) (20.1)
157 133 24 2 21 540 36 55 1181 280 299
(10.4) (8.6) (1.6) (0.1) (1.4) (37.0) (2.3) (3.5) (77.1) (19.2) (20.5)
Table 2. Women aged 35 years or older compared to women with normal glucose tolerance aged less than 35 years old. Adjusted OR (95% CI) Outcome Preterm delivery 528 Normal glucose tol. Diet Insulin Preterm delivery 28–31 Normal glucose tol. Diet Insulin Preterm delivery 32–36 Normal glucose tol. Diet Insulin Low Apgar score (57) at 5 min Normal glucose tol. Diet Insulin SGA (55th percentile) Normal glucose tol. Diet Insulin Fetal death Normal glucose tol. Diet Insulin Asphyxia Normal glucose tol. Diet Insulin Preeclampsia Normal glucose tol. Diet Insulin Admission to a neonatal unit Normal glucose tol. Diet Insulin Shoulder dystocia Normal glucose tol. Diet Insulin LGA (495th percentile) Normal glucose tol. Diet Insulin
35 y
535 y
35 y
750 (0.4) 16 (0.1) 6 (0.2)
261 (0.6) 3 (0.1) 9 (0.6)
1 0.24 (0.14–0.40) 0.50 (0.22–1.13)
1.54 (1.30–1.82) 0.12 (0.04–0.36) 1.46 (0.75–2.84)
1164 (0.6) 61 (0.4) 8 (0.3)
364 (0.8) 26 (0.4) 7 (0.5)
1 0.59 (0.45–0.77) 0.43 (0.21–0.86)
1.26 (1.10–1.45) 0.53 (0.35–0.81) 0.68 (0.32–1.45)
9750 (4.6) 770 (4.6) 216 (7.6)
2455 (5.4) 367 (5.9) 95 (6.5)
1 0.92 (0.84–0.99) 1.47 (1.27–1.70)
1.10 (1.04–1.16) 1.07 (0.96–1.20) 1.16 (0.93–1.44)
4083 (1.9) 373 (2.3) 79 (2.8)
969 (2.1) 136 (2.2) 45 (3.7)
1 0.89 (0.79–1.00) 1.06 (0.84–1.33)
1.12 (1.04–1.21) 0.86 (0.72–1.03) 1.18 (0.87–1.60)
10762 (5.1) 581 (3.5) 70 (2.5)
2232 (4.9) 235 (3.7) 43 (2.9)
1 0.72 (0.66–0.79) 0.49 (0.38–0.62)
1.04 (0.99–1.10) 0.81 (0.71–0.93) 0.58 (0.42–0.80)
662 (0.3) 37 (0.2) 4 (0.1)
221 (0.5) 11 (0.2) 6 (0.4)
1 0.64 (0.45–0.91) 0.40 (0.15–1.07)
1.51 (1.27–1.80) 0.48 (0.25–0.90) 1.16 (0.52–2.62)
8573 (4.1) 613 (3.7) 110 (3.9)
2121 (4.7) 253 (4.0) 68 (4.7)
1 0.92 (0.84–1.00) 1.06 (0.83–1.36)
1.08 (1.02–1.14) 0.97 (0.85–1.11) 1.06 (0.83–1.36)
8880 (4.2) 1161 (7.1) 238 (8.4)
2318 (5.1) 536 (8.6) 133 (9.0)
1 1.27 (1.19–1.36) 1.41 (1.22–1.62)
1.11 (1.05–1.17) 1.57 (1.42–1.72) 1.57 (1.30–1.88)
22557 (10.7) 2428 (14.6) 819 (28.8)
5471 (12.0) 987 (15.7) 475 (32.5)
1 1.26 (1.20–1.32) 2.78 (2.56–3.03)
1.07 (1.04–1.11) 1.25 (1.17–1.35) 3.30 (2.94–3.69)
479 (0.2) 87 (0.5) 14 (0.5)
113 (0.2) 31 (0.5) 8 (0.5)
1 1.88 (1.46–2.41) 1.83 (1.06–3.13)
1.19 (0.97–1.48) 1.66 (1.11–2.48) 2.12 (1.05–4.30)
7729 (3.7) 1456 (8.8) 354 (12.4)
2267 (5.0) 592 (9.4) 186 (12.7)
1 1.77 (1.66–1.88) 2.44 (2.17–1.75)
1.28 (1.21–1.34) 1.86 (1.69–2.04) 2.43 (2.07–2.86)
535 y
p 50.001 50.001 0.488 0.090 0.921 50.001 0.261 0.142 50.001 50.001 50.001
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J Matern Fetal Neonatal Med, Early Online: 1–5
Table 3. Pregnancy outcomes using first AMA women with normal glucose tolerance as a reference (row a) and then three groups of young women with either normal or abnormal glucose tolerance (further divided into those requiring diet or insulin for the treatment) as the reference groups (row b)*. Adjusted OR (95% CI)
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Outcome Preterm delivery 528 Normal glucose tol. Diet Insulin Preterm delivery 28–31 Normal glucose tol. Diet Insulin Preterm delivery 32–36 Normal glucose tol. Diet Insulin Low Apgar score (57) at 5 min. Normal glucose tol. Diet Insulin SGA (55th percentile) Normal glucose tol. Diet Insulin Fetal death Normal glucose tol. Diet Insulin Asphyxia Normal glucose tol. Diet Insulin Preeclampsia Normal glucose tol. Diet Insulin Admission to a neonatal Normal glucose tol. Diet Insulin Shoulder dystocia Normal glucose tol. Diet Insulin LGA (495th percentile) Normal glucose tol. Diet Insulin
a) 35 y
b) 535 y
35 y
1 0.08 (0.02–0.24) 0.95 (0.48–1.86)
1 1 1
1.54 (1.30–1.82) 0.49 (0.14–1.71) 2.90 (1.03–8.19)
1 0.42 (0.27–0.65) 0.54 (0.25–1.16)
1 1 1
1.26 (1.10–1.45) 0.90 (0.56–1.47) 1.60 (0.57–4.44)
1 0.98 (0.87–1.10) 1.05 (0.84–1.32)
1 1 1
1.10 (1.04–1.16) 1.17 (1.02–1.34) 0.79 (0.61–1.02)
1 0.77 (0.64–0.93) 1.05 (0.77–1.43)
1 1 1
1.12 (1.04–1.21) 0.97 (0.79–1.19) 1.11 (0.76–1.63)
1 0.78 (0.68–0.90) 0.56 (0.41–0.77)
1 1 1
1.04 (0.99–1.10) 1.13 (0.96–1.32) 1.19 (0.80–1.78)
1 0.32 (0.17–0.60) 0.77 (0.34–1.75)
1 1 1
1.51 (1.27–1.80) 0.74 (0.37–1.50) 2.93 (0.82–10.40)
1 0.90 (0.79–1.03) 0.98 (0.76–1.26)
1 1 1
1.08 (1.02–1.14) 1.06 (0.91–1.23) 1.18 (0.87–1.61)
1 1.41 (1.28–1.57) 1.42 (1.17–1.71) unit 1 1.17 (1.08–1.26) 3.07 (2.73–3.45)
1 1 1
1.11 (1.05–1.17) 1.23 (1.10–1.37) 1.23 (1.01–1.49)
1 1 1
1.07 (1.04–1.11) 1.00 (0.92–1.08) 1.18 (1.03–1.36)
1 1.39 (0.90–2.14) 1.78 (0.86–3.66)
1 1 1
1.19 (0.97–1.48) 0.88 (0.57–1.38) 1.16 (0.49–2.78)
1 1.45 (1.32–1.66) 1.91 (1.62–2.25)
1 1 1
1.28 (1.21–1.34) 1.05 (0.95–1.17) 1.00 (0.82–1.21)
*In other words, the table shows (a) effect of insulin and diet-treated gestational diabetes in women aged 35 years or older and (b) effect of AMA 35 years independently of GDM.
and admission to NICU increased by only approximately 20% (Table 3b).
Discussion The aim of this study was to compare pregnant women over 35 years old to pregnant women less than 35 years old in the following three categories: normal glucose tolerance, diet controlled GDM or insulin controlled GDM. The impact of AMA accompanied with abnormal glucose tolerance on adverse pregnancy outcomes has not been widely studied. Gestational diabetes was more prevalent in the over-35 age
group than in the younger age group. In this study, women of AMA had more insulin-treated GDM (18.9%) than younger women (14.6%). The main finding of our study was that AMA and treatment with either diet or insulin appeared to increase preeclampsia rates, which were approximately 25% more prevalent in women with AMA compared to women less than 35 with either diet- or insulin-treated GDM. It has been shown in previous studies that the combination of GDM and preeclampsia results in adverse pregnancy outcomes, such as preterm delivery and fetal growth restriction [8,12], which in turn implies that the present results are of importance. GDM requiring insulin also increased the risk of very preterm (528 weeks) delivery by threefold in older women compared to younger ones and, similarly, a maternal agedependent 20% increase in moderately preterm deliveries (between 32 and 36 weeks) was observed in GDM women. As expected, the combination of insulin-treated GDM and AMA led to an increased need for neonatal intensive care, whereas a risk increase was not observed in older GDM women on diet because the degree of prematurity was less severe than in women treated with insulin. Independently of age, GDM increased the risks for preeclampsia, admission to NICU, shoulder dystocia and LGA, whereas it was protective against SGA. These results are in line with previous studies [4,10,17]. Interestingly, children born to mothers with GDM were delivered in good condition, as judged by the Apgar score or the incidence of asphyxia. These results most likely reflect the level of highly standardized care offered to women with GDM. Independently of glucose tolerance, advanced maternal age of 35 years or older appears to increase the risks of preterm delivery, preeclampsia, fetal death and LGA. The observed risk increases were mostly between 10% and 50%. These risks led to a higher need for neonatal intensive care and higher incidences of low Apgar scores and asphyxia. These results are consistent with the current literature [8–12]. The strength of this study is the large population-based register data. It has been shown that the validity and coverage of Finnish health registers are good, as practically all events are included in the data, and the registries comply with reality [18]. The information of compulsory, population-based health registries is comprehensive and high in quality, and the information can be utilized in scientific research [19]. The limitations of our study concern the possibility of errors in the data collection, such as coding errors; however, due to the volume of data, the impact of these errors is likely to be minor. In conclusion, the prevalence of GDM increases with maternal age, as has been shown in previous studies [10,11,20,21]. AMA accompanied by abnormal glucose tolerance did not additively increase macrosomia and its sequelae, the major complications of GDM. However, the results showed that a maternal age of 35 years or more combined with GDM clearly had an increasing impact on preeclampsia. It has been suggested in previous research that treatment of GDM can prevent preeclampsia [17]. Therefore, future studies should evaluate the role of intensive preconception or early pregnancy counseling to prevent not only GDM but also preeclampsia in women of advanced age who are or are planning to become pregnant [22].
Pregnancy outcomes of AMA women with GDM
DOI: 10.3109/14767058.2014.986450
Declaration of interest The authors report no declarations of interest. This study was supported by the University of Eastern Finland, Department of Nursing Science, The Finnish Doctoral Education Network in Nursing Science and the Emil Aaltonen Foundation. The funding institutions were not involved in the study design, interpretation of results, manuscript preparation, or the decision to submit the article for publication. This research received no specific grant from any funding agency in the public, commercial, or not-forprofit sectors.
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Pregnancy outcomes in women aged 35 years or older with gestational diabetes – a registry-based study in Finland Reeta Lamminpää, Katri Vehviläinen-Julkunen, Mika Gissler, Tuomas Selander & Seppo Heinonen To cite this article: Reeta Lamminpää, Katri Vehviläinen-Julkunen, Mika Gissler, Tuomas Selander & Seppo Heinonen (2014): Pregnancy outcomes in women aged 35 years or older with gestational diabetes – a registry-based study in Finland, The Journal of Maternal-Fetal & Neonatal Medicine To link to this article: http://dx.doi.org/10.3109/14767058.2014.986450
Accepted author version posted online: 11 Nov 2014. Published online: 08 Dec 2014. Submit your article to this journal
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Date: 05 November 2015, At: 13:44
http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, Early Online: 1–5 ! 2014 Informa UK Ltd. DOI: 10.3109/14767058.2014.986450
ORIGINAL ARTICLE
Pregnancy outcomes in women aged 35 years or older with gestational diabetes – a registry-based study in Finland Reeta Lamminpa¨a¨1, Katri Vehvila¨inen-Julkunen2, Mika Gissler3,4, Tuomas Selander2, and Seppo Heinonen5,6
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1
Department of Nursing Science, University of Eastern Finland, Kuopio, Finland, 2Kuopio University Hospital, University of Eastern Finland, Kuopio, Finland, 3National Institute for Health and Welfare (THL), Helsinki, Finland, 4Nordic School for Public Health, Gothenburg, Sweden, 5Department of Obstetrics and Gynaecology, Kuopio University Hospital, University of Eastern Finland, Kuopio, Finland, and 6Helsinki University Central Hospital, Helsinki, Finland Abstract
Keywords
Objective: To compare pregnancy outcomes of women 35 years to women535 years with and without gestational diabetes. Methods: The data include 230 003 women 535 years and 53 321 women 35 years and their newborns from 2004 to 2008. In multivariate modeling, the main outcome measures were preterm delivery (528, 28–31 and 32–36 weeks’ gestation), Apgar scores 57 at 5 min, small for gestational age (SGA), fetal death, asphyxia, preeclampsia, admission to neonatal intensive care unit (NICU), shoulder dystocia and large for gestational age (LGA). Results: In comparison to women 535 with normal glucose tolerance, preeclampsia (OR 1.57, CI 1.30–1.88), admission to the NICU (OR 3.30, CI 2.94–3.69) and shoulder dystocia (OR 2.12, CI 1.05–4.30) were highest in insulin-treated women 35 years. In women 35, diet- and insulin-treated gestational diabetes mellitus (GDM) increased the rates of preeclampsia, shoulder dystocia and admission to NICU (OR 3.07 CI 2.73–3.45). The effect of advanced maternal age was observed in very preterm delivery (528 weeks), fetal death, preeclampsia and NICU. The increase in preeclampsia was statistically significant. Conclusions: GDM at advanced age is a high risk state and, more specifically, the risk caused by age and GDM appear to be increasing in preeclampsia.
Advanced maternal age, birth outcomes, diettreated GDM, insulin-treated GDM, normal glucose tolerance, register-based study
Introduction Gestational diabetes mellitus (GDM) is defined as abnormal glucose tolerance that develops or is recognized in pregnancy. The definition includes those women with previously undiagnosed diabetes, as well as those with pregnancy-induced high glucose levels. The diagnosis is based on glucose levels on a 75 g oral glucose tolerance test (OGTT). In Finland, the diagnostic criteria are defined as 5.3 mmol/l for fasting plasma glucose, 10.0 mmol/l after 1 h and 8.6 mmol/l after 2 h. The screening for GDM is performed for nearly all pregnant women with OGTT during gestational weeks 24–28. [1]. In Finland, the proportion of women with GDM has increased in recent years and was 13% in 2012 [2]. Risks factors associated with developing GDM are high maternal body mass index (BMI), advanced maternal age (AMA), polycystic ovarian syndrome, increasing maternal parity, previous GDM, family history of diabetes and twin pregnancy [3]. Women with GDM are at an increased risk
Address for correspondence: Reeta Lamminpa¨a¨, Department of Nursing Science, University of Eastern Finland, P.O Box 1627, Kuopio 70211, Finland. E-mail: [email protected]
History Received 22 September 2014 Revised 5 November 2014 Accepted 7 November 2014 Published online 8 December 2014
for cesarean delivery, macrosomia, fetal congenital malformations, preterm delivery and shoulder dystocia [4]. GDM also increases the likelihood of developing type 2 diabetes; therefore, screening for GDM enables the identification of women at increased risk of diabetes before disease onset and permits practitioners to begin preventive measures [3]. The phenomena of childbearing at an advanced age are a growing trend in developed countries. Usually AMA is defined as maternal age of 35 and older at the time of pregnancy [5]. AMA has been associated with poorer pregnancy outcomes and complications in pregnancy and labor and is an independent risk factor for adverse pregnancy outcomes [5–7]. In 2012, the proportion of women over 35 years old giving birth in Finland was 18% [2]. Women with GDM have been widely studied, but less is known about the effects of AMA on GDM. In previous studies, GDM has been related to obesity and preeclampsia, with a significant association between these conditions, as well as poorer pregnancy outcomes [8–12]. The aim of this study was to compare pregnancy outcomes of women over 35 years old to women less than 35 years old with and without GDM (categorized in normal glucose tolerance, diet-treated GDM and insulin-treated GDM).
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Methods The data for this study consist of information from the Medical Birth Register (MBR), the Hospital Discharge Register (HDR) and the Register of Congenital Malformations. Permission to use the data in this study was granted by the National Institute for Health and Welfare in September 2009 (THL/906/5.05.00/2009), as required by the national data protection legislation. Ethical considerations were performed by the register authorities. An ethical review board statement is not required for register-based studies in Finland. The MBR is a population-based registry established in 1987 and is currently maintained by the National Institute for Health and Welfare (THL). The MBR includes information on maternal and neonatal birth characteristics and perinatal outcomes of all women who have given birth in Finland and all newborns up to seven days of age. The form is filled out at hospitals and sent, mostly electronically, to THL [13]. The HDR was established in 1969 and it contains information on all aspects of inpatient care in public and private hospital visits and outpatient visits to public hospitals (since 1998). Hospitals send data electronically to THL [14]. The Register of Congenital Malformations is run by THL and contains nationwide data on congenital chromosomal and structural anomalies detected in stillborn and live-born infants and fetuses in pregnancies terminated due to fetal indication. The registration of anomalies began in 1963 [15]. The study data contains information on 292 667 women and their newborns from 2004 to 2008. Live births and stillbirths with major congenital anomalies were excluded (N ¼ 9343). The study population of the current study included women who were diagnosed with GDM. We compared women aged 35 years or older to women less than 35 years old. GDM was classified into diet- and insulintreated disease, which were compared to the normal glucose tolerance condition. Participants with gestational diabetes were identified in two ways. First, we included eligible women based on diagnoses recorded using International Statistical Classification of Diseases and Related Health Problems (10th revision) (ICD-10 codes; GDM: ICD-10 codes O24.4 and O24.9). Second, we identified participants in the data who were recorded as having a ‘‘pathological glucose tolerance test’’. Afterwards, we combined groups mentioned characterized as having ‘‘GDM’’ and separated those who were recorded as receiving ‘‘insulin treatment for GDM’’. The remainder was classified as undergoing ‘‘diet treatment’’. Statistical analyses were performed using the R-program version 2.15.2. Variables used in the binary logistic regression analysis were dichotomous and observations that had missing data values were excluded. The following definitions were used to record pregnancy outcomes: low Apgar scores at 5 min (0–6); preterm delivery, before 28, 28–31 and 32–36 weeks of gestation; small for gestational age (SGA), infants were considered small when the sex- and age-adjusted birth weight was below the 5th percentile according to the standard tables for the Finnish population data for all births [16]; large for gestational age (LGA), infants were considered large when the sex- and ageadjusted birth weight was above the 95th percentile [16].
J Matern Fetal Neonatal Med, Early Online: 1–5
Binary logistic regression adjusted for potential confounding factors, including smoking, anemia, placenta previa, In vitro fertilisation (IVF), fertility treatment other than IVF, previous caesarean section, and hospitalization because of bleeding, pre-pregnancy BMI 25 and preeclampsia. Odds ratios with 95% confidence intervals were estimated to compare the pregnancy outcomes with interaction of women aged less than 35 years old to women aged 35 years or older categorized with insulin- or diet-treated GDM and normal glucose tolerance. p values for interactions between grouped variables, maternal age and GDM were calculated and they were not statistically significant. Women younger than 35 with normal glucose tolerance were used as the reference group. In subgroup analyses, women aged 35 years or older with GDM were first compared to the group of women with normal glucose tolerance aged 35 years or older, then these women were compared to women less than 35 years old separately in each category (normal glucose tolerance, diet-treated GDM, and insulintreated GDM).
Results After excluding cases with major congenital anomalies, there were 230 003 women less than 35 years old and 53 321 women aged 35 years or older. Of those aged less than 35 years, 19 422 (8.4%) had GDM, and 2845 (14.6%) of them had insulin-treated GDM. In the group of women aged 35 years or older, there were 7732 (14.5%) women with GDM, of which 1460 (18.9%) were insulin treated. Women of AMA had higher rates of preeclampsia, IVF and other fertility treatments, previous cesarean and prepregnancy BMI 425, than younger women aged less than 35. The background information of older and younger women with normal glucose tolerance, diet-treated and insulin-treated GDM is shown in Table 1. When compared to younger women with normal glucose tolerance aged less than 35 years old, the rates of preeclampsia, admission to NICU and shoulder dystocia were the highest in insulin-treated women aged 35 years or older, with over a threefold risk in admission to NICU and over a doubled risk for shoulder dystocia. The risk for LGA infants was increased in both older and younger women, with similar results in both groups (Table 2). In a subgroup analysis, diet- and insulin-treated GDM seemed to increase the incidence of the outcomes mentioned above in women 35 years or older; admission to NICU was still the highest (OR 3.07, CI 2.73–3.45) in women with insulin-treated GDM. The risk increases in the other outcomes (preeclampsia, shoulder dystocia and LGA) were approximately 40–90% compared to women with normal glucose tolerance of the same age (Table 3a). In another subgroup analysis, women of AMA with normal glucose tolerance and diet- or insulin-treated GDM were compared to younger women of the same categories. The effect of AMA was observed in very preterm delivery (528 weeks of gestation), fetal death, preeclampsia and admission to NICU. Of these variables, the increase in preeclampsia was statistically significant. However, the risks of preeclampsia
Pregnancy outcomes of AMA women with GDM
DOI: 10.3109/14767058.2014.986450
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Table 1. Background information of women aged less than 35 years and 35 years or older categorized with normal glucose tolerance, diet-treated GDM and insulin-treated GDM. 35 y
535 y Normal glucose tol.
Diet-treated
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Smoking % 24 333 (11.9) 2241 Preeclampsia % 8880 (4.2) 1161 Anemia % 3640 (1.7) 264 Placenta previa % 454 (0.2) 36 Late pregnancy bleeding % 2195 (1.0) 207 Single % 88 448 (42.0) 7033 Fertility treatment other than IVF % 2964 (1.4) 296 IVFv % 3228 (1.5) 328 Pre-pregnancy BMI 25 50 547 (26.6) 12 117 Previous cesarean % 13 913 (6.6) 1721 Primiparous women % 9488 (47.3) 6887
(13.3) (6.7) (1.6) (0.2) (1.2) (42.4) (1.7) (1.9) (71.9) (10.4) (41.5)
Insulin-treated 420 236 84 6 50 1164 38 83 2336 374 1147
(14.1) (7.7) (3.0) (0.2) (1.8) (40.9) (1.2) (2.7) (77.3) (13.1) (40.3)
p
Normal glucose tol.
Diet-treated Insulin-treated
50.001 3375 (7.68) 609 50.001 2318 (5.1) 536 50.001 812 (1.8) 99 0.998 183 (0.4) 33 50.001 613 (1.3) 82 0.288 14 962 (32.8) 2228 0.005 1297 (2.9) 171 50.001 1944 (4.3) 255 50.001 12 540 (31.7) 4470 50.001 6019 (13.2) 1056 50.001 10 524 (23.1) 1264
(9.6) (8.2) (1.6) (0.5) (1.3) (35.5) (2.6) (3.9) (70.3) (16.8) (20.1)
157 133 24 2 21 540 36 55 1181 280 299
(10.4) (8.6) (1.6) (0.1) (1.4) (37.0) (2.3) (3.5) (77.1) (19.2) (20.5)
Table 2. Women aged 35 years or older compared to women with normal glucose tolerance aged less than 35 years old. Adjusted OR (95% CI) Outcome Preterm delivery 528 Normal glucose tol. Diet Insulin Preterm delivery 28–31 Normal glucose tol. Diet Insulin Preterm delivery 32–36 Normal glucose tol. Diet Insulin Low Apgar score (57) at 5 min Normal glucose tol. Diet Insulin SGA (55th percentile) Normal glucose tol. Diet Insulin Fetal death Normal glucose tol. Diet Insulin Asphyxia Normal glucose tol. Diet Insulin Preeclampsia Normal glucose tol. Diet Insulin Admission to a neonatal unit Normal glucose tol. Diet Insulin Shoulder dystocia Normal glucose tol. Diet Insulin LGA (495th percentile) Normal glucose tol. Diet Insulin
35 y
535 y
35 y
750 (0.4) 16 (0.1) 6 (0.2)
261 (0.6) 3 (0.1) 9 (0.6)
1 0.24 (0.14–0.40) 0.50 (0.22–1.13)
1.54 (1.30–1.82) 0.12 (0.04–0.36) 1.46 (0.75–2.84)
1164 (0.6) 61 (0.4) 8 (0.3)
364 (0.8) 26 (0.4) 7 (0.5)
1 0.59 (0.45–0.77) 0.43 (0.21–0.86)
1.26 (1.10–1.45) 0.53 (0.35–0.81) 0.68 (0.32–1.45)
9750 (4.6) 770 (4.6) 216 (7.6)
2455 (5.4) 367 (5.9) 95 (6.5)
1 0.92 (0.84–0.99) 1.47 (1.27–1.70)
1.10 (1.04–1.16) 1.07 (0.96–1.20) 1.16 (0.93–1.44)
4083 (1.9) 373 (2.3) 79 (2.8)
969 (2.1) 136 (2.2) 45 (3.7)
1 0.89 (0.79–1.00) 1.06 (0.84–1.33)
1.12 (1.04–1.21) 0.86 (0.72–1.03) 1.18 (0.87–1.60)
10762 (5.1) 581 (3.5) 70 (2.5)
2232 (4.9) 235 (3.7) 43 (2.9)
1 0.72 (0.66–0.79) 0.49 (0.38–0.62)
1.04 (0.99–1.10) 0.81 (0.71–0.93) 0.58 (0.42–0.80)
662 (0.3) 37 (0.2) 4 (0.1)
221 (0.5) 11 (0.2) 6 (0.4)
1 0.64 (0.45–0.91) 0.40 (0.15–1.07)
1.51 (1.27–1.80) 0.48 (0.25–0.90) 1.16 (0.52–2.62)
8573 (4.1) 613 (3.7) 110 (3.9)
2121 (4.7) 253 (4.0) 68 (4.7)
1 0.92 (0.84–1.00) 1.06 (0.83–1.36)
1.08 (1.02–1.14) 0.97 (0.85–1.11) 1.06 (0.83–1.36)
8880 (4.2) 1161 (7.1) 238 (8.4)
2318 (5.1) 536 (8.6) 133 (9.0)
1 1.27 (1.19–1.36) 1.41 (1.22–1.62)
1.11 (1.05–1.17) 1.57 (1.42–1.72) 1.57 (1.30–1.88)
22557 (10.7) 2428 (14.6) 819 (28.8)
5471 (12.0) 987 (15.7) 475 (32.5)
1 1.26 (1.20–1.32) 2.78 (2.56–3.03)
1.07 (1.04–1.11) 1.25 (1.17–1.35) 3.30 (2.94–3.69)
479 (0.2) 87 (0.5) 14 (0.5)
113 (0.2) 31 (0.5) 8 (0.5)
1 1.88 (1.46–2.41) 1.83 (1.06–3.13)
1.19 (0.97–1.48) 1.66 (1.11–2.48) 2.12 (1.05–4.30)
7729 (3.7) 1456 (8.8) 354 (12.4)
2267 (5.0) 592 (9.4) 186 (12.7)
1 1.77 (1.66–1.88) 2.44 (2.17–1.75)
1.28 (1.21–1.34) 1.86 (1.69–2.04) 2.43 (2.07–2.86)
535 y
p 50.001 50.001 0.488 0.090 0.921 50.001 0.261 0.142 50.001 50.001 50.001
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Table 3. Pregnancy outcomes using first AMA women with normal glucose tolerance as a reference (row a) and then three groups of young women with either normal or abnormal glucose tolerance (further divided into those requiring diet or insulin for the treatment) as the reference groups (row b)*. Adjusted OR (95% CI)
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Outcome Preterm delivery 528 Normal glucose tol. Diet Insulin Preterm delivery 28–31 Normal glucose tol. Diet Insulin Preterm delivery 32–36 Normal glucose tol. Diet Insulin Low Apgar score (57) at 5 min. Normal glucose tol. Diet Insulin SGA (55th percentile) Normal glucose tol. Diet Insulin Fetal death Normal glucose tol. Diet Insulin Asphyxia Normal glucose tol. Diet Insulin Preeclampsia Normal glucose tol. Diet Insulin Admission to a neonatal Normal glucose tol. Diet Insulin Shoulder dystocia Normal glucose tol. Diet Insulin LGA (495th percentile) Normal glucose tol. Diet Insulin
a) 35 y
b) 535 y
35 y
1 0.08 (0.02–0.24) 0.95 (0.48–1.86)
1 1 1
1.54 (1.30–1.82) 0.49 (0.14–1.71) 2.90 (1.03–8.19)
1 0.42 (0.27–0.65) 0.54 (0.25–1.16)
1 1 1
1.26 (1.10–1.45) 0.90 (0.56–1.47) 1.60 (0.57–4.44)
1 0.98 (0.87–1.10) 1.05 (0.84–1.32)
1 1 1
1.10 (1.04–1.16) 1.17 (1.02–1.34) 0.79 (0.61–1.02)
1 0.77 (0.64–0.93) 1.05 (0.77–1.43)
1 1 1
1.12 (1.04–1.21) 0.97 (0.79–1.19) 1.11 (0.76–1.63)
1 0.78 (0.68–0.90) 0.56 (0.41–0.77)
1 1 1
1.04 (0.99–1.10) 1.13 (0.96–1.32) 1.19 (0.80–1.78)
1 0.32 (0.17–0.60) 0.77 (0.34–1.75)
1 1 1
1.51 (1.27–1.80) 0.74 (0.37–1.50) 2.93 (0.82–10.40)
1 0.90 (0.79–1.03) 0.98 (0.76–1.26)
1 1 1
1.08 (1.02–1.14) 1.06 (0.91–1.23) 1.18 (0.87–1.61)
1 1.41 (1.28–1.57) 1.42 (1.17–1.71) unit 1 1.17 (1.08–1.26) 3.07 (2.73–3.45)
1 1 1
1.11 (1.05–1.17) 1.23 (1.10–1.37) 1.23 (1.01–1.49)
1 1 1
1.07 (1.04–1.11) 1.00 (0.92–1.08) 1.18 (1.03–1.36)
1 1.39 (0.90–2.14) 1.78 (0.86–3.66)
1 1 1
1.19 (0.97–1.48) 0.88 (0.57–1.38) 1.16 (0.49–2.78)
1 1.45 (1.32–1.66) 1.91 (1.62–2.25)
1 1 1
1.28 (1.21–1.34) 1.05 (0.95–1.17) 1.00 (0.82–1.21)
*In other words, the table shows (a) effect of insulin and diet-treated gestational diabetes in women aged 35 years or older and (b) effect of AMA 35 years independently of GDM.
and admission to NICU increased by only approximately 20% (Table 3b).
Discussion The aim of this study was to compare pregnant women over 35 years old to pregnant women less than 35 years old in the following three categories: normal glucose tolerance, diet controlled GDM or insulin controlled GDM. The impact of AMA accompanied with abnormal glucose tolerance on adverse pregnancy outcomes has not been widely studied. Gestational diabetes was more prevalent in the over-35 age
group than in the younger age group. In this study, women of AMA had more insulin-treated GDM (18.9%) than younger women (14.6%). The main finding of our study was that AMA and treatment with either diet or insulin appeared to increase preeclampsia rates, which were approximately 25% more prevalent in women with AMA compared to women less than 35 with either diet- or insulin-treated GDM. It has been shown in previous studies that the combination of GDM and preeclampsia results in adverse pregnancy outcomes, such as preterm delivery and fetal growth restriction [8,12], which in turn implies that the present results are of importance. GDM requiring insulin also increased the risk of very preterm (528 weeks) delivery by threefold in older women compared to younger ones and, similarly, a maternal agedependent 20% increase in moderately preterm deliveries (between 32 and 36 weeks) was observed in GDM women. As expected, the combination of insulin-treated GDM and AMA led to an increased need for neonatal intensive care, whereas a risk increase was not observed in older GDM women on diet because the degree of prematurity was less severe than in women treated with insulin. Independently of age, GDM increased the risks for preeclampsia, admission to NICU, shoulder dystocia and LGA, whereas it was protective against SGA. These results are in line with previous studies [4,10,17]. Interestingly, children born to mothers with GDM were delivered in good condition, as judged by the Apgar score or the incidence of asphyxia. These results most likely reflect the level of highly standardized care offered to women with GDM. Independently of glucose tolerance, advanced maternal age of 35 years or older appears to increase the risks of preterm delivery, preeclampsia, fetal death and LGA. The observed risk increases were mostly between 10% and 50%. These risks led to a higher need for neonatal intensive care and higher incidences of low Apgar scores and asphyxia. These results are consistent with the current literature [8–12]. The strength of this study is the large population-based register data. It has been shown that the validity and coverage of Finnish health registers are good, as practically all events are included in the data, and the registries comply with reality [18]. The information of compulsory, population-based health registries is comprehensive and high in quality, and the information can be utilized in scientific research [19]. The limitations of our study concern the possibility of errors in the data collection, such as coding errors; however, due to the volume of data, the impact of these errors is likely to be minor. In conclusion, the prevalence of GDM increases with maternal age, as has been shown in previous studies [10,11,20,21]. AMA accompanied by abnormal glucose tolerance did not additively increase macrosomia and its sequelae, the major complications of GDM. However, the results showed that a maternal age of 35 years or more combined with GDM clearly had an increasing impact on preeclampsia. It has been suggested in previous research that treatment of GDM can prevent preeclampsia [17]. Therefore, future studies should evaluate the role of intensive preconception or early pregnancy counseling to prevent not only GDM but also preeclampsia in women of advanced age who are or are planning to become pregnant [22].
Pregnancy outcomes of AMA women with GDM
DOI: 10.3109/14767058.2014.986450
Declaration of interest The authors report no declarations of interest. This study was supported by the University of Eastern Finland, Department of Nursing Science, The Finnish Doctoral Education Network in Nursing Science and the Emil Aaltonen Foundation. The funding institutions were not involved in the study design, interpretation of results, manuscript preparation, or the decision to submit the article for publication. This research received no specific grant from any funding agency in the public, commercial, or not-forprofit sectors.
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