DIABETES/METABOLISM RESEARCH AND REVIEWS REVIEW Diabetes Metab Res Rev 2015; 31: 680–690 Published online 7 May 2015 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/dmrr.2640

ARTICLE

Diabetes in pregnancy outcomes: A systematic review and proposed codification of definitions

The International Association of Diabetes in Pregnancy Study Group (IADPSG) Working Group on Outcome Definitions Denice S. Feig1,2*, Rosa Corcoy3,4, Dorte Moller Jensen5, Alexandra Kautzky-Willer6, Christopher J. Nolan7, Jeremy J. N. Oats8, David A. Sacks9, Francisca Caimari3, H. David McIntyre10 1

Department of Medicine, University of Toronto, Toronto, Canada 2 Division of Endocrinology and Metabolism, Mount Sinai Hospital, Toronto, Canada 3 Servei d’Endocrinologia i Nutrició, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain 4 Departament de Medicina, Universitat Autònoma de Barcelona, Spain; CIBERBBN, Madrid, Spain 5 Department of Endocrinology, Odense University Hospital, Odense, Denmark 6 Internal Medicine III, Endocrinology & Metabolism, Gender Medicine Unit, Medical University of Vienna, Vienna, Austria 7 Department of Diabetes and Endocrinology, The Canberra Hospital and the Australian National University Medical School, Canberra, ACT, Australia 8 Melbourne School of Population and Global Health, University of Melbourne, Victoria, Australia 9 Department of Research and Evaluation, Kaiser Permanente Southern California, CA, USA 10 Mater Research Institute and School of Medicine, The University of Queensland, (HDM), Brisbane, Australia *Correspondence to: Denice Feig, Mount Sinai Hospital, 60 Murray St. Lebovic Building, Suite 5027, Toronto, Ontario, Canada. E-mail: [email protected] Received: 21 January 2015 Accepted: 29 January 2015 Copyright © 2015 John Wiley & Sons, Ltd.

Summary Rising rates of diabetes in pregnancy have led to an escalation in research in this area. As in any area of clinical research, definitions of outcomes vary from study to study, making it difficult to compare research findings and draw conclusions. Our aim was to compile and create a repository of definitions, which could then be used universally. A systematic review of the literature was performed on published and ongoing randomized controlled trials in the area of diabetes in pregnancy between 01 Jan 2000 and 01 Jun 2012. Other sources included the World Health Organization and Academic Society Statements. The advice of experts was sought when appropriate definitions were lacking. Among the published randomized controlled trials on diabetes and pregnancy, 171 abstracts were retrieved, 64 full texts were reviewed and 53 were included. Among the ongoing randomized controlled trials published in ClinicalTrials.gov, 90 protocols were retrieved and 25 were finally included. The definitions from these were assembled and the final maternal definitions and foetal definitions were agreed upon by consensus. It is our hope that the definitions we have provided (i) will be widely used in the reporting of future studies in the area of diabetes in pregnancy, that they will (ii) facilitate future systematic reviews and formal meta analyses and (iii) ultimately improve outcomes for mothers and babies. Copyright © 2015 John Wiley & Sons, Ltd. Keywords diabetes mellitus; pregnancy; gestational diabetes; pregnancy in diabetic patients; pregnancy outcome

Introduction Increasing maternal age, along with increasing rates of diabetes worldwide, has led to growing rates of diabetes in pregnancy [1–3]. Along with this has come an abundance of research in the area looking at aetiology, diagnostic criteria, management, complications, prognosis and prevention. As in any area of clinical research, outcome definitions vary from study to study, making it difficult to compare research findings and draw conclusions [4]. Further, reported research cohorts, based on single centres or even entire countries, are frequently small, limiting the statistical power of their findings. Our knowledge may benefit substantially from systematic review and formal meta-analysis of this data. Varying definitions can contribute to heterogeneity, which in turn can preclude or complicate meta-analysis. Recognizing that such variability obstructs proper synthesis of evidence, the editors of over 50 journals have initiated the CoRe Outcomes in WomeN’s health Initiative, encouraging

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researchers to ‘develop core outcomes sets using robust consensus methodology’ [5]. Our aim was to create a repository of definitions for the outcomes that are deemed common and important in the study of diabetes in pregnancy, with the intent that they could be used universally. These outcome definitions would be derived from the ‘best available’ data sources – ideally, from recommendations provided by recognized bodies such as the World Health Organization, or from randomized controlled trials (RCTs), either completed or ongoing, and agreed upon by consensus by the international body, the International Association of Diabetes in Pregnancy Study Groups (IADPSG).

Materials and methods No patient information was used and therefore no institutional ethics approval was sought. Several sources of information were used: 1. World Health Organization recommendations for pregnancy outcomes, when available; 2. Academic societies like the American Diabetes Association or the American College of Obstetrics and Gynaecology; 3. Randomized controlled trials, either published or ongoing. A systematic review was undertaken to retrieve appropriate RCTs. The search aimed at identifying articles fulfilling inclusion criteria: (1) randomized clinical trials where (2) participants were women with pregestational or gestational diabetes or where gestational diabetes was an outcome, with (3) adequate cohort size arbitrarily defined as ≥ 100 participants in published trials. No size requirement was placed on protocols found in clinicaltrials.gov. Pubmed search was performed from the period 1 June 2000 to 1 June 2012 with the search terms: ‘diabetes’ and ‘pregnancy’ with the filters Humans, Randomized Controlled Trial and English. Clinicaltrials.gov was searched using the keywords ‘gestational diabetes’ or ‘pregnancy AND diabetes’ as of June 2012.

and D. M. J.) to ascertain if they fulfilled inclusion criteria and chosen according to predetermined criteria. Any disagreements were reviewed and decided upon by consensus. In the next step, four authors reviewed the full text of selected articles from Pubmed (H. D. Mc and D. S.) and protocols from ClinicalTrials.gov (D. F. and R. C.) to collect the reported clinical outcomes and their definitions. Again, any disagreements were reviewed and decided upon by consensus. The definitions retrieved from the published randomized trials and the ongoing randomized trials documented in ClinicalTrials.gov were compiled. The advice of specialists involved in the care of women with diabetes during pregnancy and their offspring was requested when required. This step was not planned pre hoc but required during the study because of the lack of adequate definitions for some of the outcomes.

Outcomes and definition selection Definitions from all previously mentioned sources were used as inputs for proposed definitions, without a judgement being made about their relative importance. The most appropriate definition for each outcome was chosen by consensus among the subcommittee of the IADPSG. Outside experts in neonatology were brought in to weigh some of the infant outcomes. If there was no definition that satisfied the committee, then the definition was

Figure 1. Flowchart of published randomized controlled trials on diabetes and pregnancy through the review process

Information extraction Title, authors and abstracts were downloaded for articles identified after the Pubmed search. Two reviewers (D. M. J. and R. C.) independently selected those fulfilling inclusion criteria. Any disagreement was reviewed and decided upon by consensus. For clinical trials registered in clinicaltrials.gov, the short title listing and the full text of trial information were downloaded and reviewed. The protocols on clinicaltrials. gov were reviewed by 2 members of the committee (D. F. Copyright © 2015 John Wiley & Sons, Ltd.

Figure 2. Flowchart of protocols of randomized controlled trials on diabetes and pregnancy published in ClinicalTrials.gov through the review process

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modified by the committee. All definitions were then sent to the Council of the IADPSG for their input and approval.

Results The flowchart of published RCTs and protocols through the review process is displayed in Figures 1 and 2. Of the 171 RCT abstracts found in the published literature, 64 full articles were reviewed, and 54 articles were included

(Figure 1). Of the 90 RCTs found in clinicaltrials.gov, 25 met the inclusion criteria and were included (Figure 2). The main finding of this systematic review was marked heterogeneity in definitions – ranging from providing no definition at all to a great variety of descriptions. In Table 1, an example is provided for a maternal definition (weight gain during pregnancy) and a foetal definition (large for gestational age newborn). The complete list of retrieved definitions is available as Supplementary Tables 1 to 3. During the systematic review, we found that some definitions (i.e. maternal weight gain during preg-

Table 1. Definitions used in published randomized clinical trials. An example is provided for a maternal (weight gain) and a foetal outcome (large for gestational age) (see supplementary tables 1 to 4 for further information) Definitions

Used

Definition

Maternal weight gain

33*

Large for gestational age

19

6: ND 13: Using (self-reported) prepregnancy weight 6: Prepregnancy weight ND 1: Prepregnancy, measured weight 1: Self-reported prepregnancy weight 1: Self-reported prepregnancy weight, measured height 2 1: Measured prepregnancy weight; obesity defined as BMI ≥ 27 kg/m 1. Self-reported prepregnancy weight and measured height 1: Based on measured height and self-reported prepregnancy weight 1: Pregravid BMI 5: Using weight at booking 1: Early pregnancy and enrolment 1: Early pregnancy 1: First trimester 1: Early pregnancy; BMI categorization in normal, overweight, obese 1: First antenatal visit 10: Using weight at enrolment or prespecified GA (clinical trials) 1: Early pregnancy and enrolment 1: At recruitment 1: At enrolment 1: At enrolment and at delivery 1: At study entry 1: At randomization, categorization in < or ≥ 30 1: Body weight was recorded with light clothes on and without shoes between 5–12 weeks 1: Background BMI and at 24 weeks, 36 weeks and at delivery; background ND 1: At gestational diabetes diagnosis 1: At diagnosis; inclusion if > 110% ideal body weight for height (adjusted for expected pregnancy weight gain and using a BMI of 25 as equal to 100% ideal body weight) 1: ND 12: >90th centile 1: No further details 2: According to Northern Italy growth charts 1: After Finnish reference standards 1: Based on 1990 British growth standard 1: According to local growth charts 1: According to Australian national BW percentiles by GA 1: According to sex-specific German growth charts 1: According to GA and sex (local reference) 1: According to 1994–1996 US singleton BW percentiles for GA by race, Hispanic origin and gender 1: According to general population reference 1: According to a US reference population 2: >90th centile on customized model 3: ≥ 90 1: According to growth standards derived from the San Antonio population 1: For gender, GA and maternal height classified according to the perinatal statistics in Western Australia 1: Using cutoff points defined by Oken 1: BW > 2SD Finnish specific charts adjusted for GA

ND, Not defined; BMI, body mass index; GA, Gestational age; BW, birthweight; GDM, Gestational diabetes mellitus; SD, standard deviation. *The number of trials assessing an outcome is lower than that of specific variables because some trials assess more than one.

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DM in Pregnancy: Outcome Definitions Table 2. Definitions for Maternal Outcomes Outcome Gestational age at delivery

Glycated haemoglobin (HbA1c)

HbA1c target values prepregnancy Fasting glucose

Definition

Reference

Gestational age is based on the last menstrual period, provided there is a ≤ 5-day discrepancy with ultrasound (US) dates in the first trimester and ≤ 10day discrepancy with US dates in the second trimester. If the dates from last menstrual period are outside these limits, the US dates should be used as the best estimate of gestational age. The diagnostic test should be performed using a method that is certified by the National Glycohemoglobin Standardization Program and standardized or traceable to the Diabetes Control and Complications Trial reference assay. Note: target values vary depending on national guidelines. Glucose measured after a fast (usually overnight).

13

14

Consensus

Glucose measured after eating, usually 1, 1½ or 2 h post meal after start of meal.

Consensus

Preprandial glucose

Glucose measured before eating.

Consensus

Mean overall glucose

Mean of all glucose values.

Consensus

Time in Target Time hyperglycemic Time hypoglycemic

Continuous glucose monitoring: amount of time per day the glucose level is within a stated glucose target, under a stated glucose target or over a stated glucose target during continuous glucose monitoring. Should state what length of time was assessed. Self-blood glucose monitoring: Percentage of values were within a stated glucose target. Should state what length of time was assessed. A hypoglycemic event requiring third-party assistance. An episode of hypoglycemia with symptoms consistent with hypoglycemia with confirmation by plasma glucose measurement less than 3.5 mmol/L (63 mg/dL) and which was handled by the subject herself, or any asymptomatic plasma glucose measurement less than 3.3 mmol/L (60 mg/dL). Maximum dose, length of exposure and duration of therapy prepregnancy for each trimester. Where relevant: % requiring drug therapy and description of each therapy.

Mild/Moderate hypoglycemia:

Insulin and oral and subcutaneous hypoglycemic drug use Diabetes Complications Retinopathy progression

Any retinopathy progression is defined as an increase in grade of retinopathy on the final Early Treatment Diabetic Retinopathy Study (ETDRS) scale of retinopathy severity by at least one step from the grade at baseline or from the grade at the most recent evaluation prepregnancy. Clinically meaningful, retinopathy progression is defined as at least a three-step increase in the ETDRS scale.

For studies of pre-existing diabetes: HbA1c prepregnancy and in each trimester (specify gestational age) and change over time

Consensus

Postprandial glucose

Severe hypoglycemia

Comments

Specify if using laboratory values (whole blood or plasma) or selfblood glucose values (capillary). Specify if single value, mean, or percentage within the target range. Specify target range used. Specify if using laboratory values (whole blood or plasma) or selfblood glucose values (capillary). Specify if single value, mean or percentage within the target range. Specify target range used. Specify if using laboratory values or self-blood glucose values. Specify if single value, mean or percentage within the target range. Specify target range used. Specify types of glucose values used in obtaining mean overall glucose. Specify over what period of time glucose values obtained.

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16 17,18 and consensus

Consensus

19

(Continues)

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684 Table 2. (Continued) Outcome Nephropathy (present before conception or in first trimester): No Nephropathy

Definition

Reference 17,20,21

34 mg/mmol of creatinine Glomerular filtration rate < 60 mL/min

17,20,21

Progression of dysfunction during pregnancy

Rise in serum creatinine from early pregnancy to late pregnancy as per Kidney Disease Improving Global Outcomes classification for acute kidney injury, which is a rise of 26 μmol/L or 0.3 mg/dL or a 50–99% Cr rise from baseline

22

Progression of proteinuria during pregnancy

Worsening of urine protein to: Microalbuminuria (as defined previously) OR to Overt Proteinuria with subnephrotic range proteinuria (3.5 g/day)

22

Diabetic sensorimotor polyneuropathy (DSPN)

A symmetrical, length-dependent, sensorimotor polyneuropathy. For definitions of possible DSPN, probable DSPN and confirmed DSPN, see reference 61. A disorder of the autonomic nervous system in the setting of diabetes after the exclusion of other causes. DAN may affect cardiovascular, gastrointestinal and urogenital systems and sudomotor function. Includes ischemic heart disease, cerebrovascular disease and peripheral vascular disease.

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Microalbuminuria Overt proteinuria Decreased renal function at baseline

Diabetic autonomic neuropathy (DAN)

Macrovascular disease Hypertensive Disorders Definition of Hypertension in pregnancy: Gestational hypertension Chronic hypertension Preeclampsia

Severe preeclampsia

Comments

A systolic blood pressure ≥ 140 mmHg and/or a diastolic BP ≥ 90 mmHg. De novo hypertension appearing after gestational week 20. Hypertension diagnosed prior to pregnancy or during pregnancy before 20 weeks gestational age. Definition de novo hypertension after gestational week 20 and the coexistence of one or more of the following new onset conditions: 1. Proteinuria (spot urine protein/creatinine ratio ≥ 30 mg/mmol (0.3 mg/mg) or ≥ 300 mg/day or at least 1 g/L (‘2+’) on dipstick testing) 2. Other maternal organ dysfunction: • Renal insufficiency (creatinine ≥ 0.09 umol/L; 1.02 mg/dL) • Liver involvement (elevated transaminases: at least twice upper limit of normal + right upper quadrant or epigastric abdominal pain) • Neurological complications (examples include eclampsia, altered mental status, blindness, stoke, or more commonly hyperreflexia when accompanied by clonus, severe heaches when accompanied by hyperreflexia, persistent visual scotomata) • Haematological complications (thrombocytopenia: platelet count below 150,000/dL, DIC, haemolysis) 3. Uteroplacental dysfunction Fetal growth restriction A systolic blood pressure ≥ 160 mmHg and/or a diastolic BP ≥ 110 mmHg, respectively, or the

17,20,21 17,20,21 17,20,21

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Estimated glomerular filtration rate (eGFR) is reliable only preconception, NOT in pregnancy Specify gestational age at both time points. If relevant, consider a measure of renal function 3 months postpartum to determine progression of renal function as a consequence of pregnancy If relevant, consider a measure of proteinuria 3 months postpartum to determine progression of proteinuria as a consequence of pregnancy. This definition and tests, used to define these states, refer to the nonpregnant patient. This definition and tests used to define these states refer to the nonpregnant patient.

23 23 23 23

24

(Continues)

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DM in Pregnancy: Outcome Definitions Table 2. (Continued) Outcome

Early preeclampsia Blood parameters: Measures of insulin sensitivity

Measures of insulin secretion

Disposition index

Lipids

Maternal weight Body mass index (BMI: kg/m[2])

Definition

Reference

presence of Hemolysis, Elevated Liver enzymes, Low Platelet count syndrome Preeclampsia occurring before 34 weeks gestation.

24

Comments

Specify gestational age of testing. The hyperinsulinemic–euglycemic clamp (gold standard) and the minimal model approach are direct but costly methods for measuring insulin sensitivity, which require considerable expertise. Surrogate measures of insulin sensitivity can be calculated from measures of the fasting plasma glucose and insulin (or C-peptide) levels (e.g. ISHOMA or ISQUICKI), or from the plasma glucose and insulin (or C-peptide) measurements from an oral glucose tolerance test (OGTT) (e.g. ISOGTT, OGIS). The surrogate measures, in particular from fasting measurements only, are less useful for following longitudinal changes in insulin sensitivity through pregnancy. The ISOGTT has been validated against the clamp in pregnancy. Choice of test depends on size and purpose of the study, expertise and budget. For many studies, a 75 g OGTT with measurement of plasma glucose and insulin at times 0, 60 and 120 min will allow for multiple surrogate calculations of insulin sensitivity using the various formulas available. The frequently sampled intravenous glucose tolerance test (FSIVGTT) is the gold standard, but this is costly and requires considerable expertise. Less complex intravenous glucose tolerance test methods can be used, as well as calculations from glucose and insulin measurements from the OGTT (e.g. insulinogenic (IGI) index). For many studies, a 75 g OGTT with measurement of plasma glucose and insulin at times 0, (30), 60, (90) and 120 min will allow for calculations of insulin secretion and beta-cell function. By adding C-peptide, hepatic insulin clearance can also be assessed. Measures of islet beta-cell compensation for the prevailing level of insulin resistance can be more informative about islet beta-cell function than assessments of insulin secretion alone. Calculation of the disposition index allows for this and is the product of a measure of beta-cell secretion and a measure of insulin sensitivity. The gold standards are the product of insulin sensitivity measured from a clamp or minimal model and insulin secretion measured by the frequently sampled intravenous glucose tolerance test. Again, surrogate OGTT-derived measures of the disposition index can be calculated (e.g. insulin secretion-sensitivity index-2 (ISSI-2) or the IGI/fasting insulin). Total cholesterol, triglycerides, high density lipoprotein, low density lipoprotein

Based on measured height in m and measured or self-reported prepregnancy weight in kg within 3 months of conception. If not available, then weight at first pregnancy visit within the first trimester.

25–29

26,30

26,31–33

63

Fasting is not required for cholesterol or high density lipoproteincholesterol but is required for triglycerides or indirect calculation of low density lipoprotein-cholesterol. Fasting is defined as a 9–12 h fast. Should state if done in fasting state.

34 and consensus

(Continues)

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686 Table 2. (Continued) Outcome Gestational weight gain (total)

Mode of delivery Mode of onset: spontaneous and induced Vaginal Operative vaginal delivery: vacuum and forceps Caesarean-section primary Repeat Caesarian-section Maternal birth trauma Postpartum haemorrhage

Definition

Reference

Weight from preconception (preferable) (measured or self-reported) or within 3 months of conception, or if not available, at first pregnancy visit within first trimester, until the last measured weight during pregnancy (within 4 weeks of delivery).

34 and consensus

Onset of labour is spontaneous, without mechanical or pharmacological intervention. Labour induction is the use of medications or other methods to bring on (induce) labour. Delivery through the vagina. Application of vacuum to the foetal head. Application of forceps to the foetal head. Extraction of the foetus(es) through an abdominal incision in a woman without a prior caesarean delivery. Extraction of the foetus(es) through an abdominal incision in a woman who had a caesarean delivery in a previous pregnancy. Maternal birth trauma – 3rd or 4th degree perineal laceration or uterine rupture Requiring or offered blood transfusion +/ an operative procedure

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Maternal hospitalization

Pregnant woman admitted to hospital.

Maternal mortality

Pregnancy-related death is defined as the death of a woman while pregnant or within 42 days of termination of pregnancy, irrespective of the cause of death. Breastfeeding: The child has received breast milk (direct from the breast or expressed). Exclusive breastfeeding: The infant has received only breast milk from his or her mother or a wet nurse or expressed breast milk, and no other liquids or solids with the exception of drops or syrups consisting of vitamins, mineral supplements or medicines. Predominant breastfeeding: The infant’s predominant source of nourishment has been breast milk. However, the infant may also have received water and water-based drinks (sweetened and flavoured water, teas, infusions, etc.), fruit juice, oral rehydration salts solution, drop and syrup forms of vitamins, minerals, and medicines and ritual fluids (in limited quantities). With the exception of fruit juice and sugar-water, no food-based fluid is allowed under this definition. Full breastfeeding: Exclusive breastfeeding and predominant breastfeeding together constitute full breastfeeding. Supplementary feeding: Supplementary bottlefeeding of formula to an infant receiving breast milk. Complementary feeding: The child has received both breast milk and solid (or semisolid) food. Bottle feeding: The child has received liquid or semisolid food from a bottle with a nipple/teat SF36 and SF12 Edinburgh Postnatal Depression Scale

Breastfeeding

Quality of life measures

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Comments Please specify which baseline and final measures are used and when obtained.

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Consensus Consensus

Consensus

Specify local practice guidelines regarding level of postpartum haemorrhage or anaemia used to trigger a transfusion. Describe: Days in Intensive Care Unit or higher level care Number of hospitalizations prior to admission for delivery Duration of hospital stays for the mother prior to admission for delivery and associated with delivery

37

38

Describe duration and when asking, that is, at hospital discharge, on follow-up at 6 weeks, 3 months, 6 months, 12 months and 24 months.

39,40

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DM in Pregnancy: Outcome Definitions Table 3. Definitions for Foetal Outcomes Outcome Miscarriage (early pregnancy loss) Stillbirth (foetal death) Late foetal death Infant death Early neonatal death Late neonatal death Neonatal Postneonatal death Perinatal mortality Preterm birth Early Preterm Birth Major congenital malformation

Birth injury/trauma

Shoulder dystocia

Respiratory distress of the neonate Transient Tachypnea of the Newborn

Neonatal hyperinsulinemia Neonatal hypoglycemia Polycythemia Hypocalcemia Higher level of neonatal care Hyperbilirubinemia Apgar scores Low arterial cord pH Birthweight Birthweight SD score Crown-heel length Ponderal index Maximal head circumference

Definition

Reference

Miscarriage or ‘early pregnancy loss’ is defined by American Congress of Obstetricians and Gynecologists as the loss of a pregnancy before 20 weeks. The delivery of a foetus showing no signs of life at 20 weeks, or greater, of gestation (if gestational age is known) or a weight greater than or equal to 350 g if the gestational age is not known. Foetal death at 28 weeks or greater of gestation. A live birth that results in death within the first year (22 g/dl Total plasma calcium below 2.2–2.5 mMol/L. Admission to higher level neonatal care unit or special care nursery for >24 h during the initial hospitalization after birth. Need for phototherapy or exchange transfusion. A measure of the health of a newborn infant done at 1 and 5 min. The newborn is given points (0, 1, 2) for heart rate, respiratory effort, muscle tone, response to stimulation and skin coloration. A score of 10 points indicates excellent health. Cord blood pH 90th percentile, adjusted for infant sex, gestation, 2 maternal ethnicity, parity and BMI between 20 and 30 kg/m . Birth weight greater than or equal to 4000 g. Birth weight that is below the 10th percentile for gestational age. Customized birth weight < 10th percentile, adjusted for infant sex, gestation, 2 maternal ethnicity, parity and BMI between 20 and 30 kg/m . Foetal fat mass is measured using several different methods. The method should be specified. Sum of skinfolds: triceps, subscapular, flank (suprailiac). We do not advocate any particular composite of neonatal outcomes, as there is no consensus. Different studies may require different components to make a meaningful outcome. Of note, here are 4 that have been used in randomized trials: 1. A composite of serious perinatal outcomes: one or more of the following: death, shoulder dystocia, bone fracture and nerve palsy. 2. A composite that included perinatal mortality (still birth or neonatal death) and complications that have been associated with maternal hyperglycemia – hypoglycemia, hyperbilirubinemia, neonatal hyperinsulinemia and birth trauma. 3. A composite of symptomatic neonatal hypoglycemia, respiratory distress, need for phototherapy, birth trauma, 5-min Apgar < 7 or prematurity. 4. A composite of pregnancy loss, preterm birth, birth injury, respiratory distress, neonatal symptomatic hypoglycemia (as defined previously) and Neonatal Intensive Care Unit admission > 24 h.

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nancy) were outcome definitions in some trials and used as covariates or baseline descriptors in others. In these cases, all definitions for these variables were collected, irrespective of whether the variable was being used as an outcome or a baseline descriptor in the corresponding trial. The final definitions that were agreed upon are listed in Tables 2 and 3. Discussion. Reasonable medical discourse requires common ‘language’, including a set of well-defined, universally understood and agreed-upon scientific terms [6]. The purpose of this document is to propose a set of definitions for clinical outcomes, primarily for use in studies of diabetes in pregnancy. It is important that some or all definitions are of value in studies from both high and low-income countries. Thus, both complex and simple measurements are included. It is not coincidental that the authors of this effort did so under the aegis of the IADPSG. In composing its guidelines for the diagnosis of gestational diabetes, the primary purpose of this organization was to standardize the testing method and plasma glucose thresholds defining gestational diabetes for universal application [7]. As acknowledged in a subsequent review [8], a uniform definition of gestational diabetes would serve to facilitate comparison of data from one centre to the next. The authors of the current document, the majority of whom are IADPSG members, felt it fitting to expand the principle of developing a uniform definition of gestational diabetes, by developing a reference list of uniform definitions of multiple terms used in publications concerning diabetes in pregnancy. It was noted that Copyright © 2015 John Wiley & Sons, Ltd.

59 34 44 58 52 50,59,60 61

previous definitions have included different entities under the same rubric (e.g. respiratory distress syndrome and transient tachypnea). An effort was therefore made to assure that all definitions were circumscribed and mutually exclusive. In the instance of terms not meeting these selection criteria, opinions of researchers and practitioners with extensive experience in the field were sought. Regarding composite outcomes, we do not advocate any particular composite outcome, as there is no consensus. Different studies may require different components to make a meaningful outcome. It was felt that if a trial has a composite outcome, then what is critical is the definition of each component that makes up the outcome. The final list of definitions was reviewed and approved individually by each member of the writing committee. The importance of adequate and clear terminology in both research and clinical practice cannot be overemphasized. For example, the multiplicity of definitions of gestational diabetes has largely precluded accurate comparisons of data between centres using different diagnostic processes and criteria [9]. In addition, the definition of the same term may vary from centre to centre, leading to confusion and invalid inferences about the condition defined by that term [10]. In the clinical setting, lack of standardization of medical terms has led to errors in communication between medical personnel, at times resulting in serious adverse patient outcomes [11,12]. We hope that the definitions we have provided will give clarity and an ease of communication between health care practitioners, be widely used in the reporting of studies in Diabetes Metab Res Rev 2015; 31: 680–690 DOI: 10.1002/dmrr

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the area of diabetes in pregnancy, and that they will facilitate the creation of systematic reviews and formal meta analyses. We acknowledge that future scientific advances will likely require revision of some or all of the definitions included in this document. The authors submit them now in the hope that they will provide a rational basis for continued dialogue in the field of diabetes and pregnancy.

Conflict of interest

Acknowledgements

While we tried to cover the most important outcomes in diabetes and pregnancy, there may be differences in opinion regarding what we have covered and/or the definitions we have chosen. We welcome scholars to be in touch with any comments you may have. E-mail us at http://www.iadpsg.org.

We would like to thank Dr Elizabeth Asztalos for her advice regarding definitions for neonatal outcomes. We would like to thank Dr Michelle Hladenewich for her advice regarding definitions for diabetic nephropathy during pregnancy.

There are no relevant conflicts of interest to disclose.

Comments

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11.

12.

13. 14. 15.

16.

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Diabetes Metab Res Rev 2015; 31: 680–690 DOI: 10.1002/dmrr