First-Trimester Fasting Hyperglycemia without Gestational Diabetes Mellitus is not Associated with Adverse Pregnancy Outcomes:A Prospective Cohort Study in China

Background Gestational diabetes mellitus (GDM) is a common pregnancy-induced metabolic complication worldwide. At present, a variety of strategies for diagnosis and management of GDM have been recommended. Our aim is to investigate the clinical features and pregnancy outcomes among women in whom a rst-trimester fasting glucose value ( ≥ 5.10 mmol/L but < 7.0 mmol/L) was detected and a 2-h 75-g oral glucose tolerance test (OGTT) between 24–28 weeks was negative. Methods This is a prospective cohort study of women who registered and delivered between June 2016 and November 2019 at First Hospital, Jilin University. Pregnant women who met the inclusion criteria were categorized as normal rst-trimester fasting plasma glucose(FPG)(< 5.10 mmol/L) and rst-trimester fasting hyperglycemia ( ≥ 5.10 mmol/L but < 7 mmol/L).Outcomes included weeks at time of delivery, neonatal birth weight, Apgar score at 1 min, Apgar score at 5 min, prevalence of macrosomia, hypertensive disorders of pregnancy ,primary cesarean delivery, preterm delivery ,premature rupture of membranes and sillbirth or neonatal death were compared after women who developed gestational diabetes mellitus (GDM) were excluded.

5.1 mmol/L), accounting for 11.6% of all subsequent GDM diagnosis (p < 0.01).After excluding women with a diagnosis of GDM between 24 and 28 weeks of gestation, we observed no signi cant difference between groups for adverse maternal and prenatal outcomes.
Conclusion More than two thirds of rst-trimester fasting hyperglycemia pregnant women will have a normal OGTT performed at 24-28 week and of these women whom in no increased risk of adverse pregnancy outcomes have been identi ed.

Background
Gestational diabetes mellitus (GDM) is a common pregnancy-induced metabolic complication worldwide [1]. Patients with GDM are not only associated with increased risks of maternal and perinatal morbidities but also have a high risk of development of type 2 diabetes after delivery [2]. At present, a variety of strategies for diagnosis and management of GDM have been recommended to improve pregnancy outcomes. The most striking distinction is the timing for the screen of GDM. American Diabetes Association(ADA) [3] suggest that the diagnosis of GDM is made either by "one-step strategy" or "two-step strategy" at 24-28 weeks of gestation in women without preexisting diabetes. According to the recommendation, GDM is restricted to second or third trimester of pregnancy. Whereas International Association of Diabetes and Pregnancy Study Groups (IADPSG) [4] support that fasting plasma glucose(FPG) ≥ 5.10 mmol/l but < 7.0 mmol/l as the GDM diagnostic criteria at the rst prenatal visit and women with FPG < 5.1 mmol/l are tested for GDM from 24 to 28 weeks' gestation with a 75-g oral glucose tolerance test(OGTT). The FPG diagnostic threshold that they introduced was based on the study by Riskin-Mashiah et al [5]. Similar to the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Research Group report [6], the study showed a strong continuous graded association between higher rst-trimester FPG values and adverse pregnancy outcomes. IADPSG recommendation is advantageous in two points to screen for GDM. On one hand, the result of FPG is reliable, reproducible and patients are more compliant [7]. On the other hand, early detection of GDM allows interventions prior to 24-28 weeks and might have a positive effect on maternal and fetal outcomes. Unsurprisingly, previous study [8] presented that there is no complete correspondence in diagnosing GDM between the rst-trimester fasting glucose value and the results of a 2-h 75-g OGTT performed early in the third trimester. Therefore more pregnant women are diagnosed of GDM by IADPSG recommendation. It is a matter of debate regarding costeffectiveness and bene t of detecting and treating early GDM. Since higher rst trimester fasting glucose levels are associated with increased risk for the development of GDM [9] and GDM in late pregnancy have been acknowledged deleterious, the association between fasting hyperglycemia in early pregnancy and adverse pregnancy outcomes may be exaggerated. To date, there is no clinical trial addressing the extent to which rst-trimester fasting hyperglycemia women without GDM are associated with adverse pregnancy outcomes.
Thus, the aim of the current study was to determine clinical characteristics and pregnancy outcomes among women in whom rst-trimester FPG(≥ 5.10 mmol/l but < 7.0 mmol/l) was detected and a 2-h 75-g OGTT between 24-28 weeks was negative.

Design and setting
This is a prospective cohort study conducted between June 2016 and November 2019. All consecutive pregnant women who registered at our obstetrics clinic and intended to deliver at our hospital were invited to participate in this study, if they had a rst-trimester fasting glucose value. Women were excluded if they had preexisting diabetes or overt diabetes, a previous caesarean, hypertension disorder prior to 20 weeks, a history of stillbirth, multifetal gestation, and conception by means of in vitro fertilization. All the women who participated in the study provided written informed consent. The study was approved by the Institutional Review Board.

Eligibility Criteria
In China, FPG test is provided freely to every woman as soon as pregnancy was con rmed. The result and the time of the test will be duly documented in their perinatal manual. Based on the recommendations, overt diabetes was de ned as having a fasting blood glucose of ≥ 7.0 mmol/l. Patients with overt diabetes were given instructions to glycemic control, the remainder received no interventions. Participants were required to take an OGTT, with the use of a 75-g dose of glucose, between 24 and 28 weeks of gestation. GDM diagnosis was established when any one of the following values is met or exceeded in the75-g OGTT: 0 h (fasting), ≥ 5.10 mmol/L; 1 h, ≥ 10.00 mmol/L; and 2 h, ≥ 8.50 mmol/L. Information regarding age, parity, pre-pregnancy body mass index (BMI), family history of diabetes, rst-trimester FPG level, and gestational age at delivery was recorded. Pre-pregnancy body mass index(BMI) was selfreported. Gestational age was determined from the date of the last menstrual period. If the date was uncertain, the gestational age of delivery was estimated by means of ultrasound performed between 6 and 13 weeks of gestation.

Data collection and management
For the purpose of analysis, subjects were distributed between two groups: normal rst-trimester FPG (< 5.10 mmol/L) and rst-trimester hyperglycemia (≥ 5.10 mmol/L but < 7 mmol/L) and basic patient information was compared. Pregnancy outcomes were studied and compared between groups excluding women with a diagnosis of GDM between 24 and 28 weeks of gestation. Maternal outcomes included macrosomia(≥4000g), primary cesarean delivery, gestational age at birth, and preterm birth(< 37 weeks), premature rupture of membranes, hypertensive disorders of pregnancy (de ned as pre-eclampsia or systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg in a previously normotensive pregnant woman who is at ≥ 20 weeks of gestation and has no proteinuria or new signs of end-organ dysfunction) .Neonatal outcomes comprised of birth weights, 1 minute and 5 minute Apgar score and stillbirth or neonatal death. Obstetricians were blinded to the rst-trimester FPG level when they recorded the pregnancy outcomes. At the end of study period, a special team was assigned and responsible for the nal analysis.

Statistical analysis
Statistical analysis was performed with the SPSS computer statistics program (SPSS Inc, Chicago, Ill). Mean and standard deviation are reported for continuous variables, and number and percentage are reported for categorical variables. Chi-square or Fisher's exact tests (for categorical variables) and independent-samples t tests (for continuous variables) were used to compare groups. Reported P-values were two-tailed and P-values < 0.05 were considered to be statistically signi cant.

Results
During the present study period, a total of 3783 consecutive pregnant women registered and resulted in deliver in our hospital. Of these 2124 women met the inclusion criteria. Table 1 presented the characteristics of whole study population strati ed according to rst-trimester FPG. Women with rst-trimester fasting hyperglycemia constituted 20.8% of the total study population and accounted for 27.6% of subsequent GDM diagnosis. The other 1683 had rst-trimester FPG < 5.1 mmol/L, accounting for 11.6% of all subsequent GDM diagnosis (p < 0.01). The average (SD) rst-trimester fasting FPG was 4.5(0.4)mmol/L and 5.5(0.4)mmol/L respectively (p < 0.01).The individual rates of Parity > 1 and family history of diabetes, maternal age, pre-pregnancy BMI, gestational age at fasting glucose did not differ signi cantly between the groups. After excluding women with a diagnosis of GDM between 24 and 28 weeks of gestation, patient information strati ed according to rst-trimester FPG was presented in Table 2. Maternal age and prepregnancy BMI in both groups was slightly reduced after women with subsequent GDM was excluded. The prevalence of parity > 1 and family history of diabetes, rst-trimester FPG and gestational age at fasting glucose is similar after exclusion. There is no signi cant difference for all the variables except rst-trimester FPG between the groups. Pregnancy outcomes were studied and compared in patients without GDM and the results are shown in Table 3. The rate of macrosomia (4.6% VS 5.9%), preterm delivery (5.0% VS 5.3%), primary cesarean delivery (29.2% VS 31.6%), premature rupture of membranes (18.6% VS 21.7%) were slightly higher for rst-trimester fasting hyperglycemia patients but all the differences were statistically insigni cant. In contrast, hypertensive disorders of pregnancy (5.9% VS 4.6%) occurred more frequently in normal rsttrimester FPG patients, however statistical test also fail to detect a signi cant difference. The mean birth weight and gestational age at delivery, as well as Apgar score at 1 min or 5 min were similar between the groups. There was no stillbirth or neonatal death in either group. Apgar score at 1 min 9.5 ± 1.0 9.6 ± 0.9 0.45 Apgar score at 5 min 9.9 ± 0.4 9.9 ± 0.4 0.66 Data are presented as means ± SD or as n (%).; BMI: body mass index; FPG: fasting plasma glucose GDM: gestational diabetes mellitus

Discussion
In this prospective cohort study, we found that patients with rst-trimester fasting hyperglycemia have a higher incidence of developing GDM which was diagnosed between 24 and 28 weeks of gestation. Importantly, we also found that rst-trimester hyperglycemia is not associated with adverse pregnancy including macrosomia, preterm delivery primary cesarean delivery, premature rupture of membranes and pregnancy hypertension disorders, while subsequent GDM patients were excluded in the analysis.
It is established that overt or preexisting diabetes in early pregnancy is associated with an increase in several adverse maternal outcomes and women at risk may bene t from screening and treatment in early pregnancy [10],however, importance of detecting and regulating degrees of hyperglycemia less severe than "overt" diabetes from early pregnancy is controversial. Advocates [11] argue that traditionally GDM screen which begin at the beginning of the third trimester provide only a brief period for intervention and result in little improvement for pregnancy outcomes. Critics [12] points that mild hyperglycemia does not carry anything like the same degree of risk as overt diabetes. In addition, If IADPSG proposal is adopted, rates of diagnosis of gestational diabetes will increase enormously. Interventions and costs will increase without evident bene ts [13].
Our results are consistent with the results of numerous studies which demonstrated that rst-trimester FPG level was strongly correlated with GDM diagnosed at 24-28 gestational weeks. In a large retrospective study conducted by Riskin-mashihar et al [9], it is noted that rst-trimester FPG level had a continuous associations with increased frequency of GDM development. The incidence of GDM in highest rst-trimester hyperglycemia is 11.7% (adjusted odds ratio 11.92 [95% CI 5.39 − 26.37]). F.
Corrado et al [8] reported a study including a number (n = 738) of pregnant women in Italy with an 11.9% prevalence of GDM revealed by OGTT between 24 and 28 weeks of gestation. In this study 24(45.3%) women who have a rst-trimester FPG greater or equal to 5.1 mmol/L progressed to GDM. In a study of 17,186 pregnancies among Chinese population [14], the incidences of GDM were 37.0, 52.7, and 66.2%, respectively, for women with FPG at the rst prenatal visit between 5.10 and 5.59, 5.60 and 6.09, and 6.10-6.99 mmol/L. In light of the high prevalence of GDM in pregnant women with FPG (6.10-6.99 mmol/L), the authors suggested that the same interventions should be provided for them as for GDM.
Our results are inconsistent with three previous reports which found that fasting hyperglycemia in early pregnancy is associated with adverse pregnancy. J. Seth Hawkins et al [15] described that women with an earlier diagnosis of diet-treated GDM were at increased risk of preeclampsia and the delivery of large infants compared with women who received the diagnosis at 24 weeks of gestation. Women with early diagnosis were more likely to be older, multiparous, and obese. When differences in maternal characteristics and glycemic control were adjusted, there is still a higher risk of preeclampsia in earlier diagnosis group (odds ratio, 2.4; 95% CI, 1.5, 3.8). Similar results were reported in the study of Maisa N et al [16]. In contrast with women who received a diagnosis for GDM at or after 24 weeks, women diagnosed with GDM before 24 weeks were associated with an increased risk for macrosomia (OR 2, 95% 1-4.15, p = 0.0498), but relationship with other adverse outcomes was not found. Women diagnosed with GDM before 24 weeks were more likely to be obese and they were less likely to have excess gestational weight gain. A large multiethnic cohort study conducted by Sweeting et al [17] showed that incidence of macrosomia, large for gestational age and neonatal intensive care admission in women in whom GDM was diagnosed at < 12 weeks of gestation was high and even comparable to women with pre-existing diabetes. Difference in de nitions of gestational diabetes is a potential reason for differences in study ndings. Ours have been described above, whereas their approach was based on the Carpenter-Coustan Criteria that if either a 50-g one-hour glucose challenge test (GCT) that exceeded 200 mg/dL, or if they had two or more abnormal values on a 3 hour, 100 gram oral glucose tolerance test (OGTT). Other important distinctions between the current study and that of prior reports include populations studied and study design. All of these studies were made retrospectively and in two of the three studies only patients with high risk was included in the analysis. Maternal baseline characteristics including pre-pregnancy weight, maternal age and parity, which have previously been reported to be associated with adverse pregnancy outcomes in these studies were not comparable and strategies to control the confounders was vague and poorly explained.
Our study has several strengths, to our knowledge, it is the rst prospective study with regard to the association between rst-trimester fasting hyperglycemia and adverse pregnancy outcomes while important confounder as subsequent GDM was excluded from the analysis, particularly all women were followed at a single university clinic and also delivered in the same institution warranting the consistency of results. Other strengths included the relatively large patient sample size compared to earlier studies and inclusion criteria which the HAPO Study has adopted. However, we acknowledge our study also has several limitations. First, Pre-pregnancy BMI, which is a known confounding factor for adverse pregnancy outcomes, was self-reported. Its accuracy depended on the participants' ability of memory and evidences showed [18] adults are willing to overestimate their height and underestimate their weight. Notwithstanding, we do not believe this will bias our study dramatically as pre-pregnancy BMI was comparable in the two groups. Another problem is the test of rst-trimester FPG level which was performed in different community center. The measurement lacks a standardized protocol and laboratory quantity control is impossible. Finally, our results are exclusively from Chinese population and may not be generalizable to other ethnicities. However, as Asians are more inclined to develop GDM [19], and we supposed that fewer patients with rst-trimester fasting hyperglycemia will suffer from GDM among other races.

Conclusion
In summary, majority of rst-trimester fasting hyperglycemia pregnant women will have a normal OGTT performed at 24-28 week and of these women whom in no additional risk for adverse outcomes have been observed. To classify fasting hyperglycemia in early pregnancy as GDM proposed by IADPSG is not appropriate. Medical intervention and close monitoring should only be applied to those with "standard" GDM.