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 Table of Contents  
REVIEW ARTICLES
Year : 2021  |  Volume : 12  |  Issue : 5  |  Page : 43-51

Screening, diagnosis, and management of GDM: An update


1 Endocrinology and Diabetes Department, University Hospital of Ioannina, Ioannina, Greece; Department of Population Evidence and Technologies, Warwick Medical School, University of Warwick, Coventry, UK
2 Endocrinology and Diabetes Department, University Hospital of Ioannina, Ioannina, Greece; Endocrinology and Diabetes Department, George Eliot Hospital, Nuneaton, UK
3 Department of Population Evidence and Technologies, Warwick Medical School, University of Warwick, Coventry, UK; Endocrinology and Diabetes Department, George Eliot Hospital, Nuneaton, UK

Date of Submission27-Nov-2020
Date of Decision05-Feb-2021
Date of Acceptance10-Mar-2021
Date of Web Publication20-Jul-2021

Correspondence Address:
Prof. Ponnusamy Saravanan
Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry CV4 7AL.
UK
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jod.jod_101_20

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  Abstract 

Gestational diabetes mellitus (GDM) is characterized by an imbalance between insulin supply and resistance, resulting in maternal hyperglycemia first diagnosed during pregnancy. The increasing incidence of GDM parallels the obesity epidemic. There is no universal consensus on optimal screening and diagnostic criteria but it is widely accepted that pregnancies complicated by GDM are at high risk of short- and long-term adverse outcomes for both mother and offspring. Early intervention with lifestyle changes and medical treatment has been shown to prevent perinatal complications. At the same time, the application of clinical guidelines to real world clinical practice may be challenging as it is affected by socioeconomic diversities.

Keywords: Diabetes, gestational, management


How to cite this article:
Bagias C, Xiarchou A, Saravanan P. Screening, diagnosis, and management of GDM: An update. J Diabetol 2021;12, Suppl S1:43-51

How to cite this URL:
Bagias C, Xiarchou A, Saravanan P. Screening, diagnosis, and management of GDM: An update. J Diabetol [serial online] 2021 [cited 2021 Jul 30];12, Suppl S1:43-51. Available from: https://www.journalofdiabetology.org/text.asp?2021/12/5/43/321815




  Introduction Top


Gestational diabetes mellitus (GDM) is glucose intolerance of different degrees that is first recognized during pregnancy. The increasing incidence of GDM, which can complicate 5–25% of pregnancies depending on the diagnostic criteria used and population studied, is driven by increasing rates of obesity, which is more common in women than men.[1] Worldwide, nearly 20 million pregnancies were complicated with GDM in 2019. The South East Asian region had the highest prevalence, with 27% of the pregnancies affected by hyperglycemia.[2] Of great concern, one-third of women with prediabetes or impaired glucose tolerance are of reproductive age (19–39 years) with the potential to develop GDM in future pregnancies.[2] In the past, epidemiological studies suggested a higher burden of GDM in urban areas which could be due to either increased maternal screening or the detrimental effect of rapid urbanization on the “thrifty phenotype” model suggested by Barker.[3] However, recent data suggest that rural areas are rapidly catching up in GDM prevalence.[4]

Pregnancy is a period of “hormonal challenges” for the human body. Placental hormones, such as estradiol, progesterone, and placental lactogen promote insulin resistance in order to secure adequate nutritional supply to the growing fetus.[5] GDM develops when maternal pancreatic insulin supply is not adequate to counterbalance insulin resistance and regulate the degree of hyperglycemia. Β-cell dysfunction, occurring on a background of preexisting chronic insulin resistance (obesity, ethnicity, and polycystic ovarian syndrome [PCOS]) or caused by autoimmune or monogenic mechanisms, is the major contributing factor.[6]


  Diagnosis of Gestational Diabetes Top


There is no consensus on the optimal screening and diagnostic criteria of GDM. Despite extensive research, guidelines vary globally and are adjusted according to infrastructure, cost-effectiveness, and patients’ needs.[7] When and how to screen for GDM, universal versus selective screening is still question to be answered [Table 1].
Table 1: Screening and diagnostic criteria for GDM

Click here to view


Diagnostic criteria and therapeutic approach of pregnancies complicated by GDM aimed to reduce perinatal outcomes and identify women at risk for type 2 diabetes mellitus. The HAPO study revealed a continuous association among maternal glucose, adverse perinatal outcomes, and neonatal adiposity without any clear “cut-off.”[8] Recent data, highlighting the association between GDM and childhood adverse metabolism, add further to the need of amending our approach in order to reduce the risk of future obesity for the offspring.[9] The International Association of the Diabetes and Pregnancy Study Groups (IADSPG) suggested thresholds for the diagnosis of GDM and overt diabetes at first as well as third trimesters (24–28 weeks of gestation).[10] There has been a lot of debate and controversial evidence regarding the low fasting plasma glucose cut-off of 92 mg/dL (5.1 mmol/L)[11],[12] but general consensus to the 24–28 weeks criteria. World Health Organization (WHO), Endocrine Society, the Australian Diabetes in Pregnancy Society (ADIPS), the International Federation of Gynecology and Obstetrics (FIGO), the European Association for the Study of Diabetes (EASD), and the European Board and College of Obstetrics and Gynecology (EBCOG) have accepted 2-h 75 g oral glucose tolerance test (OGTT) at 24–28 weeks of gestation as the optimal screening test for GDM. In 2015, National Institute of Clinical Excellence (NICE) published guidelines based on cost-effectiveness studies using health economic analysis. NICE guidelines recommend risk-based screening with higher fasting and lower 2-h diagnostic thresholds.[13]

Current screening recommendations are based on observational studies with no evidence that using these diagnostic “cut-off points” improves long-term adverse outcomes. Furthermore, unique ethnic characteristics, financial resources, and infrastructure put the generalizability of these guidelines into question. South Asians are known to have higher body fat content and lower muscle mass for a given body weight/body mass index (BMI) compared with White Europeans,[14] a phenotype which is present even at birth.[15],[16] The “Born in Bradford” study identified lower maternal glucose thresholds that equated to infant adiposity for South Asian compared with white British women, suggesting that ethnic specific criterion is needed for the diagnosis of GDM.[17] The study also noted that universal screening in high-risk groups (socioeconomic deprivation, ethnic minorities) identified more cases of mild/moderate hyperglycemia, resulting in lower neonatal complications (macrosomia, intensive care admissions, mortality).[18] The Government of India, after taking into consideration the ethnic diversity of the country and the variability in living conditions between rural and urban areas, published technical guidelines to address maternal and offspring morbidity associated with GDM.[19] The panel recommended universal screening with “one step approach” at two time points using a 75-g (fasting or non-fasting) OGTT and a threshold value of 2-h capillary blood glucose >140 mg/dL (7.8 mmol/L). However, evidence from the Women in India with GDM Strategy (WINGS) program questions the reliability of this approach. After analyzing data from 1000 pregnancies, Bhavadharini et al.[20] showed that a capillary glucose cut point of 140 mg/dL has low sensitivity for diagnosing GDM, whereas lower thresholds (120 mg/dL) provide higher true positive rates. Participants from the same cohort underwent OGTT at both fasting and non-fasting states, 2–3 days apart.[21] Applying non-fasting OGTT criteria failed to diagnose a significant number of GDM cases when compared with reference criteria (WHO 1999, IADPSG). The authors concluded that capillary blood glucose should be used only as a screening tool to identify high-risk groups, and venous blood glucose should remain the “gold standard” diagnostic tool during OGTT. They also proposed that if fasting OGTT is not feasible due to logistic difficulties, a “two-step” approach with 50-g glucose challenge test should be performed.


  Gestational Diabetes Consequences Top


In 1920, Jorgen Pedersen formulated the hypothesis which states that “Maternal hyperglycaemia results in fetal hyperglycaemia and hence in hypertrophy of fetal islet cells with insulin hypersecretion, leading to greater fetal utilization of insulin.”[22] The intrauterine hyperglycemic state is toxic for mother and fetus, resulting in short- and long-term adverse outcomes.

Poor glycemic control in pregnancies complicated by diabetes increases the risk of maternal urinary tract, wound, and endometrial infections.[23] The incidence of hypertension and preeclampsia is also higher in women with GDM.[24] The exact mechanism is not well described but insulin resistance seems to be one of the main contributing factors. GDM diagnosis and management leads to reduced threshold for cesarean section (CS) as preferred method of delivery, independent of birth weight.[25] Furthermore, the association of GDM with increased risk of stillbirth and excessive fetal growth during the latest stages of pregnancy has led clinical practice to earlier induction of labor.[26] In the long term, mothers who develop GDM have at least 10 times higher risk of developing type 2 diabetes in future,[27] with the incidence being higher during the first 5 years and are twice as likely to develop hypertension and coronary artery disease.[28] They are also at risk of diabetes recurrence in subsequent pregnancies, with three out of five pregnancies complicated by maternal hyperglycemia.

Fetal exposure to hyperglycemia during the first trimester is related to cardiac, neural, gastrointestinal, and genitourinary malformations.[29] Chronic maternal hyperglycemia leads to glycosylation of hemoglobin, reducing its capacity to carry oxygen. If the fetal adoptive mechanisms are not enough to counterbalance the hypoxemia, anaerobic metabolism promotes lactate production and acidemia, resulting in intrauterine death. Fetal hyperinsulinemia has detrimental effects on lung maturation and infant anthropometry. The hyperinsulinemic environment inhibits cortisol and surfactant protein A/B production leading to neonatal respiratory distress syndrome.[30] The anabolic effect of insulin results into fetal macrosomia which in turn increases the risk of perinatal complications such as shoulder dystocia, Erb’s palsy, and birth asphyxia.[31] GDM is related not only to adverse neonatal size but also to altered body composition. Studies using direct methods of adiposity showed that neonates of pregnancies complicated by GDM have higher percentage of fat mass at birth.[32],[33] Venkataraman et al.[34] after assessing sonographic data from GDM pregnancies in India highlighted that GDM fetuses had increased anterior abdominal wall thickness even at 20 weeks of gestation (even before GDM was diagnosed), with findings persisting to 32 weeks, irrespective of GDM treatment. The above observations imply that genetics, epigenetics, and intrauterine exposure to fuels other than glucose (e.g. lipids) may adversely program offspring metabolic trajectories during the early stages of pregnancy.

There is accumulating evidence of the developmental origin of diseases, with incidents occurring during intrauterine or early postnatal life having long-lasting effects on the offspring.[35] Gestational diabetes is linked to future obesity and metabolic dysfunction.[36] Exposure to diabetes in pregnancy is related to increased BMI, total, and abdominal adiposity in childhood and adolescence.[37],[38] Visceral fat is one of the strongest predictors in the development of metabolic syndrome.[39] Follow-up studies from the HAPO cohort have confirmed that maternal hyperglycemia is linked to impaired fasting glucose, impaired glucose tolerance, raised HbA1c, and reduced insulin sensitivity by the age of 14 years.[40] This adverse metabolic profile is also present in adulthood with adults exposed to GDM having two and four times higher risk for overweight and metabolic syndrome, respectively.[41]


  Management of GDM Top


Self-care is of vital importance in the management of GDM. As soon as the diagnosis is formed, information and education to the patient in order to facilitate self-care should be provided, and the effects of diabetes in pregnancy should be explained. Lifestyle changes are the most important interventions in GDM treatment, as they provide adequate control in the majority of cases. Pregnant women are advised to follow a balanced diet tailored to their needs. Low glycemic index foods and restriction of carbohydrates to 40% of the daily caloric intake are general recommendations.[13] Gestational weight gain should be based on the early pregnancy weight, as per the Institute of Medicine (IOM) guidelines.[42] In the GDM group, target should be set 10% lower from the recommended weight gain in normal pregnancy, although it is probably safe to restrict the overall weight gain to less than 5 kg in extremely obese women.[43],[44] However, in general, maternal starvation and weight loss are not recommended, as they can cause fetal malnutrition and intrauterine growth retardation.[45] Regular exercise is beneficial in GDM by increasing insulin sensitivity and glucose absorption by the skeletal muscles. Pregnant women are advised to have 150 min of mild-to-moderate exercise per week. Self-monitoring of capillary blood glucose provides data on adequate glycemic control but may also address the need to escalate medical care. Expert committees unanimously suggest daily monitoring of fasting and 1 or 2 h postprandial glucose values with a target to maintain levels below 95 (5.3 mmol/L), 140 (7.8 mmol/L), and 115 mg/dL (6.4 mmol/L), respectively.[13],[46],[47] National guidelines in India suggest more infrequent glucose monitoring, presumably taking into consideration the feasibility and economical aspects of more frequent monitoring recommended by NICE and American Diabetes Association.[19]

When treatment targets are not achieved with lifestyle changes, a medical approach is required. Injectable insulin and oral antidiabetic agents are the available options. When administering drugs during pregnancy, safety of both mother and fetus should be considered, and benefits should outweigh any potential risks.

Insulin treatment is globally considered the safest option for GDM treatment with an immediate effect on maternal glycemia. Human insulins do not cross the placenta and are not related to fetal complications.[48] Insulin treatment can lead to tight glycemic control, but caution is required to avoid hypoglycemic episodes as they are related to growth and developmental deficits. Recurrent episodes in the third trimester may be an indication of placental insufficiency.[49] Insulin treatment also results in more maternal weight gain than metformin.[50]

Currently, there are two oral agents licensed in the treatment of GDM. Glibenclamide is a second generation sulfonylurea that increases insulin release from the pancreatic β-cells. It differs from the other sulfonylureas in the high protein binding (99.8%) and short elimination half-life, resulting in very low transplacental transport.[51],[52],[53] All published data up to date agree that glibenclamide is not inferior to insulin treatment in achieving desired glycemic control. Controversy remains regarding the safety profile for the fetus. A meta-analysis[54] showed no difference in macrosomia, birth weight, large for gestational age, and neonatal hypoglycemia compared with insulin. In contrast, Balsells et al.[55] comparing glibenclamide to metformin and insulin revealed higher incidence of neonatal hypoglycemia and macrosomia in the glibenclamide group.

Metformin belongs to the biguanide class. It inhibits hepatic gluconeogenesis and increases insulin sensitivity in peripheral tissues. It is well described that metformin crosses the placental barrier exposing the fetus to levels similar to maternal circulation.[56] Randomized controlled trials (RCTs) with insulin revealed higher rates of preterm births and less maternal weight gain in the metformin group. Neonatal anthropometrics were similar between treatment arms.[50] Metformin is better received by patients but is associated with increased treatment failure rates, with the majority of mothers requiring the addition of insulin to achieve normoglycemia.[55] The increased transplacental transport of metformin should be considered with caution, as intrauterine programming and developmental effects on fetus have not been studied extensively. However, follow-up studies from the “Metformin in Gestational Diabetes” (MiG) cohort up to 9 years of age have not revealed any differences in BMI, body composition, metabolic health markers, and neurodevelopmental progress between the two groups.[57],[58] Similar results were presented from RCTs in pregnant mothers with PCOS. Metformin treatment during pregnancy did not affect motor social development in infancy and did not alter offspring’s body composition at 9 years of age when compared with the control group.[59],[60]

There is no universal consensus on which medical approach should be used when lifestyle interventions fail to achieve normoglycemia. Expert committees from England,[13] Scotland,[61] and New Zealand[62] recommend oral antidiabetics as first-line pharmacological treatment, whereas the Canadian[63] and American Associations[47] state that metformin and/or glibenclamide should be used only to women who are not adherent or refuse insulin following explanation of the “off-label use.” FIGO[46] and GoI[19] consider insulin and oral antidiabetics as safe and efficient options in the management of GDM after 20 weeks of pregnancy, but recommend insulin as first-line treatment in the management of hyperglycemia during first trimester due to the high risk of failing therapy on oral agents.

Convincing evidence suggests that treatment of GDM improves neonatal outcomes. Two RCTs comparing the effect of standard antenatal care (control) versus intensified treatment with diet, exercise, and insulin (intervention) in cases of mild GDM revealed that the later approach resulted in lower birth weight and macrosomia, lower neonatal fat mass, and lower incidence of CS and shoulder dystocia.[31],[64] Whether benefits persist beyond infancy is yet to be identified.[65],[66] A recent RCT in women with type 2 diabetes showed that metformin-treated women gain less weight, better glycemia, lower rates of CS rates, and gave birth to offspring with lower weight and lower adiposity.[67] These evidences reduce the concern about the long-term potential theoretical adverse effects to the offspring and encourage wider use of metformin in women with GDM.


  Antenatal Care Top


Antenatal care models should aim to reduce perinatal mortality, identify medical conditions related to GDM (e.g. preeclampsia), and improve women’s experience of care. Multidisciplinary approach is required to each antenatal visit to ensure both maternal and fetal well-being [Table 2].
Table 2: Antenatal and intrapartum care

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In women diagnosed with GDM before 20 weeks of pregnancy, a detailed fetal anatomy scan, including cardiac assessment, should be performed between 18 and 20 weeks. As soon as the diagnosis of GDM is established, women should attend antenatal clinics every 2 weeks or at least once monthly. Each visit should address lifestyle interventions, glycemic control, maternal blood pressure, proteinuria, and other obstetric complications. Growth scan should be performed at 28 weeks of pregnancy and repeated every 4 weeks. If fetal macrosomia or polyhydramnios is present, growth scan intervals should be reduced to 2 weeks. Pregnancies complicated by GDM are at higher risk of stillbirth between 36 and 39 weeks, with a relative risk ranging from 1.45 to 1.84[68]; therefore, fetal heart rate recording is recommended three times per week for medically treated pregnancies. Daily Fetal Activity Assessment (fetus should kick at least 10 times within 2 h after a meal) is an alternative when medical resources and access to assessment units are not available.

All women at risk of vaginal delivery between 24 and 36 weeks of gestation or elective CS before 39 weeks of gestation should have steroids to ensure fetal lung maturity.[13],[19] Two doses of betamethasone 6 mg, given intramuscularly, 12 h apart is the steroid regimen of choice. Glucose levels are expected to rise up to 5 days after the second steroid dose[69] and insulin requirements to increase by 40% within the first 2 days.[70] There is no consensus on how to maintain normoglycemia, and practices differ depending upon resources and individual preferences. Variable rate intravenous insulin infusion (VRIII) provides flexibility and more effective glucose control at the cost of intensive monitoring and patient’s inconvenience.[71] In contrast, incremental adjustments of subcutaneous insulin by 20–40% combined with vigilant monitoring do not require hospitalization but may not be as effective in controlling glucose levels.[72]


  Intrapartum Care Top


The association of GDM with increased risk of stillbirth and excessive fetal growth[68],[73] during the latest stages of pregnancy (>38 weeks of gestation) has led clinical practice to earlier induction of labor.[74] Benefits of this approach always need to be weighed against the possibility of higher rate of CS, maternal infection, neonatal mortality, and morbidity.[26] GDM by itself is not an indication for CS, and mode of delivery should be a shared decision between a clinician and mother. Specific conditions such as macrosomia, fetal distress, and risk of intrauterine death are factors leading to abdominal delivery.[75] There is global consensus that the mode and timing of delivery should be individualized and based on maternal or fetal complications. In general, pregnancies in which glycemic control is achieved only through diet should be allowed up to 41 weeks of gestation, provided that fetal growth is normal. Medically treated cases, without maternal or fetal complications, should be induced no later than 39–40 weeks of gestation. Poorly controlled maternal diabetes or fetal macrosomia is indication for earlier induction of labor at 38 weeks. In cases of fetal macrosomia, mothers should be informed about the risks of vaginal versus elective abdominal delivery.

There is no strong evidence in the current literature to set glycemic targets during labor and delivery. The majority of studies[71] suggest that maintaining maternal levels between 70 and 126 mg/dL (4–7 mmol/L) reduces the incidence of neonatal hypoglycemia. Expert panels recommend hourly capillary glucose monitoring during labor and birth and initiation of VRIII when levels are above target range [Table 3].[19],[71]
Table 3: Suggested insulin infusion algorithm during labor

Click here to view



  Neonatal Care Top


Tight glycemic control during labor may not be enough to prevent neonatal hypoglycemia, defined as capillary glucose level <45 mg/dL (2.5 mmol/l). Poorly controlled diabetes during pregnancy may lead to hyperplasia of the fetal pancreas, resulting in persistent hyperinsulinemia during the immediate neonatal period. Current guidelines emphasize the need of early feeding and tight glucose monitoring in order to prevent hypoglycemia. Infants should be fed within the first 30 min after birth and at 2–3 hourly intervals thereafter, aiming to maintain a prefeed capillary glucose level >35 mg/dL (2 mmol/L) at four consecutive glucose readings. Infants who remain hypoglycemic despite maximal feeding support should be considered for enteral tube feeding or intravenous glucose infusion.[13],[19]


  Postpartum Care Top


Glucose lowering therapy should be discontinued immediately after birth. Breastfeeding should be encouraged given the beneficial effect of breast milk on infectious and non-communicable diseases.[76],[77] All women diagnosed with GDM should be informed about the increased risk of developing type 2 diabetes and GDM in subsequent pregnancies.[27] Postnatal testing should be performed at 6 weeks postpartum and at regular intervals (ideally yearly) thereafter. The method of postnatal testing varies between different guidelines and can be a fasting glucose sample, an HbA1c, or a 75-g OGTT.[78] In each case, non-pregnancy “cut offs” should be used for the diagnosis of GDM.

Of great concern, despite the vital importance of postpartum follow-up, screening rates remain low, ranging between 15% (usual care) and 60% (studies).[79] Patient and healthcare provider-related barriers contribute equally to this poor postpartum screening uptake. Emotional stress of motherhood, breastfeeding, and unawareness of GDM-related risks have been associated with poor compliance, whereas maternal age, socioeconomic and educational status, and mode of treatment during gestation have been cited as predictors of follow-up rates. In contrast, with public health systems under constant pressure, healthcare professionals are unable to spend enough time educating patients on the impact of GDM on future life. In addition, lack of universally accepted protocols leads to uncertainty and miscommunication between delivery units and primary care providers.[78]

The necessity of adhering to postpartum screening is further supported by the fact that South Asians develop diabetes mellitus during the early postnatal period. Observational studies demonstrate that 53% of women will develop glucose intolerance by 1 year of delivery.[80] Interestingly, dysglycemia is present in one-third of this population by 12 weeks postpartum, with maternal BMI, HbA1c at booking visit, and history of previous GDM being the strongest predictors of future metabolic disorders.[81] The above emphasizes the importance of early screening but also highlights the need for annual review even if the initial postnatal screening is negative. In this regard, proactive care including patient education via consultations or information booklets, phone/text/email reminders, and communication protocols between obstetricians and primary care physicians may facilitate the bridging between antenatal and postnatal care and lead to higher follow-up rates.[81]

A pregnancy complicated by GDM should not be considered as a catastrophic event for maternal and offspring metabolism but as a chance to improve maternal health for consequent pregnancies. Therefore, lifestyle interventions and follow-up care should be implemented in the immediate postnatal period. There is global consensus that the risk of future diabetes minimizes with lifestyle changes. Normalization of BMI through healthy diet and graded physical activity is the cornerstone in the prevention of future diabetes. GDM mothers should adhere to postpartum diet with energy deficit of 500–1000 calories/day in order to achieve weight loss of 0.5–1 kg/week. Graded activity of 30 min for 5 days/week is strongly advised. Aerobic exercises such as brisk walking, yoga, and swimming combined with strength training with light weights and elastic bands are also recommended.

Financial support and sponsorship

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Conflicts of interest

The authors have no conflicts of interest to declare.



 
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Introduction
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Management of GDM
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