Research

JAMA Pediatrics | Original Investigation

Associations of Maternal Diabetes and Body Mass Index

With Offspring Birth Weight and Prematurity
Linghua Kong, MSc; Ida A. K. Nilsson, PhD; Mika Gissler, PhD; Catharina Lavebratt, MSc, PhD

Supplemental content
IMPORTANCE Maternal obesity, pregestational type 1 diabetes, and gestational diabetes
have been reported to increase the risks for large birth weight and preterm birth in offspring.
However, the associations for insulin-treated diabetes and non–insulin-treated type 2
diabetes, as well as the associations for joint diabetes disorders and maternal body mass
index, with these outcomes are less well documented.

OBJECTIVE To examine associations of maternal diabetes disorders, separately and together

with maternal underweight or obesity, with the offspring being large for gestational age
and/or preterm at birth.

DESIGN, SETTING, AND PARTICIPANTS This population-based cohort study used nationwide
registries to examine all live births (n = 649 043) between January 1, 2004, and December 31, 2014,
in Finland. The study and data analysis were conducted from April 1, 2018, to October 10, 2018.

EXPOSURES Maternalprepregnancybodymassindex,pregestationaldiabeteswithinsulintreatment,
pregestational type 2 diabetes without insulin treatment, and gestational diabetes.

MAIN OUTCOMES AND MEASURES Offspring large for gestational age (LGA) at birth and
preterm delivery. Logistic regression models were adjusted for offspring birth year; parity;
and maternal age, country of birth, and smoking status.

RESULTS Of the 649 043 births, 4000 (0.62%) were delivered by mothers who had insulin-treated
diabetes, 3740 (0.57%) by mothers who had type 2 diabetes, and 98 568 (15.2%) by mothers who
had gestational diabetes. The mean (SD) age of mothers was 30.15 (5.37) years, and 588 100
mothers (90.6%) were born in Finland. Statistically significant interactions existed between
maternal body mass index and diabetes on offspring LGA and prematurity (insulin-treated
diabetes: LGA F = 3489.0 and prematurity F = 1316.4 [P < .001]; type 2 diabetes: LGA F = 147.3 and
prematurity F = 21.9 [P < .001]; gestational diabetes: LGA F = 1374.6 and prematurity F = 434.3
[P < .001]). Maternal moderate obesity, compared with normal-weight mothers with no diabetes,
was associated with a mildly increased risk of having an offspring LGA (1069 [3.5%] vs 5151 [1.5%];
adjusted odds ratio [aOR], 2.45; 95% CI, 2.29-2.62), and mothers with insulin-treated diabetes had
Author Affiliations: Department of
markedly elevated risks of having an offspring LGA (1585 [39.6%] vs 5151 [1.5%]; aOR, 43.80; 95% Molecular Medicine and Surgery,
CI, 40.88-46.93) and a preterm birth (1483 [37.1%] vs 17 481 [5.0%]; aOR, 11.17; 95% CI, 10.46-11.93). Karolinska Institutet, Stockholm,
Motherswhoweremoderatelyobesewithtype2diabeteswereatincreasedrisksofLGA(132[16.4%] Sweden (Kong, Nilsson, Lavebratt);
Neurogenetics Unit, Center for
vs 5151 [1.5%]; aOR, 12.44; 95% CI, 10.29-15.03) and prematurity (83 [10.3%] vs 17 481 [5.0%]; aOR,
Molecular Medicine, Karolinska
2.14; 95% CI, 1.70-2.69). Mothers who were moderately obese with gestational diabetes had a University Hospital, Stockholm,
milder risk of LGA (1195 [6.7%] vs 5151 [1.5%]; aOR, 4.72; 95% CI, 4.42-5.04). Among spontaneous Sweden (Kong, Nilsson, Lavebratt);
deliveries, the risks were strongest for moderately preterm births, but insulin-treated diabetes National Institute for Health and
Welfare, Helsinki and Oulu, Finland
was associated with an increased risk also for very and extremely preterm births.
(Gissler); Division of Family Medicine,
Department of Neurobiology, Care
CONCLUSIONS AND RELEVANCE Maternal insulin-treated diabetes appeared to be associated Sciences and Society, Karolinska
with markedly increased risks for LGA and preterm births, whereas obesity in mothers with Institutet, Stockholm, Sweden
(Gissler); University of Turku,
type 2 diabetes had mild to moderately increased risks; these findings may have implications Research Centre for Child Psychiatry,
for counseling and managing pregnancies. Turku, Finland (Gissler).
Corresponding Author: Catharina
Lavebratt, MSc, PhD, Neurogenetics
Unit, Center for Molecular Medicine,
Karolinska University Hospital L8:00,
JAMA Pediatr. doi:10.1001/jamapediatrics.2018.5541 171 76 Stockholm, Sweden
Published online February 25, 2019. (catharina.lavebratt@ki.se).

(Reprinted) E1
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 Research Original Investigation
E
xposure to diabetes in the intrauterine environment has
long been recognized to affect fetus birth weight. In the
pre–insulin-treatment era, most infants to mothers with
pregestational diabetes had low birth weight, because mater-
nal starvation was used to reduce serum glucose levels and
avoid fetal death. After insulin treatment was introduced,
maternal type 1 diabetes was shown to be associated with an
elevated risk for increased infant adiposity and overweight,1 and
low infant birth weight was observed for mothers with
severe type 1 diabetes vascular complications.2 The degree of
fetal influence depends on the severity of diabetes, grade of dia-
betes control, and mode of treatment.2 More recently, in large
population-based studies, gestational diabetes was associated
with the offspring being large for gestational age (LGA).3,4
Substances thought to be involved in imbalanced fetal growth
in a diabetes milieu include insulin, glucose, leptin, ghrelin,
adiponectin, and, in poorly controlled pregnancies, growth hor-
mone and insulin-like growth factors.2 Maternal hyperglyce-
mia leads to increased levels of circulating maternal and fetal
insulin, itself a fetal growth hormone.5 Moreover, animal stud-
ies suggest that fetal hyperinsulinemia alters the expression of
hypothalamic neurotransmitters, leading to increased weight
of offspring.6 Insulin can also rewire the hypothalamic circuits
regulating food intake in mice7 and thus could potentially affect
body weight in the longer perspective.
Furthermore, maternal overweight and obesity have been
causally associated with increased offspring birth weight,8
probably through maternal and fetal dysregulation of glu-
cose, insulin, lipid, and amino acid metabolism.9 Genetic vari-
ants associated with glucose metabolism and high body mass
index (BMI) were more common in offspring with higher birth
weight.8 A prospective observational cohort study found that,
among women without gestational diabetes, maternal adipos-
ity and leptin levels were stronger metabolic determinants of
having an LGA offspring compared with glucose intolerance
and lipid levels.10 Correspondingly, a systematic review and
meta-analysis showed that underweight women had a higher
risk of an offspring with low birth weight and prematurity
(birth before gestational week 37) compared with mothers with
normal weight.11
With regard to dysmetabolic milieu and risk for prema-
turity, a national population study in Taiwan showed that
women with type 1 diabetes had an increased risk of having
a premature offspring.12 To our knowledge, no study has
been published about the association between type 2 diabe-
tes and prematurity, but a cohort study of 46 230 pregnan-
cies found that gestational diabetes and lower degrees of
maternal hyperglycemia (than gestational diabetes) during
pregnancy mildly increased the risk of spontaneous preterm
birth.13 The association between maternal obesity and pre-
maturity has been extensively studied in a large Swedish
population-based cohort study of 1.6 million births. The
study showed that maternal prepregnancy underweight,
overweight, and obesity are associated with increased risks
of preterm delivery, especially extremely preterm. 1 4
Increased risk of prematurity for mothers with obesity is
reported to be associated with medical complications,
including diabetes, anemia, and hypertension.15
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Associations of Maternal Diabetes and BMI With Birth Weight and Prematurity
Key Points
Question Are maternal diabetes disorders, alone or with maternal
underweight or obesity, associated with the offspring being large
for gestational age and/or preterm at birth?
Findings In this cohort study of 649 043 births, maternal diabetes
treated with insulin was associated with a high risk for the offspring to
be large and/or preterm at birth, regardless of prepregnancy body mass
index, whereas type 2 diabetes not treated with insulin was associated
with a mild to moderate, albeit statistically significant, risk that was
stronger in mothers who were obese or severely obese. Gestational
diabetes was associated with mild increases in birth size.
Meaning Maternal diabetes, mainly when treated with insulin,
appears to be associated with a greater risk for large birth weight
and preterm offspring.
Although previous studies have demonstrated associa-
tions of maternal prepregnancy type 1 diabetes, gestational
diabetes, and obesity with offspring LGA and prematurity, the
associations between insulin-treated pregestational diabetes
and type 2 diabetes not treated with insulin have not been
studied, and the joint associations of diabetes and BMI with
these outcomes have not been well reported. This study aimed
to examine the associations of maternal insulin-treated
diabetes, type 2 diabetes without insulin treatment, and
gestational diabetes, alone and jointly with maternal under-
weight or obesity, with offspring being LGA and premature at
birth. We used the nationwide Finnish registries of births
between January 1, 2004, and December 31, 2014.
Methods
Study Population and Data Sources
The Drugs and Pregnancy database steering committee and
the data protection authority in Finland approved this study.
Because informed consent is not required in Finland for this
type of study, the women and children included in the study
were not contacted. The study and data analysis were con-
ducted from April 1, 2018, to October 10, 2018.
All pregnancies ending in live births in Finland between
January 1, 2004, and December 31, 2014, were identified using
the Drugs and Pregnancy database16 and included 649 043
births. There were no exclusion criteria. These data came from
the Medical Birth Register, the Register on Induced Abor-
tions, and the Register of Congenital Malformations, all of
which are kept at the Finnish National Institute for Health and
Welfare. The Medical Birth Register includes information since
1987 on all live births and stillbirths in Finland with the age of
at least 22 gestational weeks or a birth weight of 500 g or more.
The Medical Birth Register data are supplemented by birth and
death certificates and are complemented by the Cause-of-
Death Register and maternity hospital records.
Information from the different registers was merged
through record linkages based on unique personal identifica-
tion numbers assigned to all Finnish citizens and permanent
residents. Register linkages were conducted as set out in the
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 Associations of Maternal Diabetes and BMI With Birth Weight and Prematurity
permission agreement between the register administrators
(National Social Insurance Institution and National Institute
for Health and Welfare).
Main Exposures
Data on maternal prepregnancy BMI, from the first prenatal
visit, were obtained from the Drugs and Pregnancy database,
which restricted the inclusion of data to 2004 as the earliest.
The information on maternal prepregnancy height and
weight was self-reported at first prenatal visit on the 10th week
of pregnancy. Body mass index was calculated as weight in
kilograms divided by height in meters squared and catego-
rized according to the World Health Organization classifica-
tion: underweight (BMI <18.5), normal weight (BMI 18.5 to <25),
overweight (BMI 25 to <30), moderately obese (BMI 30 to <35),
and severely obese (BMI ≥35).
Information on insulin-treated diabetes was identified
using the Register on Reimbursement Drugs (KELA), which
records the special reimbursement for insulin medication for
diabetes (to which all Finnish citizens and permanent resi-
dents are entitled) and is maintained by the National Social
Insurance Institution. Register on Reimbursement Drugs
automatically registers all reimbursed drug prescriptions
(ATC-code) dispensed by Finnish pharmacies since 1996.
Maternal type 2 diabetes and gestational diabetes diagnoses
were obtained from the Finnish Care Registers for Health Care,
which contains information on all hospital inpatient stays (since
1969) and outpatient treatments by physicians in specialized
care (since 1998).17 Information on type 2 diabetes was identi-
fied by using International Classification of Diseases, Tenth
Revision, codes E11, E14, and O24.1 and/or by purchase of ATC
A10B, according to the Register on Reimbursement Drugs,
with the exclusion criteria being insulin treatment according to
the purchase of insulin before or during pregnancy. Informa-
tion on gestational diabetes was identified by International
Classification of Diseases, Tenth Revision, code O24.4 recorded
in the Finnish Care Registers for Health Care. Births in the cat-
egory diabetes with insulin treatment were excluded from the
categories type 2 diabetes and gestational diabetes diagnoses,
and similarly, births in the category type 2 diagnosis were
excluded from the category gestational diabetes diagnosis.
Outcomes and Covariates
Small for gestational age (SGA) and LGA are birth weight and/or
length more than 2 SDs below (for SGA) or above (for LGA) the
sex- and gestational age–specific reference mean using
Finnish standards,18 according to the International Societies
of Pediatric Endocrinology and the Growth Hormone
Research Society.19 Appropriate for gestational age is the
measure between the SGA and LGA measures. Prematurity was
defined as birth before gestational week 37. Data on offspring
birth year, sex, number of fetuses, parity, and maternal age at
delivery, smoking status, marital status, and country of birth
were used as covariates.
Statistical Analysis
Births were categorized for maternal diabetes into 4 groups:
(1) no diabetes, (2) diabetes with insulin treatment,
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Original Investigation Research
(3) non–insulin-treated type 2 diabetes, and (4) gestational
diabetes. The distributions of possible covariates were com-
pared between groups (eTable in the Supplement). Next, the
groups were stratified by maternal prepregnancy BMI, and the
number and proportion of births with SGA, appropriate for
gestational age, LGA, and premature birth were examined in
each group. Thereafter, we assessed the statistical interac-
tion between maternal BMI (6-category variable shown in
Table 1) and maternal diabetes (yes or no) on LGA and prema-
turity for each of the 3 types of diabetes. Thereafter, odds
ratio (OR) estimates and corresponding 95% Wald CIs were
calculated using logistic regression, adjusting for prebirth
covariates with a distribution difference between exposure
groups: offspring birth year, parity; and maternal age, coun-
try of birth (Finland or other), and smoking status (yes or no),
as in previous studies.3,14 The reference group was no diabe-
tes with normal BMI (18.5-24.9). Rates (proportions) given
in the Results and tables are absolute, whereas the ORs
given are adjusted (aOR).
A second round of analysis was performed to explore to
what extent the association of diabetes with insulin treat-
ment, type 2 diabetes, and gestational diabetes with prema-
turity was explained by spontaneous deliveries, specifically ex-
tremely (22-27 weeks), very (28-31 weeks), and moderately
(32-36 weeks) preterm deliveries. For this analysis, all planned
cesarean delivery births were excluded, and aORs and 95% CIs,
adjusted as described, were calculated using full-term (≥37 ges-
tational weeks) births to mothers with no diabetes as the ref-
erence. Because the ORs for prematurity mostly overlapped
between the 5 maternal BMI groups within a diabetes cat-
egory, stratification by maternal BMI was not performed in this
second round. Finally, the association between LGA and
prematurity was estimated by calculating aORs and 95% CIs,
adjusted as described, using the full-term non–LGA births as
the reference. All statistical analyses were performed using SAS,
version 9.3 (SAS Institute Inc).
Results
Of the 649 043 births, 4000 (0.62%) were delivered by moth-
ers who had diabetes with insulin treatment, 3740 (0.58%) by
mothers who had type 2 diabetes, and 98 568 (15.2%) by moth-
ers who had gestational diabetes. The mean (SD) age of moth-
ers was 30.15 (5.37) years, and 588 100 mothers (90.6%) were
born in Finland. Of the mothers with diabetes with insulin
treatment, 3880 (97.0%) purchased insulin also during preg-
nancy. The maternal prepregnancy BMI was normal for 384 169
mothers (59.2%), whereas 23 061 mothers (3.6%) were under-
weight, 134 320 mothers (20.7%) were overweight, 49 812
mothers (7.7%) were moderately obese, and 23 747 mothers
(3.7%) were severely obese (eTable in the Supplement).
First, we tested for maternal diabetes and obesity asso-
ciation with LGA and prematurity. Of the mothers with dia-
betes with insulin treatment, 39.6% (n = 1585) of newborns
were LGA, whereas for the mothers with type 2 diabetes, the
percentage was 12.8% (n = 469); for the mothers with gesta-
tional diabetes, the proportion of LGA offspring was double
(Reprinted) JAMA Pediatrics Published online February 25, 2019 E3
 Research Original Investigation Associations of Maternal Diabetes and BMI With Birth Weight and Prematurity

Table 1. Offspring Birth Weight and Prematurity According to Maternal Diabetes

and Prepregnancy Body Mass Index

No. (%)
Variable SGA AGA LGAa Prematurityb
Diabetes category stratified by BMI
Diabetes with insulin treatment (n = 4000) 60 (1.5) 2338 (58.5) 1585 (39.6) 1483 (37.1)
<18.5 2 (3.1) 41 (63.1) 22 (33.9) 24 (36.9)
18.5-24 23 (1.3) 1088 (59.1) 724 (39.4) 702 (38.2)
25-29 15 (1.4) 579 (54.2) 472 (44.2) 397 (37.2)
30-34 12 (2.5) 275 (57.9) 186 (39.2) 186 (39.2)
≥35 6 (1.7) 230 (65.9) 113 (32.4) 101 (28.9)
Missing 2 (1.0) 125 (61.6) 68 (33.5) 73 (36.0)
Type 2 diabetesb (n = 3740) 109 (21.9) 3152 (84.3) 469 (12.8) 376 (10.1)
<18.5 4 (13.8) 24 (82.8) 1 (3.5) 2 (6.9)
18.5-24 31 (3.5) 817 (91.0) 50 (2.2) 92 (10.2)
25-29 22 (2.6) 745 (86.9) 90 (3.9) 81 (9.5)
30-34 23 (2.9) 648 (80.4) 132 (16.4) 83 (10.3)
≥35 24 (2.6) 747 (79.4) 169 (18.0) 96 (10.2)
Missing 5 (2.4) 171 (81.2) 27 (12.9) 22 (10.5)
Gestational diabetesc (n = 98 568) 2367 (2.4) 90 666 (92.0) 5316 (5.4) 5023 (5.1)
<18.5 61 (5.3) 1059 (92.1) 25 (2.2) 71 (6.2)
18.5-24 821 (2.5) 30 401 (92.6) 1263 (3.9) 1543 (4.8) Abbreviations: AGA, appropriate for
25-29 668 (2.2) 28 554 (92.6) 1547 (5.0) 1507 (4.9) gestational age; BMI, body mass
30-34 401 (2.3) 16 240 (90.9) 1195 (6.7) 948 (5.3) index (calculated as weight in
kilograms divided by height in meters
≥35 278 (2.4) 10 217 (88.8) 999 (8.7) 664 (5.8) squared); LGA, large for gestational
Missing 138 (2.9) 4195 (89.1) 287 (6.1) 290 (6.2) age; SGA, small for gestational age.
a
No diabetes (n = 542 735) 18 472 (3.4) 512 249 (94.4) 10 213 (1.9) 28 661 (5.3) Missing data on birthweight are not
<18.5 1389 (6.4) 20 280 (93.0) 118 (0.5) 1381 (6.3) indicated but are below 0.5%.
b
Births in the category
18.5-24 11 854 (3.4) 331 320 (95.0) 5151 (1.5) 17 481 (5.0)
insulin-treated diabetes were
25-29 2930 (2.9) 95 600 (94.1) 2835 (2.8) 5315 (5.2) excluded from the categories type 2
30-34 885 (2.9) 28 642 (93.4) 1069 (3.5) 1833 (6.0) diabetes and gestational diabetes.
c
≥35 340 (3.1) 10 068 (92.0) 513 (4.7) 731 (6.7) Births in the category type 2
diabetes were excluded from the
Missing 1074 (3.7) 26 339 (91.4) 527 (1.8) 1920 (6.7)
category gestational diabetes.

that of mothers with no diabetes (gestational diabetes: 5.4%
[n = 5316] vs no diabetes: 1.9% [n = 10 213] (Table 1). Thus, using
births to normal-weight mothers with no diabetes as the ref-
erence, the aOR for LGA for maternal diabetes with insulin
treatment was larger (1585 [39.6%] vs 5151 [1.5%]; aOR, 43.80;
95% CI, 40.88-46.93) than for maternal type 2 diabetes (469
[12.8%] vs 5151 [1.5%]; aOR, 9.57; 95% CI, 8.65-10.58), whereas
maternal gestational diabetes showed the lowest risk for LGA
(5316 [5.4%] vs 5151 [1.5%]; aOR, 3.80; 95% CI, 3.66-3.96)
(Table 2; eFigure 1a in the Supplement). Statistically signifi-
cant interactions were found between maternal prepreg-
nancy BMI and maternal diabetes (yes or no) on offspring LGA
(diabetes with insulin treatment: F = 3489.0 [P < .001]; type
2 diabetes: F = 147.3 [P < .001]; gestational diabetes: F = 1374.6
[P < .001]). Stratification by maternal BMI and using births to
normal-weight mothers with no diabetes as the reference, the
OR for LGA for maternal diabetes with insulin treatment was
very high in all maternal BMI strata (pointwise aOR, 30-53) but
peaked for the mothers who were overweight. For mothers with
type 2 diabetes or gestational diabetes or with no diabetes, as
maternal prepregnancy BMI increased, the ORs for offspring
LGA increased gradually. For example, mothers who were
moderately obese with no diabetes had a 3-fold higher risk of
having an LGA offspring (1069 [3.5%] vs 5151 [1.5%]; aOR, 2.45;
95% CI, 2.29-2.62); aOR, 3.38; 95% CI, 3.08-3.71). Moderate obe-
sity plus gestational diabetes doubled the aOR (1195 [6.7% vs
5151 [1.5%]; aOR, 4.72; 95% CI, 4.42-5.04), and moderate obe-
sity plus type 2 diabetes further doubled it (132 [16.4%] vs 5151
[1.5%]; aOR, 12.44; 95% CI, 10.29-15.03). In addition, moth-
ers who were underweight with no diabetes had a markedly
lower risk of having an LGA offspring (118 [0.5%] vs 5151 [1.5%];
aOR, 0.40; 95% CI, 0.33-0.48) (Tables 1 and 2).
For mothers with diabetes with insulin treatment, the pro-
portion of premature offspring was 37.1% (1483), whereas among
mothers with type 2 diabetes, the proportion was 10.1% (376);
mothers with gestational diabetes had a similar proportion of
preterm births (5.1% [5023]) as mothers with no diabetes (5.3%
[28 661]) (Table 1). Furthermore, among mothers with no dia-
betes, maternal underweight and obesity were associated with
a mildly increased risk of offspring prematurity compared with
normal weight. Thus, using births to normal-weight mothers
with no diabetes as the reference, the aOR for prematurity for
maternal diabetes with insulin treatment was larger (1483 [37.1%]
vs 17 481 [5.0%]; aOR, 11.17; 95% CI, 10.46-11.93) than for

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 Associations of Maternal Diabetes and BMI With Birth Weight and Prematurity Original Investigation Research

Table 2. Adjusted Odds Ratio for Offspring Large for Gestational Age According to Maternal Body Mass Index and Diabetes

aOR (95% CI)

Diabetes With
Variable No Diabetes Insulin Treatment Type 2 Diabetesb Gestational Diabetesc
a
Maternal BMI
<18.5 0.40 (0.33-0.48) 43.69 (25.98-73.48) 2.43 (0.33-17.91) 1.59 (1.07-2.37)
18.5–24 1.00 (NA) 45.80 (41.51-50.53) 3.85 (2.89-5.13) 2.61 (2.48-2.81)
25–29 1.91 (1.83-2.00) 53.44 (47.18-60.53) 7.40 (5.93-9.23) 3.42 (3.23-3.63)
30–34 2.45 (2.29-2.62) 45.04 (37.33-54.34) 12.44 (10.29-15.03) 4.72 (4.42-5.04)
≥35 3.38 (3.08-3.71) 30.02 (23.92-37.69) 13.90 (11.73-16.47) 6.37 (5.94-6.84)
Missing 1.08 (0.98-1.18) 30.82 (22.93-41.42) 8.56 (5.68-12.91) 3.79 (3.35-4.29)
Total 1.28 (1.24-1.32) 43.80 (40.88-46.93) 9.57 (8.65-10.58) 3.80 (3.66-3.96)
b
Abbreviations: aOR, adjusted odds ratio; BMI, body mass index (calculated as Births in the category insulin-treated diabetes were excluded from the
weight in kilograms divided by height in meters squared). categories type 2 diabetes and gestational diabetes.
a c
The models were adjusted for offspring birth year; parity; and maternal age, Births in the category type 2 diabetes were excluded from the category
country of birth, and smoking status. Reference for BMI strata: births to gestational diabetes.
normal-weight mothers with no diabetes.

Table 3. Adjusted Odds Ratio for Offspring Prematurity According to Maternal Body Mass Index and Diabetes

aOR (95% CI)

Variable No Diabetes Insulin-Treated Diabetes Type 2 Diabetesb Gestational Diabetesc
Maternal BMIa
<18.5 1.32 (1.24-1.39) 11.54 (6.96-19.12) 1.39 (0.33-5.85) 1.26 (0.99-1.60)
18.5-24 1.00 (NA) 11.73 (10.66-12.90) 2.19 (1.76-2.72) 0.93 (0.88-0.98)
25-29 1.04 (1.00-1.08) 11.12 (9.81-12.61) 1.95 (1.55-2.45) 0.96 (0.91-1.01)
30-34 1.20 (1.14-1.26) 11.66 (9.69-14.04) 2.14 (1.70-2.69) 1.05 (0.98-1.12)
≥35 1.36 (1.26-1.47) 7.39 (5.85-9.32) 2.11 (1.71-2.61) 1.15 (1.06-1.24)
Missing 1.36 (1.29-1.43) 10.89 (8.16-14.53) 2.31 (1.48-3.60) 1.25 (1.11-1.41)
Total 0.99 (0.97-1.01) 11.17 (10.46-11.93) 2.12 (1.90-2.36) 1.02 (0.99-1.05)
b
Abbreviations: aOR, adjusted odds ratio; BMI, body mass index (calculated as Births in the category insulin-treated diabetes were excluded from the
weight in kilograms divided by height in meters squared). categories type 2 diabetes and gestational diabetes.
a c
The models were adjusted for offspring birth year; parity; and maternal age, Births in the category type 2 diabetes were excluded from the category
country of birth, and smoking status. Reference for BMI strata: births to gestational diabetes.
normal-weight mothers with no diabetes.

maternal type 2 diabetes (376 [10.1%] vs 17 481 [5.0%]; aOR, 2.12;
95% CI, 1.90-2.36), whereas maternal gestational diabetes was
not associated with prematurity (Tables 1 and 3; eFigure 1b in
the Supplement). Statistically significant interactions were
found between maternal pregestational BMI and maternal
diabetes (yes or no) on offspring prematurity (diabetes with
insulin treatment: F = 1316.4 [P < .001]; type 2 diabetes: F = 21.9
[P < .001]; gestational diabetes: F = 434.3 [P < .001]). Stratifi-
cation by maternal BMI and using births to normal-weight
mothers with no diabetes as the reference, the aOR for prema-
turity for maternal diabetes with insulin treatment (pointwise
aOR, 11.12-11.73) and type 2 diabetes (pointwise aOR, 1.39-2.19)
was similar in all maternal BMI strata, except for a lower diabe-
tes with insulin treatment OR for the mothers who were se-
verely obese (101 [28.9%] vs 17 481 [5.0%]; aOR, 7.39; 95% CI,
5.85-9.32). For mothers who were moderately obese with type
2 diabetes, the risk for prematurity was 2-fold compared with
mothers without diabetes of normal weight (83 [10.3%] vs 17 481
[5.0%]; aOR, 2.14; 95% CI, 1.70-2.69). For mothers with gesta-
tional diabetes or with no diabetes, as maternal prepregnancy
BMI increased, ORs for offspring prematurity tended to
increase slightly (eFigure 1b in the Supplement).
Second, of all the deliveries, 604 973 (93.2%) were spon-
taneous (ie, without planned cesarean delivery). We ex-
plored the associations of diabetes with insulin treatment, type
2 diabetes, and gestational diabetes with the rates of ex-
tremely (22-27 weeks), very (28-31 weeks), and moderately
(32-36 weeks) preterm deliveries within the spontaneous de-
liveries (Table 4). Because the aORs for prematurity mostly
overlapped between the 5 maternal BMI groups within a dia-
betes category (Table 1 and Table 3), stratification by mater-
nal BMI was not performed here. The increased adjusted risk
for spontaneous prematurity was strongest for moderately pre-
term deliveries (diabetes with insulin treatment: 944 [34.2%]
vs no diabetes: 22 435 [4.4%]; diabetes with insulin treat-
ment aOR, 11.25 [95% CI, 10.39-12.19]; type 2 diabetes: 274
[8.4%] vs no diabetes: 22 435 [4.4%]; type 2 diabetes aOR, 1.98
[95% CI, 1.75-2.24]; gestational diabetes: 4136 [4.6%] vs no dia-
betes: 22 435 [4.4%]; gestational diabetes aOR, 1.04 [95% CI,
1.00-1.07]) and was, for diabetes with insulin treatment,
statistically significant also for very preterm and extremely
preterm deliveries (Table 5; eFigure 2 in the Supplement).
Third, we tested for LGA association with prematurity.
Compared with non–LGA, LGA was associated with a doubled

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 Research Original Investigation Associations of Maternal Diabetes and BMI With Birth Weight and Prematurity

Table 4. Description of Offspring Prematurity According to Maternal Diabetes

Prematurity Category No. (%)

Stratified by No Insulin-Treated Type 2 Gestational
Cesarean Deliverya Diabetes Diabetes Diabetesb Diabetesc
Planned cesarean delivery
(n = 44 070)
All 34 326 (100.0) 1239 (100.0) 466 (100.0) 8039 (100.0)
Extremely 81 (0.2) 2 (0.2) 1 (0.2) 10 (0.1)
Very 330 (1.0) 18 (1.4) 3 (0.6) 54 (0.7) a
Extremely preterm: <28 weeks’
Moderately 2309 (6.7) 444 (35.8) 60 (12.9) 364 (4.5) gestation; very preterm: 28-31
Term 31 606 (92.1) 775 (62.6) 402 (86.3) 7611 (94.7) weeks’ gestation; moderately
preterm: 32-36 weeks’ gestation;
Spontaneous delivery term: ⱖ37 weeks’ gestation.
(n = 604 973)
b
Births in the category
All 508 409 (100.0) 2761 (100.0) 3274 (100.0) 90 529 (100.0)
insulin-treated diabetes were
Extremely 1044 (0.2) 16 (0.6) 10 (0.3) 125 (0.1) excluded from the categories type 2
Very 2462 (0.5) 59 (2.1) 28 (0.8) 334 (0.4) diabetes and gestational diabetes.
c
Moderately 22 435 (4.4) 944 (34.2) 274 (8.4) 4 136 (4.6) Births in the category type 2
diabetes were excluded from the
Term 482 468 (94.9) 1742 (63.1) 2962 (90.5) 85 934 (94.9)
category gestational diabetes.

Table 5. Adjusted Odds Ratio for Offspring Spontaneous Delivery According to Maternal Diabetesa

aOR (95% CI)

Prematurity Categories Stratified by Cesarean Deliveryb Insulin-Treated Diabetes Type 2 Diabetesc Gestational Diabetesd
All preterms 10.88 (10.06-11.77) 1.96 (1.74-2.20) 0.99 (0.96-1.03)
Extremely preterm 2.83 (1.73-4.65) 1.49 (0.80-2.78) 0.67 (0.55-0.81)
Very preterm 4.49 (3.46-5.83) 1.77 (1.22-2.58) 0.76 (0.68-0.85)
Moderately preterm 11.25 (10.39-12.19) 1.98 (1.75-2.24) 1.04 (1.00-1.07)
Abbreviation: aOR, adjusted odds ratio. moderately preterm: 32-36 weeks’ gestation; term: ⱖ37 weeks’ gestation.
a c
Spontaneous delivery excluded planned cesarean delivery. Births in the category insulin-treated diabetes were excluded from the
b
The models were adjusted for offspring birth year; parity; and maternal age, categories type 2 diabetes and gestational diabetes.
d
country of birth, and smoking status. Reference: no diabetes and being full term. Births in the category type 2 diabetes were excluded from the category
Extremely preterm: <28 weeks’ gestation; very preterm: 28-31 weeks’ gestation; gestational diabetes.

risk for prematurity irrespective of maternal diabetes (all
births aOR, 2.61 [95% CI, 2.49-2.74]; spontaneous births aOR,
2.62 [95% CI, 2.49-2.76]).
Discussion
In this large population-based cohort study, with nationwide
effect estimates for 11 years (2004 through 2014), we provide
evidence of a markedly increased risk for LGA and prematu-
rity at birth after intrauterine exposure to maternal diabetes with
insulin treatment. Smaller, but clearly statistically significant,
increased LGA risks were found also for mothers with type 2
diabetes and gestational diabetes not treated with insulin,
especially in combination with prepregnancy overweight or
obesity that were stronger for type 2 diabetes than gestational
diabetes. In addition, prematurity was increased for mothers
with type 2 diabetes, independent of prepregnancy BMI. The
implication for spontaneous deliveries was strongest for the
moderately preterm births, but diabetes with insulin treat-
ment increased the risk also for very and extremely preterm
deliveries. Prepregnancy BMI, with no diabetes, affected the
risk for LGA and prematurity. The associations of maternal
diabetes with LGA and prematurity were not independent, as
LGA was associated with a mildly increased risk for premature
birth. To our knowledge, this is the first study to explore an
association for diabetes with insulin treatment, type 2 diabe-
tes, and gestational diabetes, stratified by maternal BMI, with
the risk of LGA and prematurity.
Maternal glucose metabolism during pregnancy differs
from that in the nonpregnant state; insulin resistance is in-
creased, directing fat as the mother’s energy source to ensure
adequate carbohydrate supply for the growing fetus. This
increase in insulin resistance is mediated by a number of
factors, such as increased levels of progesterone, estrogen, and
human placental lactogen.20 As the fetus grows, insulin resis-
tance increases, and with this postprandial glucose levels, basal
and stimulated insulin secretion as well as hepatic glucose pro-
duction rise, compared with the nonpregnant state. The pres-
ence of diabetes can aggravate these pregnancy-related meta-
bolic changes. The association of maternal diabetes with insulin
treatment with offspring LGA could also be a consequence of
hyperinsulinemia as a result of the treatment with the growth
hormone insulin. However, the effect size of diabetes with
insulin treatment on LGA in this study was much larger than
that reported in a nationwide cohort in Taiwan (OR, 4.44; 95%
CI, 3.99-4.95),12 despite similar adjustment for potential con-
founders. The association of type 2 diabetes and gestational
diabetes with increased risk of LGA was found primarily for
mothers who were obese, probably because both obesity and

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 Associations of Maternal Diabetes and BMI With Birth Weight and Prematurity Original Investigation Research

diabetes are associated with hyperglycemia and insulin
resistance,21-24 leading to increased placental glucose trans-
fer and fetal secretion of insulin1 in combination with an
excess of blood lipids, adiponectin, and leptin.9 In addition,
other metabolic factors (eg, ghrelin) seem to be involved.2
Adiponectin, leptin, and ghrelin are hormones that directly
affect the hypothalamic regulation of energy homeostasis,25
a system that develops in utero, particularly during the last
trimester. 26 A direct correlation between the levels of
these hormones in cord blood and birth weight has
been documented.2
No large study exists, to our knowledge, on the associa-
tion of maternal type 2 diabetes with LGA, but our effect sizes
of gestational diabetes on LGA are in agreement with those in
previous studies,3,4 although the joint association with prepreg-
nancy BMI has been explored only to a small extent. In addi-
tion, a population-based cohort study showed that gesta-
tional diabetes was associated with both increased birth
weight and body weight at 5 years.27 Even maternal hypergly-
cemia, milder than for gestational diabetes diagnosis,
showed an association with higher birth weight.28
With regard to the association of maternal diabetes with pre-
maturity, we found a markedly high aOR of diabetes with insu-
lin treatment, and a smaller, but clearly statistically significant
aOR of type 2 diabetes, but no association with gestational
diabetes. The same was seen for spontaneous deliveries. An
increased risk was seen mainly for moderate prematurity,
but diabetes with insulin treatment increased the risk also for
very and extremely preterm deliveries. Mechanisms that may
contribute to preterm delivery for mothers with obesity and dia-
betes include hyperglycemia, lipotoxicity, insulin resistance,
and oxidative stress leading to endothelial dysfunction.29,30 The
Hyperglycemia Adverse Pregnancy Outcome study demon-
strated increasing risks of preterm delivery with increasing
maternal glucose levels in women with no diabetes.28 Further-
more, diabetes increases the risk of preeclampsia, which is
associated with higher risk for preterm births.31
Only a few large studies exist on maternal diabetes and off-
spring prematurity. The cohort study in Taiwan showed that
mothers with type 1 diabetes had an increased risk of preterm
birth (<37 weeks; OR, 4.21 [95% CI, 3.78–4.71]).12 With regard
to the association of gestational diabetes with spontaneous
preterm birth, an OR of 1.42 (95% CI,1.15–1.77) was reported
in a US study, which was not very different to the present
study’s finding.13 Furthermore, in this study, mothers who
were underweight or obese had a slightly elevated risk of
a preterm delivery. Our risk estimates for mothers who were
underweight, obese, or severely obese delivering prema-
turely were similar to those previously reported in a nation-
wide study of the assoc iation of maternal BMI with
prematurity in Sweden.14
Strengths and Limitations
To our knowledge, this study is the largest and most compre-
hensive population-based study to explore the joint associa-
tion of maternal diabetes and prepregnancy BMI with the risk
for offspring LGA and prematurity. It also covers different
diagnoses separately, including diabetes with insulin treat-
ment and non–insulin-treated type 2 diabetes and gestational
diabetes, and the BMI groups from underweight to severe obe-
sity, thereby providing novel data. The LGA measure was based
on Finnish standards of both body weight and length. For
prematurity at birth, we stratified for gestational age.
Limitations of this study should be taken into account as
well. First, data on offspring congenital anomalies, maternal
complications (eg, preeclampsia), and grade of diabetes con-
trol during pregnancy were not available. Second, maternal
BMI information was available from only 1 time point; thus,
risk of change in maternal gestational BMI on offspring could
not be studied. The prepregnancy weight was self-reported but
indirectly controlled given that the height and weight are
routinely measured during the Finnish prenatal care.
Conclusions
Using data from a large nationwide registry cohort, we esti-
mated the risks of maternal prepregnancy BMI and different
types of diabetes, considering both separate and joint associa-
tions with offspring birth size and prematurity. In utero expo-
sure to maternal diabetes treated with insulin appeared to be
associated with large risks for offspring LGA and prematurity
regardless of the maternal prepregnancy BMI. Maternal type 2
diabetes not treated with insulin was also associated with in-
creased risks of offspring LGA and prematurity. The increased
rate of prematurity was primarily for moderately preterm de-
liveries. These findings may have implications for counseling and
managing pregnancies to prevent adverse birth outcomes.

ARTICLE INFORMATION
Accepted for Publication: December 17, 2018.
Published Online: February 25, 2019.
doi:10.1001/jamapediatrics.2018.5541
Author Contributions: Dr Gissler had full access to
all of the data in the study and takes responsibility
for the integrity of the data and the accuracy of the
data analysis.
Concept and design: Gissler, Lavebratt.
Acquisition, analysis, or interpretation of data:
Kong, Gissler, Lavebratt.
Drafting of the manuscript: Kong, Lavebratt.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Kong, Gissler.
Obtained funding: Kong, Lavebratt.
Administrative, technical, or material support:
Kong, Gissler.
Supervision: Gissler, Lavebratt.
Conflict of Interest Disclosures: Dr Kong reported
grants from China Scholarship Council during the
conduct of the study. Dr Lavebratt reported grants
from the Swedish Research Council (2014-10171),
grants from the Swedish Brain Foundation
(FO2017-0129, FO2018-0141) and grants from
Stockholm County Council (SLL20170292)
during the conduct of the study. No other
disclosures were reported.
Funding Support: This study was funded by the
THL National Institute for Health and Welfare: Drug
and Pregnancy project (Dr Gissler), the Swedish
Research Council (Dr Lavebratt), the regional
agreement on medical training and clinical research
(ALF) between Stockholm County Council and
Karolinska Institutet Stockholm County Council
(Dr Lavebratt), the China Scholarship Council
(Ms Kong), and the Swedish Brain Foundation
(Dr Lavebratt).
Role of the Funder/Sponsor: The funders had no
role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or

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 Research Original Investigation
approval of the manuscript; and decision to submit
the manuscript for publication.
Additional Contributions: We thank Anna-Maria
Lahesmaa-Korpinen, PhD, THL National Institute
for Health and Welfare, for excellent register
assistance. Dr Lahesmaa-Korpinen received
no compensation for her contribution.
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