Despite treatment, HbA1c &gt; 37mmol/mol in the first trimester is associated with premature delivery among South Asian women with gestational diabetes mellitus: a retrospective cohort study

doi:10.21203/rs.3.rs-3395926/v1

Purpose: To examine the effects of first-trimester HbA1c (HbA1c-FT) >37mmol/mol on preterm birth (PTB) and large-for-gestational-age (LGA) babies in a retrospective cohort of South Asian pregnant women with gestational diabetes (GDM).

Methods: The cohort (n = 686) was separated into two groups based on HbA1c-FT values: Group A (n=97) and Group B (n=589), with values of 37-46 mmol/mol (5.5-6.4%) and <37 mmol/mol (5.5%), respectively. HbA1c-FT's independent influence on PTB and LGA babies was examined using multivariable logistic regression in groups A and B women. The reference group (Group C) included 2031 non-GDM women with HbA1c-FT <37 mmol/mol (<5.5%). The effects of HbA1c-FT on PTB and LGA babies in obese women in Groups A, B, and C (designated as A-ob, B-ob, and C-ob, respectively) were re-analyzed using multivariable logistic regression.

Results: Group A GDM women with greater HbA1c-FT had a higher risk for PTB (aOR: 1.90, 95% CI: 1.12 to 3.20) but not LGA babies (aOR: 1.20, 95%: 0.74 to 1.95). The risk of PTB was higher for obese women in Group A-ob: aOR 3.15 [95% CI 1.62 to 6.15]. However, GDM women with normal HbA1c-FT exhibited no elevated risk for PTB: Groups B and B-ob had aORs of 1.17.(95% CI 0.89 to 1.55) and 1.29 (95% CI 0.84 to 1.97) respectively.

Conclusions: South Asian GDM women with prediabetic HbA1c FT; 37-46 mmol/mol (5.5-6.4%) are more likely to deliver preterm babies despite treatment, while the risk for LGA babies was the same as non-GDM women.

South Asian

Gestational diabetes

HbA1c

Preterm Birth

Prediabetes

Currently, there is a lack of international consensus on the benefits of screening and managing gestational diabetes mellitus (GDM) before 24 gestational weeks. Many of these ‘early GDM’ women have undetected prediabetes. The present study revealed that GDM women with first trimester HbA1c >37 mmol/mol (likely to have preexisting prediabetes), despite best practice treatment, had a higher risk for preterm babies, but the frequency of large for gestational age babies was comparable to non-GDM women. We speculate that the higher risk for preterm delivery triggered by first-trimester ‘hyperglycemia’ may not be reversed by optimal glycemic control in later pregnancy. We strongly recommend further randomized control trials to identify the mechanisms for preterm delivery and the benefits of periconceptual glycemic control for its prevention.

The World Health Organization (WHO) subcategorizes hyperglycemia first recognized during pregnancy (HIP) into two distinct categories: (a) diabetes in pregnancy (DIP); women satisfying 2006 WHO criteria for diabetes; (b) gestational diabetes mellitus (GDM); women satisfying the criteria proposed by the International Association of Diabetes in Pregnancy Study Group (IADPSG) [1, 2]. Several preeminent professional organizations, like the American Diabetes Association (ADA), the International Federation of Gynecology and Obstetrics (FIGO), and the International Diabetes Federation (IDF), recommend screening for DIP at the first prenatal visit, regardless of the stage of pregnancy [3, 4, 5]. HbA1c estimations at the first prenatal visit reveal many women with intermediate hyperglycemia, suggestive of prediabetes: below < 48mmol/mol(6.5%)) and above ‘normal’ values. Unfortunately, there is no international consensus on an HbA1c threshold value for prediabetes diagnosis in the general population [6]. The International Expert Committee (IEC) of the ADA, IDF, and European Association for the Study of Diabetes observed a continuum of risk for prediabetes with rising HbA1c levels but did not suggest a threshold value for its diagnosis [7]. Ignoring the IEC recommendation, the ADA recommended diagnosing prediabetes with an HbA1c of 39–47 mmol/mol (5.7–6.5%), whereas the National Institute for Health Care Excellence (NICE) recommended 42–47 (6-6.4%) [8, 9]. WHO maintained the IEC stance without an HbA1c threshold value for prediabetes diagnosis [10]. This lack of agreement on an HbA1c value for the diagnosis or prediction of GDM is also seen in the obstetric population [11, 12, 13]. Furthermore, many studies linked HbA1c levels in pregnancy with adverse pregnancy outcomes, but the threshold levels varied between studies [14, 15, 16]

Asian women of reproductive age have a high frequency of undiagnosed prediabetes [17]. In a large population of 2.2 million Chinese women planning for pregnancy, prediabetes and diabetes were 12.9% and 1.4%, respectively [18]. Similarly, a pan-India study revealed a prevalence of prediabetes of ~ 12% among women 20–50 years of age [19 ]. There is emerging evidence linking pregestational prediabetes with several adverse pregnancy events. In a large population-based study among Chinese women, a higher risk of preterm birth and large gestational-age babies was observed among women with impaired glucose tolerance before pregnancy [20]. Similarly, among the multiethnic population in the United States, women with HbA1c of 39–46 mmol/mol (5.7–6.4%) before pregnancy had a higher risk for preterm birth [21]. Therefore, the high frequency of undiagnosed prediabetes before conception might lead to the emergence of a number of obstetric complications.

Even though not validated for use before 24 gestational weeks (GW), the oral glucose tolerance test (OGTT) is often used in South Asia to diagnose GDM in early pregnancy [22, 23]. This strategy identified early-onset ‘hyperglycemia’ in 15–70% of GDM women of South Asian ethnicity, and such hyperglycemia was associated with a significantly increased risk for adverse pregnancy outcomes [24, 25, 26, 27]. Additionally, GDM identified in the first trimester is associated with much more adverse events than observed among women with ‘standard’ GDM diagnosed after 24 GW [27, 28]. In the iconic 2020 Norbert Frienkel lecture, David Simmons denoted early onset GDM as ‘Prevalent GDM’ indicating it as preexisting glucose intolerance, discovered in early pregnancy [29]. Accordingly, prediabetic state detected by HbA1c estimates in the first trimester (HbA1c-FT) is probably pregestational in origin.

In the present study, we compared the prevalence of large-for-gestational-age (LGA) babies and preterm birth (PTB) between two cohorts of South Asian (Asian Indian) GDM women with and without prediabetes in the first trimester and received best practice treatment. The HbA1c-FT estimates were used to make the diagnosis of prediabetes based on a cutoff value of 37 mmol/mol (5.5%), which is the higher HbA1c reference value in the first trimester among Asian Indian women [30].

Subjects

This retrospective cohort study involved pregnant women who attended the prenatal clinic in St. Stephen’s Hospital, a 600-bed tertiary-care hospital in New Delhi, between January 2011 and December 2017. The hospital manages ~ 2000 pregnant women annually, who are all of South Asian descent and reside in New Delhi. Our center follows a universal thalassemia screening strategy for pregnant women at the first prenatal visit. The protocol includes the estimation of HbA, HbA2, and HbF through hemoglobin (Hb) electrophoresis, which concurrently estimates HbA1c in all pregnant women. The GDM screening was done by a one-step 75-g OGTT, and the timing of the screening was at the discretion of the treating obstetrician. Women with GDM risk factors such as advanced age, previous GDM, family history of diabetes, obesity, or poor obstetric history were subjected to early GDM screening. The low-risk women and those who had negative GDM screening results before 24 GW were advised to have OGTT after 24 weeks. We followed the GDM diagnostic criteria proposed by the IADPSG: any glucose value in the 75-g OGTT above the threshold level: FPG ≥ 5.1 mmol/L, 1-h post-load plasma glucose ≥ 10 mmol/L, or 2-h PG ≥ 8.5 mmol/L.[2] After GDM diagnosis, all women received nutritional counseling and lifestyle modification from a qualified dietician and were trained for self-monitoring of blood glucose (SMBG) by a diabetic educator nurse. After 2 weeks of medical nutrition therapy, if 20% of the SMBG values were above the glycaemic targets (fasting glucose 5.3 mmol/L, 2-h post-prandial (after breakfast, lunch, and dinner) glucose 6.7 mmol/L), insulin therapy was initiated. All pregnant women were jointly managed by the endocrinology and obstetric teams.

Selection of the study cohort

The selection of the study population is shown in Fig. 1. Of the 3986 singelton pregnant women who had HbA1c estimation in the first trimester and OGTT in later pregnancy, 1117 women were excluded from the study due to delivery outside our center (n = 822), hemoglobinopathy (n = 274), and DIP diagnosis (n = 21). Of the 729 GDM women, 43 were excluded as the initiation of GDM treatment was delayed beyond 32 GW. The remaining 686 GDM women were divided into two groups: Group A, HbA1c-FT > 37–46 mmol/mol (5.5–6.4%) (n = 97), and Group B, HbA1c FT < 37 mmol/mol (5.5%) (n = 589). 2031 non-GDM women with HbA1c-FT < 37 mmol/mol (5.5%) (Group C) formed the control group.

Clinical data collection

Clinical and demographic data were obtained from the prenatal booking and clinic visit charts. The pregnancy outcome data were collected from the maternal-neonatal birth records and the computerized discharge summary records. Laboratory data were retrieved from the computerized hospital information system. The gestational age at the time of sampling for HbA1c-FT, OGTT, and the time of delivery were calculated from the last menstrual period (LMP). The gestational age was changed to the date calculated from the earliest available ultrasound if the gestational age differed by more than 7 or 14 days in the first or second trimester, respectively, or if the LMP was unknown. The maternal characteristics included age, gravidity, education (12, 13–15, > 15 years), socioeconomic status (high or middle/low), family history of diabetes in first-degree relatives, history of abortion, and previous GDM. The body mass index (BMI) was calculated from the height and weight measured at the first prenatal visit (weight in kg/height in meters²). The mean SMBG values of the week prior to delivery and the gestational weight gain (from the first trimester visit to the end of gestation) were available for 186 and 214 GDM women, respectively (mainly for the 2015–2017 period).

Adverse pregnancy events

This study examined unfavorable pregnancy outcomes: (a) PTB before 37 weeks and (i) LGA babies at or above the 90th percentile for Asian Indians [31, 32]. All data were entered into the central database and double-checked before statistical analysis.

This study was approved by the institutional ethics committee (SSHEC/RO 275) with a waiver for informed consent

Laboratory Methods

Our laboratory is certified by the National Accreditation Board for Testing and Calibration Laboratories and uses Bio-Rad laboratory equipment for proficiency testing. We performed the OGTT according to the established protocol, ingesting 75 g of anhydrous d-glucose. In a vacuette containing sodium fluoride and EDTA, a sample of plasma glucose was taken. On a Beckman AU680/480 analyzer, the hexokinase technique was used to estimate glucose. Daily tests were conducted using two levels of plasma glucose controls (from Bio-Rad): Level 1: 4.53 mmol/L, and Level 2: 15.57 mmol/L. For the Level-1 and Level-2 controls, the computed monthly coefficient of variation (CV) was 1.7% and 1.4%, respectively.

The blood sample for HbA1c estimation was a non-fasting sample collected in an EDTA vial. Estimation was done within two hours of sampling by ion-exchange high-performance liquid chromatography (Bio-Rad D 10TM machine, Bio-Rad Laboratories, Hercules, CA). The estimation was traceable to the reference methods of both the National Glycohemoglobin Standardization Program and the International Federation of Clinical Chemistry and Laboratory Medicine. The inter-assay CVs were 1.3% and 1.5% for low (mean HbA1c 37 mmol/mol, 5.45%) and high controls (mean 86 mmol/mol, 9.95%), respectively. The laboratory participated in an external quality assurance scheme for both glucose and HbA1c. The Z score for glucose was 0.60, and that for HbA1c was 0.65.

Statistical Methods

Data analysis was performed on the statistical software SPSS version 16.0 (Chicago, SPSS Inc.). The data were summarized with the mean and standard deviation for continuous variables and as numbers with percentages for qualitative variables. The clinical data and other parameters in Groups A, B, and C were analyzed for any linear trend using a one-way analysis of variance for continuous variables and chi-square for trends in qualitative variables. Multivariable logistic regression analysis was applied to assess the independent effect of HbA1c-FT on PTB and LGA babies. The plausible confounding factors are derived from previous studies. The unpaired student t-test and chi-square were applied to compare GDM treatment duration, gestational weight gain, and insulin therapy between women in Groups A and B. The missing BMI values of 519 women were imputed by a regression method using STATA (version 12) statistical software with 20 imputed data sets. The impact of HbA1c-FT on PTB and LGA babies was re-analyzed in a subgroup of obese pregnant women with a BMI > 25 kg/m²; obese as per Asian criteria [33]. The obese women for the Groups A, B, and C groups were selected for this analysis, and these groups were redefined as: Group A-Obese (A-ob), Group B-Obese (B-ob), and Group C (C-ob) (control).

The clinical and biochemical parameters of the study (A and B) and control (C) groups are shown in Table 1. All GDM risk factors and glycemic parameters were highest among Group A women, with a decreasing trend in Groups B and C. The analysis of these parameters among obese GDM women is shown in Table 2. The treatment details in different groups of GDM women are shown in Table 3. The GDM women in Groups A and A-Ob received longer-term treatment than those in Groups B and B-Ob. Limited data available for gestational weight gain and on the glycemic parameters in the last week of gestation were comparable between women in the A and B groups and the A-Ob and B-Ob groups. In the multivariable regression analysis with Group C as the reference category, the aORs for PTB for Group A and Group B were 1.90 [95% CI 1.12 to 3.20]; p = 0.016 and 1.17[ 95% CI 0.89 to 1.55]; p = 0.264, respectively; and the aORs for LGA for Group A and B were 1.20 [0.74 to 1.95]; p = 0.454 and 1.26 [1.01 to 1.57]; p = 0.042, respectively (Table 4). In a subgroup analysis of obese women, the aOR for PTB in the Group A-ob group was 3.15 [1.62 to 6.15]; p = 0.001 (Table 5). The p values of the aOR of PTB in Group B-Ob and of the LGA in Group A-Ob and Group B-Ob did not reach levels of significance.

Table 1: Clinical, biochemical characteristics of Study population

Parameter	Group A HbAIc>5.5 % GDM n=97	Group B HbA1c <5.5 % GDM n=589	Group C HbA1c <5.5% No GDM n=2031	P value of linear Trend
Age (years) ,[mean + SD]	29.91 +3.95	28.56+3.75	26.94+3.64	<0.001^*
Gravida>2 , %(n)	59.79 ( 58)	46.86 (276)	44.31(900)	0.008^*
BMI kg/m² [mean +SD] n=2198	27.30 +5.16	26.28+4.38	24.61+5.11	<0.001^*
Education >12 years, %(n)	70.10( 69)	72.16( 425)	72.53(1473)	0.753
High Income, %(n)	42.27(41)	35.99(212)	28.11 (571)	<0.001^*
Family history DM, %(n)	38.14(37)	26.99 (159)	17.92(364)	<0.001^*
History of Abortion ,%(n)	38.14( 37)	27.16(160)	22.84(464)	<0.001^*
History of GDM ,% (n)	56.70(55)	52.80 (311)	0.74 (15)	<0.001^*
OGTT -Gest age –wks,[mean +SD]	18.32+6.99	21.36+6.45	24.25+4.53)	<0.001^*
HbA1c -Gest age (wks) [mean +SD]	9.09+2.85	8.86+2.60	9.21+2.61	0.021^*
Gestational weight gain Kg [mean+SD]^$	7.09+3.85	8.37+4.20	10.35+5.32	<0.001^*
HbA1c, %, [mean +SD]	5.66 + 0.19	4.97+0.32	4.87+0.33	<0.001^*
FPG , mg/dL ,[mean +SD]	96.64 +9.60	93.67+7.36	79.56+6.68	<0.001^*
1-h PG, mg/dL,[mean +SD]	175.00 +34.30	164.85 +29.35	126.33+23.33	<0.001^*
2-hPG , mg/dL ,[mean + SD]	142.10+26.68	133.88+24.46	104.44+18.55	<0.001^*
Hb , g/dl {mean +SD]	11.49 +1.24	11.68+1.28	11.65+1.28	0.702
MCV ,fl [mean + SD]	80.93+7.16	85.83 +6.58	86.78+6.91	<0.001^*
RDW ,fL [mean +SD] n=2534	15.53+1.87	15.04+2.20	15.07+2.33	0.134

*P value Significant. $= data limited to 446 women

BMI=Body mass Index, DM =Diabetes mellitus, GDM=Gestational diabetes, GTT= Oral Glucose tolerance test, FPG = Fasting plasma glucose, 1-h PG= I hour post load plasma glucose, 2-h PG = 2 hour post load plasma glucose , Hb =Hemoglobin , MCV = Mean Corpuscular Volume, RDW =RBC diameter width.

Table 2 : Clinical and biochemical characteristics of Obese women ( BMI >25 kg/m2)

Parameter	GDM HbAIc>5.5 % n=52	GDM HbA1c <5.5 % n=275	Non GDM HbA1c <5.5 % n=690	P value of the linear trend
Age (years) ,[Mean + SD]	30.00+4.06	29.09+3.60	27.46+3.64	<0.001^*
Gravda>2 % (n)	63.46 % (33)	50.55% (139)	49.0% (338)	0.106
BMI kg/m²[mean + SD], n=2198	30.13+3.61	29.13+3.22	28.75+3.64	0.005^*
Education >12 years, %(n)	69.23% (36)	78.55%(216)	73.07(510)	0.338
High Income , %(n)	44.23% (23)	40.73%(112)	30.95(216)	0.007^*
Family history DM, %(n)	32.69% (17)	29.4% (81)	23.35(163)	0.025^*
History of Abortion, %(n)	42.31% (22)	28% (77)	24.93(174)	0.019^*
History of GDM, %(n)	67.31%(35)	59.64%(164)	1.29(9)	<0.001^*
Gestational weight gain (kg) [mean +SD]	6.78+3.96)	8.16 +4.38	9.84+4.32)	<0.001^*
Gestational age of GT,wk,[mean+ SD]	17.81+7.24	21.45+6.36	24.23+4.43	<0.001^*
Gestational age of HbA1c,wk[mean+SD]	9.21+2.93	8.90 +2.67	9.28+2.51	0.129
HbA1c % ,[mean + SD]	5.65 +0.18	5.04+0.31	4.91+0.31	<0.001*
FPG mg/dL [mean + SD]	97.85+9.61	94.63+6.82	81.08+6.50	<0.001^*
1-h PG mg/dL [mean + SD]	180.48+34.84	165.81+28.97	130.57+22.46	<0.001^*
2-hPG mg/dL [mean + SD]	143.81+27.87	134.03+23.89	106.93+18.26	<0.001*
Hb g/dl, [mean +SD]	11.54+1.33	11.79+1.17	11.76+1.23	0.505
MCV (fl) ,[mean + SD]	80.93+6.88	85.59+6.40	86.07+6.28	<0.01^*
RDW (fL), [ mean + SD]	15.53+1.64	15.21+2.24	15.06+2.23	0.112

*P value Significant. BMI=Body mass Index, DM =Diabetes mellitus, GDM=Gestational diabetes, GTT= Oral Glucose tolerance test, FPG = Fasting plasma glucose, 1-h PG= I hour post load plasma glucose, 2-h PG = 2 hour post load plasma glucose , Hb =Hemoglobin , MCV = Mean Corpuscular Volume, RDW =RBC diameter width

Table 3: Treatment details of GDM women

Parameter	Whole GDM women, n= 686			Obese GDM women, n=327
	Group A n= 97	Group B n= 589	P value	Group A –Ob n=52	Grpup B-Ob n=275	P value
GDM Treatment duration (weeks)	19.09+6.84	16.32+6.45	<0.001	19.19+6.73	16.21+6.39	0.002
Insulin therapy , % (n)	28.87 (28)	17.32 ( 102)	0.008	26.92% (14)	18.91%(52)	0.189
Gestational Weight gain , Kg - mean+ SD (data of 446 women)	7.09+3.85 ( 22 women)	8.37+4.20 (143 women)	0.181	6.78+3.96 (19 women)	8.16+4.38 (95 women)	0.206
Blood glucose in last gestational week mmol /L , mean +SD, ( data of 165 women)	5.83+0.51 ( 22 women )	5.73+0.75 (143 women)	0.545	5.82+0.53 (19 women)	5.83+0.63 (113 women)	0.937

GDM= Gestational Diabetes Mellitus , Group A = GDM women with HbA1c in first trimester (HbA1c-FT) >5.5 % , Group B = GDM women with HbA1c –FT <5.5 % , Group A-Ob = Obese GDM women with HbA1c-FT >5.5 %, Group B-Ob = Obese GDM women with HbA1c-FT <5.5 %.

Table 4

Adverse events among GDM women having HbA1c –FT ≥ 5.5% and < 5.5% in comparison with Non –GDM women with HbA1c-FT < 5.5%
Adverse events	Group A Treated GDM HbA1c ≥ 5.5% n = 97	Group B Treated GDM HbA1c < 5.5% n = 589	Group C Non GDM HbA1c < 5.5% n = 2031	Odds Ratio[95% Confidence Interval]; P-value
Adverse events	Group A Treated GDM HbA1c ≥ 5.5% n = 97	Group B Treated GDM HbA1c < 5.5% n = 589	Group C Non GDM HbA1c < 5.5% n = 2031	Group A versus C	Group B versus C
Preterm < 37 wks- % (n)	21.65% ( 21)	13.77% (81)	11.62% ( 236)	Crude 2.10[1.27 to 3.47] p = 0.004 Adjusted 1.90[1.12 to 3.20]; p = 0.016	Crude 1.25[0.95 to 1.63] ;p = 0.107 Adjusted 1.17[0.89 to 1.55]; p = 0.264
LGA - % (n)	25.77%(25)	23.37% ( 147)	20.19% (410)	Crude 1.37[0.86 to 2.19] ;p 0.184 Adjusted 1.20[0.74 to 1.95]; p = 0.454	Crude 1.33 [1.07 to 1.65] p = 0.010 Adjusted 1.26[1.01 to 1.57]; p = 0.042
Adjusted for Age, Gravida, Body Mass Index, Mean Corpuscular Volume, income. GDM = Gestational diabetes, HbA1c FT = HBA1c in first trimester LGA = Large for gestational age

Table 5

Comparison of Odds for adverse events among Obese women (BMI ≥ 25 Kg/m2)
Adverse events				Odds ratio[95% Confidence Interval]; p-value
Adverse events	Group A-Ob GDM HbA1c ≥5.5% n = 52	Group B-Ob GDM HbA1c < 5.5% n = 275	Group C-Ob Non GDM HbA1c < 5.5% n = 690	Group A-Ob versus Group C Ob HbA1c-FT ≥5.5% n = 52	Group B –Ob versus Group C -Ob HbA1c –FT < 5.5% N = 275
Premature Delivery < 37 weeks- % (n)	30.76 (16)	14.54 ( 40)	11.03% (77)	Crude: 3.64[1.93 to 6.88]; p < 0.001 Adjusted: 3.15[1.62 to 6.15]; p = 0.001	Crude: 1.40[0.92 to 2.11]; p = 0.113 Adjusted: 1.29[0.84 to 1.97]; p = 0.236
LGA -% (n)	23.08% (12)	27.27%(75)	22.64% (158)	Crude: 1.29[0.94 to 1.78]; p = 0.114 Adjusted: 1.27[0.91 to 1.76]; p = 0.157	Crude:1.04[0.53 to 2.02] ;p = 0.919 Adjusted: 0.91[0.46 to 1.81];p = 0.787
Adjusted for Age, Gravida, BMI, MCV. Income. GDM = Gestational Diabetes, HbA1c –FT = HbA1c in First trimester ,LGA = Large for gestational age

Despite receiving best-practice care, GDM women had a significantly greater risk of PTB than non-GDM women (aOR 1.9) when their HbA1c FT was above 37 mmol/mol (5.5%). This risk increased markedly (aOR 3.15) among obese GDM women having higher HbA1c levels. However, early GDM care could bring these women's risk of LGA births into line with that of non-GDM women. Strikingly, in GDM women with HbA1c FT < 37 mmol/mol (5.5%), the risk for PTB was comparable to that in non-GDM women. These data imply an independent relationship between HbA1c FT and PTB in South Asian GDM women that was unaffected by glycemic management later in pregnancy. Earlier, we observed a similar association of HbA1c FT > 37 mmol/mol (5.5%) with PTB among Asian women with normal glucose tolerance in later pregnancy [23]. Several studies have shown an association between early pregnancy HbA1c levels and PTB among non-GDM women, including Hughes et al. for HbA1c > 41 mmol/mol (5.9%) before 20 GW, Bender et al. for HbA1c > 39 mmol/mol (5.7%) before 14 GW, and Iwama N et al. for an increase in PTB of 27% for every rise in HbA1c of 11mmol/mol (1%) [14, 34, 35]. Therefore, women with early hyperglycemia in the first trimester increase the risk for PTB regardless of the glycemic levels in the second and third trimesters.

Many pregnancy-related complications of later pregnancy, such as PTB and pre-eclampsia, are now regarded as originating from abnormalities in placental implantation [36]. The putative pathogenetic factor is the failure of the myometrial segment of uterine spiral arteries from small-diameter high-resistance vessels to large-diameter low-resistance conduits to perfuse chorionic villi, resulting in placental underperfusion [37]. The pattern of unfavorable events is determined by the severity of these placentation anomalies; minor defects are linked to PTB and premature rupture of amniotic membranes, whilst more severe defects result in pre-eclampsia [36]. So, based on the results of the current study, we hypothesize that a placentation abnormality may contribute to a higher risk of PTB in GDM women with higher HbA1c-FT. The seminal Hyperglycemia and Adverse Pregnancy Outcome Study found that hyperglycemia had different effects on pregnancy outcomes in early and late pregnancy; the risks of PTB, primary cesarean delivery, and pre-eclampsia were related to glycemia in early pregnancy, whereas macrosomia was related to glycemia later in pregnancy [38]. Accordingly, the higher PTB among Group A/A-Ob women in the present study can be the effect of hyperglycemia in early pregnancy, while proper glycemic control in later pregnancy might have reduced the risks for LGA babies. The shorter duration of GDM treatment in Group B women (HbA1c < 37 mmol/mol [5.5%]) may be the cause of the observed greater incidence of LGA babies in these women. (Table 3).The failure to reduce PTB in Group A/A-Ob women despite optimum GDM treatment suggests that good glycemic management later in pregnancy may not reverse the negative effects of early pregnancy hyperglycemia. There is a lack of research data on the beneficial effects of periconceptual glycemic control on the prevention of PTB. Additional randomized control trials are urgently needed to assess the benefits of glycemic control in the first trimester, particularly for pregnant South Asian women who have a high prevalence of undiagnosed prediabetes in the general population [19]. The recently published TOBOGM (Treatment of Booking Gestational Mellitus) trial looked at the benefits of starting treatment straight away for a group of GDM women who had been diagnosed before 20 GW [39]. In a subgroup analysis in this study, better composite neonatal outcomes (PTB, neonatal respiratory distress, and phototherapy were the main components) were observed when the treatment was started before 14 GW.

There are a few studies linking early pregnancy HbA1c with poor pregnancy outcomes in GDM patients. Sweeting et al found a positive correlation of HbA1c with LGA infants, macrosomia, caesarean sections, and hypertensive problems in a treated cohort of GDM women, but this association was not observed for PTB [40]. This study cannot be compared to the present study because of the variations in their research design: estimation of HbA1c during the second trimester, and using GDM women with HbA1c < 26 mmol/mol (4.5%) as the reference category. There were two small randomized control trials to assess the benefits of early initiation of treatment among pregnant women with HbA1c of 39–46 mmol/mol (5.7–6.4%) in the first trimester [41, 42]. Both studies lacked information on PTB, but they found no differences in neonatal fat mass or birthweight between the women who received early therapy and those who received standard care.

Being a retrospective data analysis, there are several limitations to this study. Due to deliveries outside our center, 20% of pregnant women could not be included in the study. However, similar percentages of delivery data were missing in several prospective studies [14, 43]. Iron deficiency and iron supplementation are known to impact the accuracy of HbA1c estimation, and the lack of data on the iron status of our study cohort is a significant limitation [44]. We added Hb and MCV as confounding variables to the multivariable analysis to lessen the impact of this missing data. The exclusion of women with hemoglobinopathy (which interferes with HbA1c calculation), the homogeneity of obstetric care for all GDM women in a single center, and the choice of non-GDM women as the control group are the strengths of this study.

Our retrospective study suggests that, despite treatment, South Asian GDM women with HbA1c FT > 37 mmol/mol (> 5.5%) are at higher risk of delivering preterm babies. On the contrary, optimal treatment could reduce the risk for LGA babies to the levels observed among non-GDM women. We speculate that hyperglycemia in the first trimester may be the trigger for a placentation defect and a higher risk for PTB. Further randomized control studies are required to prove this speculation as well as to assess the potential to prevent this adverse event by good glycemic control in the periconceptual period.

Funding: There is no funding for this research work.

Competing interests: The authors declare that they have no conflict of interest.

Author Contributions: The contribution of each author to this manuscript is given before the reference section and statement is submitted.

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Despite treatment, HbA1c > 37mmol/mol in the first trimester is associated with premature delivery among South Asian women with gestational diabetes mellitus: a retrospective cohort study

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Abstract

Figures

What does this study add to the clinical work?

Introduction

Subjects and methods

Subjects

Selection of the study cohort

Clinical data collection

Adverse pregnancy events

Laboratory Methods

Statistical Methods

Results

Discussion

Conclusions

Declarations

References

Status:

Journal Publication

Version 1