Early-Pregnancy Intermediate Hyperglycemia and Adverse Pregnancy Outcomes Among Women Without Gestational Diabetes.

CONTEXT: Universal early-pregnancy screening for overt diabetes reveals intermediate hyperglycemia (fasting plasma glucose [FPG] [5.1-6.9 mM]).
OBJECTIVE: We evaluated the association between early-pregnancy intermediate hyperglycemia and adverse pregnancy outcomes among women without gestational diabetes.
METHODS: This retrospective cohort study was conducted at the Obstetrics and Gynecology Hospital, Shanghai, China, from 2013 to 2017. All singleton pregnancies with FPG less than or equal to 6.9 mM in early pregnancy and receiving a 75-g oral glucose tolerance test (OGTT) were included. Women with prepregnancy diabetes were excluded. Individuals with normal OGTT were analyzed. Pregnancy outcomes for FPG less than 5.1 mM and intermediate hyperglycemia were evaluated. The primary outcomes were large for gestational age (LGA) and primary cesarean delivery. Multivariate logistic regressions were conducted. Statistical significance was defined as P less than .05.
RESULTS: In total, 24 479 deliveries were included, of which 23 450 (95.8%) had normal OGTTs later in pregnancy (NGT). There were 807 (3.4%) women who had an FPG of 5.1 to 6.9 mM in early pregnancy. Compared to the NGT group with an FPG of less than 5.1 mM in early pregnancy (N = 20692), the intermediate hyperglycemia NGT group (N = 693) had a higher age and body mass index (BMI), and significantly higher rates of LGA, primary cesarean delivery, preterm birth, preeclampsia, and neonatal distress. The rates of primary cesarean delivery (adjusted odds ratio [AOR] 1.24; 95% CI, 1.05-1.45), preterm birth (AOR 1.75; 95% CI, 1.29-2.36), and neonatal distress (AOR 3.29; 95% CI, 1.57-6.89) remained statistically significantly higher after adjustments for maternal age, BMI, and other potential confounding factors.
CONCLUSION: Women with intermediate hyperglycemia in early pregnancy are at an increased risk for adverse maternal-fetal outcomes, even with normal future OGTTs.

Women with gestational diabetes (GDM) are at an increased risk for adverse perinatal and maternal outcomes, including macrosomia, cesarean delivery, preeclampsia, and birth trauma (1). Screening and treatment of GDM reduce the risk of adverse pregnancy outcomes (2, 3). Most international guidelines recommend universal screening for GDM between 24 and 28 gestational weeks (gws) (4-7), based on findings by the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study(1) showing a relationship between glucose and adverse pregnancy outcomes, including increased risks of primary cesarean delivery, birth weight, and preeclampsia.

In contrast to screening for GDM at 24 to 28 weeks, it is recommended to screen for overt diabetes by measuring fasting plasma glucose (FPG) in early pregnancy (4, 6-9), leading to the identification of intermediate hyperglycemia (5.1 ≤ FPG ≤ 6.9 mM), within a nondiabetic range. However, it is debatable whether these women should be treated as GDM patients in early pregnancy, even though the International Association of Diabetes and Pregnancy Study Group (IDAPSG) has recommended classifying these women as having GDM (8). Generally, an isolated FPG is a poor predictor of developing GDM in later pregnancy, as approximately 50% of women with an FPG level higher than 5.1 mM during early pregnancy turn out to have normal glucose tolerance (NGT) at 24 to 28 weeks (10). In addition, in women with hyperglycemia, FPG significantly decreases from early pregnancy to 24 to 28 weeks of gestation, whereas the 1-hour and 2-hour values of the 75-g oral glucose tolerance test (OGTT) remain unchanged (10). Thus, use of an isolated FPG for early diagnosis of GDM may be associated with increased medicalization of pregnancy and an increased risk of small for gestational age due to overtreatment (11, 12), and a further OGTT may be needed to establish GDM. In fact, most obstetric centers in China tend to implement a further OGTT to identify intermediate hyperglycemia in early pregnancy, and those who have a normal OGTT are classified as having normal pregnancies. However, evidence from one study with a small sample size showed that despite a normal OGTT result, women with mild hyperglycemia (5.1 ≤ FPG < 5.6 mM) had more neonatal intensive care unit admissions than women with an FPG of less than 5.1 mM in early pregnancy (13), indicating that early-pregnancy intermediate hyperglycemia among non-GDM patients is related to an increased risk of adverse pregnancy outcomes, though this needs confirmation by a study with a larger sample size.

The detection of women at higher risk for adverse pregnancy outcomes among those who are not diagnosed with GDM is a desirable goal because proper management, such as diet and exercise, may have positive effects on maternal and fetal outcomes. Therefore, we aimed to retrospectively evaluate the associations between intermediate hyperglycemia in early pregnancy and adverse pregnancy outcomes among women who have a normal OGTT.

Materials and Methods

This was a retrospective study of deliveries that took place in Obstetrics and Gynecology Hospital of Fudan University from January 2013 to December 2017. Cases of singleton pregnancy with a recorded fasting glucose result before 14 weeks of gestation were included. Women with pre-GDM or the development of GDM were excluded. Gestational age was determined by the last menstrual period and validated by ultrasonography during early pregnancy. The study was approved by the ethics committee at Obstetrics and Gynecology Hospital of Fudan University.

Computerized medical records in the labor-and-delivery ward were extracted into a computerized database by a specialized medical information officer. Gestational age for the various glucose tests was calculated using the date of the actual or calibrated last menstrual period and the date of the glucose test.

There are no uniform worldwide guidelines for the screening and diagnosis of GDM during early pregnancy. In China, we recommend universal testing for FPG at the first prenatal visit and a universal 75-g OGTT at 24 to 28 weeks of gestation or at the time that intermediate hyperglycemia is identified. Women with early-pregnancy intermediate hyperglycemia were informed of the risk of GDM and could choose to undergo an immediate OGTT (within 1 week) or routine GDM screening at 24 to 28 weeks according to personal preference, and those who did not have an abnormal OGTT in early pregnancy underwent a second OGTT at 24 to 28 weeks of gestation. All women with early-pregnancy intermediate hyperglycemia were educated about the necessity of appropriate diet and exercise at the first pregnancy visit.

FPG was measuring in venous plasma and determined by the glucose oxidation method within 4 hours in the laboratory of Obstetrics and Gynecology Hospital of Fudan University.

GDM was diagnosed when one or more abnormal values were obtained in the 75-g OGTT, namely, 0 hours, greater than or equal to 5.1 mM; 1 hour, greater than or equal to 10.0 mM; or 2 hours, greater than or equal to 8.5 mM. Large for gestational age (LGA), defined as a neonatal birth weight greater than 90% for gestational age and sex, was determined based on the Intergrowth-21st Weight Standard (14). Preeclampsia was defined as new-onset hypertension after 20 weeks of gestation, accompanied by dysfunction in at least one organ. Preterm birth was defined as delivery before 37 weeks of gestation.

The primary outcomes were LGA and primary cesarean delivery. The secondary outcomes were preeclampsia; delivery by forceps or with concomitant dystocia; preterm birth; neonatal hyperbilirubinemia; and neonatal distress (1-min Apgar ≤ 3). We analyzed the correlations between early-pregnancy FPG and adverse pregnancy outcomes among women without a diagnosis of GDM.

FPG was first analyzed in 2 categories (< 5.1 and 5.1-6.9 mM) to carry out the overall comparisons between intermediate hyperglycemia and normal glucose. In sensitivity analyses, cases with immediate OGTT at the identification of intermediate hyperglycemia were excluded from logistic regression models. In the post hoc analysis, FPG was categorized into 3 levels (< 5.1, 5.1-5.5, and 5.6-6.9 mM) to analyze the graded relationships among increasing glucose levels. We made no attempt to impute missing data because we had no information about whether these data were missing at random. Data were tested for a normal distribution by means of the Kolmogorov-Smirnov test. Pearson correlation tests and multivariate logistic regressions were conducted in SPSS version 23.0. Statistical significance was set at P less than .05.

Results

There were 42 423 deliveries between January 2013 to December 2017, among which there were 628 multipregnancies, 12 180(28.7%) women with FPG tested at or after 14 weeks of gestation, 4758 women (11.2%) with missing FPG data, 361 (0.9%) women with missing OGTT data, and 17 (0.04%) pre-GDM women were excluded from further analysis. Thus, 24 479 singleton deliveries who underwent both FPG testing in early pregnancy and further 75-g OGTTs either immediately after the discovery of intermediate hyperglycemia or at 24 to 28 gws were left. Of these patients, 31 with prepregnancy diabetes (0.1%) and 998 with GDM (4.1%) were excluded, leaving 23 450 (95.8%) women with a normal OGTT (Fig. 1). Among the remaining participants, a total of 807 (3.4%) had intermediate hyperglycemia, and 114 (14.1%) and 1951 (8.5%) individuals with missing data about delivery in groups of intermediate hyperglycemia and FPG less than 5.1 mM respectively were excluded, resulting in 693 cases and 20 692 cases respectively for further analysis (see Fig. 1). Additionally, among women with GDM, 108 (10.8%) had early-pregnancy intermediate hyperglycemia, which was significantly higher than that of non-GDM women with early-pregnancy intermediate hyperglycemia (3.4%, P < .01, data not shown).

Figure 1.

Overview of the cohort.

The characteristics of the mothers and newborns are shown in Table 1. Compared to women with low FPG, women with intermediate hyperglycemia tended to be older (aged 29.3 ± 3.1 vs 29.0 ± 2.9 years), have a higher body mass index; BMI (23.0 ± 3.6 vs 22.0 ± 2.9), have lower educational levels (< college, 37.8% vs 29.8%), have higher proportions of both a maternal and paternal family history of diabetes (11.5% vs 5.8%), and have a higher proportion of previous polycystic ovary syndrome (0.9% vs 0.3%) and previous macrosomia (0.7% vs 0.3%) (P < .05; see Table 1). There was no significant difference in the proportion of primiparous patients or smoking status between groups (P > .05; see Table 1). The fasting glucose levels in early pregnancy were 4.3 mM (range, 4.1-4.5 mM) and 5.2 mM (range, 5.1-5.5 mM) in the low FPG group and intermediate-hyperglycemia group, respectively (P < .05; see Table 1 and Supplementary Fig. S1) (15). Generally, women with intermediate hyperglycemia tended to undergo OGTT earlier than those with low glucose levels (22.54 ± 5.60 vs 24.97 ± 1.67 gws, P < .01) and had significantly higher glucose levels of OGTT (0 h: 4.50 ± 0.31 vs 4.27 ± 0.30, 1 h: 7.31 ± 1.37 vs 6.98 ± 1.34, 2 h: 6.30 ± 1.09 vs 6.11 ± 1.03 mM; P < .01) (see Table1). In addition, neonatal birth weight and the proportion of male newborns were not different between groups (P > .05, see Table 1).

Table 1.

Characteristics of group with intermediate hyperglycemia and fasting plasma glucose less than 5.1 mM during early pregnancy among women without gestational diabetes mellitus

	FPG < 5.1 mM N = 20692	5.1 ≤ FPG ≤ 6.9 mM N = 693	P
Maternal age, y	29.0 ± 2.9	29.3 ± 3.1	.04
BMI at first visit	22.0 ± 2.9	23.0 ± 3.6	< .01
Education
< College	6069 (29.8%)	260 (37.8%)	< .01
≥ College	14 329 (69.1%)	427 (60.5%)
Primiparous	18512 (89.5%)	618 (89.2%)	.77
Smoking	289 (1.4%)	13 (1.9%)	.29
Family history of diabetes	1196 (5.8%)	80 (11.5%)	< .01
Previous PCOS	59 (0.3%)	6 (0.9%)	< .01
Previous macrosomia	56 (0.3%)	5 (0.7%)	.03
Time of first pregnancy visit, gw	12 (11-13)	12 (10-13)	< .01
FPG at first pregnancy visit, mM	4.3 (4.1-4.5)	5.2 (5.1-5.5)	< .01
Time of OGTT, gw	24.97 ± 1.67	22.54 ± 5.60	< .01
0 h, mM	4.27 ± 0.30	4.50 ± 0.31	< .01
1 h, mM	6.98 ± 1.34	7.31 ± 1.37	< .01
2 h, mM	6.11 ± 1.03	6.30 ± 1.09	< .01
Gestational age at delivery, gw	39.3 (38.4-40.2)	39.2 (38.4-40.1)	< .01
Birth weight, g	3345.6 ± 445.9	3335.9 ± 500.4	.57
Male newborn	10042 (48.5%)	312 (45.0%)	.07

Abbreviations: BMI, body mass index; FPG, fasting plasma glucose; gw, gestational week; HbA1c, glycated hemoglobin A1c; OGTT, oral glucose tolerance test; PCOS, polycystic ovary syndrome.

Continuous variables are shown as mean ± SD if normally distributed and as median (25th-75th) if not normally distributed; categorical variables are presented as frequencies, % (n).

Table 2 shows the associations of maternal FPG levels with each pregnancy outcome and includes the adjusted odds ratios (AORs) and 95% CIs, compared with low FPG and NGT. In terms of primary outcomes, compared with those in the low FPG NGT group, women with intermediate hyperglycemia NGT had a statistically significantly higher rate of LGA and primary cesarean delivery (15.9% vs 12.7%, P = .01 and 38.5% vs 31.9%; P < .01, respectively), and this association remained significant for primary cesarean delivery in the adjusted models (AOR 1.24; 95% CI, 1.05-1.45) but did not remain significant for LGA (AOR 1.10; 95% CI, 0.89-1.37) (see Table 2). Regarding secondary outcomes, intermediate hyperglycemia was statistically significantly associated with increased odds of preterm birth, preeclampsia, and neonatal distress in the unadjusted models, and these trends remained significant in the adjusted models for preterm birth (AOR 1.75; 95% CI, 1.29-2.36) and neonatal distress (AOR 3.29; 95% CI, 1.57-6.89) but became not statistically significant for preeclampsia (AOR 1.47; 95% CI, 0.99-2.19) (see Table 2). No statistically significant relationships were shown for forceps or shoulder dystocia, neonatal hyperbilirubinemia, or neonatal hypoglycemia between the low FPG and intermediate-hyperglycemia groups (P > .05) (see Table 2). In sensitivity analyses by excluding cases with immediate OGTT, trends for all pregnancy outcomes remained the same, except for preeclampsia in the unadjusted model (AOR 1.51; 95% CI, 0.96-2.39) (Supplementary Table S1) (16).

Table 2.

Associations between early-pregnancy fasting glucose and pregnancy outcomes

	FPG < 5.1 mM N = 20 692	5.1 ≤ FPG ≤ 6.9 mM N = 693	P	Model 1	Model 2	Model 3
Primary outcomes
LGA (> 90th)	2624 (12.7%)	110 (15.9%)	.01	1.30 (1.06-1.60)	1.14 (0.92-1.41)	1.10 (0.89-1.37)
Primary cesarean	6612 (31.9%)	267 (38.5%)	< .01	1.34 (1.14-1.56)	1.25 (1.07-1.46)	1.24 (1.05-1.45)
Secondary outcomes
Preterm birth	845 (4.1%)	50 (7.2%)	< .01	1.83 (1.36-2.46)	1.75 (1.30-2.36)	1.75 (1.29-2.36)
Preeclampsia	481 (2.3%)	27 (3.9%)	< .01	1.70 (1.15-2.53)	1.50 (1.01-2.24)	1.47 (0.99-2.19)
Forceps or shoulder dystocia	794 (3.8%)	21 (3.0%)	.28	0.78 (0.50-1.22)	0.83 (0.53-1.29)	0.84 (0.54-1.31)
Neonatal hyperbilirubinemia	788 (3.8%)	33 (4.8%)	.20	1.26 (0.88-1.80)	1.25 (0.87-1.78)	1.19 (0.83-1.71)
Neonatal hypoglycemia	23 (0.1%)	2 (0.3%)	.18	2.60 (0.61-11.06)	2.43 (0.57-10.35)	2.49 (0.58-10.67)
Neonatal distress	79 (0.4%)	8 (1.2%)	< .01	3.05 (1.48-6.33)	3.15 (1.51-6.57)	3.29 (1.57-6.89)

Model 1: unadjusted model; model 2: adjusted for maternal age and BMI; model 3: adjusted for maternal age, BMI, educational levels, previous PCOS, and family history of diabetes.

Abbreviations: BMI, body mass index; FPG, fasting plasma glucose; LGA, large for gestational age; PCOS, polycystic ovary syndrome.

According to the definition of impaired fasting glucose, a post hoc analysis was performed by further dividing intermediate hyperglycemia into 2 ranges: 5.1 mM less than or equal to FPG less than 5.6 mM and 5.6 mM less than or equal to FPG less than or equal to 6.9 mM (impaired fasting glucose ), containing 562 and 131 women, respectively. The association between FPG and preterm birth statistically significantly increased with increasing fasting glycemia categories (AOR 2.00; 95% CI, 1.04-3.83) for the highest level (Table 3). In contrast, a statistically significantly increased risk of primary cesarean distress (AOR 1.21; 95% CI, 1.02-1.45) and neonatal distress (AOR 3.56; 95% CI, 1.62-7.80) was shown for the middle level (5.1 ≤ FPG < 5.6 mM), but these statistically significant relationships were not retained for the highest level (P > .05) (see Table 3). There were trends for an increased risk of LGA and preeclampsia with increased levels of FPG, although no statistical significance was shown (P > .05) (see Table 3).

Table 3.

Adjusted odds for associations between maternal glucose as categorical variable and indicated pregnancy outcomes

FPG, mM	LGA	Primary cesarean	Preterm birth	Preeclampsia	Neonatal distress
< 5.1 (N = 20 692)	Reference	Reference	Reference	Reference	Reference
5.1 ≤ FPG < 5.6 (N = 562)	1.06 (0.84-1.35)	1.21 (1.02-1.45)	1.69 (1.21-2.37)	1.43 (0.92-2.23)	3.56 (1.62-7.80)
5.6 ≤ FPG ≤ 6.9 (N = 131)	1.32 (0.82-2.13)	1.33 (0.93-1.91)	2.00 (1.04-3.83)	1.60 (0.65-3.95)	2.19 (0.30-15.93)

Abbreviations: BMI, body mass index; FPG, fasting plasma glucose; LGA, large for gestational age; PCOS, polycystic ovary syndrome.

Adjusted for maternal age, BMI, educational levels, previous PCOS, and family history of diabetes. dfdsfdsfdsf…..

Discussion

Our results indicate positive associations between early-pregnancy intermediate hyperglycemia and adverse pregnancy outcomes among women with normal OGTTs, including primary cesarean birth, preterm birth, and neonatal distress. To the best of our knowledge, this is the first study to present the relevance of early-pregnancy FPG and adverse pregnancy outcomes among women without a diagnosis of GDM in a Chinese population. Our study provides evidence to interpret the clinical significance of intermediate hyperglycemia in early pregnancy.

In the present study, we found that early-pregnancy intermediate hyperglycemia, within nondiabetic levels, was associated with an increased risk of adverse pregnancy outcomes, even when further OGTT results were normal. Our findings were consistent but not limited to previous findings of a positive relationship between mild FPG (5.1-5.5 mM) in early pregnancy and an increased risk of neonatal intensive care unit admission among women with a normal OGTT (13). We found intermediate hyperglycemia and increased risk of primary cesarean delivery, preterm birth, and neonatal distress, which was in accordance with the HAPO study (17). In sensitivity analyses after excluding individuals with immediate OGTT, these associations remained. We speculate that the increased risk of neonatal distress might be related to respiratory distress syndrome because this was more common in preterm birth (18)and cesarean deliveries (19). However, no statistically significant association was shown between intermediate hyperglycemia and LGA, which were the most frequent outcomes and concerns of hyperglycemia (17). In addition to the underestimation of women with intermediate hyperglycemia receiving recommendations about diet and exercise in early pregnancy, this may be due to the intermediate phenotype of impaired insulin secretion and insulin sensitivity between non-GDM individuals with intermediate hyperglycemia and those with GDM (20). Altered maternal metabolism during intermediate hyperglycemia may create a complex environment that has more effects on fetal respirational maturation and placental development than on excessive birth weight (21). Overall, though our results showed that early-pregnancy intermediate hyperglycemia increased the risk of adverse pregnancy outcomes, it did not support the recommendation of IDAPSG to diagnose early-pregnancy intermediate hyperglycemia as GDM.

In the subgroup analysis, we could not find a statistically significant graded association between FPG levels and most pregnancy outcomes, including primary cesarean delivery, preeclampsia, and neonatal distress. This may be due to the small sample size, especially the highest FPG group. In addition, one should be careful in the interpretation of the relationship between graded FPG levels and adverse pregnancy outcomes, as this was a post hoc analysis. Furthermore, the effect of isolated hyperglycemia in early pregnancy on the later development of metabolic disorders among women with normal OGTTs remains to be investigated.

There is evidence showing that FPG in early pregnancy is a poor predictor of the further development of GDM (22). In the Chinese population, the incidence of GDM for women with FPG between 5.1 and 6.9 mM was reported to range from 37.0% to 66.2% (13), indicating that approximately half of women with early-pregnancy intermediate hyperglycemia had a normal OGTT in later pregnancy. Consistently, our present study shows a lower value of 0-hour OGTT than early-pregnancy FPG. Thus, isolated hyperglycemia in early pregnancy, at least in this population, could not be supported as a criterion for the diagnosis of GDM. Interestingly, our data showed that women with early-pregnancy intermediate hyperglycemia were associated with an increased risk of GDM. Furthermore, even though further OGTTs were normal, these women were at an increased risk of adverse pregnancy outcomes. We hypothesize that the possibility of these seemingly contradictory findings may be related to the lack of reproducibility of the FPG result at the beginning of pregnancy (23-25). Additionally, hyperglycemia in early pregnancy could be related only to maternal metabolic disturbance due to a specific health status, such as concomitant abnormal lipid metabolism (26) or maternal obesity (27). Overall, isolated FPG in early pregnancy could not be used as an independent risk factor for GDM.

Given these findings, early-pregnancy intermediate hyperglycemia may merit further randomized controlled trials as a potential target for the prevention of adverse pregnancy outcomes. Universal screening conducted during early pregnancy to avert diabetes inevitably leads to the identification of many women with intermediate hyperglycemia. Biologically, it is plausible that early-pregnancy intermediate hyperglycemia could directly affect pregnancy outcomes through, for example, maternal metabolic disturbances or disrupted fetal organ development (26, 28, 29). In the present study, although diet-exercise guidance was involved and further OGTTs were normal, those individuals with intermediate hyperglycemia were still at an increased risk of adverse pregnancy outcomes. These women need attention during pregnancy. Additional research is needed to determine the effectiveness of lifestyle interventions.

The strength of our study is that it is a large retrospective cohort study with detailed data on clinical characteristics and maternal-fetal outcomes. However, there were some disadvantages of our study. First, the sample size of the higher FPG group was small. Second, although women with hyperglycemia in early pregnancy were educated about lifestyle changes, compliance and effectiveness were not evaluated. However, the outcomes were still comparable between women with FPG of less than 5.1 mM and those with 5.1 less than or equal to FPG less than or equal to 6.9 mM, as the former did not receive any recommendations about diet and exercise. Thus, our positive findings of early-pregnancy intermediate hyperglycemia and an increased risk of adverse pregnancy outcomes could only be underestimated.

Conclusion

In conclusion, we found that early-pregnancy intermediate hyperglycemia is associated with increased adverse pregnancy outcomes, even when further OGTTs are normal. It may help to identify and manage women with early-pregnancy intermediate hyperglycemia but normal OGTTs, namely, apparently healthy women, to improve pregnancy outcomes. A large, prospective study on maternal-fetal outcomes is needed to better evaluate the relationships of early-pregnancy FPG and the usefulness of proper management with pregnancy outcomes.