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The International Federation of Gynecology and Obstetrics (FIGO) Initiative on gestational diabetes mellitus: A pragmatic guide for diagnosis, management, and care#

Authors:
  • World Diabetes Foundation

Abstract and Figures

Hyperglycemia is one of the most common medical conditions women encounter during pregnancy. The International Diabetes Federation (IDF) estimates that one in six live births (16.8%) are to women with some form of hyperglycemia in pregnancy. While 16% of these cases may be due to diabetes in pregnancy (either preexisting diabetes type 1 or type 2 which antedates pregnancy or is first identified during testing in the index pregnancy), the majority (84%) is due to gestational diabetes mellitus (GDM). The occurrence of GDM parallels the prevalence of impaired glucose tolerance (IGT), obesity, and type 2 diabetes mellitus (T2DM) in a given population. These conditions are on the rise globally. Moreover, the age of onset of diabetes and pre-diabetes is declining while the age of childbearing is increasing. There is also an increase in the rate of overweight and obese women of reproductive age; thus, more women entering pregnancy have risk factors that make them vulnerable to hyperglycemia during pregnancy. GDM is associated with a higher incidence of maternal morbidity including cesarean deliveries, shoulder dystocia, birth trauma, hypertensive disorders of pregnancy (including preeclampsia), and subsequent development of T2DM. Perinatal and neonatal morbidities also increase; the latter include macrosomia, birth injury, hypoglycemia, polycythemia, and hyperbilirubinemia. Long-term sequelae in offspring with in utero exposure to maternal hyperglycemia may include higher risks for obesity and diabetes later in life. In most parts of low-, lower middle-, and upper middleincome countries (which contribute to over 85% of the annual global deliveries), the majority of women are either not screened or improperly screened for diabetes during pregnancy even though these countries account for 80% of the global diabetes burden as well as 90% of all cases of maternal and perinatal deaths and poor pregnancy outcomes. Given the interaction between hyperglycemia and poor pregnancy outcomes, the role of in utero imprinting in increasing the risk of diabetes and cardiometabolic disorders in the offspring of mothers with hyperglycemia in pregnancy, as well as increasing maternal vulnerability to future diabetes and cardiovascular disorders, there needs to be a greater global focus on preventing, screening, diagnosing, and managing hyperglycemia in pregnancy. The relevance of GDM as a priority for maternal health and its impact on the future burden of noncommunicable diseases is no longer in doubt, but how best to deal with the issue remains contentious as there are many gaps in knowledge on how to prevent, diagnose, and manage GDM to optimize care and outcomes. These must be addressed through future research. The International Federation of Gynecology and Obstetrics (FIGO) brought together international experts to develop a document to frame the issues and suggest key actions to address the health burden posed by GDM. FIGO's objective, as outlined in this document, is: (1) to raise awareness of the links between hyperglycemia and poor maternal and fetal outcomes as well as to the future health risks to mother and offspring, and demand a clearly defined global health agenda to tackle this issue; and (2) to create a consensus document that provides guidance for testing, management, and care of women with GDM regardless of resource setting and to disseminate and encourage its use. Despite the challenge of limited high-quality evidence, the document outlines current global standards for the testing, management, and care of women with GDM and provides pragmatic recommendations, which because of their level of acceptability, feasibility, and ease of implementation, have the potential to produce significant impact. Suggestions are provided for a variety of different regional and resource settings based on their financial, human, and infrastructure resources, as we ll as for research priorities to bridge the current knowledge andevidence gap. To address the issue of GDM, FIGO recommends the following: Public health focus: There should be greater international attention paid to GDM and to the links between maternal health and noncommunicable diseases on the sustainable developmental goals agenda. Public health measures to increase awareness, access, affordability, and acceptance of preconception counselling, and prenatal and postnatal services for women of reproductive age must be prioritized. Universal testing: All pregnant women should be tested for hyperglycemia during pregnancy using a one-step procedure and FIGO encourages all countries and its member associations to adapt and promote strategies to ensure this. Criteria for diagnosis: The WHO criteria for diagnosis of diabetes mellitus in pregnancy [1] and the WHO and the International Association of Diabetes in Pregnancy Study Groups (IADPSG) criteria for diagnosis of GDM [1,2] should be used when possible. Keeping in mind the resource constraints in many low-resource countries, alternate strategies described in the document should also be considered equally acceptable. Diagnosis of GDM: Diagnosis should ideally be based on laboratory results of venous serum or plasma samples that are properly collected, transported, and tested. Though plasmacalibrated handheld glucometers offer results that are less accurate and precise than those from quality-controlled laboratories, it is acceptable to use such devices for the diagnosis of glucose intolerance in pregnancy in locations where laboratory support is either unavailable or at a site remote to the point of care. Management of GDM: Management should be in accordance with available national resources and infrastructure even if the specific diagnostic and treatment protocols are not supported by high-quality evidence, as this is preferable to no care at all. Lifestyle management: Nutrition counselling and physical activity should be the primary tools in the management of GDM.Women with GDM must receive practical nutritional education and counselling that will empower them to choose the right quantity and quality of food and level of physical activity. They should be advised repeatedly during pregnancy to continue the same healthy lifestyle after delivery to reduce the risk of future obesity, T2DM, and cardiovascular diseases. Pharmacological management: If lifestyle modification alone fails to achieve glucose control, metformin, glyburide, or insulin should be considered as safe and effective treatment options for GDM. Postpartum follow-up and linkage to care: Following a pregnancy complicated by GDM, the postpartum period provides an important platform to initiate beneficial health practices for both mother and child to reduce the future burden of several noncommunicable diseases. Obstetricians should establish links with family physicians, internists, pediatricians, and other healthcare providers to support postpartum follow-up of GDM mothers and their children. A follow-up program linked to the child's vaccination and regular health check-up visits provides an opportunity for continued engagement with the high risk mother?child pair. Future research: There should be greater international research collaboration to address the knowledge gaps to better understand the links between maternal health and noncommunicable diseases. Evidence-based findings are urgently needed to provide best practice standards for testing, management, and care of women with GDM. Cost-effectiveness models must be used for countries to make the best choices for testing and management of GDM given their specific burden of disease and resources.
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Ocial publication of FIGO
The International Federation
of Gynecology and Obstetrics
Volume 131 Supplement 3 October 2015 ISSN 0020-7292
e International Federation of Gynecology
and Obstetrics (FIGO) Initiative on Gestational
Diabetes Mellitus: A Pragmatic Guide for Diagnosis,
Management, and Care
The International Federation of Gynecology and Obstetrics (FIGO)
Initiative on Gestational Diabetes Mellitus: A Pragmatic Guide for
Diagnosis, Management, and Care
Publication of this Supplement was supported by funding from an unrestricted
educational grant provided by Novo Nordisk.
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& OBSTETRICS
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The International Federation of Gynecology and Obstetrics
(FIGO) Initiative on Gestational Diabetes Mellitus: A Pragmatic
Guide for Diagnosis, Management, and Care
Moshe Hod, Anil Kapur, David A. Sacks, Eran Hadar, Mukesh Agarwal, Gian Carlo Di Renzo,
Luis Cabero Roura, Harold David McIntyre, Jessica L. Morris, Hema Divakar
Publication of this Supplement was supported by funding from an unrestricted
educational grant provided by Novo Nordisk.
Contents
The International Federation of Gynecology and Obstetrics (FIGO) Initiative on Gestational Diabetes
Mellitus: A Pragmatic Guide for Diagnosis, Management, and Care
Authors and contributors
Abbreviations
1. Executive summary
2. The target audience of the FIGO Initiative on gestational diabetes mellitus
3. Quality assessment of evidence and grading of strength of recommendations
4. Gestational diabetes mellitus: Background, definition, epidemiology, pathophysiology
5. Diagnosing gestational diabetes mellitus
6. Glucose measurement: Technical considerations in laboratory and point-of-care testing
7. Management of hyperglycemia during pregnancy
8. Postpartum management
9. Preconception care
10. Research priorities
11. Appendices
Appendix 1. Current approaches to GDM diagnosis in selected countries
Appendix 2. Gestational Diabetes Formulas for Cost-Effectiveness: GeDiForCE
Appendix 3. Research priorities in gestational diabetes
International Journal of Gynecology and Obstetrics 131 S3 (2015) S173S211
Contributors
In addition to the authors, t he following people provided
important contributions during the creation of the document.
Thanks go to international experts: Tao Duan, Huixia Yang,
Andre Van Assche, Umberto Simeoni, Tahir Mahmood, Biodun
Olagbuji, Eugene Sobngwi, Maicon Falavigna, Rodolfo Martinez,
Carlos Ortega, Susana Salzberg, Jorge Alvariñas, Gloria Lopez
Steward, Silvia Lapertosa, Roberto Estrade, Cristina Faingold,
Silvia García, Argyro Syngelaki, Stephen Colagiuri, Yoel Toledano,
Mark Hanson, and Blami Dao. Special thanks, for FIGO guidance
and coordination, go to President Sabaratnam Arulkumaran,
President Elect CN Purandare, Chief Executive Hamid Rushwan,
and Chair of the SMNH Committee, William Stones.
The following external groups evaluated the document and
support its contents: European Board and College of Obstetrics
and Gynaecology (EBCOG), The Society of Obstetricians and
Gynaecologists of Canada (SOGC), Chinese Society of Perinatal
Medicine, Diabetic Pregnancy Study Group (DPSG), African
Federation of Obstetrics and Gynaecology (AFOG), South Asian
Federation of Obstetrics and Gynecology (SAFOG), Australian
Diabetes in Pregnancy Society (ADIPS), International Association
of Diabetes in Pregnancy Study Groups (IADPSG), European
Association of Perinatal Medicine (EAPM), Diabetes in Pregnancy
Study Group of India (DIPSI), and the Diabetes in Pregnancy Study
Group of Latin America. In addition to the FIGO Executive Board,
all relevant FIGO Committees and Working Groups contributed
to and supported the document.
Acknowledgments
This project was funded by an unrestricted educational grant
from Novo Nordisk.
Conflict of interest
The authors have no conflicts of interest to declare.
Women queue for gestational diabetes services in Barranquilla, Colombia.
Photograph by Jesper Westley for the World Diabetes Foundation.
The International Federation of Gynecology and Obstetrics (FIGO)
Initiative on gestational diabetes mellitus: A pragmatic guide for
diagnosis, management, and care#
Moshe Hod a, Anil Kapur b, David A. Sacks c, Eran Hadar d,e, Mukesh Agarwal f, Gian Carlo Di Renzo g,
Luis Cabero Roura h, Harold David McIntyre i, Jessica L. Morris j,*, Hema Divakar k
a Division of Maternal Fetal Medicine, Rabin Medical Center, Tel Aviv University, Petah Tikva, Israel
b World Diabetes Foundation, Gentofte, Denmark
c Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA, USA
d Helen Schneider Hospital for Women, Rabin Medical Center, Petah Tikva, Israel
e Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
f Department of Pathology, UAE University, Al Ain, United Arab Emirates
g Centre of Perinatal and Reproductive Medicine, Department of Obstetrics and Gynecology, University of Perugia, Perugia, Italy
h Maternal Fetal Medicine Unit, Vall d’Hebron University Hospital, Barcelona, Spain
i University of Queensland Mater Clinical School, Brisbane, Australia
j International Federation of Gynecology and Obstetrics, London, UK
k Divakars Specialty Hospital, Bangalore, India
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics
journal homepage: www.elsevier.com/locate/ijgo
# This document was endorsed by the FIGO Executive Board at its annual
meeting held on May 3031, 2015, in Melbourne, Australia
* Corresponding author at FIGO House, Suite 3, Waterloo Court, 10 Theed Street,
London, SE1 8ST. Tel.: +44 207 928 1166
E-mail address: Jessica@figo.org (J.L. Morris).
0020-72922015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
S174 M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211
List of abbreviations/acronyms
ACOG American College of Obstetrics and Gynecology
ADA American Diabetes Association
BMI Body mass index
CGM Continuous glucose monitoring
DIP Diabetes mellitus in pregnancy
FPG Fasting plasma glucose
GCT Glucose challenge test
GDM Gestational diabetes mellitus
GI Glycemic index
HbA1c Glycosylated hemoglobin (hemoglobin A1c)
IADPSG International Association of Diabetes in Pregnancy Study Groups
IDF International Diabetes Federation
IGT Impaired glucose tolerance
IOM Institute of Medicine
LGA Large for gestational age
NICE National Institute for Health and Care Excellence
NPH Neutral protamine Hagedorn insulin
OAD Oral antidiabetic agents
OGTT Oral glucose tolerance test
PCOS Polycystic ovarian syndrome
POC Point of care
SGA Small for gestational age
SMBG Self-monitoring of blood glucose
T2DM Type 2 diabetes mellitus
M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 S175
1. Executive summary
Hyperglycemia is one of the most common medical conditions
women encounter during pregnancy. The International Diabetes
Federation (IDF) estimates that one in six live births (16.8%) are to
women with some form of hyperglycemia in pregnancy. While 16%
of these cases may be due to diabetes in pregnancy (either pre-
existing diabetestype 1 or type 2which antedates pregnancy
or is first identified during testing in the index pregnancy), the
majority (84%) is due to gestational diabetes mellitus (GDM).
The occurrence of GDM parallels the prevalence of impaired
glucose tolerance (IGT), obesity, and type 2 diabetes mellitus
(T2DM) in a given population. These conditions are on the rise
globally. Moreover, the age of onset of diabetes and pre-diabetes
is declining while the age of childbearing is increasing. There is
also an increase in the rate of overweight and obese women of
reproductive age; thus, more women entering pregnancy have
risk factors that make them vulnerable to hyperglycemia during
pregnancy.
GDM is associated with a higher incidence of maternal
morbidity including cesarean deliveries, shoulder dystocia, birth
trauma, hypertensive disorders of pregnancy (including pre-
eclampsia), and subsequent development of T2DM. Perinatal
and neonatal morbidities also increase; the latter include
macrosomia, birth injury, hypoglycemia, polycythemia, and
hyperbilirubinemia. Long-term sequelae in offspring with in
utero exposure to maternal hyperglycemia may include higher
risks for obesity and diabetes later in life.
In most parts of low-, lower middle-, and upper middle-
income countries (which contribute to over 85% of the annual
global deliveries), the majority of women are either not screened
or improperly screened for diabetes during pregnancyeven
though these countries account for 80% of the global diabetes
burden as well as 90% of all cases of maternal and perinatal
deaths and poor pregnancy outcomes.
Given the interaction between hyperglycemia and poor
pregnancy outcomes, the role of in utero imprinting in
increasing the risk of diabetes and cardiometabolic disorders
in the offspring of mothers with hyperglycemia in pregnancy,
as well as increasing maternal vulnerability to future diabetes
and cardiovascular disorders, there needs to be a greater global
focus on preventing, screening, diagnosing, and managing
hyperglycemia in pregnancy. The relevance of GDM as a priority
for maternal health and its impact on the future burden of
noncommunicable diseases is no longer in doubt, but how best
to deal with the issue remains contentious as there are many
gaps in knowledge on how to prevent, diagnose, and manage
GDM to optimize care and outcomes. These must be addressed
through future research.
The International Federation of Gynecology and Obstetrics
(FIGO) brought together international experts to develop a
document to frame the issues and suggest key actions to address
the health burden posed by GDM. FIGO’s objective, as outlined
in this document, is: (1) to raise awareness of the links between
hyperglycemia and poor maternal and fetal outcomes as well as
to the future health risks to mother and offspring, and demand
a clearly defined global health agenda to tackle this issue; and
(2) to create a consensus document that provides guidance for
testing, management, and care of women with GDM regardless
of resource setting and to disseminate and encourage its use.
Despite the challenge of limited high-quality evidence, the
document outlines current global standards for the testing,
management, a
nd care of women with GDM and provides
pragmatic recommendations, which because of their level of
acceptability, feasibility, and ease of implementation, have the
potential to produce significant impact. Suggestions are provided
for a variety of different regional and resource settings based
on their financial, human, and infrastructure resources, as well
as for research priorities to bridge the current knowledge and
evidence gap.
To a ddress the issue of GDM, FIGO recommends the following:
Public health focus: There should be greater international
attention paid to GDM and to the links between maternal
health and noncommunicable diseases on the sustainable
developmental goals agenda. Public health measures to increase
awareness, access, affordability, and a cceptance of preconception
counselling, and prenatal and postnatal services for women of
reproductive age must be prioritized.
Universal testing: All pregnant women should be tested for
hyperglycemia during pregnancy using a one-step procedure
and FIGO encourages all countries and its member associations
to adapt and promote strategies to ensure this.
Criteria for diagnosis: The WHO criteria for diagnosis
of diabetes mellitus in pregnancy [1] and the WHO and the
International Association of Diabetes in Pregnancy Study Groups
(IADPSG) criteria for diagnosis of GDM [1,2] should be used
when possible. Keeping in mind the resource constraints in
many low-resource countries, alternate strategies described in
the document should also be considered equally acceptable.
Diagnosis of GDM: Diagnosis should ideally be based on
laboratory results of venous serum or plasma samples that are
properly collected, transported, and tested. Though plasma-
calibrated handheld glucometers offer results that are less
accurate and precise than those from quality-controlled labora-
tories, it is acceptable to use such devices for the diagnosis of
glucose intolerance in pregnancy in locations where laboratory
support is either unavailable or at a site remote to the point of
care.
Management of GDM: Management should be in accordance
with available national resources and infrastructure even if the
specific diagnostic and treatment protocols are not supported by
high-quality evidence, as this is preferable to no care at all.
Lifestyle management: Nutrition counselling and physical
activity should be the primary tools in the management of GDM.
Women with GDM must receive practical nutritional education
and counselling that will empower them to choose the right
quantity and quality of food and level of physical activity. They
should be advised repeatedly during pregnancy to continue the
same healthy lifestyle after delivery to reduce the risk of future
obesity, T2DM, and cardiovascular diseases.
Pharmacological management: If lifestyle modification
alone fails to achieve glucose control, metformin, glyburide, or
insulin should be considered as safe and effective treatment
options for GDM.
Postpartum follow-up and linkage to care: Following a
pregnancy complicated by GDM, the postpartum period provides
an important platform to initiate beneficial health practices for
both mother and child to reduce the future burden of several
noncommunicable diseases. Obstetricians should establish
links with family physicians, internists, pediatricians, and other
healthcare providers to support postpartum follow-up of GDM
mothers and their children. A follow-up program linked to the
child’s vaccination and regular health check-up visits provides
an opportunity for continued engagement with the high risk
motherchild pair.
Future research: There should be greater international
research collaboration to address the knowledge gaps to
better understand the links between maternal health and
noncommunicable diseases. Evidence-based findings are
urgently needed to provide best practice standards for testing,
S176 M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211
management, and care of women with GDM. Cost-effectiveness
models must be used for countries to make the best choices for
testing and management of GDM given their specific burden of
disease and resources.
References
[1] World Health Organization. Diagnostic criteria and classification of hyper-
glycaemia first detected in pregnancy. WHO/NMH/MND/13.2. Geneva:
WHO; 2013. http://apps.who.int/iris/bitstream/10665/85975/1/WHO_NMH_
MND_13.2_eng.pdf
[2] International Association of Diabetes and Pregnancy Study Groups
Consensus Panel, Metzger BE, Gabbe SG, Persson B, Buchanan TA, Catalano
PA, et al. International association of diabetes and pregnancy study groups
recommendations on the diagnosis and classification of hyperglycemia in
pregnancy. Diabetes Care 2010;33(3):67682.
M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 S177
This document is directed at multiple stakeholders with the
intention of bringing attention to hyperglycemia in pregnancy,
with particular focus on gestational diabetes. GDM is a hitherto
less-prioritized but common medical condition associated
with pregnancy that has serious consequences. This document
proposes to create a global framework for action to improve the
diagnosis and care of women with GDM.
The intended target audience includes:
Healthcare providers: All those who are qualified to care
for women with GDM and their offspring (obstetricians,
diabetologists, endocrinologists, internists, pediatricians, neo-
natologists and general practitioners, midwives, nurses, advance
practice clinicians, nutritionists, pharmacists, community health
workers, laboratory technicians, etc.)
Healthcare delivery organizations and providers: govern-
ments, federal and state legislators, healthcare management
organizations, health insurance organizations, international
development agencies, and nongovernmental organizations.
Professional organizations: international, regional, and
national professional organizations of obstetricians and gyne-
cologists, endocrinologists, diabetologists, internists, family
practi tioners, pediatricians, neonatologists, and worldwide
national organizations dedicated to the care of pregnant women
with diabetes.
2. The target audience of the FIGO Initiative on gestational diabetes mellitus
S178 M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211
In assessing the quality of evidence and grading of strength
of recommendations, the document follows the terminology
proposed by the Grading of Recommendations, Assessment,
Development and Evaluation (GRADE) Working Group (http://
www.gradeworkinggroup.org/index.htm). This system uses
consistent language and graphical descriptions for the strength
and quality of the recommendations and the evidence on which
they are based. Strong recommendations are numbered as 1 and
conditional (weak) recommendations are numbered 2. For the
quality of evidence, cross-filled circles are used:
䊊䊊䊊
denotes
very low-quality evidence; 丣丣
䊊䊊
low quality; 丣丣丣
moderate
quality; and 丣丣丣丣 high quality of evidence (Tables 1 and 2).
The overall quality of evidence was assessed for each of the
recommendations and expressed using four levels of quality:
very low, low, moderate, and high (Table 2). Considerations
for quality of evidence include primarily the study design and
methodology. As such, evidence based on randomized controlled
trials is considered high-quality evidence, observational studies
provide moderate or low quality of evidence, and all others are
very low. However, other parameters must be considered while
assessing the level of evidence: risk of bias, study limitations,
directness, consistency of results, precision, publication bias,
indirectness of evidence, and scarcity of evidence. Therefore, a
limited randomized trial is downgraded a
nd level of evidence
is considered moderate or low. These limitations include loss
to follow-up, inadequacy of allocation concealment, or an
unblinded study with subjective outcomes susceptible to bias.
Similarly, an observational study may be upgraded if it supplies
large and consistent estimates of the magnitude of a treatment
effect.
Additionally, each recommendation is denoted with its
strength (strong or weak) while considering the balance of
desirable and undesirable consequences, quality of evidence,
values and preferences, and resource use (Table 2). Therefore,
the quality of evidence is only one possible consideration
for the strength of evidence. The decision to apply a possible
examination or intervention is also based on potential risk
benefit, cost, and resource allocation. Some recommendations
may be based on low-quality evidence but still represent a
benefit that outweighs the risks and burdens, and therefore may
be strongly recommended.
A pregnant woman waits for her gestational diabetes screening in Tamil Nadu,
India. Photograph by Jesper Westley for the World Diabetes Foundation.
3. Quality assessment of evidence and grading of strength of recommendations
Table 1
Interpretation of strong and conditional (weak) recommendations according to GRADE.
a
1 = Strong recommendation phrased aswe recommend2 = Conditional (weak) recommendation phrased aswe suggest
For patients Nearly all patients in this situation would accept the
recommended course of action. Formal decision aids are not
needed to help patients make decisions consistent with their
values and preferences.
Most patients in this situation would accept the suggested course of
action.
For clinicians According to the guidelines, performance of the recommended
action could be used as a quality criterion or performance
indicator, unless the patent refuses.
Decision aids may help patients make a management decision
consistent with their values and preferences.
For policy makers The recommendation can be adapted as policy in most
situations.
Stakeholders need to discuss the suggestion.
a
Adapted with permission from Swiglo et al. A case for clarity, consistency, and helpfulness: state-of-the-art clinical practice guidelines in endocrinology using
the grading of recommendations, assessment, development, and evaluation system. J Clin Endocrinol Metab. 2008;93(3):666-73. Copyright Endocrine Society
(2008).
Note: Both caregivers and care recipients need to be involved in the decision-making process before adopting recommendations.
Table 2
Interpretation of quality of evidence levels according to GRADE.
a
Level of evidence Definition
High
丣丣丣丣
We are very confident that the true effect corresponds to that of the estimated effect.
Moderate
丣丣丣䊊
We are moderately confident in the estimated effect. The true effect is generally close to the estimated effect, but it may be slightly
different.
Low
丣丣䊊䊊
Our confidence in the estimated effect is limited. The true effect could be substantially different from the estimated effect.
Very low
丣䊊䊊䊊
We have very little confidence in the estimated effect. The true effect is likely to be substantially different from the estimated effect.
a
Adapted with permission from Balshem et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol. 2011;64(4):401-6. Copyright Elsevier (2011).
M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 S179
4.1. Introduction
Despite decades of research, multiple studies, and numerous
global consensus conferences, aspects of hyperglycemia in
pregnancyparticularly those related to classification and
diagnosis of GDM—remain controversial [1]. GDM diagnosis
was originally linked to an increased risk of maternal diabetes
in later life. Due to remarkable advances in recent years, the
metabolic processes that occur during pregnancy and their
effect on intrauterine fetal development have been clarified.
Consequently, clinicians are more aware of the need to precisely
identify and manage metabolic dysfunction in pregnancy
manifested especially by aberrant glucose metabolism. This has
led to an increased focus on the ability to predict and prevent
many potential fetal and maternal complications in the index
pregnancy [1].
4.2. Classification of hyperglycemia in pregnancy and
definition of GDM
The definition of GDM is evolving. Until recently, the accepted
definition was “any degree of glucose intolerance with onset or
first recognition during pregnancy” [2]. Because this definition
includes women with pre-existing diabetes who were not
identified prior to pregnancy and because this definition blurs the
line between morbidities associated with diabetes in pregnancy
and gestational diabetes, renewed efforts a
re being made to
improve the definition and classification of hyperglycemia during
pregnancy. These efforts are also spurred by the increasing
prevalence of diabetes and GDM [3] and of greater prevalence of
maternal and fetal complications resulting from diabetes mellitus
antedating pregnancy. Therefore, hyperglycemia first detected at
any time during pregnancy should be classified either as diabetes
mellitus in pregnancy (DIP) or GDM [4].
4.3. Diabetes in pregnancy
DIP may either have been pre-existing diabetes (type 1 or
type 2) antedating pregnancy, or diabetes first diagnosed during
pregnancy (Figure 1).
Notwithstanding its severity, hyperglycemia that is already
present at conception and embryogenesis increases the
women’s vulnerability and risk of complications. A woman
with undiagnosed diabetes antedating pregnancy may also
have undiagnosed diabetic complications including retinopathy
and nephropathy, which markedly increase pregnancy risks
[5]. Furthermore, hyperglycemia during the critical period of
organogenesis may lead to a high risk of spontaneous abortions
and congenital anomalies. Diabetes in pregnancy, because of
the attendant greater risk of hyperglycemia, may also result in
aberrations in fetal growth and macrosomia. This can lead to
additional short-term complications, for example, obstructed
labor, shoulder dystocia, neonatal hypoglycemia, or risk of
neurological damage. Moreover, there is a risk of onset or
exacerbation of microvascular complications, such as retinopathy
or nephropathy during pregnancy. For these reasons, ensuring
meticulous glucose control before conception and throughout
pregnancy is recommended.
The age at onset of T2DM is decreasing globally and many
women with previously unknown T2DM may become pregnant,
with their diabetes first detected during routine testing in
pregnancy. Alternatively, women at high risk of diabetes may
be unable to withstand the metabolic stress of pregnancy and
develop diabetes for the first time during pregnancy (Figure 2).
When the level of hyperglycemia first detected by testing at
any time during the course of pregnancy meets the criteria for
diagnosis of diabetes in the nonpregnant state, the condition
is called DIP. Those criteria are: fasting plasma glucose (FPG)
≥7.0 mmol/L or 126 mg/dL, and/or 2-hour 75-g oral glucose
tolerance test (OGTT) value11.1 mmol/L or 200 mg/dL, or
random plasma glucose (RPG)11.1 mmol/L or 200 mg/dL
associated with signs and symptoms of diabetes. In DIP the
vulnerability to complications is high because of the degree
of hyperglycemia and the uncertainty as to whether the onset
of hyperglycemia was prior to pregnancy or developed during
early pregnancy. While diabetes diagnosed for the first time in
pregnancy might be type1 or type 2, a diagnosis of type 2 is more
likely. Compared with gestational diabetes, DIP is more likely to
be detected as early as the first trimester provided appropriate
testing is undertaken.
Hyperglycemia in pregnancy
Diabetes in pregnancy Gestaonal diabetes mellitus
Diagnosed before the start of
pregnancy
Diagnosed for the first me
during pregnancy
Type 1 Type 2 Type 1 Type 2
Figure 1 Types of hyperglycemia in pregnancy.
4. Gestational diabetes mellitus: Background, definition, epidemiology,
pathophysiology
S180 M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211
4.4. Gestational diabetes mellitus
When hyperglycemia detected during routine testing in
pregnancy (generally between 24 and 28 weeks) does not meet
the criteria of DIP it is called GDM. Diagnostic criteria and
glucose cut-off values of GDM have been proposed by a number
of organizations and professional groups and are described later
in this document.
Due to its usual diagnosis and appearance later in pregnancy
and less severe hyperglycemia, GDM implies a relatively milder
form of hyperglycemia compared with that of DIP, but is
nonetheless associated with a heightened risk of poor pregnancy
outcome and future risk of diabetes and cardiovascular disease,
and must be managed appropriately.
4.5. Epidemiology of GDM
Hyperglycemia is one of the most common medical
conditions associated with pregnancy. The occurrence of GDM
parallels the prevalence of impaired glucose tolerance (IGT),
obesity, and T2DM in a given population, conditions that have
risen globally during recent years [68]. Moreover, the age of
onset of diabetes and pre-diabetes is declining, while the age of
childbearing is rising in some countries. An increasing number of
women of reproductive age are overweight and obese, thus more
women entering pregnancy are vulnerable to hyperglycemia
during pregnancy [9,10]. Global GDM prevalence rates show
wide variations due to ethnicity and ethnic heterogeneity among
different populations tested, which are further exacerbated
by the different screening and diagnostic criteria used. GDM
prevalence has been reported to vary between 1%−28% [11],
while the International Diabetes Federation (IDF) estimates that
one in six live births (16.8%) are to women with some form of
hyperglycemia in pregnancy; 16% of these may be due to DIP,
while the majority (84%) is related to GDM [8].
4.6. Risk factors
Publications show that risk factors for GDM include ethnicity
and maternal factors such as older age, high parity, overweight
and obesity, excessive weight gain in the index pregnancy, short
stature, polycystic ovarian syndrome (PCOS), history of diabetes
mellitus in first degree relatives, a past history of poor pregnancy
outcome (abortion, fetal loss), macrosomia in previous and/or
index pregnancy, GDM in a previous pregnancy, pre-eclampsia,
and multifetal pregnancy [12]. In practice, slightly over half of
the women with GDM have one or more of these risk factors,
supporting the contention that identification of women who
have GDM requires testing of all pregnant women [1316].
4.7. Fetal and maternal morbidity associated with GDM
GDM is associated with a higher incidence of maternal
morbidity, including cesarean deliveries, birth trauma, hyper-
tensive disorders of pregnancy (including pre-eclampsia), and
subsequent development of T2DM. Perinatal and neonatal
morbidities are also increased; the latter include macrosomia,
shoulder dystocia and other birth injuries, respiratory distress,
hypoglycemia, poly cythemia, and hyperbilirubinemia. Long-
term sequelae in off spring with in utero exposure to maternal
hyperglycemia include higher risks of obesity, impaired glucose
metabolism, and diabetes later in life. Table 3 summarizes the
implications of GDM for both the mother and her offspring
from fetal through adult life [17–25] and Figure 3 shows the
short-term fetal and neonatal complications from intrauterine
exposure to maternal hyperglycemia.
4.8. Pathophysiology
Pregnancy induces changes in maternal metabolism to
accommodate and nurture the growth of the fetus in the womb
from conception until full term birth. Even though the mother
eats intermittently, the fetus must be nourished continuously.
This is achieved by complex interactions of the feto-placental-
maternal unit, through secretion of hormones and metabolic
mediators that create insulin resistance and modify maternal
carbohydrate, lipid, and amino acid metabolism to ensure
adequate nutrient supply to the fetus. These interactions are
geared to create a harmonious balance between the needs of the
mother, those of the fetus, and the mother’s ability to provide for
Diabetes in pregnancy Gestaonal diabetes
mellitus
Pregnancy in previously known
diabetes
OR
Hyperglycemia diagnosed for
the first me during pregnancy
that meets WHO criterion for
diabetes mellitus in the
nonpregnant state
May occur anyme during
pregnancy including the first
trimester
Hyperglycemia during
pregnancy that is not diabetes
Hyperglycemia diagnosed for
the first me during
pregnancy
May occur anyme during
pregnancy but most likely aer
24 weeks
Figure 2 The difference between diabetes in pregnancy and gestational diabetes mellitus.
M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 S181
these needs. I n response to increasing insulin resistance, maternal
insulin secretion increases and euglycemia is maintained. This is
achieved at the cost of higher maternal insulin level and lower
than normal nonpregnant fasting glucose levels.
Insulin resistance continues to increase a s pregnancy a dvances
and is well established by the 24th week. As long as the maternal
pancreas continues to increase insulin production and secretion,
hyperglycemia is prevented. When this capacity is overwhelmed
by rising insulin resistance, maternal hyperglycemia ensues.
Maternal insulin production capacity is thus put under immense
stress during pregnancy. This explains why women with pre-
existing insulin resistance (e.g. overweight, obese, or excessive
weight gain during pregnancy, PCOS, I GT, or metabolic syndrome)
or those with lower ability to produce insulin (e.g. short stature,
stunted) are more prone to GDM.
4.9. Fetal implications
Growth and development of the human conceptus occurs
within the metabolic milieu provided by the mother, and the fetus
Table 3
Maternal and fetal morbidity associated with gestational diabetes mellitus.
Maternal morbidity Fetal/neonatal/child morbidity
Early pregnancy Stillbirth
Spontaneous abortions Neonatal death
Pregnancy Nonchromosomal congenital malformations
Pre-eclampsiaShoulder dystocia
Gestational hypertension Respiratory distress syndrome
Excessive fetal growth (macrosomia, large for gestational age) Cardiomyopathy
Hydramnios Neonatal hypoglycemia
Urinary tract infections Neonatal polycythemia
Delivery Neonatal hyperbilirubinemia
Preterm labor Neonatal hypocalcemia
Traumatic labor Erb’s palsy (as consequence of birth injury)
Instrumental delivery Programming and imprinting; fetal origins of disease: diabetes, obesity, hypertension,
metabolic syndrome
Cesarean delivery
Postoperative/postpartum infection
Postoperative/postpartum hemorrhage
Thromboembolism
Maternal morbidity and mortality
Hemorrhage
Puerperium
Failure to initiate and/or maintain breastfeeding
Infection
Long-term postpartum
Weight retention
GDM in subsequent pregnancy
Future overt diabetes
Future cardiovascular disease
Maternal excess circulang
glucose, lipids, amino acids Fetal substrates transfer
Fetal hyperinsulinemia
Fetal substrate uptake
Macrosomia
Tissue oxygen consumpon Lung surfactant
synthesis
Hypoxia Altered oxygen
delivery
Myocardiopathy
Erythropoien
Polycythemia
Hyperbilirubinemia
Sllbirth,
perinatal
asphyxia
Respiratory distress
syndrome
Figure 3 Intrauterine exposure to maternal hyperglycemia: Fetal and neonatal complications in the short term. Adapted and republished with permission from Elsevier,
from: Mitanchez D, Yzydorczyk C, Siddeek B, Boubred F, Benahmed M, Simeoni U. The offspring of the diabetic mother--short- and long-term implications. Best Pract Res
Clin Obstet Gynaecol 2015;29(2):25669.
S182 M. Hod et al. / International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211
is totally dependent on transfer of nutrients from the maternal
circulation via the placenta. As early as 1954, Pedersen et al.
[26] demonstrated that newborns of diabetic mothers suffered
from hypoglycemia and hypothesized that this was due to fetal
hyperinsulinism as a result of increased transplacental transfer
of sugar. Van Assche and Gepts [27] later confirmed the presence
of hyperplasia of the insulin-producing beta cells in infants of
diabetic mothers and postulated that the hyperplasia was related
to beta-cell hyperactivity and could have consequences in later
life.
In animal experiments, Aerts and Van Assche [28] showed
that modifications in the endocrine pancreas during intrauterine
life caused persistent changes that manifest in later adult life
(in the second generation). Though not perceptible under
basal conditions, these changes become apparent in situations
stressing the beta cell activity, such as pregnancy. Pregnancy
in second generation rats showed increased nonfasting blood
glucose, with no apparent adaptation of the beta cells. This
inadequate adaptation to pregnancy caused changes in the fetal
endocrine pancreas in fetuses of the third generation, thereby
suggesting a transgenerational transmission of risk.
It is now evident that a n a bnormal intrauterine environment has
consequences in later life mediated through epigenetic changes.
This phenomenon is known as developmental programming. An
increasing body of evidence supports the hypothesis that the
abnormal metabolic environment of the mother with diabetes
mellitus may affect certain developing fetal tissues, organs, and
control systems, eventually leading to permanent long-term
functional implications in adult life. The fetal tissues most likely
to be affected are neural cells, adipocytes, muscle cells, and
pancreatic beta cells. Freinkel [29] introduced the concept of
pregnancy as a “tissue culture experiment,in which the placenta
and the fetus develop in anincubating mediumtotally derived
from maternal fuels. All these fuels traverse the placenta from
the maternal compartment either with (e.g. glucose, lipids) or
against (e.g. amino acids) concentration gradients and contribute
to the fetal milieu. Since these constituents are