Vous êtes sur la page 1sur 9

Seminar

Gestational diabetes: the need for a common ground


E Albert Reece, Gustavo Leguizamn, Arnon Wiznitzer

Gestational diabetes mellitus is a substantial and growing health concern in many parts of the world. Certain populations are especially vulnerable to developing this condition because of genetic, social, and environmental factors. Gestational diabetes has serious, long-term consequences for both baby and mother, including a predisposition to obesity, metabolic syndrome, and diabetes later in life. Early detection and intervention can greatly improve outcomes for women with this condition and their babies. Unfortunately, screening and diagnostic tests are not uniform worldwide, which could lead not only to underdiagnosis but also undermanagement of the illness. Here, we report the controversies surrounding the causes, screening, diagnosis, management, and prevention of gestational diabetes, and give specic recommendations for research studies to address the major issues of this medical condition.

Lancet 2009; 373: 178997 See Editorial page 1735 University of Maryland School of Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, Baltimore, MD, USA (Prof E A Reece MD); Center for Medical Education and Clinical Research, CEMIC University, Department of Obstetrics and Gynecology, Buenos Aires, Argentina (G Leguizamn MD); and Department of Obstetrics and Gynecology, Faculty of Health Sciences, Soroka University Medical Centre, Ben-Gurion University of the Negev, Israel (A Wiznitzer MD) Correspondence to: Prof E Albert Reece, University of Maryland School of Medicine, 655 W Baltimore Street, Room 14-029, Baltimore, MD 21201-1559, USA deanmed@som.umaryland.edu

Introduction
Gestational diabetes mellitus is characterised by glucose intolerance of variable severity that begins or is rst diagnosed during pregnancy and usually resolves not long after delivery.1 Documenting resolution of the condition after birth is crucial because many pregnant women with previously undiagnosed type 2 diabetes are often mistakenly diagnosed as having gestational diabetes.2 Although this medical condition has previously been regarded as benign,3 some studies have recently found increased perinatal morbidity associated with hyperglycaemia during pregnancy. Fortunately, these complications seem to be lessened by better detection and management of this condition,4,5 which are however hampered by disagreement on many aspects of its diagnosis and treatment. Here, we discuss the epidemiology, pathophysiology, screening, and diagnosis of gestational diabetes. We also examine the available technologies and approaches for the management of this condition and their relative ecacies, and make recommendations about research needed to address controversies.

Epidemiology
Diabetes mellitus and less serious forms of glucose intolerance are widespread in almost every population in the world.6 However, an accurate estimation of the global incidence of gestational diabetes in many countries does not exist because of the lack of uniform standards in glucose tolerance testing around the world.7 In 2000, about 171 million people worldwide had some form of diabetes. By 2030, an estimated 361 million people will be aected by this condition.6 Gestational
Search strategy and selection criteria We searched the PubMed and Cochrane databases with the search terms gestational and diabetes for clinical trials, review articles, and best-practice guidelines published in all languages between 2005 and 2008. We also searched references listed in articles identied by our search strategy, and selected those we judged as relevant. Some older articles (reviews and clinical trials) are cited to give readers additional context. Reviewers suggested some additional studies.

diabetes is more frequent in certain ethnic groups than in the general population. For example, the frequency of gestational diabetes was measured in 11 205 women consecutively attending a multiracial antenatal clinic in UK, and 04% white, 15% African, 3573% Asian, 44% Indian, and about 14% mixed-origin women were shown to have gestational diabetes.8 The rate of gestational diabetes was also shown to be 510 times higher in pregnant Asian women than in white women.9 Additionally, in an ethnic mixed population of women with diabetes entering a prenatal care programme in the USA, African American women had signicantly poorer glycaemic control than did other racial groups.10 The increasing incidence of gestational diabetes can be halted or at least slowed. This condition is most widespread in the USA with as many as 200 000 women, or 10%, of pregnancies being complicated by the illness every year.11 Although the frequency of occurrence of pre-existing diabetes in pregnancy has increased rapidly in the USA over the past decade (gure 1), that of gestational diabetes has remained relatively stable since the late 1990s,11 and the reasons for this are still not fully understood. However, a high rate of screening nationwide seems to be at least partly responsible.11 Many women who are rst diagnosed with diabetes mellitus during pregnancy are classied as having gestational diabetes even though they have pre-existing, or pregestational, diabetes that had gone undiagnosed. This distinction is crucial because pregestational diabetes is associated with more serious consequences for the fetus than is diabetes in the second and third trimester of pregnancy.12 Women with pregestational diabetes who become pregnant are at increased risk of giving birth to a baby with a serious birth defect, including cardiac,13 neurological,14 and vascular anomalies.15

Pathophysiology
Increase in the concentration of pregnancy hormones including oestrogens and progestinsleads to lower fasting glucose concentrations and deposition of fat, delay in gastric emptying, and increased appetite. As gestation progresses, however, postprandial glucose concentrations steadily increase as tissue sensitivity to insulin decreases.16
1789

www.thelancet.com Vol 373 May 23, 2009

Seminar

To maintain proper glucose control in pregnancy, pancreatic cells of the mother have to increase insulin secretion enough to counteract the corresponding fall in tissue sensitivity to insulin. For some reason, pregnant women who develop gestational diabetes are unable to increase insulin production to compensate for their increased resistance to insulin. Post-receptor defects in the insulin-signalling cascade seem to be implicated in the development of insulin resistance. The downregulation of the insulin receptor substrate-1 (IRS-1) might contribute to decreased insulin-mediated glucose uptake in the skeletal muscle.17 Patients with gestational diabetes also present with a reduced ability of the insulin receptor B to undergo tyrosine phosphorylation.18 Investigators have suggested that pregnancy triggers a series of metabolic imbalances that lead to a diabetic state in some women who are already genetically predisposed to develop diabetes (gure 2). Some naturally occurring genetic variations are associated with a greater risk of developing this condition.19,20 66 genes are upregulated in placental cells of women with gestational diabetes.21 These genes participate in several cell functions, including cell activation, immune response, organ development, and regulation of cell death.

Fetal eects
Glucose travels freely from the mother to the fetus, but maternal insulin does not. Thus, maternal gestational diabetes exposes the fetus to higher concentrations of glucose than normal, which force the fetus to increase
18 16 14
Diabetes cases (millions)

12 10 8 6 4 2 0

1980

1982 1984 1986 1988 1990

1992 1994 1996 1998 2000 Year

2002

2004 2006

Figure : Number of diabetes cases from 1980 to 2006 in the USA Data from Centers for Disease Control and Prevention, National Center for Health Statistics, Division of Health Interview Statistics. Data were computed by the Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Division of Diabetes Translation.

its own insulin production. Unfortunately, excess insulin produced by the fetus in response to the mothers gestational diabetes can cause the fetus to grow excessively, a condition known as large for gestational age. A fetus with a birthweight exceeding 40004500 g is referred to as macrosomic. Mean glucose concentration is strongly associated with neonatal birthweight in women with gestational diabetes.22 Furthermore, increased insulin concentration in both fetal blood23 and amniotic uid24 correlates with an increased rate of occurrence of fetal macrosomia. To assess the contribution of maternal carbohydrate metabolism to fetal growth, Catalano and colleagues25 measured the eect of maternal metabolism, parental demographic and morphometric measures, neonate sex, and gestational age on placental weight, neonatal birthweight, and newborn body composition. Insulin sensitivity in late gestation had the strongest correlation with placental weight (R=028), neonatal birthweight (R=028), and fat-free mass (R=033). Large-for-gestational-age fetuses have an increased risk of injury, such as shoulder dystocia and newborn asphyxia, during vaginal birth delivery.26,27 Therefore, a caesarean section is often the preferred way to deliver a large-for-gestational-age baby, even though it can lead to increased trauma to the mother. Fetuses exposed to a high glucose environment have other medical complications after delivery, including infant respiratory distress syndrome, cardiomyopathy, hypoglycaemia, hypocalcaemia, hypomagnesaemia, polycythaemia, and hyperviscosity.28 Robust evidence linking mild hyperglycaemia and adverse perinatal outcomes has been lacking. However, the hyperglycaemia and adverse pregnancy outcome (HAPO) study,29 which investigated about 25 000 pregnant women in 15 centres, found that even subclinical hyperglycaemia was signicantly and dose-dependently associated with large-for-gestational-age births and increased cord-blood serum C-peptide concentrations. The HAPO study also showed a weaker but still signicant association between neonatal hypoglycaemia and primary caesarean delivery. Clausen and colleagues30 found that a hyperglycaemic intrauterine environment signicantly increases the probability of developing type 2 diabetes in adult ospring of white women with either diet-treated gestational diabetes or type 1 diabetes during pregnancy. After birth, the high glucose environment disappears in infants, but they often have life-long increased risk of glucose intolerance and obesity. Yogev and Visser31 showed that gestational diabetes is associated with increased risk of early obesity, type 2 diabetes during adolescence, and development of metabolic syndrome in early childhood. Additionally, this condition is a marker for the development of overt type 2 diabetes and metabolic syndrome for the mother in the near term. Children born to mothers with gestational diabetes have nearly double the risk of developing childhood
www.thelancet.com Vol 373 May 23, 2009

1790

Seminar

obesity, metabolic syndrome, or both, compared with children born to non-diabetic mothers.32 Pima Indians, a group of Native Americans residing in the western part of the USA and northwest Mexico, have one of the highest rates of gestational diabetes in the world. Research in Pima Indians has shown that diabetes during pregnancy is a major risk factor for type 2 diabetes and hyperglycaemia in the ospring. Children of Pima Indian women who had diabetes during pregnancy were more obese and had a signicantly higher prevalence of type 2 diabetes at 2534 years of age than children born to Pima women without diabetes.33 Exposure to hyperglycaemia in utero led to the development of type 2 diabetes in 40% of children (519 years old) of Pima Indian women. More than two thirds (70%) of Pima Indians between 25 and 34 years of age with prenatal hyperglycaemia exposure developed type 2 diabetes later in life.

Genetic vulnerability

Demographic characteristics Age Sex Education Knowledge/intelligence

Behavioural factors Diet and exercise Obesity Stress and coping Substance abuse

Incidence of diabetes and course of the disease Complications Comorbid disease Disability

Psychological factors Social group eects Culture Ethnicity Economic status Attitudes Depression Cognition

Clinical factors Timely diagnosis and treatment Quality of care Regimen adherence

Maternal eects
The main maternal eect of gestational diabetes is a higher long-term risk for developing metabolic syndrome and type 2 diabetes. A review of the literature has shown that women with a history of gestational diabetes and obesity (and their children) have a signicantly greater risk of developing a metabolic syndrome than mothers (and their children) with no history of gestational diabetes or obesity.34 In the ospring, the increased risk of metabolic syndrome increased with age. In a multicentre study in France,35 investigators assessed long-term outcomes in healthy women (n=221), women with abnormal glucose tolerance during pregnancy (n=322), and women with gestational diabetes (n=466). The main predictors for women to develop type 2 diabetes were gestational diabetes, medical history of hypertension, being 33 years or older at delivery, a family history of diabetes, fasting glucose concentration during pregnancy of 55 mmol/L or more, and severity of hyperglycaemia during pregnancy.

Figure : Factors that might contribute to the development of gestational diabetes in genetically vulnerable individuals Reproduced, with permission, from the Weld County Colorado Health Departments Diabetes Project.

of about 97 000 singleton births,40 obese women had a 3-fold increased risk of developing gestational diabetes than non-obese women. Not only obese (body-mass index [BMI] >30) but also overweight women (BMI 2529) have a greatly increased risk of developing gestational diabetes. Comparison of pregnancy complications and outcomes between obese and non-obese women shows a rate of gestational diabetes of 245% for obese versus 22% for non-obese women.41 The rate of obesity is rising dramatically worldwide,42 consequently increasing the rate of gestational diabetes.

Screening and diagnostic tests


Screening for gestational diabetes enables identication of risk factors. Furthermore, most clinicians in developed countries recommend a blood test, known as oral glucose tolerance test, between 24 and 28 weeks of pregnancy, or earlier if a woman is at high risk for developing the disease. Glucose tolerance testing is usually done by giving a pregnant woman a drink containing 50 g of glucose 1 h before a blood glucose measurement is taken. After 1 h, a normal blood glucose concentration is anything below 130140 mg/dL (7278 mmol/L) on a 50-g oral glucose tolerance test. The 1 h oral glucose tolerance test can identify potential cases of diabetes in various populations.43,44 However, in many developed countries, women with a positive 50 g oral glucose tolerance test receive a more invasive follow-up diagnostic test to avoid false-positive results, which is typically a 100 g, 3 h oral glucose tolerance test. Some investigators have reported that
1791

Risk factors
Women with a history of gestational diabetes have also increased risk of developing gestational diabetes in subsequent pregnancies.36 The delivery of a macrosomic infant or a suspected glucose intolerance test in a previous pregnancy are also risk factors for gestational diabetes. Other risk factors include glucosuria, a strong rst-degree family history of type 2 diabetes or gestational diabetes, or a history of unexplained fetal demise.37 The frequency of gestational diabetes is 710 times higher in pregnant women older than 24 years of age than in those younger than 24,38 suggesting that universal screening is most eective in the older group.39 Obesity also is strongly linked to the development of gestational diabetes. In a population-base cohort study
www.thelancet.com Vol 373 May 23, 2009

Seminar

even a single abnormal test is associated with mild glucose intolerance later on.45,46 However, the diagnosis of gestational diabetes usually requires at least two abnormal values in this test.47 The 100 g, 3 h oral glucose tolerance test has been the gold standard for diagnosing gestational diabetes for many years in North America. However, this two-step approach to diagnosis (table), which has a reported reproducibility of about 78%,49 is expensive to administer and, therefore, not practical in many developing countries. The WHO recommends a one-step, 75 g oral glucose tolerance test50 in the developing world. The results of the HAPO study support the usefulness of
Plasma glucose concentration cuto (mmol/L) Screening test 50 g, 1 h screening Diagnostic test 100 g, 3 h OGTT Fasting 1h 2h 3h 53 100 86 78 7278

OGTT=oral glucose tolerance test. Cuto values were taken from reference 48.

Table: Screening and diagnostic tests

Panel: Screening strategy for detection of gestational diabetes Risk assessment of gestational diabetes should be ascertained at the rst prenatal visit Low risk: blood glucose testing not routinely required if all of the following characteristics are present: Member of an ethnic group with a low prevalence of gestational diabetes No known diabetes in rst-degree relatives Age <25 years old Weight normal before pregnancy Weight normal at birth No history of abnormal glucose metabolism No history of poor obstetric outcome Average risk: do blood glucose testing at weeks gestation using either: Two-step procedure: 50-g glucose challenge test followed by a diagnostic oral glucose tolerance test in those meeting the threshold value in the glucose challenge test One-step procedure: diagnostic oral glucose tolerance test done in all individuals High risk: do blood glucose testing as soon as possible, using the procedures described above if one or more of these are present: Severe obesity Strong family history of type 2 diabetes Previous history of: gestational diabetes, impaired glucose metabolism, or glucosuria If gestational diabetes is not diagnosed, blood glucose testing should be repeated at 2428 weeks gestation or at any time a patient has symptoms or signs that are suggestive of hyperglycaemia.
Reproduced, with permission, with minor modications from Metzger and colleagues.48

the one-step, 75 g screening approach for detecting gestational diabetes in the general population.29,51,52 The panel shows a screening strategy for gestational diabetes based on a one-step or two-step approach. The usefulness of the WHO one-step screening approach for gestational diabetes in a group of more than 1600 pregnant women has recently been assessed:53 this approach showed an acceptable sensitivity rate of 85% and could rule out gestational diabetes in more than two-thirds of women. Fasting blood glucose and random blood glucose tests are becoming popular because they are easy to do and do not cause major inconvenience to the patient. Unfortunately, reproducibility, sensitivity, and specicity of these tests are not proven.54 Although some evidence exists that the measurement of fasting glucose can reliably detect gestational diabetes, some patients were later found to have gestational diabetes but had high blood glucose only after a meal, with normal fasting concentrations.55 Other commonly available screening tests include glycosylated haemoglobin, capillary blood glucose measurement with a haemocue, breakfast tests, lunch tests, glycosuria, blood fructosamine, and the fetal abdominal circumference. However, all these tests have weak sensitivity and are not recommended in most cases.5659 A study has shown that women younger than 25 years old and without high risk factors for gestational diabetes have a very low risk of developing this condition at a later stage and, ultimately, do not need follow-up diagnostic tests.60 However, in another study, certain risk factors, such as obesity, a rst-degree relative with type 2 diabetes, history of gestational diabetes or macrosomia, advanced maternal age, non-white ethnic origin, and any poor obstetric outcome, were all high-risk indicators for developing gestational diabetes, and these women needed further diagnostic testing.61 Despite evidence that risk-factor screening is eective in the detection of women who could develop gestational diabetes, it is nevertheless controversial. One review of the literature has shown that screening tests are not very eective in detecting gestational diabetes: their positive likelihood ratio of screening for risk factors is only 175.62 Therefore, women who are deemed only by risk-factor screening to be likely to develop gestational diabetes have only a minimally increased likelihood of developing the disease. The North American diabetes in pregnancy study group and the Canadian Diabetes Association recommend universal screening for all pregnant women. The American Diabetes Association (ADA) and the British Diabetic Association recommend selective, risk-related screening. As previously mentioned, rates of gestational diabetes are so low in some populations that universal screening might not be cost eective.63,64 Diagnosis of gestational diabetes is controversial, with dierent international bodies issuing slightly dierent
www.thelancet.com Vol 373 May 23, 2009

1792

Seminar

recommendations. Shirazian and colleagues65 recently compared the dierent diagnostic criteria for gestational diabetes proposed by various international organisationsincluding ADA, WHO, and the Australian Diabetes in Pregnancy Society (ADIPS)in a group of 670 pregnant women diagnosed with a 75 g, 2 h oral glucose tolerance test. The investigators diagnosed gestational diabetes in 41 (61%), 81 (121%), and 126 (188%) women on the basis of ADA, WHO, and ADIPS criteria, respectively. Women who were gestational-diabetes positive only on the basis of WHO criteria had lower fasting plasma glucose concentration (49 vs 57 mmol/L; p<00001) and 1 h plasma glucose concentration (81 vs 111 mmol/L; p<00001), but higher 2 h plasma glucose concentration (83 vs 61 mmol/L; p<00001) than women diagnosed only on the basis of ADA criteria.

Rationale for screening and intervention


The eect of screening, diagnosis, and treatment of gestational diabetes has been controversial for many years, leading to lack of agreement. The Australian carbohydrate intolerance study in pregnant women (ACHOIS) trial group did a randomised clinical trial4 to assess whether treating women with gestational diabetes reduced the risk of perinatal complications. 1000 pregnant women with gestational diabetes at 2428 weeks of gestation were randomly assigned to receive dietary advice, blood glucose monitoring, and insulin therapy, or routine care. Serious perinatal outcomes were reduced from 4% to 1% in pregnant women treated for gestational diabetes. Furthermore, induction rate and admission to the neonatal nursery increased in women of the intervention group. The rate of cesarean section was similar for both intervention and control groups. However, at 3 months after delivery, rates of depression were lower and quality of life scores were higher, which is consistent with improved health status, in the intervention group. Langer and collegues5 found a 2-fold to 4-fold increase in metabolic complications and large-for-gestationalage births for an untreated group of women with gestational diabetes compared with a treated group.

concentration at any time and to take steps to decrease the long-term risks of diabetic complications for her and her baby. Many different kinds of blood glucose meters exist, but they all work in a similar way and are reasonably accurate (these are less accurate during episodes of hypoglycaemia than during episodes of hyperglycaemia).67 Researchers are currently assessing less intrusive continuous glucose monitoring systems, the ecacy of which has mainly been tested in patients with type 1 diabetes.68 However, continuous glucose monitoring systems technology is becoming of increasing clinical interest for the management of gestational diabetes. Murphy and colleagues69 analysed the eectiveness of continuous glucose monitoring systems in 71 pregnant women with type 1 (n=46) or type 2 (n=25) diabetes allocated to antenatal care and continuous glucose monitoring (n=38) or to standard antenatal care (n=33). Women who were randomly assigned to continuous glucose monitoring systems devices had lower mean glycosylated haemoglobin concentrations at 3236 weeks gestation compared with diabetic women who were randomly assigned to standard antenatal care (58% vs 64%). Furthermore, the investigators showed decreased mean birthweight SD scores (09 vs 16), decreased median customised birthweight centiles (69% vs 93%), and reduced risk of macrosomia (odds ratio [OR] 036 vs 013098) in the continuous glucose monitoring intervention group compared with the control group. McLachlan and colleagues70 obtained similar ndings when they analysed the eectiveness of continuous glucose monitoring systems in 68 pregnant women with diabetes (37 with gestational diabetes, 10 with type 2 diabetes, and eight with type 1 diabetes). These investigators also showed that information gathered from continuous glucose monitoring systems altered clinical management decisions in almost two-thirds (62%) of cases, with indication of undetected and potentially dangerous postprandial hyperglycaemia and overnight hypoglycaemia.

Nutrition and diet


In addition to blood glucose monitoring, the rst line of management of women with gestational diabetes consists of medical nutrition therapy with adjunctive exercise for at least 30 min per day. Patients who fail to maintain glycaemic targets through diet and exercise therapy receive insulin injections or other antihyperglycaemia medications. Although a growing number of studies suggest that nutritional support during pregnancy can have a substantial eect on incidence and severity of gestational diabetes, nutritional management of this condition is controversial. A 2003 Cochrane review71 showed no dierence in the prevalence of birthweights greater than 4000 g or cesarean deliveries in women with gestational diabetes
1793

Management
Close monitoring and treatment of gestational diabetes are important to the long-term health of a pregnant woman and her baby. The fth international workshopconference on gestational diabetes66 recommended the following blood glucose concentrations: fasting plasma glucose of 9099 mg/dL (5055 mmol/L); 1-h postprandial plasma glucose below 78 mmol/L (<140 mg/dL); and 2-h postprandial plasma glucose below 6771 mmol/L (<120127 mg/dL).

Glucose monitoring
Self-glucose monitoring enables a pregnant woman with gestational diabetes to check her blood glucose
www.thelancet.com Vol 373 May 23, 2009

Seminar

who were randomly assigned to primary dietary therapy or no specic treatment. The authors concluded that insucient evidence exists to recommend dietary therapy in patients with altered glucose metabolism. Nevertheless, ADA recommends that women with gestational diabetes receive nutrition counselling and follow a diet that adequately meets the needs of their pregnancy but restricts carbohydrates to 3540% of daily calories.72 This recommendation is based on research showing that restricting carbohydrates to 3540% of calories decreases maternal glucose concentrations and improves maternal and fetal outcomes.73 Research has also shown that restricting carbohydrates to 3033% of daily calories (to about 25 kcal/kg actual weight per day) could be benecial for obese women (BMI >30).74

Exercise
Investigators have shown that prenatal exercise can delay or prevent the development of gestational diabetes, and exercise during pregnancy can prevent complications to the baby. Zhang and colleagues75 did a prospective cohort study in about 22 000 women to assess whether the amount, type, and intensity of pregravid physical activity and sedentary behaviours are associated with the risk of developing gestational diabetes. Women who spent 20 h per week or more watching television and did not do any vigorous activity had a higher risk of developing the condition than women who spent less than 2 h per week watching television and did physical activity. Women with gestational diabetes who exercised regularly during pregnancy were less likely than those who did not exercise to deliver a large-for-gestational-age infant.76

Treatment
For several years, human insulin has been the only treatment option for diabetes that could not be controlled by diet and lifestyle modications alone. Diet-controlled gestational diabetes is classied as class A1 diabetes. Gestational diabetes needing insulin therapy is classied as class A2 diabetes. Insulin therapy for class A2 diabetes needs substantial patient training to keep the number of injections that patients need on a daily basis to a minimum to bring their blood glucose values within the normal range. Some insulin analogues have recently come on the market. Of the three rapid-acting insulin analogues, only two28B-L-lysine-29B-L-proline insulin (lispro) and 28B-aspartic-acid insulin (aspart)have been investigated in pregnancy. Both have shown clinical eectiveness, minimal transfer across the placenta, and no evidence of teratogenesis. Both analogues improve postprandial glucose excursions in type 1 diabetes patients compared with human insulin, and might be associated with a lower risk of delayed postprandial hypoglycaemia.77,78
1794

Oral antihyperglycaemic drugs have not been used in pregnant women because of reports of fetal anomalies and other adverse outcomes in animal studies and in some human cases. However, recent evidence suggests that some oral antihyperglycaemic drugs can be benecial in pregnancy.79,80 Using the single-cotyledon placental model, Elliot and colleagues79 reported almost no transfer of glibenclamide, in spite of maternal glibenclamide being 100 times above therapeutic concentrations. In a later study, Langer and colleagues80 examined more than 400 women with pregnancies complicated by gestational diabetes requiring treatment. They observed no signicant dierences between patients receiving glibenclamide or insulin in mean maternal blood glucose, proportion of largefor-gestational-age fetuses (12% vs 13%, respectively), macrosomia (7% vs 4%), lung complications (8% vs 6%), hypoglycaemia (9% vs 6 %), admission to neonatal intensive-care unit (6% vs 7 %), or fetal anomalies (2% vs 2%). Additionally, a similar percentage of women achieved the desired glycaemic control in the glibenclamide and insulin groups (82% vs 88%, respectively). Glibenclamide was not found in the cord serum of any infants. The eectiveness of three oral antihyperglycaemic drugs used in pregnancyglibenclamide, metformin, and acarbosewas assessed.81 In two prospective studies,80,82 one of which was a randomised controlled trial,80 glibenclamide seemed to be as eective and safe as insulin in the treatment of gestational diabetes. Furthermore, metformin did not increase fetal anomalies or malformations in several small trials in pregnant women with polycystic ovary syndrome.83,84 Metformin also prevents early pregnancy loss, decreases insulin resistance, reduces insulin and testosterone concentrations, and reduces the incidence of gestational diabetes. In one small study,85 acarbose also did not cause any adverse eects during pregnancy. In a systematic review of evidence, maternal glycaemic control, caesarean delivery rates, and birthweights did not dier greatly between insulin and glibenclamide groups.86 Furthermore, there was no dierence in the rate of congenital malformations between individuals treated with insulin and those treated with oral agents. Thus, although evidence is still scarce, glibenclamide and metformin seem to be safe and might be used to treat patients with gestational diabetes.87,88

Conclusions
Gestational diabetes is a growing health concern, especially in certain predisposed populations. Although traditionally deemed not as dangerous for the developing fetus as pregestational diabetes, gestational diabetes has serious, long-term consequences for both baby and mother. Evidence now suggests that screening, early detection, and management can greatly improve outcomes for women with this condition and their babies. Unfortunately, screening and diagnostic standards are
www.thelancet.com Vol 373 May 23, 2009

Seminar

not uniform worldwide, which might lead to underdiagnosis and undermanagement of the disease. Regular nger stick monitoring is still the preferred method for measurement of glucose concentrations. However, continuous glucose monitoring seems to be not only accurate, but might also detect transient episodes of hyperglycaemia and hypoglycaemia, both of which can be detrimental to the fetus. Although human insulin or human insulin analogues have been the preferred treatment for gestational diabetes for some time, oral antihyperglycaemic agentssuch as glibenclamide and metformincould be just as eective for the management of the disease. To resolve the controversies on causes, diagnosis, and management of gestational diabetes, the diagnostic denition of the condition needs to be revised on the basis of the new information obtained from the HAPO study.29 Furthermore, additional research is needed on: mechanisms of insulin resistance; ideal glucose targets to decrease perinatal morbidity in women with gestational diabetes; eectiveness of oral hypoglycaemic drugs versus insulin analogues; identication of all predictors of future development of diabetes; and eectiveness of postpartum interventions to decrease the later incidence of diabetes in women with gestational diabetes and in their children.
Contributors EAR was responsible for the initial literature search and selection of articles to include in the Seminar. GL and AW suggested additional articles to include in the Seminar and appropriate gures and tables. Each author contributed equally to the writing of the Seminar and to addressing reviewers comments. Conicts of interest EAR routinely receives honoraria for invited lectures on diabetes and diabetic embryopathy by medical societies and academic medical institutions around the world, and owns a patent for a dietary intervention to reduce the risk of birth defects in pregnant women with pregestational diabetes (Patent No D6599: USSN 11/299,031). AW is the chairman of the Department of Obstetrics and Gynecology at Soroka University Medical Center (NY, USA). GFL declares that he has no conicts of interest. Acknowledgments We thank Jim Swyers who helped in the early stages of the development of this manuscript. References 1 Reece EA, Homko C, Miodovnik M, Langer O. A consensus report of the Diabetes in Pregnancy Study Group of North America Conference, Little Rock, Arkansas, May, 2002. J Matern Fetal Neonatal Med 2002; 12: 36264. 2 Turok DK, Ratclie SD, Baxley AG. Management of gestational diabetes mellitus. Am Fam Physician 2003; 68: 176972. 3 Jarrett RJ. Gestational diabetes: a non-entity? BMJ 1993; 306: 3738. 4 Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeries WS, Robinson JS. Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS) Trial Group. Eect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med 2005; 352: 247786. 5 Langer O, Yogev Y, Most O, Xenakis EM. Gestational diabetes: the consequences of not treating. Am J Obstet Gynecol 2005; 192: 98997. 6 WHO. Diabetes Program. Country and Regional Data. http://www. who.int/diabetes/facts/world_gures/en/ (accessed Jan 8, 2009).

10

11

12

13

14

15

16 17

18

19

20

21

22

23

24

25

26 27 28

Ben-Haroush A, Yogev Y, Hod M. Epidemiology of gestational diabetes mellitus and its association with Type 2 diabetes. Diabet Med 2004; 21: 10313. Dornhorst A, Paterson CM, Nicholls JSD, et al. High prevalence of gestational diabetes in women from ethnic minority groups. Diabet Med 1992; 9: 82025. Chawla A, Amundsen AL, Hanssen KF, Iversen PO. Gestational diabetes in women from South Asia. Tidsskr Nor Laegeforen 2006; 126: 104143. Lawrence JM, Contreras R, Chen W, Sacks DA. Trends in the prevalence of preexisting diabetes and gestational diabetes mellitus among a racially/ethnically diverse population of pregnant women, 19992005. Diabetes Care 2008; 31: 899904. Coustan DR. Gestational diabetes. In: National Institutes of Diabetes and Digestive and Kidney Diseases. Diabetes in America. 2nd edn. Bethesda, MD: NIDDK, 1995. Cheung NW, McEldu A, Ross GP. Type 2 diabetes in pregnancy: a wolf in sheeps clothing. Aust N Z J Obstet Gynecol 2005; 45: 47983. Jenkins KJ, Correa A, Feinstein JA, et al. American Heart Association Council on Cardiovascular Disease in the Young. Noninherited risk factors and congenital cardiovascular defects: current knowledge: a scientic statement from the American Heart Association Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation 2007; 115: 29953014. Ornoy A. Growth and neurodevelopmental outcome of children born to mothers with pregestational and gestational diabetes. Pediatr Endocrinol Rev 2005; 3: 10413. Sivan E, Weisz B, Shteinman N, Schi E, Lipitz S, Achiron R. Alterations in segmentary branch pulmonary artery blood ow velocimetry in fetuses of diabetic mothers. J Ultrasound Med 2004; 23: 33945. Lain KY, Catalano PM. Metabolic changes in pregnancy. Clin Obstet Gynecol 2007; 50: 93848. Pratipanawatr W, Pratipanawatr T, Cusi K, et al. Skeletal muscle insulin resistance in normoglycemic subjects with a strong family history of type 2 diabetes is associated with decreased insulinstimulated insulin receptor substrate-1 tyrosine phosphorylation. Diabetes 2001; 50: 257278. Friedman JE. Impaired glucose transport and insulin receptor tyrosine phosphorylation in skeletal muscle from obese women with gestational diabetes. Diabetes 1999; 48: 180714. Robitaille J, Grant AM. The genetics of gestational diabetes mellitus: evidence for relationship with type 2 diabetes mellitus. Genet Med 2008; 10: 24050. Shaat N, Karlsson E, Lernmark A, et al. Common variants in MODY genes increase the risk of gestational diabetes mellitus. Diabetologia 2006; 49: 154551. Enquobahrie DA,Williams MA, Qiu C, Meller M, Sorensen TK. Global placental gene expression in gestational diabetes mellitus. Am J Obstet Gynecol 2009; 200: e113. Langer O, Levy J, Brustman L, Anyaegbunam A, Merkatz R, Divon M. Glycemic control in gestational diabeteshow tight is tight enough: small for gestational age versus large for gestational age? Am J Obstet Gynecol 1989; 61: 64653. Salvesen DR, Brudenell JM, Proudler AJ, Crook D, Nicolaides KH. Fetal pancreatic beta-cell function in pregnancies complicated by maternal diabetes mellitus: relationship to fetal macrosomia. Am J Obstet Gynecol 1993; 168: 136369. Carpenter MW, Canick JA, Hogan JW, Shellum C, Somers M, Star JA. Amniotic uid insulin at 1420 weeks gestation: association with maternal glucose intolerance and birth macrosomia. Diabetes Care 2001; 24: 125963. Catalano PM, Drago NM, Amini SB. Fetus-placenta-newborn: maternal carbohydrate metabolism and its relationship to fetal growth and body composition. Am J Obstet Gynecol 1995; 172: 146470. Gottlieb AG, Galan HL. Shoulder dystocia: an update. Obstet Gynecol Clin North Am 2007; 34: 50131. Henriksen T. The macrosomic fetus: a challenge in current obstetrics. Acta Obstet Gynecol Scand 2008; 87: 13445. Jones CW. Gestational diabetes and its impact on the neonate. Neonatal Netw 2001; 20: 1723.

www.thelancet.com Vol 373 May 23, 2009

1795

Seminar

29 30

31 32

33

34

35

36

37

38 39 40

41 42 43

44

45

46

47 48

49

50

51

52

HAPO Study Cooperative Research Group. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 2008; 358: 19912002. Clausen TD, Mathiesen ER, Hansen T, et al. High prevalence of type 2 diabetes and pre-diabetes in adult ospring of women with gestational diabetes mellitus or type 1 diabetes: the role of intrauterine hyperglycemia. Diabetes Care 2008; 31: 34046. Yogev Y, Visser GH. Obesity, gestational diabetes and pregnancy outcome. Semin Fetal Neonatal Med 2009; 14: 7784. Sebire NJ, Jolly M, Wadsworth J, et al. Maternal obesity and pregnancy outcome: a study of 287 213 pregnancies in London. Int J Obes 2001; 25: 117582. Dabelea D, Knowler WC, Pettitt DJ. Eect of diabetes in pregnancy on ospring: follow-up research in the Pima Indians. J Matern Fetal Med 2000; 9: 8388. Vohr BR, Boney CM. Gestational diabetes: the forerunner for the development of maternal and childhood obesity and metabolic syndrome? J Matern Fetal Neonatal Med 2008; 21: 14957. Vambergue A, Dognin C, Boulogne A, Rjou MC, Biausque S, Fontaine P. Increasing incidence of abnormal glucose tolerance in women with prior abnormal glucose tolerance during pregnancy: DIAGEST 2 study. Diabet Med 2008; 25: 5864. Bottalico JN. Recurrent gestational diabetes: risk factors, diagnosis, management, and implications. Semin Perinatol 2007; 31: 17684. Ben-Haroush A, Yogev Y, Hod M. Epidemiology of gestational diabetes mellitus and its association with Type 2 diabetes. Diabet Med 2004; 21: 10313. Marquette GP, Klein VR, Niebyl JR. Ecacy of screening for gestational diabetes. Am J Perinatol 1985; 2: 79. Marquette GP, Klein VR, Repke JT, Niebyl JR. Cost-eective criteria for glucose screening. Obstet Gynecol 1985; 66: 18184. Blanco AT, Semilen SW, Davis Y, Lopez S, Lapinski R, Lockwood CJ. Pregnancy outcome and weight gain recommendations for the morbidly obese women. Obstet Gynecol 1998; 91: 97102. Kumari. A pregnancy outcome in women with morbid obesity. Int J Gynecol Obstet 2001: 73: 10107. Kosti RI, Panagiotakos DB. The epidemic of obesity in children and adolescents in the world. Eur J Public Health 2006: 14: 15159. Abdul-Ghani MA, Abdul-Ghani T, Ali N, Defronzo RA. One-hour plasma glucose concentration and the metabolic syndrome identify subjects at high risk for future type 2 diabetes. Diabetes Care 2008: 31: 165055. Tanir HM, Sener T, Grer H, Kaya M. A ten-year gestational diabetes mellitus cohort at a university clinic of the mid-Anatolian region of Turkey. Clin Exp Obstet Gynecol 2005: 3: 24144. Phaloprakarn C, Tangjitgamol S. Use of oral glucose tolerance test in early pregnancy to predict late-onset gestational diabetes mellitus in high-risk women. J Obstet Gynecol Res 2008; 34: 33136. Gruendhammer M, Brezinka C, Lechleitner M. The number of abnormal plasma glucose values in the oral glucose tolerance test and the feto-maternal outcome of pregnancy. Eur J Obstet Gynecol Reprod Biol 2003; 108: 13136. Carpenter MW, Coustan DR. Criteria for screening tests for gestational diabetes. Am J Obstet Gynecol 1982; 144: 76873. Metzger BE, Coustan DR, the Organizing Committee. Summary and recommendations of the Fourth International WorkshopConference on Gestational Diabetes Mellitus. Diabetes Care 1998; 21 (suppl 2): 16167. Harlass FE, Brady K, Read JA. Reproducibility of the oral glucose tolerance test in pregnancy. Am J Obstet Gynecol 1991; 164: 56468. Alberti KG, Zimmet PZ. Denition, diagnosis and classication of diabetes mellitus and its complications. Part I: diagnosis and denition of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998; 15: 53953. HAPO Study Cooperative Researcg Group. Hyperglycemia and adverse pregnancy outcome (HAPO) study: association with neonatal anthropometrics. Diabates 2009; 58: 45359. Yogev Y, Metzger BE, Hod M. Establishing diagnosis of diabetes mellitus: impact of hyperglycemia and adverse pregnancy outcome study. Semin Fetal Neonatal Med 2009; 14: 94100.

53

54 55

56

57

58

59

60 61

62

63

64

65

66

67

68

69

70

71 72 73

74

75

76

Agarwal MM, Dhatt GS, Safraou MF. Gestational diabetes: using a portable glucometer to simplify the approach to screening. Gynecol Obstet Invest 2008; 66: 17883. Berger H, Crane J, Farine D. Screening for gestational diabetes mellitus. J Obstet Gynecol Can 2002; 24: 894912. Jovanovic-Peterson L, Peterson CM, Reed GF, et al. Maternal postprandial glucose levels and infant birth weight: the diabetes in early pregnancy study. Am J Obstet Gynecol 1991; 164: 10311. Cousins L, Dattel BJ, Hollingsworth DR, Zettner A. Glycosylated hemoglobin as a screening test for carbohydrate intolerance in pregnancy. Am J Obstet Gynecol 1984; 150: 45560. Carr S, Coustan DR, Martelly P, Brosco F, Rotondo R. Precision of reectance meters in screening for gestational diabetes. Obstet Gynecol 1989; 73: 72731. Nasrat HA, Ajabnoor MA, Ardawi MSM. Fructosamine as a screening-test for gestational diabetes mellitus: a reappraisal. Int J Gynaecol Obstet 1990; 34: 2733. Grandjean H, Sarramon MF, de Mouzon J, Reme JM, Pontonnier G. Detection of gestational diabetes by means of ultrasonic diagnosis of excessive fetal growth. Am J Obstet Gynecol 1980; 138: 79092. Reece EA, Homko CJ. How, when, and why to test for gestational diabetes mellitus. Contemp Obstet Gynecol 2005; 50: 4252. Nicholson WK, Wilson LM, Witkop CT, et al. Therapeutic management, delivery, and postpartum risk assessment and screening in gestational diabetes. Evid Rep Technol Assess 2008; 162: 196. Hollander MH, Paarlberg KM, Huisjes AJ. Gestational diabetes: a review of the current literature and guidelines. Obstet Gynecol Surv 2007; 62: 12536. Erem C, Cihanyurdu N, Deger O, Karahan C, Can G, Telatar M. Screening for gestational diabetes mellitus in northeastern Turkey (Trabzon City). Eur J Epidemiol 2003; 18: 3943. Lemen PM, Wigton TR, Miller-McCarthey AJ, Cruikshank DP. Screening for gestational diabetes mellitus in adolescent pregnancies. Am J Obstet Gynecol 1998; 178: 125156. Shirazian N, Mahboubi M, Emdadi R, et al. Comparison of dierent diagnostic criteria for gestational diabetes mellitus based on the 75-g oral glucose tolerance test: a cohort study. Endocr Pract 2008; 14: 31217. Metzger BE, Buchanan TA, Coustan DR, et al. Summary and recommendations of the Fifth International WorkshopConference on Gestational Diabetes Mellitus. Diabetes Care 2007; 30: S25160. Murata GH, Duckworth WC, Shah JH, Wendel CS, Homan RM. Factors aecting hypoglycemia awareness in insulin-treated type 2 diabetes: The Diabetes Outcomes in Veterans Study (DOVES). Diabetes Res Clin Pract 2004; 65: 6167. JDRF CGM Study Group. JDRF randomized clinical trial to assess the ecacy of real-time continuous glucose monitoring in the management of type 1 diabetes: research design and methods. Diabetes Technol Ther 2008; 10: 31021. Murphy HR, Rayman G, Lewis K, et al. Eectiveness of continuous glucose monitoring in pregnant women with diabetes: randomised clinical trial. BMJ 2008; 337: a1680. McLachlan K, Jenkins A, ONeal D. The role of continuous glucose monitoring in clinical decision-making in diabetes in pregnancy. Aust N Z J Obstet Gynaecol 2007; 47: 18690. Walkinshaw SA. Dietary regulation for gestational diabetes. Cochrane Database Syst Rev 2003; 2: CD000070. American Diabetes Association. Gestational diabetes. Diabetes Care 2003; 26: S10305. Major CA, Henry MJ, De Veciana M, Morgan MA. The eects of carbohydrate restriction in patients with diet-controlled gestational diabetes. Obstet Gynecol 1998; 91: 60004. Franz MJ, Horton ES, Bantle JP, et al. Nutrition principles for the management of diabetes and related complications (Technical Review). Diabetes Care 1994; 17: 490518. Zhang C, Solomon CG, Manson JE, Hu FB. A prospective study of pregravid physical activity and sedentary behaviors in relation to the risk for gestational diabetes mellitus. Arch Intern Med 2006; 166: 54348. Snapp CA, Donaldson SK. Gestational diabetes mellitus: physical exercise and health outcomes. Biol Res Nurs 2008; 10: 14555.

1796

www.thelancet.com Vol 373 May 23, 2009

Seminar

77

78

79

80

81

82

Lapolla A, Dalfr MG, Spezia R, et al. Outcome of pregnancy in type 1 diabetic patients treated with insulin lispro or regular insulin: an Italian experience. Acta Diabetol 2008; 45: 6166. Insulin Aspart Pregnancy Study Group. Fetal and perinatal outcomes in type 1 diabetes pregnancy: a randomized study comparing insulin aspart with human insulin in 322 subjects. Am J Obstet Gynecol 2008; 198: 18687. Elliott BD, Langer O, Schenker S. Insignicant transfer of glyburide occurs across the human placenta. Am J Obstet Gynecol 1991; 165: 80712. Langer O, Conway DL, Berkus MD, Xenakis EM, Gonzales O. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med 2000; 343: 113438. Ho FL, Liew CF, Cunanan EC, Lee KO. Oral hypoglycaemic agents for diabetes in pregnancyan appraisal of the current evidence for oral anti-diabetic drug use in pregnancy. Ann Acad Med Singapore 2007; 36: 67278. Kremer CJ, Du P. Glyburide for the treatment of gestational diabetes. Am J Obstet Gynecol 2004; 190: 143839.

83

84

85

86

87 88

Jakubowicz DJ, Iuorno MJ, Jakubowicz S, Roberts KA, Nestler JE. Eects of metformin on early pregnancy loss in the polycystic ovary syndrome. J Clin Endocrinol Metab 2002; 87: 52429. Glueck CJ, Goldenberg N, Praniko J, Loftspring M, Sieve L, Wang P. Height, weight, and motor-social development during the rst 18 months of life in 126 infants born to 109 mothers with polycystic ovary syndrome who conceived on and continued metformin through pregnancy. Hum Reprod 2004; 19: 132330. Zarate A, Ochoa R, Hernandez M, Basurto L. Eectiveness of acarbose in the control of glucose tolerance worsening in pregnancy. Ginecol Obstet Mex 2000; 68: 4245. Nicholson W, Bolen S, Witkop CT, Neale D, Wilson L, Bass E. Benets and risks of oral diabetes agents compared with insulin in women with gestational diabetes: a systematic review. Obstet Gynecol 2009; 113: 193205. Moor TR. Glyburide for the treatment of gestational diabetes. A critical appraisal. Diabetes Care 2007; 30: S20913. Kapoor N, Sankaran S, Hyer S, Shehata H. Diabetes in pregnancy: a review of current evidence. Curr Opin Obstet Gynecol 2007; 19: 58690.

www.thelancet.com Vol 373 May 23, 2009

1797