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doi: 10.1111/ppe.12198
271
The Risk of Gestational Diabetes Mellitus Following Bereavement: A Cohort Study from Denmark and Sweden Krisztina D. László,a Jørn Olsen,b,c Jiong Li,b Martina Persson,a Mogens Vestergaard,d,e Tobias Svensson,a Carsten Obel,d,e,f Sven Cnattingiusa a
Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden b
Section for Epidemiology, Department of Public Health
d
Research Unit for General Practice, Department of Public Health
e
Section for General Practice, Department of Public Health, Aarhus University
f
Research Program for Mental Child Health, Department of Public Health, Aarhus University and Institute of Handicap and Communication, Aarhus, Denmark c
Department of Epidemiology, School of Public Health, University of California, Los Angeles, CA
Abstract Background: We investigated whether bereavement of a close family member – a source of severe psychological stress exposure – the year before pregnancy is associated with gestational diabetes mellitus (GDM). Methods: We studied pregnant women with livebirths in Denmark during 1994–2008 and with births in Sweden during 1987–2006 (n = 2 569 446). We obtained data on death of women’s parents, siblings, and older children, and on demographic and health- and pregnancy-related factors through linkage between nationwide registers. Results: In multivariable models, death of a close relative the year before pregnancy was associated with a 14% increased odds of GDM [95% confidence intervals (CIs) 1.03, 1.26]. The odds ratios corresponding to the loss of a child, parent, and sibling were 1.51 (95% CI: 1.17, 1.95), 1.12 (95% CI: 1.00, 1.25), and 0.68 (95% CI: 0.40, 1.25), respectively. Deaths due to cardiovascular diseases or diabetes were more closely related to the risk of GDM than other types of deaths. We found no association between unnatural deaths and the risk of GDM. Conclusions: Death of a close relative the year before pregnancy was associated with a modestly increased GDM risk. Our findings according to the relative’s cause of death suggest that differences in screening for GDM among exposure groups and residual confounding by familial factors related to metabolic and cardiovascular diseases may have contributed to this association. If there is a causal stress effect on GDM in this predominantly Nordic population, it is most likely small. Keywords: stress, bereavement, gestational diabetes mellitus, cohort study.
Gestational diabetes mellitus (GDM), defined as glucose intolerance that is initiated by or is detected during pregnancy,1 is a common condition that generally affects between 2 and 10% of pregnancies in a population.2–4 It is associated with a number of perinatal complications1,5–7 and with increased risks of type 2 diabetes and cardiovascular diseases (CVD) for the mother as well as for the offspring.6,7 The aetiology of GDM is poorly understood, but – as in the case of type 2 diabetes – its causes may be both genetic and environmental.6 A recent study Correspondence: Krisztina D. László, Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska University Hospital and Karolinska Institute, Eugeniahemmet T2, 17176 Stockholm, Sweden. E-mail: [email protected]
© 2015 John Wiley & Sons Ltd Paediatric and Perinatal Epidemiology, 2015, 29, 271–280
suggested that stressful life events the year before delivery may increase the risk of GDM.8 However, exposure to antenatal stress was assessed several months after delivery8 and recall bias is possible. We are not aware of other studies estimating the effect of stress on the risk of GDM, but there is some, although not consistent, evidence to suggest that chronic psychosocial stress may influence the development of type 2 diabetes.9–13 Possible mechanisms involve direct effects of stress hormones, including increased glucose production, impaired insulin secretion, and insulin resistance.14,15 In addition, stress may contribute indirectly to the development of gestational and type 2 diabetes by changes in diet and lifestyle.16 Death of a close family member is one of the most severe sources of stress.17–20 Losses of children17,21 and
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K. D. László et al.
sudden, unnatural deaths22 are considered particularly stressful and are often associated with complicated grief.23,24 Using prospectively collected data from Danish and Swedish nationwide registries, we investigated whether death of a close family member the year before pregnancy is associated with an increased risk of GDM, and whether this association differs according to the relative’s cause of death and the mother’s relationship to the deceased.
Methods Study population and data sources We studied pregnancies resulting in livebirths during 1994–2008 recorded in the Danish Medical Birth Register (DMBR) and pregnancies with births during 1987–2006 recorded in the Swedish Medical Birth Register (SMBR) (n = 3 087 434) (Figure 1). Both registries have been computerized since 1973 and include prospectively collected data from early pregnancy until the neonatal period for approximately 99% of births in the countries.18–20,25,26 To obtain data on death of family members and on demographic and health-related characteristics, the two birth registries were linked to several national registries by means of the unique personal identification number assigned to all residents in both countries.18–20 The DMBR was linked to the Danish
n = 3 087 434 births recorded in the Medical Birth Register during 1994–2008 in Denmark and during 1987–2006 in Sweden
Exclusions n = 59 768 births with gestaonal age missing, shorter than 22 weeks, or longer than 45 (in Denmark)/46 weeks (in Sweden)
n = 3 027 666 births n = 409 045 births with missing register links to the woman’s parents
n = 2 618 621 births n = 29 416 births by women who lost a relave during pregnancy and who were unexposed during the year before pregnancy n = 2 589 205 births n = 19 759 births where the mother had a history of diabetes (pre-gestaonal diabetes or GDM in a previous pregnancy) n = 2 569 446 births were included in the study
Figure 1. Flow chart of study participants.
Civil Registration System, the National Hospital Register, the Psychiatric Central Register, and the Integrated Database for Longitudinal Labour Market Research.19,20 The SMBR was linked to the MultiGeneration Register, the Cause of Death Register, the Patient Register, and the Education Register.18–20 Coding of medical conditions and causes of death in both countries are based on the International Classification of Diseases (ICD). Denmark used ICD-8 during 1967–1993 and ICD-10 from 1994 onwards, whereas in Sweden ICD-8 was used during 1968–1986, ICD-9 during 1987–1996, and ICD-10 since 1997. The ICD codes we used to define medical conditions or to classify causes of death are presented in the Appendix. We restricted our study period to 1994–2008 in Denmark and to 1987–2006 in Sweden because in ICD-8 it is not possible to separate GDM from pregestational (type 1 or type 2) diabetes. We excluded (i) pregnancies with missing information on gestational age, shorter than 22 weeks or longer than 45 weeks (in Denmark)/46 weeks (in Sweden); (ii) women without registry links to parents; (iii) who lost a close family member (i.e. parent, sibling, older child, and partner) during pregnancy and who were unexposed the year before pregnancy (see Study variables section); or (iv) who had a history of diabetes. History of diabetes was defined as having a diagnosis of (i) pre-gestational type 1 or type 2 diabetes or (ii) GDM in a previous pregnancy recoded in the Danish National Hospital Register or in the SMBR. After these exclusions, our study population consisted of 2 569 446 pregnancies (Figure 1). After excluding women with a diagnosis of pre-gestational type 1 or type 2 diabetes, the overall rate of GDM was 8.91 per 1000 (10.94 per 1000 in Denmark and 7.89 per 1000 in Sweden); the corresponding rates were 6.93 per 1000 in the group included (9.36 per 1000 in Denmark and 5.74 per 1000 in Sweden) and 19.14 per 1000 in the group excluded from our study (18.04 per 1000 in Denmark and 19.80 per 1000 in Sweden). Compared with women included in the study, excluded women were more likely to be from Denmark than Sweden, be 35 years or older, be multiparous, have lower education, and originate outside Denmark/Sweden; they were less likely to be aged 25–29 years and to deliver during 1987–1991. The study was approved by the Scientific Ethics Committee of Central Region Jutland (no. M-20100252), the Danish Data Protection Agency in Copenhagen (no. 2008-41-2680), and the Research © 2015 John Wiley & Sons Ltd Paediatric and Perinatal Epidemiology, 2015, 29, 271–280
Bereavement and gestational diabetes Ethics Committee at Karolinska Institutet, Stockholm (no. 2008/4:6).
Exposure We identified women’s close family members in the Danish Civil Registration System and in the Swedish Multi-Generation Register. The major criterion for this linkage was the woman’s and her family members’ residency in Denmark and Sweden, respectively. Information on the relatives’ date and cause of death was obtained from the Danish Civil Registration System and from the Swedish Cause of Death Register. To ensure that bereavement preceded GDM (which in Sweden was recorded only at the time of delivery), we defined exposure as the loss of a parent, sibling, or child the year before pregnancy. We categorized exposed women based on (i) their relationship to the deceased (parent, sibling, or older child) and (ii) the cause of the relative’s death (unnatural death, death due to CVD or diabetes, or death due to other natural causes).
Outcome Women diagnosed with GDM were identified in the Danish National Hospital Register and in the SMBR. Both countries have a national screening programme for GDM as part of the antenatal care programme. There are a few local variations,27 but selection for the oral glucose tolerance test (OGTT) is based primarily on (i) abnormal glucosuria tests in Denmark/random capillary plasma glucose measurements in Sweden and/or (ii) traditional risk factors, usually GDM in a previous pregnancy, previous delivery of an infant with a birthweight ≥4500 g [in Sweden also previous delivery of a large for gestational age (LGA) infant], family history of diabetes mellitus, and obesity.28,29 Women are tested for glucosuria/hyperglycaemia repeatedly during pregnancy; in most cases the first measurement takes place in the first trimester.29 In Denmark, an OGTT is offered after a positive test, irrespective of gestational age.29 In addition, women with a high underlying risk of GDM undergo an OGTT in gestational weeks 14–20 (if the woman has a history of GDM or two other traditional risk factors) and gestational weeks 27–30 (in case of any traditional risk factor or if the woman had an OGTT earlier in pregnancy, but had not received a diagnosis of diabetes).29 In Sweden, the OGTT is usually performed © 2015 John Wiley & Sons Ltd Paediatric and Perinatal Epidemiology, 2015, 29, 271–280
273
between gestational weeks 24 and 28,30 but may be offered earlier in some regions, if hyperglycaemia or specific traditional risk factors are present.31 In the southern part of Sweden, all pregnant women undergo a simplified 2-h OGTT (omitting the fasting blood glucose measurement) in gestational week 28 since 1995.32 The main diagnostic criteria for GDM are based on the Diabetes in Pregnancy Study Group recommendation from 1991, i.e. a fasting plasma glucose ≥7.0 mmol/L and/or 2-h plasma glucose ≥10 mmol/L after a 75-g OGTT. As GDM may have been classified as unspecified diabetes in pregnancy in some cases, we also defined the combination of GDM and unspecified diabetes during pregnancy as a secondary outcome.
Other variables Information on date of birth, maternal age at delivery, parity, smoking in early pregnancy, length of gestation, birthweight, and the number of fetuses in pregnancy was obtained from the birth registries. Estimation of gestational age was based usually on ultrasound examinations performed in early second trimester; if this was not available – primarily before the early 1990s – information from the last menstrual period was used.26,29 The ultrasound examination is free of charge and the great majority of the pregnant women (95% in Sweden)33 attend it. We defined LGA as a birthweight that is above the 90th percentile of the Swedish sex-specific standard curve for normal fetal growth.34 In addition, data on maternal height and weight in early pregnancy have been registered in Sweden since 1992; women with a body mass index of 30 or higher were considered obese. Data on chronic hypertension were retrieved from the Danish National Hospital Register and from the SMBR. Maternal psychiatric diagnoses were obtained from the Danish Central Psychiatric Register and the Swedish Patient Register. The Danish National Hospital Register and the Swedish Patient Register provided data on diagnoses of diabetes mellitus in the women’s parents and siblings; information on CVD of these relatives was available only from the Danish National Hospital Register. The Danish National Hospital Register contains all in-hospital diagnoses in the country since 1977 and also all outpatient diagnoses since 1995. The Danish Central Psychiatric Register contains all diagnoses from psychiatric hospitals in the country since 1969;
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data from outpatient psychiatric care centres have been included since 1995. The Swedish Patient Register started in 1964; the geographic coverage of the registry increased gradually until 1987, when it became nationwide and covered all inpatient diagnoses in the country. Information on maternal education was obtained from the Swedish Education Register and from the Danish Integrated Database for Longitudinal Labour Market Research. In Denmark, we also obtained information on women’s citizenship from the Integrated Database for Longitudinal Labour Market Research, while in Sweden we obtained information on women’s country of birth from the SMBR.
Statistical analysis We used logistic regression models to estimate the odds of GDM according to exposure to death of a close relative the year before pregnancy. Analysis were performed with (i) the loss of any relative the year before pregnancy and with exposure categories based on (ii) the cause of death and (iii) the woman’s relationship to the deceased. Our primary models included the following potential confounders: country (Denmark or Sweden), year of delivery, maternal age at delivery, country of origin, education, parity, chronic hypertension, psychiatric disorder, and family history of diabetes mellitus before the exposure period. In addition, we adjusted for (i) family history of CVD in analysis restricted to the Danish cohort and (ii) for obesity among women who gave birth in Sweden in 1992 or later. We repeated our analyses after excluding women who reported smoking in early pregnancy. We re-ran analysis after excluding women with stillbirths from the Swedish cohort. In case a woman lost several relatives during the exposure period, in the primary analyses we gave coding priority to the death which occurred first. We performed secondary analyses with the number of relatives (one vs. none and two or three vs. none) who died during the year before pregnancy. To study whether the association between bereavement of any relative and GDM differed by country, year of delivery, maternal age, education, country of origin, obesity, chronic hypertension, previous psychiatric disorder, family history of diabetes mellitus, and the number of fetuses in the pregnancy, we conducted stratified analysis and performed tests of interaction in multiplicative models.
We repeated the main analysis with the combined outcome of GDM and unspecified diabetes during pregnancy. In addition, to study whether the investigated association differed according to the severity of the disease, we re-ran the main analysis among women with singleton pregnancies after categorizing GDM as presenting with or without delivery of a LGA infant; we hypothesized that GDM with LGA is more severe than GDM without LGA.35
Results A total of 17 799 (6.93 per 1000) women included in the study were diagnosed with GDM. The prevalence of the studied demographic, lifestyle, and healthrelated covariates in the study population and the rate of GDM according to the categories of these covariates is presented in Table 1. Altogether 42 640 (1.7%) women experienced death of a close relative the year before pregnancy (Table 2). Compared with women who did not lose a close relative the year before pregnancy, exposed women had higher odds of GDM (Table 2). The adjusted odds ratios (ORs) corresponding to the loss of a child, parent, and sibling were 1.51 [95% confidence interval (CI): 1.17, 1.95], 1.12 (95% CI: 1.00, 1.25), and 0.68 (95% CI: 0.40, 1.25), respectively (Table 3). Deaths due to CVD or diabetes were more closely related to women’s risk of GDM than other type of deaths. The association corresponding to the loss of a parent was stronger for deaths due to diabetes than CVD; the ORs were 1.87 (95% CI: 1.16, 3.01) and 1.37 (95% CI: 1.15, 1.63), respectively (data not shown in table). We observed an increased GDM risk also among women who lost an older child due to natural deaths other than CVD or diabetes. We found no association between unnatural deaths and the outcome (Tables 2, 3). The association between death of any relative the year before pregnancy and GDM was not considerably altered after (i) adjustment for family history of CVD in analysis restricted to the Danish cohort [OR: 1.13 (95% CI: 0.98, 1.31) before and 1.12 (95% CI: 0.97, 1.30) after adjustment]; (ii) adjustment for prepregnancy obesity among women who gave birth in Sweden in 1992 or later [OR: 1.23 (95% CI: 1.04, 1.46) before and 1.18 (95% CI: 0.99, 1.40) after adjustment]; (iii) excluding women who reported smoking in the first trimester [OR 1.12 (95% CI: 1.01, 1.25) among women with data on smoking before exclusion and 1.12 (95% CI: 0.99, 1.26) after exclusion]; or (iv) © 2015 John Wiley & Sons Ltd Paediatric and Perinatal Epidemiology, 2015, 29, 271–280
Bereavement and gestational diabetes
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Table 1. Characteristics of study participants Total Characteristics Country Sweden Denmark Age at offspring’s birth (in years) 19 or less 20–24 25–29 30–34 35 or more Highest education Basic education Secondary education College or university Missing Country of origin Denmark or Sweden Other country Missing Year of offspring’s birth 1987–1991 1992–1996 1997–2001 2002–2008 Parity Primipara Multipara Number of fetuses in the pregnancy Singleton Multiple Missing Stillbirth No Yes Missing Smoking in early pregnancy No Yes Missing Body mass indexb ≥30 No Yes Missing Psychiatric diagnosis prior to the year preceding pregnancy No Yes Chronic hypertension No Yes Diabetes mellitus (type 1 and 2) in women’s parents or siblings prior to the year preceding pregnancy No Yes CVD in women’s parents or siblings prior to the year preceding pregnancyc No Yes Missing a
GDM
n
(%)
Rate per 1000
1 725 760 843 686
67.16 32.84
5.74 9.36
51 121 411 072 924 832 818 830 363 591
1.99 16.00 35.99 31.87 14.15
3.17 4.23 5.45 7.67 12.60
316 747 1 185 379 1 0475 512 19 809
12.33 46.13 40.77 0.77
8.80 6.92 6.30 11.01
2 476 457 91 638 1 351
96.38 3.57 0.05
6.74 11.87 12.58
498 493 631 663 644 962 794 328
19.40 24.58 25.10 30.91
4.74 5.82 6.27 9.71
1 115 533 1 453 913
43.42 56.58
6.72 7.09
2 486 880 82 438 128
96.79 3.21 0
6.80 10.80 15.63
1 720 141 5 619 843 686
66.95 0.22 32.84
5.74 6.94 9.36
1 932 474 447 810 189 162
75.21 17.43 7.36
6.62 6.66 10.66
953 671 94 839 1 520 936
37.12 3.69 59.19
4.54 22.39 7.46
2 503 187 66 259
97.42 2.58
6.86 9.40
2 556 184 13 262
99.48 0.52
6.82 27.60
2 509 647 59 799
97.67 2.33
6.44 27.38
505 152 338 534 1 725 760
19.66 13.18 67.16
7.84 11.62 5.74
P-valuea
doi: 10.1111/ppe.12198
271
The Risk of Gestational Diabetes Mellitus Following Bereavement: A Cohort Study from Denmark and Sweden Krisztina D. László,a Jørn Olsen,b,c Jiong Li,b Martina Persson,a Mogens Vestergaard,d,e Tobias Svensson,a Carsten Obel,d,e,f Sven Cnattingiusa a
Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden b
Section for Epidemiology, Department of Public Health
d
Research Unit for General Practice, Department of Public Health
e
Section for General Practice, Department of Public Health, Aarhus University
f
Research Program for Mental Child Health, Department of Public Health, Aarhus University and Institute of Handicap and Communication, Aarhus, Denmark c
Department of Epidemiology, School of Public Health, University of California, Los Angeles, CA
Abstract Background: We investigated whether bereavement of a close family member – a source of severe psychological stress exposure – the year before pregnancy is associated with gestational diabetes mellitus (GDM). Methods: We studied pregnant women with livebirths in Denmark during 1994–2008 and with births in Sweden during 1987–2006 (n = 2 569 446). We obtained data on death of women’s parents, siblings, and older children, and on demographic and health- and pregnancy-related factors through linkage between nationwide registers. Results: In multivariable models, death of a close relative the year before pregnancy was associated with a 14% increased odds of GDM [95% confidence intervals (CIs) 1.03, 1.26]. The odds ratios corresponding to the loss of a child, parent, and sibling were 1.51 (95% CI: 1.17, 1.95), 1.12 (95% CI: 1.00, 1.25), and 0.68 (95% CI: 0.40, 1.25), respectively. Deaths due to cardiovascular diseases or diabetes were more closely related to the risk of GDM than other types of deaths. We found no association between unnatural deaths and the risk of GDM. Conclusions: Death of a close relative the year before pregnancy was associated with a modestly increased GDM risk. Our findings according to the relative’s cause of death suggest that differences in screening for GDM among exposure groups and residual confounding by familial factors related to metabolic and cardiovascular diseases may have contributed to this association. If there is a causal stress effect on GDM in this predominantly Nordic population, it is most likely small. Keywords: stress, bereavement, gestational diabetes mellitus, cohort study.
Gestational diabetes mellitus (GDM), defined as glucose intolerance that is initiated by or is detected during pregnancy,1 is a common condition that generally affects between 2 and 10% of pregnancies in a population.2–4 It is associated with a number of perinatal complications1,5–7 and with increased risks of type 2 diabetes and cardiovascular diseases (CVD) for the mother as well as for the offspring.6,7 The aetiology of GDM is poorly understood, but – as in the case of type 2 diabetes – its causes may be both genetic and environmental.6 A recent study Correspondence: Krisztina D. László, Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska University Hospital and Karolinska Institute, Eugeniahemmet T2, 17176 Stockholm, Sweden. E-mail: [email protected]
© 2015 John Wiley & Sons Ltd Paediatric and Perinatal Epidemiology, 2015, 29, 271–280
suggested that stressful life events the year before delivery may increase the risk of GDM.8 However, exposure to antenatal stress was assessed several months after delivery8 and recall bias is possible. We are not aware of other studies estimating the effect of stress on the risk of GDM, but there is some, although not consistent, evidence to suggest that chronic psychosocial stress may influence the development of type 2 diabetes.9–13 Possible mechanisms involve direct effects of stress hormones, including increased glucose production, impaired insulin secretion, and insulin resistance.14,15 In addition, stress may contribute indirectly to the development of gestational and type 2 diabetes by changes in diet and lifestyle.16 Death of a close family member is one of the most severe sources of stress.17–20 Losses of children17,21 and
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K. D. László et al.
sudden, unnatural deaths22 are considered particularly stressful and are often associated with complicated grief.23,24 Using prospectively collected data from Danish and Swedish nationwide registries, we investigated whether death of a close family member the year before pregnancy is associated with an increased risk of GDM, and whether this association differs according to the relative’s cause of death and the mother’s relationship to the deceased.
Methods Study population and data sources We studied pregnancies resulting in livebirths during 1994–2008 recorded in the Danish Medical Birth Register (DMBR) and pregnancies with births during 1987–2006 recorded in the Swedish Medical Birth Register (SMBR) (n = 3 087 434) (Figure 1). Both registries have been computerized since 1973 and include prospectively collected data from early pregnancy until the neonatal period for approximately 99% of births in the countries.18–20,25,26 To obtain data on death of family members and on demographic and health-related characteristics, the two birth registries were linked to several national registries by means of the unique personal identification number assigned to all residents in both countries.18–20 The DMBR was linked to the Danish
n = 3 087 434 births recorded in the Medical Birth Register during 1994–2008 in Denmark and during 1987–2006 in Sweden
Exclusions n = 59 768 births with gestaonal age missing, shorter than 22 weeks, or longer than 45 (in Denmark)/46 weeks (in Sweden)
n = 3 027 666 births n = 409 045 births with missing register links to the woman’s parents
n = 2 618 621 births n = 29 416 births by women who lost a relave during pregnancy and who were unexposed during the year before pregnancy n = 2 589 205 births n = 19 759 births where the mother had a history of diabetes (pre-gestaonal diabetes or GDM in a previous pregnancy) n = 2 569 446 births were included in the study
Figure 1. Flow chart of study participants.
Civil Registration System, the National Hospital Register, the Psychiatric Central Register, and the Integrated Database for Longitudinal Labour Market Research.19,20 The SMBR was linked to the MultiGeneration Register, the Cause of Death Register, the Patient Register, and the Education Register.18–20 Coding of medical conditions and causes of death in both countries are based on the International Classification of Diseases (ICD). Denmark used ICD-8 during 1967–1993 and ICD-10 from 1994 onwards, whereas in Sweden ICD-8 was used during 1968–1986, ICD-9 during 1987–1996, and ICD-10 since 1997. The ICD codes we used to define medical conditions or to classify causes of death are presented in the Appendix. We restricted our study period to 1994–2008 in Denmark and to 1987–2006 in Sweden because in ICD-8 it is not possible to separate GDM from pregestational (type 1 or type 2) diabetes. We excluded (i) pregnancies with missing information on gestational age, shorter than 22 weeks or longer than 45 weeks (in Denmark)/46 weeks (in Sweden); (ii) women without registry links to parents; (iii) who lost a close family member (i.e. parent, sibling, older child, and partner) during pregnancy and who were unexposed the year before pregnancy (see Study variables section); or (iv) who had a history of diabetes. History of diabetes was defined as having a diagnosis of (i) pre-gestational type 1 or type 2 diabetes or (ii) GDM in a previous pregnancy recoded in the Danish National Hospital Register or in the SMBR. After these exclusions, our study population consisted of 2 569 446 pregnancies (Figure 1). After excluding women with a diagnosis of pre-gestational type 1 or type 2 diabetes, the overall rate of GDM was 8.91 per 1000 (10.94 per 1000 in Denmark and 7.89 per 1000 in Sweden); the corresponding rates were 6.93 per 1000 in the group included (9.36 per 1000 in Denmark and 5.74 per 1000 in Sweden) and 19.14 per 1000 in the group excluded from our study (18.04 per 1000 in Denmark and 19.80 per 1000 in Sweden). Compared with women included in the study, excluded women were more likely to be from Denmark than Sweden, be 35 years or older, be multiparous, have lower education, and originate outside Denmark/Sweden; they were less likely to be aged 25–29 years and to deliver during 1987–1991. The study was approved by the Scientific Ethics Committee of Central Region Jutland (no. M-20100252), the Danish Data Protection Agency in Copenhagen (no. 2008-41-2680), and the Research © 2015 John Wiley & Sons Ltd Paediatric and Perinatal Epidemiology, 2015, 29, 271–280
Bereavement and gestational diabetes Ethics Committee at Karolinska Institutet, Stockholm (no. 2008/4:6).
Exposure We identified women’s close family members in the Danish Civil Registration System and in the Swedish Multi-Generation Register. The major criterion for this linkage was the woman’s and her family members’ residency in Denmark and Sweden, respectively. Information on the relatives’ date and cause of death was obtained from the Danish Civil Registration System and from the Swedish Cause of Death Register. To ensure that bereavement preceded GDM (which in Sweden was recorded only at the time of delivery), we defined exposure as the loss of a parent, sibling, or child the year before pregnancy. We categorized exposed women based on (i) their relationship to the deceased (parent, sibling, or older child) and (ii) the cause of the relative’s death (unnatural death, death due to CVD or diabetes, or death due to other natural causes).
Outcome Women diagnosed with GDM were identified in the Danish National Hospital Register and in the SMBR. Both countries have a national screening programme for GDM as part of the antenatal care programme. There are a few local variations,27 but selection for the oral glucose tolerance test (OGTT) is based primarily on (i) abnormal glucosuria tests in Denmark/random capillary plasma glucose measurements in Sweden and/or (ii) traditional risk factors, usually GDM in a previous pregnancy, previous delivery of an infant with a birthweight ≥4500 g [in Sweden also previous delivery of a large for gestational age (LGA) infant], family history of diabetes mellitus, and obesity.28,29 Women are tested for glucosuria/hyperglycaemia repeatedly during pregnancy; in most cases the first measurement takes place in the first trimester.29 In Denmark, an OGTT is offered after a positive test, irrespective of gestational age.29 In addition, women with a high underlying risk of GDM undergo an OGTT in gestational weeks 14–20 (if the woman has a history of GDM or two other traditional risk factors) and gestational weeks 27–30 (in case of any traditional risk factor or if the woman had an OGTT earlier in pregnancy, but had not received a diagnosis of diabetes).29 In Sweden, the OGTT is usually performed © 2015 John Wiley & Sons Ltd Paediatric and Perinatal Epidemiology, 2015, 29, 271–280
273
between gestational weeks 24 and 28,30 but may be offered earlier in some regions, if hyperglycaemia or specific traditional risk factors are present.31 In the southern part of Sweden, all pregnant women undergo a simplified 2-h OGTT (omitting the fasting blood glucose measurement) in gestational week 28 since 1995.32 The main diagnostic criteria for GDM are based on the Diabetes in Pregnancy Study Group recommendation from 1991, i.e. a fasting plasma glucose ≥7.0 mmol/L and/or 2-h plasma glucose ≥10 mmol/L after a 75-g OGTT. As GDM may have been classified as unspecified diabetes in pregnancy in some cases, we also defined the combination of GDM and unspecified diabetes during pregnancy as a secondary outcome.
Other variables Information on date of birth, maternal age at delivery, parity, smoking in early pregnancy, length of gestation, birthweight, and the number of fetuses in pregnancy was obtained from the birth registries. Estimation of gestational age was based usually on ultrasound examinations performed in early second trimester; if this was not available – primarily before the early 1990s – information from the last menstrual period was used.26,29 The ultrasound examination is free of charge and the great majority of the pregnant women (95% in Sweden)33 attend it. We defined LGA as a birthweight that is above the 90th percentile of the Swedish sex-specific standard curve for normal fetal growth.34 In addition, data on maternal height and weight in early pregnancy have been registered in Sweden since 1992; women with a body mass index of 30 or higher were considered obese. Data on chronic hypertension were retrieved from the Danish National Hospital Register and from the SMBR. Maternal psychiatric diagnoses were obtained from the Danish Central Psychiatric Register and the Swedish Patient Register. The Danish National Hospital Register and the Swedish Patient Register provided data on diagnoses of diabetes mellitus in the women’s parents and siblings; information on CVD of these relatives was available only from the Danish National Hospital Register. The Danish National Hospital Register contains all in-hospital diagnoses in the country since 1977 and also all outpatient diagnoses since 1995. The Danish Central Psychiatric Register contains all diagnoses from psychiatric hospitals in the country since 1969;
274
K. D. László et al.
data from outpatient psychiatric care centres have been included since 1995. The Swedish Patient Register started in 1964; the geographic coverage of the registry increased gradually until 1987, when it became nationwide and covered all inpatient diagnoses in the country. Information on maternal education was obtained from the Swedish Education Register and from the Danish Integrated Database for Longitudinal Labour Market Research. In Denmark, we also obtained information on women’s citizenship from the Integrated Database for Longitudinal Labour Market Research, while in Sweden we obtained information on women’s country of birth from the SMBR.
Statistical analysis We used logistic regression models to estimate the odds of GDM according to exposure to death of a close relative the year before pregnancy. Analysis were performed with (i) the loss of any relative the year before pregnancy and with exposure categories based on (ii) the cause of death and (iii) the woman’s relationship to the deceased. Our primary models included the following potential confounders: country (Denmark or Sweden), year of delivery, maternal age at delivery, country of origin, education, parity, chronic hypertension, psychiatric disorder, and family history of diabetes mellitus before the exposure period. In addition, we adjusted for (i) family history of CVD in analysis restricted to the Danish cohort and (ii) for obesity among women who gave birth in Sweden in 1992 or later. We repeated our analyses after excluding women who reported smoking in early pregnancy. We re-ran analysis after excluding women with stillbirths from the Swedish cohort. In case a woman lost several relatives during the exposure period, in the primary analyses we gave coding priority to the death which occurred first. We performed secondary analyses with the number of relatives (one vs. none and two or three vs. none) who died during the year before pregnancy. To study whether the association between bereavement of any relative and GDM differed by country, year of delivery, maternal age, education, country of origin, obesity, chronic hypertension, previous psychiatric disorder, family history of diabetes mellitus, and the number of fetuses in the pregnancy, we conducted stratified analysis and performed tests of interaction in multiplicative models.
We repeated the main analysis with the combined outcome of GDM and unspecified diabetes during pregnancy. In addition, to study whether the investigated association differed according to the severity of the disease, we re-ran the main analysis among women with singleton pregnancies after categorizing GDM as presenting with or without delivery of a LGA infant; we hypothesized that GDM with LGA is more severe than GDM without LGA.35
Results A total of 17 799 (6.93 per 1000) women included in the study were diagnosed with GDM. The prevalence of the studied demographic, lifestyle, and healthrelated covariates in the study population and the rate of GDM according to the categories of these covariates is presented in Table 1. Altogether 42 640 (1.7%) women experienced death of a close relative the year before pregnancy (Table 2). Compared with women who did not lose a close relative the year before pregnancy, exposed women had higher odds of GDM (Table 2). The adjusted odds ratios (ORs) corresponding to the loss of a child, parent, and sibling were 1.51 [95% confidence interval (CI): 1.17, 1.95], 1.12 (95% CI: 1.00, 1.25), and 0.68 (95% CI: 0.40, 1.25), respectively (Table 3). Deaths due to CVD or diabetes were more closely related to women’s risk of GDM than other type of deaths. The association corresponding to the loss of a parent was stronger for deaths due to diabetes than CVD; the ORs were 1.87 (95% CI: 1.16, 3.01) and 1.37 (95% CI: 1.15, 1.63), respectively (data not shown in table). We observed an increased GDM risk also among women who lost an older child due to natural deaths other than CVD or diabetes. We found no association between unnatural deaths and the outcome (Tables 2, 3). The association between death of any relative the year before pregnancy and GDM was not considerably altered after (i) adjustment for family history of CVD in analysis restricted to the Danish cohort [OR: 1.13 (95% CI: 0.98, 1.31) before and 1.12 (95% CI: 0.97, 1.30) after adjustment]; (ii) adjustment for prepregnancy obesity among women who gave birth in Sweden in 1992 or later [OR: 1.23 (95% CI: 1.04, 1.46) before and 1.18 (95% CI: 0.99, 1.40) after adjustment]; (iii) excluding women who reported smoking in the first trimester [OR 1.12 (95% CI: 1.01, 1.25) among women with data on smoking before exclusion and 1.12 (95% CI: 0.99, 1.26) after exclusion]; or (iv) © 2015 John Wiley & Sons Ltd Paediatric and Perinatal Epidemiology, 2015, 29, 271–280
Bereavement and gestational diabetes
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Table 1. Characteristics of study participants Total Characteristics Country Sweden Denmark Age at offspring’s birth (in years) 19 or less 20–24 25–29 30–34 35 or more Highest education Basic education Secondary education College or university Missing Country of origin Denmark or Sweden Other country Missing Year of offspring’s birth 1987–1991 1992–1996 1997–2001 2002–2008 Parity Primipara Multipara Number of fetuses in the pregnancy Singleton Multiple Missing Stillbirth No Yes Missing Smoking in early pregnancy No Yes Missing Body mass indexb ≥30 No Yes Missing Psychiatric diagnosis prior to the year preceding pregnancy No Yes Chronic hypertension No Yes Diabetes mellitus (type 1 and 2) in women’s parents or siblings prior to the year preceding pregnancy No Yes CVD in women’s parents or siblings prior to the year preceding pregnancyc No Yes Missing a
GDM
n
(%)
Rate per 1000
1 725 760 843 686
67.16 32.84
5.74 9.36
51 121 411 072 924 832 818 830 363 591
1.99 16.00 35.99 31.87 14.15
3.17 4.23 5.45 7.67 12.60
316 747 1 185 379 1 0475 512 19 809
12.33 46.13 40.77 0.77
8.80 6.92 6.30 11.01
2 476 457 91 638 1 351
96.38 3.57 0.05
6.74 11.87 12.58
498 493 631 663 644 962 794 328
19.40 24.58 25.10 30.91
4.74 5.82 6.27 9.71
1 115 533 1 453 913
43.42 56.58
6.72 7.09
2 486 880 82 438 128
96.79 3.21 0
6.80 10.80 15.63
1 720 141 5 619 843 686
66.95 0.22 32.84
5.74 6.94 9.36
1 932 474 447 810 189 162
75.21 17.43 7.36
6.62 6.66 10.66
953 671 94 839 1 520 936
37.12 3.69 59.19
4.54 22.39 7.46
2 503 187 66 259
97.42 2.58
6.86 9.40
2 556 184 13 262
99.48 0.52
6.82 27.60
2 509 647 59 799
97.67 2.33
6.44 27.38
505 152 338 534 1 725 760
19.66 13.18 67.16
7.84 11.62 5.74
P-valuea
