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. Author manuscript; available in PMC: 2022 Dec 1.
Published in final edited form as: J Matern Fetal Neonatal Med. 2021 Jan 31;35(25):5291–5300. doi: 10.1080/14767058.2021.1878142

Association between Pregestational Diabetes and Mortality among Appropriate-for-Gestational Age Birthweight Infants

Abdul Shour a,c, Emma Garacci b,c, Anna Palatnik c,d, Aprill Z Dawson b,c, Ronald Anguzu a,c, Rebekah J Walker b,c, Leonard Egede b,c,*
PMCID: PMC8324595  NIHMSID: NIHMS1695832  PMID: 33517824

Abstract

Background/Objective:

Existing studies have shown that pre-gestational diabetes is a significant risk factor for adverse birth outcomes. However, it is unclear, whether pre-gestational diabetes and neonatal birthweight that is Appropriate for the Gestational Age (AGA), a proxy for overall adequate glycemic control, is associated with higher infant mortality. To address this controversy, this study investigated the relationship between pre-gestational diabetes and infant mortality in appropriate-for-gestational age infants in the United States.

Methods:

Data from the National Vital Statistics System-Linked Birth-Infant Death dataset, including 6,962,028 livebirths between 2011–2013 were analyzed. The study was conducted in the US and data were analyzed in Milwaukee, Wisconsin. The outcome was mortality among AGA newborns, defined as annual deaths per 1,000 live births with birthweights between the 10th and 90th percentiles for gestational age delivering at ≥37 weeks. The exposure was pre-gestational diabetes. Covariates were maternal demographics, behavioral/clinical and infant factors. Logistic regression was used with p-values <0.05 considered statistically significant.

Results:

A total of 6,962,028 live births met inclusion criteria. Of these, a total of 11,711 (1.0%) term AGA birthweight infants died before their first birthday. About 35,689 (0.5%) mothers were diagnosed with pregestational diabetes prior to pregnancy with 0.3% of infants whose mothers had diabetes dying in their first year of life. In the unadjusted model, pregestational diabetes had a significant association with increased odds of mortality in term AGA infants (OR 1.9 95% CI: 1.6 – 2.3). AGA mortality remained significantly higher for women with pre-gestational diabetes compared to controls, after adjusting for maternal demographics (OR:1.9, 95% CI: 1.6–2.3), behavioral/clinical characteristics (OR:1.6, 95% CI:1.3–2.0), and infant factors (OR:1.3,95% CI:1.1–1.6).

Conclusions:

In term pregnancies, pre-gestational diabetes was significantly associated with 30% higher mortality among AGA birthweight infants. Our study is innovative in its focus on AGA infants that overall is associated with good maternal glycemic control during pregnancy and in theory should confer a risk for infant mortality that is similar to pregnancies not complicated by pregestational diabetes. Despite this, we still found that even term AGA infants have higher risk of mortality in the setting of maternal pregestational diabetes. Implications of our findings underscore the importance of close antepartum surveillance and optimization of glycemic control preconception, identification of treatment targets and health policies to reduce infant mortality. The results from this study may assist other researchers and clinicians understand how best to target future interventions to reduce term infant mortality and the burden of pregestational diabetes in the US.

Keywords: Pregestational diabetes, infant mortality, appropriate-for-gestational age birthweight infants, United States

Introduction

Infant mortality, defined as the death of a child prior to their first birthday, is a major public health concern in the United States, despite significant progress in promoting maternal and infant health services during the past century.1,2 Infant mortality is measured using the Infant Mortality Rate (IMR), a significant measure of a country’s overall health and wellbeing used in many countries,3,4 and refers to the number of infant deaths per calendar year for every 1000 live births.5,6 Over the past decade, the overall IMR in the U.S. has declined from 6.9 infant deaths per 1,000 live births in 2005 to 5.8 in 2014.7,8 Nevertheless, the U.S. IMR remains higher than the IMR in all other industrialized countries and is twice the rate for that of other high-income countries.9 Annually, more than 7,000 term infant deaths (born at 37–42 weeks of gestation), not including preterm infant deaths, occur in the U.S.10 Therefore, reducing the overall U.S. IMR remains a priority.11

The risk factors that are associated with high infant mortality in the US include a combination of biological and social determinants.10,12–14 The impact of low birth weight and preterm births are two major challenges that characterize the high infant mortality rate in the US.15,16 An additional risk factor is maternal pregestational diabetes mellitus.17 The number of pregnancies complicated by pregestational diabetes is increasing, having a substantial burden on families and the health care system.18,19 Data from clinical cohorts and hospital discharges suggest that pregestational diabetes complicates approximately 1 to 2% of all pregnancies and its prevalence continues to increase.20

Pre-gestational diabetes is a risk factor for several adverse birth outcomes, including congenital anomalies, polyhydramnios, fetal macrosomia and large-for-gestational-age (LGA) infant, low Apgar score, prematurity, neonatal intensive care unit admission, neonatal hypoglycemia and hyperbilirubinemia, and even perinatal death.17,20 Most of these complications and specifically the complication of intrauterine fetal demise or postnatal neonatal death occur in poorly controlled pregestational diabetes, reflected in the presence of congenital anomalies, prematurity, LGA and polyhydramnios.21–23 However, it is unclear, whether pregnancies with maternal pregestational diabetes and neonatal birth weight that is appropriate for the gestational age (AGA), a proxy for overall adequate glycemic control, and in the absence of congenital anomalies, are associated with higher infant mortality. In this study, we responded to this question by analyzing mortality rates among AGA infants (defined as annual deaths per 1,000 infants born alive with birth weight between 10th and 90th percentiles for the gestational age) born and term (≥ 37 weeks) to women with pregestational diabetes.

Materials and Methods

Data and Population

This study utilized the 2011 to 2013 Cohort Linked Birth–Infant Death dataset collected by the Centers for Disease Control and Prevention (CDC) National Vital Statistic System (NVSS). This is the most recent data (2011–2013) available on the NVSS website as of August 20, 2020. The CDC collected information from death certificates across all US states that have been linked to corresponding birth certificates to provide IMR for children under one year in the US.24 These datasets were publicly available, de-identified, and did not require approval from the Institutional Review for human subject research. The study was conducted in the United States and data were analyzed in Milwaukee, Wisconsin. In this analysis 6,962,028 live births between 2011 and 2013, delivering at >=37 weeks were included. Pregnancies complicated by congenital anomalies were excluded.

Study Measures

The dependent variable was mortality among term AGA infants, defined as annual deaths per 1,000 infants born alive with birth weight at the 10th and 90th percentiles for the gestational age at or greater than 37 weeks. This outcome was chosen as AGA or normal birthweight is typically associated with good glycemic control.25 The American Diabetes Association defines glycemic control during pregnancy as typical levels of blood glucose in women with diabetes mellitus prior to pregnancy. The ADA in 2015, redefined its pre-prandial glycemic target from 70–130 mg/dL (3.9–7.2 mmol/L) to 80–130 mg/dL (4.4–7.2 mmol/L), and recent studies found that hyperglycemic intrauterine environment (High blood sugar within the uterus) and maternal glucose control during pregnancy are significantly associated with short-term infant morbidity, such as LGA.26,27 In contrast, LGA, defined as birth weight >90th percentile for gestational age is associated with poor glycemic control and hyperglycemia during pregnancy, and small for gestational age (SGA), defined as birthweight <10th percentile, is associated with placental insufficiency due to vascular disease that can occur with pregestational diabetes.26,27

The primary independent variable was pregestational diabetes, either type 1 or type 2. Prepregnancy diabetes (diagnosis prior to this pregnancy) data was collected from the Medical and Health Information section of the US Standard Certificate of Live Birth (Rev. 11/2003). Diabetes information is under the “risk factors in this pregnancy” section, question 41. The birth certificate does not differentiate between type 1 and type 2 diabetes. Women with gestational diabetes mellitus were excluded.

The covariates were grouped by maternal demographic, clinical and obstetric factors, and infant characteristics.28 Maternal demographics included age at delivery (19 years or less, 20–34 years, and 35 years or older), race and ethnicity (Non-Hispanic White (NHW), Non-Hispanic Black (NHB), Hispanic and Other), maternal education (12th grade or less, high school diploma/some college, associate/bachelor’s degree, and graduate degree / professional degree), marital status (married, not married), and maternal residence status (US-born/resident, and foreign-born U.S resident).

Behavioral/clinical characteristics factors included cigarette smoking (no smoking, smoking), number of prenatal visits (no visit, 1–9 visits, 10–13 visits, 14 or more visits), pregnancy body mass index (BMI) (underweight (<18.4), normal (18.5 – 24.9), overweight (25 – 29.9), obese (>=30), pregnancy weight gain measured in pounds (15 or less, 16–35, 36–55, 56 and over), previous preterm birth defined as previous delivery at <37 weeks (yes, no), breech presentation (yes, no), delivery method (vaginal, cesarean), birthplace (hospital/clinic, freestanding birth center, residence/other), and birth attendant (physician, certified nurse-midwife, other).

Infant characteristics included infant sex (male, female), plurality (single, multiple), 5-minute Apgar score (9–10, 7–8, <7), gestational age at delivery in weeks (37–38 weeks, 39–40 weeks, 41–42 weeks), and birth weight (analyzed as continuous).

Finally, our analysis did not include any known underlying causes of infant death in the U.S that were or were not related to diabetes, such as Sudden Infant Death Syndrome (SIDS) or infant injuries (e.g., suffocation).

Statistical Analysis

All analyses were performed with SAS version 9.4.29 All tests were two-tailed and p<0.05 was used to define statistical significance. First, maternal and infant characteristics were summarized and compared between the groups using Chi-square and ANOVA tests to investigate univariate differences by the study outcome (mortality among AGA infants), and by the primary independent variable (maternal pregestational diabetes status). Secondly, to determine whether there was any interaction between maternal race/ethnicity, age, education and maternal diabetes on the risk of AGA mortality, we created three interaction terms of maternal diabetes and each of the three maternal characteristics mentioned above and entered them separately in the logistic regression. Interactions between maternal race and ethnicity (p=0.446), age (p=0.984) and education (p=0.917) with diabetes on the risk of AGA infant mortality were not significant. Therefore, the model was run without stratification. Third, an unadjusted regression, followed by an adjusted logistic regression was run to identify the independent association of pre-gestational diabetes and mortality among AGA infants while controlling for mother’s demographics, behavioral/ clinical characteristics, and infant-related factors. Variables were added in blocks sequentially according to; mother’s demographics (adjusted model 1), mother’s demographics and behavioral/clinical characteristics (model 2), mother’s demographics, behavioral/clinical characteristics, and infant factors (model 3). Independent association between pregestational diabetes and mortality among AGA infants were presented using adjusted Odds Ratios (OR) and respective 95% confidence intervals.

Results

A total of 6,962,028 live births met inclusion criteria. There were 11,711 (1.0%) term AGA newborns that died before their first birthday. Table 1 presents maternal demographic, behavioral/clinical characteristics, and infant characteristics broken by mortality status. Table 2 shows AGA infants cohort descriptions by pregestational diabetes status. About 35,689 (0.5%) mothers were diagnosed with pregestational diabetes prior to pregnancy with 0.3% of infants whose mothers had diabetes dying in their first year of life.

Table 1.

AGA Birthweight Infants’ sample descriptions by Mortality status in the US., 2011–2013

All Alive % Deceased % p-value
Count 6,962,028 6,950,317 (99.0) 11,711 (1.0)
Birth Cohort group 0.29
 2011 32.4 32.4 32.9
 2012 33.4 33.4 33.5
 2013 34.2 34.2 33.6
Mother’s Age <.01
 19 years or less 7.4 7.4 12.4
 20–34 years 78.1 78.1 77.6
 35 years or older 14.5 14.5 10.0
Mother’s Race/ethnicity <.01
 NH White 55.3 55.3 54.8
 NH Black 13.3 13.3 21.3
 Hispanic 24.1 24.2 18.6
 Other 7.3 7.2 5.3
Mother’s Education <.01
 12th grade or less 16.2 16.2 24.6
 High school / some college 45.4 45.4 53.9
 Associate / Bachelor’s degree 27.4 27.4 16.7
 Grad / Professional degree 11.0 11.0 4.8
Mother’s Marital status <.01
 Married 61.1 61.2 44.3
 Not married 38.9 38.8 55.7
Mother’s Residence status 0.01
 Us-born/resident 99.8 99.8 99.9
 Foreign resident 0.2 0.2 0.1
Cigarettes Smoking <.01
 No smoking 92.2 92.3 80.5
 Smoking 7.8 7.7 19.5
Number of Prenatal visit category <.01
 No visit 1.1 1.1 3.2
 1–9 visits 22.2 22.2 31.9
 10–13 visits 52.2 52.2 44.0
Pre-gestational BMI category <.01
 Underweight 3.7 3.7 3.4
 Normal 48.3 48.3 40.4
 Overweight 25.5 25.5 26.2
 Obese 22.5 22.5 30.0
Pregnancy Weight gain category <.01
 15 pounds or less 13.6 13.6 18.5
 16–35 pounds 52.9 52.9 48.4
 36–55 pounds 28.7 28.7 26.5
 56 pounds and over 4.8 4.8 6.6
Pre-gestational Diabetes <.01
 No 99.5 99.5 99.0
 Yes 0.5 0.5 1.0
Previous Preterm Birth <.01
 No 98.2 98.2 97.0
 Yes 1.8 1.8 3.0
Complications of Labor & Delivery: <.01
 Breech
 No 95.3 95.3 93.9
 Yes 4.7 4.7 6.1
Delivery Method <.01
 Vaginal 70.6 70.6 63.1
 C-Section 29.4 29.4 36.9
Birthplace <.01
 Hospital/Clinic 98.5 98.5 98.2
 Freestanding Birth Center 0.5 0.5 0.4
 Residence/other 1.0 1.0 1.4
Birth Attendant <.01
 Doctor MD/DO 89.7 89.7 91.2
 Certified Nurse Midwife 8.8 8.8 6.8
 Midwife/other 1.5 1.5 2.0
Infant Gender <.01
 Female 49.1 49.1 43.4
 Male 50.9 50.9 56.6
Plurality 0.29
 Single 98.9 98.9 98.7
 Multiple 1.1 1.1 1.3
Apgar score 5 mins <.01
 Apgar score 9–10 88.1 88.1 66.1
 Apgar score 7–8 10.8 10.8 18.4
 Apgar score 0–6 1.1 1.1 15.5
Gestation in weeks/ Gestation in weeks category <.01
 37–38 weeks 29.2 29.2 39.1
 39–40 weeks 58.1 58.1 50.3
 41–42 weeks 12.7 12.7 10.6
Birth Weight <.01
 Mean ± SD Min-Max 3376.3 ± 319.7 2461.0 – 4345 3376.4 ± 319.6 2461.0 −4345 3280.3 ± 331.8 2464.0 −4338
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Table 2.

AGA Birthweight Infant sample descriptions by Pregestational Diabetes status in the US., 2011–2013

All no Pre-gestational Diabetes with Pre-gestational Diabetes P-value
Count 6,962,028 6,926,339 35,689 
Birth Cohort group 0.31
 2011 32.4 32.4 32.0
 2012 33.4 33.4 33.5
 2013 34.2 34.2 34.5
Mother’s Age <.01
 19 years or less 7.4 7.4 3.0
 20–34 years 78.1 78.1 68.6
 35 years or older 14.5 14.5 28.4
Mother’s Race/ethnicity <.01
 NH White 55.3 55.3 45.9
 NH Black 13.3 13.3 19.0
 Hispanic 24.1 24.1 26.7
 Other 7.3 7.3 8.4
Mother’s Education <.01
 12th grade or less 16.2 16.2 19.1
 High school / some college 45.4 45.4 49.4
 Associate / Bachelor’s degree 27.4 27.4 23.5
 Grad / Professional degree 11.0 11.0 8.0
Mother’s Marital status 0.03
 Married 61.1 61.1 60.6
 Not Married 38.9 38.9 39.4
Mother’s Residence status <.01
 Us-born/resident 99.8 99.8 99.9
 Foreign resident 0.2 0.2 0.1
Cigarettes Smoking <.01
 No smoking 92.2 92.3 89.8
 Smoking 7.8 7.7 10.2
Number of Prenatal visit category <.01
 No visit 1.1 1.1 0.9
 1–9 visits 22.2 22.2 16.5
 10–13 visits 52.2 52.3 39.4
 14 or more visits 24.5 24.4 43.2
Pre-gestational BMI category <.01
 Underweight 3.7 3.7 1.1
 Normal 48.3 48.4 22.1
 Overweight 25.5 25.6 23.6
 Obese 22.5 22.3 53.2
Pregnancy Weight gain category <.01
 15 pounds or less 13.6 13.5 25.1
 16–35 pounds 52.9 52.9 47.9
 36–55 pounds 28.7 28.7 21.5
 56 pounds and over 4.8 4.8 5.5
Previous Preterm Birth <.01
 No 98.2 98.2 95.4
 Yes 1.8 1.8 4.6
Complications of Labor & Delivery: <.01
Breech
 No 95.3 95.32 92.8
 Yes 4.7 4.68 7.2
Delivery Method <.01
 Vaginal 70.6 70.7 48.7
 C-Section 29.4 29.3 51.3
Birthplace <.01
 Hospital/Clinic 98.5 98.5 99.8
 Freestanding Birth Center 0.5 0.5 0.0
 Residence/other 1.0 1.0 0.2
Birth Attendant <.01
 Doctor (MD/DO) 89.7 89.7 95.6
 Certified Nurse Midwife 8.8 8.8 4.0
 Midwife/other 1.5 1.5 0.4
Infant Gender 0.35
 Female 49.1 49.1 48.8
 Male 50.9 50.9 51.2
Plurality <.01
 Single 98.9 98.9 98.5
 Multiple 1.1 1.1 1.5
Apgar score 5 mins <.01
 Apgar score 9–10 88.1 88.1 82.8
 Apgar score 7–8 10.8 10.8 14.8
 Apgar score 0–6 1.1 1.1 2.4
Gestation in weeks category <.01
 37–38 weeks 29.2 29.1 43.6
 39–40 weeks 58.1 58.2 48.1
 41–42 weeks 12.7 12.7 8.3
Birth Weight <.01
Mean ± SD Min-Max 319.7 2461.0  319.6 2461.0   ± 330.9 2462.0  
Median IQR 3147.0 – 3600.0 3147.0 – 3600.0 3119.0 – 3600.0
Infant Mortality status <.01
 Alive 99.8 99.8 99.7
 Deceased 0.2 0.2 0.3
Infant Age at death category <.01
 Neonatal before 28 days 30.9 30.8 44.3
 Post-Neonatal after 28 days-1 year 69.1 69.2 55.7
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Table 3 shows unadjusted and adjusted models for AGA infant mortality. In the unadjusted model, pregestational diabetes had a significant association with increased odds of mortality in term AGA infants (OR 1.9 95% CI: 1.6 – 2.3). In addition, maternal age, race and ethnicity, maternal education, cigarette smoking, number of prenatal visits, BMI before delivery, birthplace, birth attendant, and 5 mins Apgar score were statistically significantly associated with mortality among term AGA infants in mothers with pre-gestational diabetes (all p values <0.01).

Table 3:

Predictors of AGA Birthweight infant mortality in the US., 2011–2013

Unadjusted Adjusted Model 1: Mother’s Demographics Adjusted Model 2: Mother’s Demographics, Behavioral/Clinical Characteristics Adjusted Model 3: Mother’s Demographics, Behavioral/Clinical Characteristics All (Infant Factors)
Odds Ratio 95% CI Odds Ratio 95% CI Odds Ratio 95% CI Odds Ratio 95% CI
Pregestational Diabetes
 No Ref Ref Ref Ref
 Yes 1.9  1.6 – 2.3 1.9  1.6 – 2.3 1.6  1.3 – 1.8 1.3 1.1 – 1.6
Mother’s Age
 19 years or less 1.7 1.6 – 1.8 1.1 1.0 – 1.2 1.3 1.2 – 1.4 1.2 1.2 – 1.3
 20–34 years Ref Ref Ref Ref
 35 years or older 0.7 0.6 – 0.8 0.9 0.8 – 0.9 0.8 0.8– 0.9 0.8 0.8 – 0.9
Mother’s Race/ethnicity
 NH White Ref Ref Ref Ref
 NH Black 1.6 1.5 – 1.7 1.1 1.0 – 1.2 1.1 1.0 – 1.2 1.0 1.0 – 1.15
 Hispanic 0.7 0.6 – 0.8 0.5 0.5 – 0.6 0.6 0.6 – 0.7 0.6 0.5 – 0.7
 Other 0.7 0.6 – 0.8 0.8 0.6 – 0.9 0.9 0.8 – 1.0 0.9 0.8 – 1.0
Mother’s Education
 12th grade or less 1.2 1.0 – 1.3 1.4 1.3 – 1.5 1.2 1.0 – 1.3 1.1 1.0 – 1.3
 High school / some college Ref Ref Ref Ref
 Associate / Bachelor’s degree 0.5 0.4 – 0.6 0.5 0.5 – 0.6 0.6 0.6 – 0.7 0.6 0.5 – 0.7
 Grad / Professional degree 0.3 0.2 – 0.4 0.4 0.4 – 0.5 0.5 0.4 – 0.6 0.5 0.5 – 0.6
Mother’s Marital status
 Married Ref Ref Ref Ref
 Not married 1.9 1.9 – 2.1 1.4 1.4 – 1.5 1.3 1.2 – 1.4 1.2 1.2 – 1.3
Cigarettes Smoking
 No smoking Ref Ref Ref
 Smoking 2.8 2.7 – 3.0 1.9 1.8 – 2.0 1.8 1.7 – 1.9
Number of Prenatal visit category
 No visit 3.4 3.0 – 3.7 2.5 2.2 – 2.9 2.3 2.0 – 2.6
 1–9 visits 1.7 1.6 – 1.8 1.3 1.4 – 1.5 1.4 1.3 – 1.5
 10–13 visits Ref Ref Ref
 14 or more visits 1.0 0.9 – 1.1 0.9 0.9 – 1.1 1.0 0.9 – 1.1
Pregestational BMI category
 Underweight 1.1 1.0 – 1.2 0.9 0.8 – 1.1 0.9 0.8 – 1.0
 Normal Ref Ref Ref
 Overweight 1.2 1.1 – 1.3 1.1 1.0 – 1.2 1.1 1.0 – 1.2
 Obese 1.6 1.5 – 1.7 1.3 1.2 – 1.4 1.3 1.2 – 1.4
Pregnancy Weight gain category
 15 pounds or less 1.4 1.2 – 1.6 1.1 1.0 – 1.2 1.1 1.0 – 1.2
 16–35 pounds Ref Ref Ref
 36–55 pounds 1.0 0.9 – 1.1 0.9 0.9 – 1.0 1.0 0.9 – 1.1
 56 pounds and over 1.4 1.3 – 1.6 1.1 1.0 – 1.3 1.2 1.1 – 1.3
Previous Preterm Birth
 No Ref Ref Ref
 Yes 1.6 1.5 – 1.8 1.4 1.2 – 1.6 1.3 1.2 – 1.5
Complications of Labor & Delivery: Breech
 No Ref Ref Ref
 Yes 1.3 1.2 – 1.4 1.1 1.0 – 1.3 1.0 0.9 – 1.2
Delivery Method
 Vaginal Ref Ref Ref
 C-Section 1.4 1.3 – 1.5 1.3 1.2 – 1.4 1.2 1.0 – 1.3
Infant Gender
 Female Ref Ref
 Male 1.2 1.1 – 1.3 1.3 1.2 – 1.4
Plurality
 Single Ref Ref
 Multiple 1.0 0.9 – 1.3 0.7 0.6 – 0.9
Birth Weight category
 Under 3000 grams 1.6 1.5 – 1.7 1.4 1.3 – 1.5
 3000 – 3499 grams Ref Ref
 3500 grams and over 0.7 0.6 – 0.8 0.7 0.6 – 0.8
Apgar score (5 mins)
 Apgar score 9–10 Ref Ref
 Apgar score 7–8 2.2 2.1 – 2.4 2.1 1.9 – 2.2
 Apgar score 0–6 19.2 18.2 – 20.2 16.0 15.1 – 17.0
Gestation in weeks category
 37–38 weeks 1.5 1.4 – 1.6 1.2 1.1 – 1.3
 39–40 weeks Ref Ref
 41–42 weeks 0.9 0.9 – 1.0 0.9 0.9 – 1.1
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After adjusting for maternal demographics (model 1), maternal pregestational diabetes remained to be significantly associated with higher rate of term AGA infant mortality (OR of 1.9 95% CI: 1.6 – 2.3) (Table 3). Similarly, after adding behavioral/clinical characteristics (model 2), the association remained significant (OR 1.6 95% CI: 1.3 – 2.0). In the fully adjusted model 3, controlling for maternal demographics, behavioral/clinical characteristics, and infant factors (model 3), maternal pregestational diabetes remained to be significantly associated with higher rates of term AGA infant mortality (OR 1.3, 95% CI 1.1–1.6).

In addition to pre-gestational diabetes, in the fully adjusted model, the following additional factors were significantly associated with higher mortality in term AGA infants: maternal age of <20 years (OR 1.2, 95% CI 1.2 −1.3), maternal education of 12th grade or less (OR 1.1, 95% CI 1.0 – 1.3), cigarette smoking (OR 1.8, 95% CI 1.7 – 1.9), no prenatal visits (OR 2.3, 95% CI 2.0 – 2.6), maternal obesity (OR 1.3, 95% CI 1.2 – 1.4), pregnancy weight gain greater than 56 pounds (OR 1.2, 95% CI 1.1 – 1.3), prior preterm birth (OR 1.3, 95% CI 1.2 – 1.5), birth weight under 3000 grams (OR 1.4, 95% CI 1.3 – 1.5), 5 minutes Apgar score less than 6 (OR 16.0, 95% CI 15.1 – 17.0), and gestational age between 37–38 weeks (OR 1.2, 95% CI 1.1 – 1.3) compared to 39–40 weeks. In contrast, several factors were associated with lower risk of AGA infant mortality including maternal age > 35 years old (OR 0.8, 95% CI 0.8 – 0.9) compared to age 20–34 years old, Hispanic ethnicity (OR 0.6, 95% CI 0.5 – 0.7), having an Associate /Bachelor’s degree (OR 0.6, 95% CI 0.5 – 0.7), and birth weight greater than 3500 grams (OR 0.7, 95% CI 0.6 – 0.8).

Discussion

This study examined the relationship between pregestational diabetes and infant mortality among term AGA infants. Using the National Vital Statistics System - Linked Birth-Infant Death dataset (2011–2013) we found that pregestational diabetes was significantly associated with infant mortality among term AGA birthweight infants in the U.S. The odds of mortality among AGA infants remained statistically significantly higher for women diagnosed with pregestational diabetes compared to those who were not diagnosed, after adjusting for maternal demographics, maternal behaviors and clinical characteristics and infant factors. In addition, our study identified mutable risk factors associated with AGA infant mortality such as, cigarette smoking, lack of prenatal care, maternal obesity and excessive gestational weight gain. The results from this study may assist other researchers and clinicians understand how best to target future interventions to reduce term infant mortality and the burden of pregestational diabetes in the U.S.

Previous studies have examined factors associated with infant mortality in the U.S. and the impact of pregestational diabetes on adverse birth outcomes, however they did not focus on AGA infant mortality.17,30–32 Poor glycemic control of pregestational diabetes is a well-established risk factor for fetal death and neonatal complications, often manifesting in the infant measuring SGA or LGA, reflecting suboptimal glycemic control during pregnancy.26,33,34 However, data is limited on rates of complications in term AGA infants in the setting of pregestational diabetes. Our study is innovative in its focus on AGA infants that overall is associated with good maternal glycemic control during pregnancy25and in theory should confer a risk for infant mortality that is similar to pregnancies not complicated by pregestational diabetes. Despite this, we still found that even term AGA infants have higher risk of mortality in the setting of maternal pregestational diabetes. This underscores the importance of looking into additional risk factors that are associated with infant mortality in women with pregestational diabetes, focusing on preconception and also on postpartum course and early infancy.

Public Health Implications

First, our findings highlight that normal in-utero growth trajectory in pregnancies with pregestational diabetes may not be protective against postnatal complications.35 While it is accepted that LGA, a complication of pregestational diabetes’ suboptimal control, carries postnatal risks (ACOG reference), it is unclear whether term AGA or average birth weight infants born to mothers with pre-gestational diabetes are considered to be at a lower risk for poor health outcomes.25 Our finding of higher mortality rate in this population of infants was surprising and merits additional research to investigate effects of pregestational diabetes on the postnatal child morbidity and mortality and investigation of additional risks factors for infant mortality during postnatal period and pediatric follow-up data during the first year of life.

While this study used a nationally representative sample and controlled for a variety of possible confounding variables, it comes with limitations. First, the data do not have information on glycemic control of the mother or whether the mother received insulin or an oral antidiabetic medication during pregnancy. Therefore, we can only assume that control may have been optimal based on AGA birthweight. Second, the analysis did not include infant death cases with clear diagnosis that was not related to maternal diabetes, such as sudden infant death syndrome or injuries such as suffocation or accidents. Third, another limitation is lack of adequate measures of maternal comorbidities which may have increased mortality independent of pre-gestation diabetes including preeclampsia, and preexisting chronic hypertension, and heart disease. In pregestational diabetic mothers- long duration of diabetes, and other comorbidities such as hypertension or smoking can all cause placental dysfunction and SGA. Adjustment was made to smoking, BMI and weight gain but not to hypertension, duration of diabetes or pre-gestational glycemic control. Variables were not available and did not exist across the study years. Finally, we did not have the information of the type of antidiabetic pharmacotherapy women received in our study.

In conclusion, maternal pregestational diabetes was significantly associated with infant mortality among term AGA birthweight infants in the U.S. Future research should focus on identifying additional risks factors for infant mortality in women with pregestational diabetes, encompassing the postnatal period and pediatric follow-up data during the first year of life. Importantly, studies investigating social determinants factors that may be associated with higher fetal and neonatal complications in the setting of maternal diabetes are needed.

Funding:

Effort for this project was partially supported by the National Institute of Diabetes and Digestive and Kidney Diseases (K24DK093699, R01DK118038, R01DK120861, PI: Egede); the National Institute for Minority Health and Health Disparities (R01MD013826, PI: Egede/Walker), and the American Diabetes Association (1-19-JDF-075, PI: Walker). Funding organizations had no role in the analysis, interpretation of data, or writing of the manuscript.

Footnotes

Presented in an oral format: This paper received the “Greg Alexander Outstanding Student Paper Award” on Nov. 4th, 2019 at the Maternal and Child Health Section of the 147th Annual Meeting of the American Public Health Association (APHA) in Philadelphia.

Data availability statement: Human participants were not involved in this research. The study uses a deidentified publicly available dataset available at http://data.nber.org/data/vital-statistics-natality-data.html

Declaration of Interest Statement: The authors report no conflict of interest. The authors report no potential conflicts of interest relevant to this manuscript. Grant numbers (K24DK093699, R01DK118038, R01DK120861, PI: Egede); (R01MD013826, PI: Egede/Walker)

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