Abstract
OBJECTIVE
To assess pregnancy outcomes in young women with youth-onset type 2 diabetes followed in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study.
RESEARCH DESIGN AND METHODS
Pregnancy information (outcome and any maternal or fetal complications) was obtained from the female participants by self-report. Additionally, medical records for the pregnancy and the child’s neonatal course were obtained with data abstracted into standardized forms.
RESULTS
Over a maximum of 15 years, 260 pregnancies were reported by 141 women (aged 21.5 ± 3.2 years, BMI 35.6 ± 7.2 kg/m2, and diabetes duration 8.1 ± 3.2 years). Contraception use prior to pregnancy was reported by 13.5% of the women. Complications were reported by 65% of the women during their pregnancy. Pregnancy loss was observed in 25.3% and preterm birth in 32.6% of pregnancies. HbA1c ≥8% was observed in 31.9% of the pregnancies, and 35% of the pregnancies were complicated by chronic hypertension. Nephropathy prior to pregnancy was observed in 25% of the women. In the offspring, 7.8% were classified as small for gestational age, 26.8% large for gestational age, and 17.9% in the macrosomic range.
CONCLUSIONS
Based on observations from the TODAY cohort, young women with pregestational, youth-onset type 2 diabetes had very high rates of maternal complications stemming from significant socioeconomic disadvantage. The substantial maternal and infant complications seen in these young moms could potentially be avoided with improved contraception rates and reproductive planning.
Introduction
With the increase in youth-onset type 2 diabetes (1), the number of pregnancies in women complicated by preexisting type 2 diabetes is increasing (2). From 2000 to 2010, the prevalence of pregestational diabetes (including type 2 diabetes) increased by 37% (3). According to the most recent report by the Centers for Disease Control and Prevention (CDC) in 2016, the national prevalence of pregestational diabetes during pregnancy (type 1 diabetes and type 2 diabetes) was 0.9% (4).
Diabetes during pregnancy has long been associated with morbidity in the mother and offspring, as well as infant mortality. While gestational diabetes is the most common form of diabetes during pregnancy (4), pregestational diabetes has been associated with worse outcomes for both the mother and her offspring (5,6), with type 1 and type 2 diabetes having equal contributions to pregestational diabetes (7). With the overall increase in the incidence of type 2 diabetes, especially in youth, the percentage of pregnancies affected by type 2 diabetes has increased ∼85% over an 8-year period (8). Type 2 diabetes during pregnancy has been associated with increased risk for adverse outcomes (9,10). Perinatal mortality in infants born to mothers with adult-onset type 2 diabetes has been reported to be approximately fourfold higher than in infants born to mothers with type 1 diabetes (11).
Few studies have examined the impact of youth-onset type 2 diabetes during pregnancy on maternal and fetal outcomes. In prior reports of pregestational diabetes in pregnancy, the average age of the women at pregnancy onset ranges from 33 to 36 years, with a diabetes duration averaging ∼5 years (11,12). The Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study was a multisite intervention study designed to examine the effectiveness of varying approaches to diabetes management on maintenance of glycemic control, followed by an observational follow-up through early adulthood to understand the long-term outcomes of youth-onset type 2 diabetes (13). The TODAY study offers a unique opportunity to understand the impact of type 2 diabetes in women who are younger, with a longer duration of diabetes. We previously reported pregnancy outcomes from the intervention phase of the trial, in which participants’ mean maternal age was 18.4 years with a mean diabetes duration of 3.17 years at the time of the first pregnancy (14). The initial report included 63 pregnancies in 46 women in TODAY. In 53 pregnancies with available outcomes, 22.4% of the pregnancies resulted in pregnancy loss. Stillbirth was reported in two pregnancies. Of the 39 live-born infants during the trial, 15% were born preterm and 20.5% were born with a major congenital anomaly.
Since the initial report (14), pregnancy data for an additional 197 pregnancies have been collected prospectively to allow assessment of maternal pregnancy complications and expanded perinatal complications in the offspring in a more structured fashion. Given that more participants in the TODAY cohort experienced glycemic failure (15) since the initial report, it was expected that the prevalence of pregnancy and perinatal complications would increase as a result of worse glycemia; thus, the purpose of the current analysis was to assess pregnancy and perinatal complications associated with preexisting youth-onset type 2 diabetes in women (median age 22.3 years, minimum 14.5 years, and maximum 30.4 years) from the TODAY cohort and their offspring.
Research Design and Methods
The TODAY study has been previously described in detail (16). The study included 699 participants 10–17 years of age diagnosed with type 2 diabetes using prevailing American Diabetes Association criteria, with illness duration of ≤2 years at the time of enrollment (17). Other inclusion criteria included BMI ≥85th percentile for age and sex and confirmed type 2 diabetes (for <2 years’ duration) based on fasting C-peptide >0.6 ng/mL and absence of pancreatic autoantibodies (17). Participants were randomized to one of three treatment arms—metformin alone, metformin with rosiglitazone, or metformin plus a lifestyle intervention program—and followed longitudinally for 2–6 years. The primary outcome of the trial was time to treatment failure, defined as a persistently elevated HbA1c (≥8%) over a period of 6 months or inability to wean from insulin after metabolic decompensation. An observational follow-up study (TODAY2) was conducted in two phases. During the first phase, participants were transitioned to standard diabetes care with metformin and insulin if needed for glycemic control. In the second phase of the observational study, all participants were transitioned to local providers within their communities, but continued to have annual visits to collect serum and urine samples, assess microvascular and macrovascular complications, and conduct structured interviews to capture demographic and health information data.
Of the 699 participants, 452 (64.7%) of the cohort were female (16). In the initial phase of the trial, counseling was provided to all females regarding the risks of rosiglitazone use during pregnancy; consent for the study required the use of adequate contraception. Additionally, the female participants were counseled on the risk of pregnancy loss and fetal malformations associated with poor glucose control throughout all phases of the study.
Pregnancy information, including outcome and any maternal or fetal complications, was obtained prospectively from the female participants by self-report at regularly scheduled study visits, which occurred every 3–6 months in the initial phase of the trial and annually in the second phase of the trial. Additionally, participants provided consent to obtain the pregnancy records for the pregnancy, birth, and the baby, from which data were abstracted into standardized forms for reporting maternal and infant health outcomes; medical records were available for review in 97% of the pregnancies reported. All medical records were reviewed and the data abstracted from the records used for analysis. In cases in which a discrepancy arose between the subject report and the record, the medical record information was used for the data collection. Information on mode of delivery (cesarean sections) was only captured from 2014 to 2020. Pregnancy was defined as a reported or documented positive urine pregnancy test.
For maternal pregnancy outcomes, miscarriage was defined as pregnancy loss at <20 weeks, and stillbirth defined as pregnancy loss during or after 20 weeks’ gestation in which the infant was not live-born. Pregnancy losses with undetermined gestational age at the time of the loss were classified as unknown losses. Maternal hospitalization was defined as any hospitalization other than a scheduled delivery. Women were considered to have preeclampsia based on stated diagnosis by a physician documented within the medical records reviewed. Hypertension was defined as use of medications, consecutive measures ≥130 mmHg systolic and/or ≥80 mmHg diastolic, or stated diagnosis per the physician notes. Those with documented hypertension prior to pregnancy during analysis were subtracted from the total number with hypertension to determine the number women with gestational hypertension. Microalbuminuria was defined as urine albumin-to-creatinine ratio >30 mg/g on two occasions prior to the pregnancy. Macroalbuminuria was defined as one urine albumin-to-creatinine ratio >300 mg/g prior to pregnancy. Micro- and macroalbuminuria during pregnancy excludes women diagnosed prior to the pregnancy. HbA1c >8% was defined as one elevated value at any point in the pregnancy. Documentation of the diagnosis by a physician in the medical records also was sufficient to meet the criteria for these conditions.
Preterm deliveries were classified as delivery of a live infant between 20 and 37 weeks’ gestation and term as ≥37 weeks’ gestation. Very low birth weight was defined as <1,500 g, low birth weight 1,500–2,499 g, normal birth weight 2,500–3999 g, and macrosomia as ≥4,000 g, according to the World Health Organization standards. Birth weight classification was described as small for gestational age (SGA) (<10th percentile), appropriate for gestational age (10–90th percentiles), and large for gestational age (LGA) (>90th percentile) adjusted for infant sex and race, according to the criteria established by Alexander et al. (18). For neonatal complications such as hypoglycemia and respiratory distress, physician documentation within the medical record was the criteria used to define these conditions.
Statistical Analysis
Prevalence of adverse maternal and fetal outcomes is reported based upon all pregnancies, known outcomes, or live births. Descriptive statistics reported are frequencies, percentages, means, and SDs. Comparisons between groups for continuous variables were conducted using two-sided t tests when the assumption of approximate normality was satisfied and using the Wilcoxon rank sum test otherwise. For noncontinuous outcomes, χ2 tests or Fisher exact tests were used to compare groups. P values <0.05 were considered statistically significant. Given the descriptive and exploratory nature of the analysis, no adjustments were made for multiple comparisons for overall testing; however, Bonferroni adjustments were used for pairwise comparisons when the overall test indicated statistical significance. Analyses were performed using SAS 9.4 (SAS Institute, Cary, NC).
Results
In the 15 years of the combined TODAY study data collection, 260 pregnancies were reported by 141 young women (Supplementary Fig. 1). Baseline characteristics were similar between the women who reported pregnancies and those who did not, with the exception that those reporting a pregnancy had lower household income at baseline with a higher proportion of non-Hispanic Black race/ethnicity (Supplementary Table 1).
A full description of the cohort is contained in Table 1. The average age at first pregnancy was 20.5 ± 3.2 years with an average duration of diabetes prior to the pregnancy of 7.3 ± 3.4 years. Overall, the non-Hispanic Black group accounted for the most pregnancies. The majority of participants who experienced a pregnancy came from a low-income household, with 62.1% having an income <$25,000. Educational attainment was also low for the women who experienced a pregnancy, with 22.7% having less than a high school education and 54% having only a high school degree or equivalent. Prior to first pregnancy, 36.9% of the women had hypertension, and 24% had diabetic nephropathy. Preconception counseling was reported in 16.3% of women prior to first pregnancy, and only 14.9% used any method of contraception prior to the first pregnancy. In comparing women with different reported numbers of pregnancies, no difference was appreciated in any of the measures.
Table 1.
Characteristics at the start and during pregnancy and pregnancy outcome
| All (N = 260) | Gestation ≥20 weeks (N = 184) | |||||||
|---|---|---|---|---|---|---|---|---|
| Pregnancy order | Pregnancy order | |||||||
| All | 1 (N = 141) | 2 (N = 71) | ≥3 (N = 48) | All | 1 (N = 98) | 2 (N = 55) | ≥ 3 (N = 31) | |
| Characteristics at start of pregnancy | ||||||||
| Age (years) | 21.5 (3.16) | 20.5 (3.08) | 22.1 (2.65) | 23.7 (2.79) | 21.6 (3.09) | 20.5 (3.04) | 22.2 (2.57) | 24.0 (2.46) |
| Diabetes duration (years) | 8.1 (3.20) | 7.3 (3.37) | 8.4 (2.78) | 9.9 (2.48) | 8.0 (3.22) | 7.2 (3.47) | 8.4 (2.80) | 9.6 (2.36) |
| BMI* | 35.6 (7.16) | 35.4 (7.17) | 36.0 (7.26) | 35.9 (7.11) | 35.5 (6.97) | 35.3 (6.70) | 35.8 (7.70) | 35.6 (6.75) |
| Race/ethnicity | ||||||||
| Non-Hispanic Black | 39.2 | 41.9 | 43.8 | 41.2 | 38.0 | 40.8 | 36.4 | 32.3 |
| Hispanic | 29.6 | 34.9 | 18.8 | 29.4 | 29.3 | 30.6 | 30.9 | 22.6 |
| Non-Hispanic White | 15.0 | 9.3 | 18.8 | 5.9 | 16.8 | 16.3 | 14.5 | 22.6 |
| Other | 16.2 | 14.0 | 18.8 | 23.5 | 15.8 | 12.2 | 18.2 | 22.6 |
| Income* | ||||||||
| <$25,000 | 62.1 | 62.9 | 57.4 | 66.7 | 64.1 | 64.8 | 58.7 | 71.4 |
| $25,000–49,999 | 4.7 | 4.8 | 3.3 | 6.7 | 3.4 | 4.2 | 2.2 | 3.6 |
| ≥$50,000 | 0.9 | 0.0 | 1.6 | 2.2 | 0.0 | 0.0 | 0.0 | 0.0 |
| Refused/unknown | 32.2 | 32.4 | 37.7 | 24.4 | 32.4 | 31.0 | 39.1 | 25.0 |
| Education (%)* | ||||||||
| Less than high school | 22.7 | 26.7 | 16.4 | 22.2 | 23.4 | 26.8 | 17.4 | 25.0 |
| High school degree or equivalent | 54.0 | 49.5 | 55.7 | 62.2 | 55.2 | 52.1 | 54.3 | 64.3 |
| Some college | 2.8 | 1.9 | 1.6 | 6.7 | 0.7 | 0.0 | 0.0 | 3.6 |
| College degree or higher | 3.8 | 5.7 | 3.3 | 0.0 | 4.1 | 5.6 | 4.3 | 0.0 |
| Refused/unknown | 16.6 | 16.2 | 23.0 | 8.9 | 16.6 | 15.5 | 23.9 | 7.1 |
| HbA1c (%)* | 8.7 (2.78) | 8.9 (2.80) | 8.6 (2.82) | 8.1 (2.65) | 8.3 (2.60) | 8.4 (2.58) | 8.3 (2.70) | 8.0 (2.54) |
| HbA1c (mmol/mol)* | 71.6 (30.41) | 74.1 (30.59) | 70.5 (30.77) | 65.3 (28.96) | 67.5 (28.41) | 68.7 (28.17) | 68.7 (28.17) | 63.5 (27.78) |
| Diabetes complications and comorbidities* | ||||||||
| Hypertension | 35.0 | 36.9 | 36.6 | 27.1 | 34.2 | 34.7 | 40.0 | 22.6 |
| Microalbuminuria | 25.0 | 24.1 | 29.6 | 20.8 | 27.2 | 24.5 | 34.5 | 22.6 |
| Macroalbuminuria | 7.3 | 5.7 | 8.5 | 10.4 | 7.6 | 5.1 | 10.9 | 9.7 |
| LDL dyslipidemia | 17.7 | 14.2 | 22.5 | 20.8 | 17.4 | 12.2 | 25.5 | 19.4 |
| Triglyceride dyslipidemia | 35.4 | 31.2 | 42.3 | 37.5 | 35.9 | 30.6 | 47.3 | 32.3 |
| Preconception counseling | 20.0 | 16.3 | 22.5 | 27.1 | 23.9 | 21.4 | 25.5 | 29.0 |
| Contraception | 13.5 | 14.9 | 12.7 | 10.4 | 14.1 | 15.3 | 12.7 | 12.9 |
| Gestational age prenatal care initiated (weeks) | 10.6 (8.73) | 11.3 (9.60) | 9.2 (5.43) | 10.6 (9.78) | 11.1 (9.13) | 11.9 (10.05) | 9.4 (5.57) | 11.2 (10.51) |
| Characteristics during pregnancy | ||||||||
| Medications during pregnancy | ||||||||
| Prenatal vitamins | 78.1 | 78.0 | 77.5 | 79.2 | 93.5 | 96.9 | 89.1 | 90.3 |
| Metformin | 21.9 | 22.0 | 23.9 | 18.8 | 20.1 | 21.4 | 21.8 | 12.9 |
| Insulin | 67.3 | 71.6 | 67.6 | 54.2 | 73.9 | 79.6 | 72.7 | 58.1 |
| Sulfonylurea | 5.0 | 4.3 | 4.2 | 8.3 | 7.1 | 6.1 | 5.5 | 12.9 |
| Other diabetes medications | 0.8 | 1.4 | 0.0 | 0.0 | 1.1 | 2.0 | 0.0 | 0.0 |
| Statins | 0.4 | 0.0 | 1.4 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 |
| ACE inhibitors | 4.2 | 5.0 | 4.2 | 2.1 | 3.3 | 4.1 | 3.6 | 0.0 |
| Other antihypertensive medications | 8.8 | 9.2 | 11.3 | 4.2 | 12.5 | 13.3 | 14.5 | 6.5 |
| Acetylsalicylic acid | 4.6 | 3.5 | 7.0 | 4.2 | 6.5 | 5.1 | 9.1 | 6.5 |
| Maternal hospitalization | 27.7 | 31.2 | 22.5 | 25.0 | 35.3 | 39.8 | 29.1 | 32.3 |
| Preeclampsia | 14.2 | 14.2 | 16.9 | 10.4 | 20.1 | 20.4 | 21.8 | 16.1 |
| Maternal hypertension# | 11.9 | 10.6 | 14.1 | 12.5 | 16.8 | 15.3 | 18.2 | 19.4 |
| Microalbuminuria (30 mg/g ≤ UACR < 300 mg/g)# | 7.7 | 12.1 | 4.2 | 0.0 | 10.9 | 17.3 | 5.5 | 0.0 |
| Macroalbuminuria/proteinuria (UACR ≥300 mg/g)# | 5.0 | 7.8 | 2.8 | 0.0 | 6.5 | 10.2 | 3.6 | 0.0 |
| HbA1c >8.0% (64 mmol/mol) | 31.9 | 30.5 | 32.4 | 35.4 | 32.1 | 31.6 | 30.9 | 35.5 |
| Other complications** | 4.6 | 5.7 | 2.8 | 4.2 | 6.0 | 8.2 | 3.6 | 3.2 |
| Pregnancy outcome | ||||||||
| Unknown outcome | 3.4 | 5.0 | 1.4 | 0.0 | 0.0 | 0.0 | 0.0 | 0.0 |
| Voluntary or elective termination | 4.8 | 3.5 | 8.5 | 4.2 | 0.5 | 0.0 | 1.8 | 0.0 |
| Preterm delivery | 23.8 | 21.3 | 26.8 | 22.9 | 32.6 | 30.6 | 34.5 | 35.5 |
| Term delivery | 42.8 | 44.7 | 45.1 | 41.7 | 62.5 | 64.3 | 58.2 | 64.5 |
| Miscarriage or fetal death (stillbirth) | 25.3 | 25.5 | 18.3 | 31.3 | 4.3 | 5.1 | 5.5 | 0.0 |
| Unknown pregnancy loss | 9.3 | 8.5 | 7.1 | 16.7 | 0.0 | 0.0 | 0.0 | 0.0 |
| Fetal death (stillbirth) | 3.7 | 3.5 | 4.2 | 0.0 | 4.3 | 5.1 | 5.5 | 0.0 |
| Miscarriage | 12.3 | 13.5 | 7.0 | 14.6 | 0.0 | 0.0 | 0.0 | 0.0 |
Data are mean (SD) or percent.
UACR, urine albumin-to-creatinine ratio.
Data are as of the visit prior to start of pregnancy other than age and diabetes duration.
Other complications included heart failure, tachycardia, twin-to-twin transfer syndrome, and placenta abruption.
Does not include participants with preexisting diagnosis.
Pregnancy order for all pregnancies, not just pregnancies of at least 20 weeks’ gestation.
Maternal complications were experienced in 65% of the reported pregnancies. In women with gestation ≥20 weeks, hospitalization at some point in the pregnancy not directly linked to delivery was reported in 35.3% of the young women (Table 1). Preeclampsia was the most common complication, reported in 20.1% of pregnancies, followed by hypertension in 16.8%. An HbA1c >8% was documented on at least one occasion in 31.9% of pregnancies. Of the 174 pregnancies resulting in live birth, 73.9% of the women received insulin for glycemic control during the pregnancy, with 20.1% reporting use of metformin during the pregnancy. Only 6.5% of the women with gestation ≥20 weeks received therapy with acetylsalicylic acid for preeclampsia prophylaxis. Antihypertensive therapy was used by 15.8% of the women with gestation ≥20 weeks.
A full-term delivery was achieved in 62.5% of pregnancies, with 32.6% of pregnancies resulting in preterm delivery in pregnancies ≥20 weeks’ gestation (Table 1). The rate of known miscarriage for the entire study was 12.3%. The rate of known stillbirth in the cohort was 3%. Approximately 10% of pregnancy loss could not be classified due to inadequate records related to the timing of the loss. The HbA1c was significantly higher in pregnancies complicated by miscarriage and preterm delivery compared with full-term deliveries (Supplementary Table 2).
The average birth weight for the entire offspring cohort was 3.201 ± 0.847 kg, with an overall birth weight z-score (adjusted for gestational age and sex) of −0.329 ± 0.847 (Table 2). The overall negative z-score was driven by very low birth weight z-scores in the preterm infants (Supplementary Fig. 2). In the offspring, 7.8% were classified as SGA, while 26.8% were classified as LGA. Macrosomia was reported in 17.9% of the infants.
Table 2.
Live offspring characteristics
| Preterm (<37 weeks’ gestation) (N = 64) | Term (≥37 weeks’ gestation) (N = 115) | Overall (N = 179) | ||||
|---|---|---|---|---|---|---|
| N | Mean ± SD or % | N | Mean ± SD or % | N | Mean ± SD or % | |
| Infant sex | ||||||
| Female | 28 | 43.8 | 61 | 53.0 | 89 | 49.7 |
| Male | 36 | 56.3 | 54 | 47.0 | 90 | 50.3 |
| Infant birth weight (kg) | 63 | 2.759 ± 1.012 | 113 | 3.448 ± 0.619 | 176 | 3.201 ± 0.847 |
| Birth weight z-score | 63 | −1.408 ± 2.386 | 113 | 0.273 ± 1.27 | 176 | −0.329 ± 1.924 |
| Birth weight percentile | 63 | 31.9 ± 36.88 | 113 | 55.5 ± 33.57 | 176 | 47.0 ± 36.49 |
| SGA (<10th percentile)* | 7 | 10.9 | 7 | 6.1 | 14 | 7.8 |
| LGA (>90th percentile)* | 13 | 20.3 | 35 | 30.4 | 48 | 26.8 |
| Birth weight categories | ||||||
| Unknown | 1 | 1.6 | 2 | 1.7 | 3 | 1.7 |
| Very low (<1,500 g) | 9 | 14.1 | 0 | 0 | 9 | 5.0 |
| Low (1,500–2,499 g) | 17 | 26.6 | 4 | 3.5 | 21 | 11.7 |
| Normal (2,500–3,999 g) | 30 | 46.9 | 84 | 73.0 | 114 | 63.7 |
| Macrosomia (≥4,000 g) | 7 | 10.9 | 25 | 21.7 | 32 | 17.9 |
Based upon the criteria of Alexander et al. (18).
The offspring complication reported most frequently was neonatal hypoglycemia, affecting 29.4% of infants overall and 42.2% in preterm births (Table 3). Cardiac anomalies were found in 10% of infants. Respiratory distress affected 18.6% of infants, again with higher frequency in those born preterm. Other complications and congenital anomalies were noted in 10% of infants, including anencephaly, renal anomalies, and complications related to prematurity. Neonatal hypoglycemia, respiratory distress, and cardiac anomalies were associated with suboptimal glycemic control (as evidenced by a documented HbA1c >8%) during pregnancy (P < 0.05) (Table 4).
Table 3.
Number and type of offspring complications for live births overall and by term status
| Preterm (N = 64) | Term (N = 115) | P value | Overall (N = 179) | |
|---|---|---|---|---|
| Neonatal hypoglycemia | 27 (42.2) | 25 (22.1) | 0.0049 | 52 (29.4) |
| Respiratory distress requiring surfactant or ventilation | 23 (35.9) | 10 (8.9) | <0.0001 | 33 (18.6) |
| Neonatal hypocalcemia* | 4 (6.3) | 3 (2.7) | 0.2609 | 7 (4.0) |
| Shoulder dystocia* | 3 (4.7) | 2 (1.8) | 0.3551 | 5 (2.8) |
| Cardiac anomaly | 12 (18.8) | 6 (5.4) | 0.0048 | 18 (10.2) |
| Other congenital anomalies# | 10 (15.6) | 8 (7.3) | 0.0811 | 18 (10.3) |
Data are N (%) unless otherwise indicated.
P value from Fisher exact test.
Other congenital anomalies include anencephaly, congenital hemivertebra, multicystic dysplastic kidney, butterfly vertebra, asymmetrical crying face, duplex ureters, pelvic kidney, and macroglossia.
Table 4.
Complications and outcomes by glycemic control (HbA1c ≤8% vs. >8%) during pregnancy as extracted from obstetric chart
| During pregnancy loss of glycemic control | |||||
|---|---|---|---|---|---|
| HbA1c ≤8%# | HbA1c >8%# | P value | |||
| N | % | N | % | ||
| Maternal | 121 | 59 | |||
| Hospitalization | 37 | 30.6 | 27 | 45.8 | 0.0458 |
| Preeclampsia | 17 | 14.1 | 19 | 32.2 | 0.0043 |
| Gestational hypertension | 20 | 23.3 | 11 | 33.3 | 0.2622 |
| Microalbuminuria (30 mg/g ≤ UACR < 300 mg/g)* | 6 | 6.12 | 4 | 12.9 | 0.2512*** |
| Macroalbuminuria/proteinuria (UACR ≥300 mg/g)* | 8 | 6.84 | 4 | 8.51 | 0.7441*** |
| Other complications | 8 | 6.61 | 3 | 5.08 | 1.0000*** |
| Neonatal | 117 | 59 | |||
| SGA (<10th percentile)** | 8 | 6.9 | 5 | 8.8 | 0.7606*** |
| LGA (>90th percentile)** | 29 | 25.0 | 19 | 33.3 | 0.2499 |
| Hypoglycemia | 28 | 23.9 | 24 | 42.1 | 0.0140 |
| Respiratory distress requiring surfactant or ventilation | 16 | 13.7 | 16 | 28.1 | 0.0214 |
| Hypocalcemia | 3 | 2.6 | 4 | 7.1 | 0.2167*** |
| Shoulder dystocia | 2 | 1.7 | 3 | 5.3 | 0.3329*** |
| Caudal regression | 0 | 0.0 | 0 | 0.0 | – |
| Cardiac anomaly | 6 | 5.2 | 11 | 19.3 | 0.0033 |
| Other congenital anomalies | 10 | 8.6 | 7 | 12.7 | 0.4019 |
UACR, urine albumin-to-creatinine ratio.
Excludes participants with existing diagnosis.
Based upon the criteria of Alexander et al. (18).
P value from Fisher exact test.
Equivalent to HbA1c of 64 mmol/mol.
Conclusions
In the 15 years encompassing all phases of the TODAY study, young women have reported 260 total pregnancies, making it the largest collection of pregnancy outcomes in a multiethnic cohort of women with pregestational youth-onset type 2 diabetes. Furthermore, the women in TODAY had longer average diabetes duration at the time of pregnancy than other cohorts involving preestational type 2 diabetes (11,12,19,20). The women in TODAY uniquely demonstrate significant socioeconomic disadvantage, high BMI, and suboptimal glycemic control, along with very low rates of contraceptive use and preconception counseling. These pregnancy outcomes from TODAY extend our previous findings to demonstrate that pregnancy and offspring complications are common in young women with type 2 diabetes and have increased significantly from the previous report (14).
The average age at first pregnancy in the TODAY cohort was 21.6 years compared with the national average in the U.S. of 29.1 years (21) and the averages in Sub-Saharan Africa and Latin America of 20.9 and 21.7 years, respectively (22). Relative socioeconomic disadvantage in the young women in TODAY contributes to inadequate contraceptive use and preconception counseling, as evidenced by the high rates of suboptimal glycemic control during pregnancy, leading to adverse pregnancy outcomes.
Maternal complications during pregnancy, including hypertension and preeclampsia, are more common in women who have pregestational diabetes (23). The rates of maternal chronic hypertension in the TODAY cohort were almost triple those most recently reported in the National Pregnancy in Diabetes (NPID) cohort, a population-based cohort in the U.K., which included 8,685 women (median age of 34 years [range 27–41]) (7); however, the diabetes duration at time of pregnancy was over twice as long in the young women in TODAY. Maternal hypertension is a significant risk factor for preeclampsia, which affects ∼2–7% of all pregnancies and 10–14% of pregnancies complicated by pregestational type 2 diabetes (24). In TODAY, the prevalence of preeclampsia was 20.1%, which is more consistent with rates reported in pregnancies complicated by pregestational type 1 diabetes. This higher rate of preeclampsia in TODAY is perhaps related to the higher BMI, HbA1c, and hypertension rates when compared with other cohorts with type 2 diabetes–exposed pregnancies (9,25,26).
One of the most striking findings in the TODAY cohort was the high rate of pregnancy loss (25%), excluding elective terminations, compared with the national rate of uninduced pregnancy loss in the U.S. of 19.7% (27). Furthermore, stillbirth in TODAY (3.7%) is more than triple the national rates reported by the CDC (1%) (28). The U.K. NPID cohort reported stillbirth in women with type 2 diabetes at 1.3% (7), while other groups reported rates similar to those in TODAY (19). However, in the NPID cohort, the mean HbA1c was 6.9% in the first trimester and 6.0% in the third trimester (7); therefore, the higher average glycemia during pregnancy in TODAY, a likely consequence of very low rates of preconception counseling, may explain the higher rates of stillbirth.
Preterm birth was documented in ∼33% of the pregnancies in TODAY, which is more than triple that in the general U.S. population (9.5%) per the most recent CDC report (21) and higher than reported in NPID (23.4%) (7). The high rates of maternal complications, including preeclampsia and hypertension as well as inadequate glycemic control, prior to contraception significantly contribute to the high rate of preterm births.
In TODAY, 7.8% of the infants were classified as SGA, while 26.8% were LGA, compared with national averages of 1.5% (29) and ∼9% (30), respectively. These rates may be underreported as they are based on World Health Organization guidelines, which have demonstrated underreporting of SGA, especially in preterm infants. Rates of LGA and SGA in TODAY were similar to women from the NPID cohort with type 2 diabetes (7). Within the NPID cohort, risk factors associated with LGA included third trimester HbA1c and younger age (7). In TODAY, the high rates of chronic hypertension combined with inadequate prepregnancy counseling leading to hyperglycemia, specifically later in pregnancy, may have had the greatest impact on birth weight (31).
Diabetes during pregnancy is also known to be associated with risks of morbidity in infants, including perinatal complications. One of the greatest risks is hypoglycemia due to neonatal hyperinsulinemia (32). The rate of hypoglycemia in the infants born during the TODAY follow-up study—approaching 30%—almost doubled from the initial report by Klingensmith et al. (14). While the percentage of young women with HbA1c ≥8% is similar between the two reports, prenatal records were not as readily available for offspring in the earlier analysis, which may have resulted in underreporting of hypoglycemia cases. In adolescents with type 1 diabetes who experienced pregnancy, the reported rate of hypoglycemia was even higher, at 60.9% (33). Cardiac anomalies were also more prevalent in the infants born to mothers who experienced an HbA1c ≥8% during their pregnancy. It is well established that cardiac anomalies are directly linked to hyperglycemia during pregnancy, particularly during organogenesis in the first trimester (34). The TODAY cohort is notable for inadequate contraceptive use, unplanned pregnancies, and later establishment of prenatal care, likely in part related to the significant psychosocial stressors in the lives of these young women and similar to adolescents with type 1 diabetes who experience pregnancy.
The present analysis has several strengths, including a well-characterized cohort of youth-onset type 2 diabetes with known duration of diabetes. While no data were collected directly by the study during the pregnancy, detailed medical records, including medical summaries and laboratory results, were systematically collected and abstracted. A few limitations are also acknowledged. The HbA1c measures were not collected at consistent times during the pregnancy, making it difficult to determine the glucose control during each trimester. Also, some information from the earliest pregnancies, including mode of delivery, was missing. While every effort was made to obtain pregnancy records, they were not obtained in 20 pregnancies. Infant outcomes were also only obtained at birth; therefore, early neonatal deaths could not be ascertained.
In conclusion, the TODAY cohort demonstrated that young women with pregestational youth-onset type 2 diabetes demonstrate high rates of complications when compared with older women with pregestational type 2 diabetes, though the TODAY women had higher BMI and longer diabetes duration at the time of pregnancy. The inadequate glycemic control seen on average in this adolescent population with type 2 diabetes, combined with inadequate access to effective contraception and preconception counseling, likely contributes to the significant prenatal hyperglycemia and resulting complications. The key to improving pregnancy outcomes in young women with youth-onset type 2 diabetes is to aggressively and adequately treat the type 2 diabetes in youth and to identify barriers to adequate contraceptive use and access to prepregnancy counseling.
Article Information
Acknowledgments. The authors gratefully acknowledge the participation and guidance of the American Indian partners associated with the clinical center located at the University of Oklahoma Health Sciences Center, including members of the Absentee Shawnee Tribe, Cherokee Nation, Chickasaw Nation, Choctaw Nation of Oklahoma, and Oklahoma City Area Indian Health Service.
The opinions expressed in this article are those of the authors and do not necessarily reflect the views of the respective Tribes and the Indian Health Service.
Funding. This work was completed with funding from National Institute of Diabetes and Digestive and Kidney Diseases and the National Institutes of Health Office of the Director through grants U01-DK61212, U01-DK61230, U01-DK61239, U01-DK61242, and U01-DK61254.
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The National Institute of Diabetes and Digestive and Kidney Diseases project office was involved in all aspects of the study, including: design and conduct, collection, management, analysis, and interpretation of the data, review and approval of the manuscript, and decision to submit the manuscript for publication.
Duality of Interest. The TODAY Study Group thanks the following companies for donations in support of the efforts of the TODAY Study Group: Becton, Dickinson and Company, Bristol-Myers Squibb, Eli Lilly and Company, GlaxoSmithKline, LifeScan, Inc., Pfizer, and Sanofi. No other potential conflicts of interest relevant to this article were reported.
Author Contributions. J.B.T. wrote the manuscript. K.L.D. conducted the statistical analyses and wrote sections of the manuscript. M.M.K., K.L.D., S.D.C., E.N.E., E.I., S.Ma., S.Mc., J.S., and S.W. wrote sections of, reviewed, and edited the manuscript. K.L.D. is the guarantor of this work and, as such, 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.
Appendix
Today Study Group Writing Committee. Jeanie B. Tryggestad (University of Oklahoma Health Sciences Center, Oklahoma City, OK), Megan M. Kelsey (University of Colorado Anschutz Medical Campus, Children’s Hospital Colorado, Aurora, CO), Kimberly L. Drews (The Biostatistics Center, George Washington University, Rockville, MD), Steven D. Chernausek (University of Oklahoma Health Sciences Center, Oklahoma City, OK), Elia N. Escaname (UT Health San Antonio, San Antonio, TX), Elvira Isganaitis (Joslin Diabetes Center and Harvard Medical School, Boston, MA), Sarah Macleish (Rainbow Babies and Children’s Hospital and Case Western Reserve University School of Medicine, Cleveland, OH), Siripoom McKay (Baylor College of Medicine, Houston, TX), Jennifer Sprague (Washington University School of Medicine, St. Louis, MO), and Steve Willi (Children’s Hospital of Philadelphia, Philadelphia, PA).
Footnotes
Clinical trial reg. nos. NCT00081328, NCT01364350, and NCT02310724, clinicaltrials.gov
This article contains supplementary material online at https://doi.org/10.2337/figshare.16967332.
Members of the TODAY Study Group Writing Committee are listed in the appendix. A complete list of the TODAY Study Group members can be found in the supplementary material online.
This article is part of a special article collection available at diabetesjournals.org/journals/collection/268/Serious-Later-Risks-Associated.
This article is featured in a podcast available at diabetesjournals.org/journals/pages/diabetes-core-update-podcasts.
Contributor Information
Collaborators: Marsha D. Marcus, Rachelle Gandica, Laure El ghormli, Janine Higgins, Bereket Tesfaldet, Dorit Koren, Sarah Macleish, Elia Nila Escaname, and Ruth S. Weinstock
References
- 1. Mayer-Davis EJ, Dabelea D, Lawrence JM. Incidence trends of type 1 and type 2 diabetes among youths, 2002-2012. N Engl J Med 2017;377:301. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Temple R, Murphy H. Type 2 diabetes in pregnancy - an increasing problem. Best Pract Res Clin Endocrinol Metab 2010;24:591–603 [DOI] [PubMed] [Google Scholar]
- 3. Bardenheier BH, Imperatore G, Devlin HM, Kim SY, Cho P, Geiss LS. Trends in pre-pregnancy diabetes among deliveries in 19 U.S. states, 2000-2010. Am J Prev Med 2015;48:154–161 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Deputy NP, Kim SY, Conrey EJ, Bullard KM. Prevalence and changes in preexisting diabetes and gestational diabetes among women who had a live birth - United States, 2012-2016. MMWR Morb Mortal Wkly Rep 2018;67:1201–1207 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Sugiyama T, Saito M, Nishigori H, et al.; Japan Diabetes and Pregnancy Study Group . Comparison of pregnancy outcomes between women with gestational diabetes and overt diabetes first diagnosed in pregnancy: a retrospective multi-institutional study in Japan. Diabetes Res Clin Pract 2014;103:20–25 [DOI] [PubMed] [Google Scholar]
- 6. Sweeting AN, Ross GP, Hyett J, et al. Gestational diabetes mellitus in early pregnancy: evidence for poor pregnancy outcomes despite treatment. Diabetes Care 2016;39:75–81 [DOI] [PubMed] [Google Scholar]
- 7. Murphy HR, Howgate C, O’Keefe J, et al.; National Pregnancy in Diabetes (NPID) advisory group . Characteristics and outcomes of pregnant women with type 1 or type 2 diabetes: a 5-year national population-based cohort study. Lancet Diabetes Endocrinol 2021;9:153–164 [DOI] [PubMed] [Google Scholar]
- 8. Peng TY, Ehrlich SF, Crites Y, et al. Trends and racial and ethnic disparities in the prevalence of pregestational type 1 and type 2 diabetes in Northern California: 1996-2014. Am J Obstet Gynecol 2017;216:177.e1–177.e8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Sato T, Sugiyama T, Kurakata M, et al.; Japan Diabetes and Pregnancy Study Group . Pregnancy outcomes in women with type 1 and type 2 diabetes mellitus in a retrospective multi-institutional study in Japan. Endocr J 2014;61:759–764 [DOI] [PubMed] [Google Scholar]
- 10. Vangen S, Stoltenberg C, Holan S, et al. Outcome of pregnancy among immigrant women with diabetes. Diabetes Care 2003;26:327–332 [DOI] [PubMed] [Google Scholar]
- 11. Clausen TD, Mathiesen E, Ekbom P, Hellmuth E, Mandrup-Poulsen T, Damm P. Poor pregnancy outcome in women with type 2 diabetes. Diabetes Care 2005;28:323–328 [DOI] [PubMed] [Google Scholar]
- 12. Dunne FP, Avalos G, Durkan M, et al.; ATLANTIC DIP collaborators . ATLANTIC DIP: pregnancy outcome for women with pregestational diabetes along the Irish Atlantic seaboard. Diabetes Care 2009;32:1205–1206 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. TODAY Study Group; Bjornstad P, Drews KL, Caprio S, et al. Long-term complications in youth-onset type 2 diabetes. N Engl J Med 2021;385:416–426 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Klingensmith GJ, Pyle L, Nadeau KJ, et al.; TODAY Study Group . Pregnancy outcomes in youth with type 2 diabetes: the TODAY Study experience. Diabetes Care 2016;39:122–129 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. TODAY Study Group . Postintervention effects of varying treatment arms on glycemic failure and β-cell function in the TODAY Trial. Diabetes Care 2021;44:75–80 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Zeitler P, Hirst K, Pyle L, et al.; TODAY Study Group . A clinical trial to maintain glycemic control in youth with type 2 diabetes. N Engl J Med 2012;366:2247–2256 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Zeitler P, Epstein L, Grey M, et al.; TODAY Study Group . Treatment options for type 2 diabetes in adolescents and youth: a study of the comparative efficacy of metformin alone or in combination with rosiglitazone or lifestyle intervention in adolescents with type 2 diabetes. Pediatr Diabetes 2007;8:74–87 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Alexander GR, Himes JH, Kaufman RB, Mor J, Kogan M. A United States national reference for fetal growth. Obstet Gynecol 1996;87:163–168 [DOI] [PubMed] [Google Scholar]
- 19. Van Zyl H, Levitt NS. Pregnancy outcome in patients with pregestational and gestational diabetes attending Groote Schuur Hospital, Cape Town, South Africa. S Afr Med J 2018;108:772–776 [DOI] [PubMed] [Google Scholar]
- 20. Cyganek K, Hebda-Szydlo A, Skupien J, et al. Glycemic control and pregnancy outcomes in women with type 2 diabetes from Poland. The impact of pregnancy planning and a comparison with type 1 diabetes subjects. Endocrine 2011;40:243–249 [DOI] [PubMed] [Google Scholar]
- 21. Martin JA, Hamilton BE, Osterman MJK, Driscoll AK. Births: final data for 2019. Natl Vital Stat Rep 2021;70:1–51 [PubMed] [Google Scholar]
- 22. Bongaarts J, Blanc AK. Estimating the current mean age of mothers at the birth of their first child from household surveys. Popul Health Metr 2015;13:25. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Negrato CA, Mattar R, Gomes MB. Adverse pregnancy outcomes in women with diabetes. Diabetol Metab Syndr 2012;4:41. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Weissgerber TL, Mudd LM. Preeclampsia and diabetes. Curr Diab Rep 2015;15:9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Hillman N, Herranz L, Vaquero PM, Villarroel A, Fernandez A, Pallardo LF. Is pregnancy outcome worse in type 2 than in type 1 diabetic women? Diabetes Care 2006;29:2557–2558 [DOI] [PubMed] [Google Scholar]
- 26. Owens LA, Sedar J, Carmody L, Dunne F. Comparing type 1 and type 2 diabetes in pregnancy- similar conditions or is a separate approach required? BMC Pregnancy Childbirth 2015;15:69. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Rossen LM, Ahrens KA, Branum AM. Trends in risk of pregnancy loss among US women, 1990-2011. Paediatr Perinat Epidemiol 2018;32:19–29 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Hoyert DL, Gregory EC. Cause of fetal death: data from the fetal death report, 2014. Natl Vital Stat Rep 2016;65:1–25 [PubMed] [Google Scholar]
- 29. Ewing AC, Ellington SR, Shapiro-Mendoza CK, Barfield WD, Kourtis AP. Full-term small-for-gestational-age newborns in the U.S.: characteristics, trends, and morbidity. Matern Child Health J 2017;21:786–796 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Donahue SMA, Kleinman KP, Gillman MW, Oken E. Trends in birth weight and gestational length among singleton term births in the United States: 1990-2005. Obstet Gynecol 2010;115:357–364 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Peaceman AM, Clifton RG, Phelan S, et al.; LIFE-Moms Research Group . Lifestyle interventions limit gestational weight gain in women with overweight or obesity: LIFE-Moms Prospective Meta-Analysis. Obesity (Silver Spring) 2018;26:1396–1404 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Stone RG, Scully P, Troy E, et al. Pregnancy outcomes in women with onset of type 1 diabetes mellitus less than 18 years of age. BMJ Open Diabetes Res Care 2020;8:e001080. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33. Helle E, Priest JR. Maternal obesity and dabetes mellitus as risk factors for congenital heart disease in the offspring. J Am Heart Assoc 2020;9:e011541. [DOI] [PMC free article] [PubMed] [Google Scholar]