Patterns of congenital anomalies and relationship to initial maternal fasting glucose levels in pregnancies complicated by type 2 and gestational diabetes

doi:10.1016/S0002-9378(00)70217-1

American Journal of Obstetrics and Gynecology

Volume 182, Issue 2, February 2000, Pages 313-320

https://doi.org/10.1016/S0002-9378(00)70217-1 Get rights and content

Abstract

Objectives: We sought to determine the types of congenital anomalies affecting infants of women with gestational diabetes mellitus or type 2 diabetes and to examine the relationship between those malformation types and measures of initial glycemia of women at entry into prenatal care with type 2 diabetes or at time of diagnosis in women with gestational diabetes mellitus. Study Design: A total of 4180 pregnancies complicated by gestational diabetes mellitus (n = 3764) or type 2 diabetes (n = 416) that were delivered after 20 weeks of gestation were reviewed for the presence of congenital malformations diagnosed before hospital discharge. Anomalies were categorized as being absent, minor, major, genetic syndromes, or aneuploidies. Major anomalies were further categorized by the number and type of affected organ systems. In addition to maternal clinical and historical parameters, the initial fasting serum glucose either from the diagnostic glucose tolerance test (gestational diabetes mellitus) or at entry to prenatal care (type 2 diabetes) and the initial glycosylated hemoglobin before insulin therapy were examined for a relationship to anomalies. Results: The initial fasting serum glucose and glycosylated hemoglobin levels were significantly higher in pregnancies with major (n = 143) and minor (n = 112) anomalies and genetic syndromes (n = 9) compared with pregnancies with no anomalies (n = 3895). Of those pregnancies with major anomalies, the most commonly affected organ systems were the cardiac (37.6%), musculoskeletal (14.7%), and central nervous systems (9.8%) and anomalies involving multiple organ systems (16%). There was no increased predominance of any specific organ system involvement seen with increasing fasting serum glucose levels in pregnancies with major congenital anomalies. Pregnancies with major anomalies affecting multiple organ systems had significantly higher initial fasting serum glucose levels (166 ± 64 mg/dL) compared with pregnancies in which one organ system was affected (141 ± 55 mg/dL, P < .04) or no organ systems were affected (115 ± 38 mg/dL, P < .0001). Conclusion: Congenital anomalies in offspring of women with gestational and type 2 diabetes affect the same organ systems that have been previously described in pregnancies complicated by type 1 diabetes. Increasing hyperglycemia at diagnosis or presentation for care was associated with an increasing risk of anomalies in general and with anomalies involving multiple organ systems without a preferential increase in involvement of specific organ system. (Am J Obstet Gynecol 2000;182:313-20.)

Section snippets

Subjects

The study cohort comprised consecutive pregnancies complicated by GDM or type 2 diabetes that were delivered after 20 weeks of gestation at the Los Angeles County + University of Southern California Women and Children’s Hospital from January 1987 to July 1995. The hospital serves as the major referral center for the care of indigent patients with pregnancies complicated by diabetes in Los Angeles County. During the period of study, type 2 diabetes was diagnosed in nonpregnant women by World

Study population

A total of 4180 infants were born to women with GDM (n = 3764) or known type 2 diabetes (n = 416) during the period of the study. Major anomalies were diagnosed before hospital discharge in 143 infants (3.4%, Table I), with a prevalence of 2.9% in the GDM group and 8.9% in women whose type 2 diabetes was known before pregnancy. Included in the major anomaly group were 2 infants with syndromes that have previously been associated with diabetes (caudal regression and VATER [vertebral defects,

Comment

To our knowledge, this is the first large-scale study examining the pattern of major anomalies in relationship to the initial maternal glycemic indexes in infants born to women with GDM or known type 2 diabetes. Our investigation revealed 3 important findings. First, cardiovascular defects were the most frequently occurring anomalies, followed by musculoskeletal and central nervous system anomalies. Thus the pattern of anomalies found in infants of women with type 2 diabetes and GDM appeared to

References (19)

JL Simpson et al.
Diabetes in pregnancy, Northwestern University Series (1977-1981). I. Prospective study of anomalies in offspring of mothers with diabetes mellitus
Am J Obstet Gynecol
(1983)
UM Schaefer et al.
Congenital malformations in offspring of women with hyperglycemia first detected during pregnancy
Am J Obstet Gynecol
(1997)
N Freinkel et al.
Fuel-medicated teratogenesis during early organogenesis: the effects of increased concentrations of glucose, ketones or somatomedin inhibitor during rat embryo culture
Am J Clin Nutr
(1986)
JE Becerra et al.
Diabetes mellitus during pregnancy and the risk of specific birth defects: a population-based case control study
Pediatrics
(1990)
LJ Comess et al.
Congenital anomalies and diabetes in the Pima Indians of Arizona
Diabetes
(1969)
EA Reece et al.
Diabetic embryopathy: pathogenesis, prenatal diagnosis and prevention
Obstet Gynecol Survey
(1986)
E Miller et al.
Elevated maternal hemoglobin A_1c in early pregnancy and major congenital anomalies in infants of diabetic mothers
N Engl J Med
(1981)
JL Mills et al.
Lack of relation of increased malformation rates in infants of diabetic mothers to glycemic control during organogenesis
N Engl J Med
(1988)
MA Ramos-Arroyo et al.
Maternal diabetes: the risk for specific birth defects
Eur J Epidemiol
(1992)

There are more references available in the full text version of this article.

Cited by (208)

Preconception SGLT2 or DPP4 inhibitor use and adverse pregnancy outcomes
2023, Diabetes Research and Clinical Practice
To compare preconception use of sodium-glucose cotransporter-2 (SGLT2i) and dipeptidyl peptidase-4 (DPP4i) inhibitors to sulfonylurea agents, and associated peri-conceptional A1c concentration, and risk of pregnancy loss and congenital anomalies.
This population-based cohort study used administrative datasets for all of Ontario, Canada, and included women eligible for free medication coverage and who achieved a recognized pregnancy from April 2007-November 2021. Exposure was a SGLT2i, DPP4i or sulfonylurea (referent) dispensed at least 90 days preconception. Study outcomes included differences in periconceptional A1c; miscarriage, induced abortion, or stillbirth; and any congenital anomaly – the latter two outcomes assessed using propensity score overlap weighting.
The mean (SD) periconceptional A1c was 8.1 % (2.0) among those prescribed any sulfonylurea, compared with 8.3 % (2.0) with a DPP4i and 7.8 % (1.6) with any SGLT2i. The risk of pregnancy loss was lowest among those exclusively prescribed a SGLT2i (relative risk [RR] 0.51, 95 % CI 0.22 to 0.91). Risk of a congenital anomaly at birth did not differ significantly comparing DPP4i or SGLT2i to sulfonylurea agents.
Neither SGLT2i nor DPP4i use before pregnancy was associated with a difference in A1c, or a higher risk of selective adverse outcomes, compared to sulfonylureas. Future larger studies are required, including assessment of medication use after conception, during the critical period of embryogenesis.
Glucose and oxygen in the early intrauterine environment and their role in developmental abnormalities
2022, Seminars in Cell and Developmental Biology
The early life environment can have profound impacts on the developing conceptus in terms of both growth and morphogenesis. These impacts can manifest in a variety of ways, including congenital fetal anomalies, placental dysfunction with subsequent effects on fetal growth, and adverse perinatal outcomes, or via effects on long-term health outcomes that may not be detected until later childhood or adulthood. Two key examples of environmental influences on early development are explored: maternal hyperglycaemia and gestational hypoxia. These are increasingly common pregnancy exposures worldwide, with potentially profound impacts on population health. We explore what is known regarding the mechanisms by which these environmental exposures can impact early intrauterine development and thus result in adverse outcomes in the immediate, short, and long term.
Comprehensive assessment of the associations between maternal diabetes and structural birth defects in offspring: a phenome-wide association study
2021, Annals of Epidemiology
Our objective was to comprehensively evaluate the risk of a broad range of birth defects among offspring of women with diabetes, overall and stratified by pregestational versus gestational diagnosis, using the phenome-wide association (PheWAS) methodology.
We performed a registry linkage study of all live births (>6,500,000) and birth defects cases (>290,000) in Texas, 1999–2015. We ascertained diabetes from birth and fetal death certificates. We calculated prevalence rate ratios (PRR) for phenotypes with ≥10 cases among exposed offspring (n = 130).
Diabetes was associated with the prevalence of any defect (PRR 1.40, 95% confidence interval [CI] 1.38–1.42), multiple defects (PRR 1.86, 95% CI 1.81–1.91), and 60 specific phenotypes, including novel (hypospadias, mitral stenosis) and previously reported phenotypes (renal a-/dysgenesis, spinal anomalies). Pregestational diabetes was a stronger risk factor for any defect (PRR 2.00, 95% CI 1.93–2.07), multiple defects (PRR 3.27, 95% CI 3.11–3.44), and the 60 specific phenotypes evaluated. Gestational diabetes was associated with any defect (PRR 1.21, 95% CI 1.19–1.23) and 47 specific birth defects phenotypes, although associations were weaker than for pregestational diabetes.
The PheWAS is an efficient way to identify risk factors for disease using population-based registry data. Pregestational diabetes is associated with a broader range of phenotypes than previously reported. Because diabetes is diagnosed in 1% of women prior to pregnancy and 6%–9% during pregnancy, our results highlight a significant public health concern.
In ovo hyperglycemia causes congenital limb defects in chicken embryos via disruption of cell proliferation and apoptosis
2020, Biochimica et Biophysica Acta - Molecular Basis of Disease
While the correlation between diabetes during pregnancy and birth defects is well-established, how hyperglycemia causes developmental abnormalities remains unclear. In this study, we developed a novel “hyperglycemic” chicken embryonic model by administrating various doses of glucose to fertilized eggs at embryonic stages HH16 or HH24. When the embryos were collected at HH35, the LD50 was 1.57 g/Kg under HH16 treatment and 0.93 g/Kg under HH24 treatment, indicating that “hyperglycemic” environments can be lethal for the embryos. When exposed to a dose equal to or higher than 1 g/Kg glucose at HH16 or HH24, more than 40% of the surviving chicken embryos displayed heart defects and/or limb defects. The limb defects were associated with proliferation defects of both the wing and leg buds indicated by reduced numbers of p-H3S10 labeled cells. These limb defects were also associated with ectopic apoptosis in the leg bud and expression changes of key apoptotic genes. Furthermore, glucose treatment induced decreased expression of genes involved in Shh-signaling, chondrogenesis, and digit patterning in the limb bud. In summary, our data demonstrated that a high-glucose environment induces congenital heart and limb defects associated with disrupted cell proliferation and apoptosis, possibly through depressed Shh-signaling.
Maternal influences on fetal brain development: The role of nutrition, infection and stress, and the potential for intergenerational consequences
2020, Early Human Development
An optimal early life environment is crucial for ensuring ideal neurodevelopmental outcomes. Brain development consists of a finely tuned series of spatially and temporally constrained events, which may be affected by exposure to a sub-optimal intra-uterine environment. Evidence suggests brain development may be particularly vulnerable to factors such as maternal nutrition, infection and stress during pregnancy. In this review, we discuss how maternal factors such as these can affect brain development and outcome in offspring, and we also identify evidence which suggests that the outcome can, in many cases, be stratified by socio-economic status (SES), with individuals in lower brackets typically having a worse outcome. We consider the relevant epidemiological evidence and draw parallels to mechanisms suggested by preclinical work where appropriate. We also discuss possible transgenerational effects of these maternal factors and the potential mechanisms involved. We conclude that modifiable factors such as maternal nutrition, infection and stress are important contributors to atypical brain development and that SES also likely has a key role.
Evaluation of H19, Mest, Meg3, and Peg3 genes affecting growth and metabolism in umbilical cord blood cells of infants born to mothers with gestational diabetes and healthy mothers in Rafsanjan City, Iran
2023, Journal of Developmental Origins of Health and Disease

View all citing articles on Scopus

^☆: Supported in part by grant M 01-RR43 from the General Clinical Research Center Branch, National Center for Research Resources, and the US National Institutes of Health.

^☆☆: Reprint requests: Siri L. Kjos, MD, Department of Obstetrics and Gynecology, University of Southern California School of Medicine, Women and Children’s Hospital, 1240 North Mission Rd, Rm L1017, Los Angeles, CA 90033.

View full text

Patterns of congenital anomalies and relationship to initial maternal fasting glucose levels in pregnancies complicated by type 2 and gestational diabetes☆,☆☆

Abstract

Section snippets

Subjects

Study population

Comment

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Clin Nutr

Diabetes mellitus during pregnancy and the risk of specific birth defects: a population-based case control study

Pediatrics

Congenital anomalies and diabetes in the Pima Indians of Arizona

Diabetes

Diabetic embryopathy: pathogenesis, prenatal diagnosis and prevention

Obstet Gynecol Survey

Elevated maternal hemoglobin A1c in early pregnancy and major congenital anomalies in infants of diabetic mothers

N Engl J Med

Lack of relation of increased malformation rates in infants of diabetic mothers to glycemic control during organogenesis

N Engl J Med

Maternal diabetes: the risk for specific birth defects

Eur J Epidemiol

Elevated maternal hemoglobin A_1c in early pregnancy and major congenital anomalies in infants of diabetic mothers