Draft Research Plan

Gestational Diabetes: Screening

February 28, 2019

Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

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This figure is the analytic framework depicting the key questions (KQs) and research approach that will guide the evidence review outlined in this research plan. The far left of the framework describes the target population as asymptomatic, pregnant women without known pre-existing diabetes mellitus. To the right of the population is an arrow representing GDM screening, which results in either a positive or negative GDM diagnosis. Above this line is indication of accuracy of screening tests (KQ4) and prognosis of GDM in patients diagnosed at lower vs. higher glucose thresholds (KQ5). An arrow below this line indicates harms of screening or diagnosis (KQ2). An arrow to the right of the population diagnosed with GDM represents treatment, and another arrow going down indicates harms of treatment (KQ7). To the right of treatment, an arrow (KQ6) leads first to intermediate outcomes and then further to health outcomes. For the mother, short-term outcomes are diagnosis of GDM, pre-eclampsia/hypertension, cesarean delivery, induction of labor, and excessive weight gain; for the fetus/neonate, short-term outcomes are fetal overgrowth (large for gestational age, macrosomia), shoulder dystocia, hypoglycemia, and acute morbidity (e.g., hyperbilirubinemia, respiratory distress syndrome, NICU admission). Long-term intermediate outcomes for mother and child are metabolic impairment (impaired glucose tolerance, type 2 diabetes), obesity, and cardiovascular health. An additional long-term outcome for the child is neurocognitive outcomes. Maternal and childhood health outcomes are mortality and morbidity from type 2 diabetes (e.g., retinopathy, neuropathy) or cardiovascular disease, and quality of life. Health outcomes for the fetus or neonate are mortality and birth injury (i.e., fracture, permanent nerve injury). An overarching arrow extending from the screened population to the intermediate and clinical health outcomes symbolizes KQ1 (the direct benefits of screening) and KQ3 (the comparative effectiveness of different screening strategies based on diagnostic criteria or timing during pregnancy).

* No assumptions will be made about whether hyperglycemia first discovered early in pregnancy (e.g., the first trimester) is GDM or some other form of diabetes; the term “GDM” will include all women who have hyperglycemia but do not meet criteria for overt diabetes at any time point during pregnancy.
† Using two-step (screening and, when indicated, diagnostic testing) or one-step (diagnostic testing only) screening strategies, each based on various criteria and thresholds, and offering treatment to women diagnosed with GDM.
‡ Harms from screening or diagnosis include, but are not limited to, adverse effects of screening tests (e.g., vomiting); anxiety or depression for the mother from screening tests or a GDM diagnosis; and consequences of labeling for the mother, fetus, or newborn (e.g., unnecessary delivery interventions, additional interventions with formula, or separation of newborn and mother).
§ Harms from treatment include severe maternal or fetal/neonatal hypoglycemia and delivery of small for gestational age newborns.

Abbreviations: GDM = gestational diabetes mellitus; IGT = impaired glucose tolerance; KQ = key question; LGA = large for gestational age; NICU = neonatal intensive care unit; T2DM = type 2 diabetes mellitus.

1 a. Does screening for gestational diabetes mellitus (GDM) reduce poor maternal, fetal/neonatal, and childhood health outcomes?
   b. Does screening for GDM reduce poor maternal, fetal/neonatal, and childhood intermediate outcomes?
   c. Does the effectiveness of screening for GDM differ for subpopulations defined by timing during pregnancy, body mass index (BMI), age, or ethnicity/race?
2. What are the harms of screening for GDM to the mother, fetus, or newborn?
3 a. What is the comparative effectiveness of different screening, diagnostic, or combined strategies for maternal, fetal/neonatal, and childhood health outcomes?
   b. What is the comparative effectiveness of different screening, diagnostic, or combined strategies for maternal, fetal/neonatal, and childhood intermediate outcomes?
   c. Does the comparative effectiveness of different screening strategies differ for subpopulations defined by timing during pregnancy, BMI, age, or ethnicity/race?
4  a. What is the diagnostic accuracy of commonly used screening tests for GDM?
    b. Does the accuracy of these screening tests differ for subpopulations defined by timing during pregnancy, BMI, ethnicity/race, or prevalence of GDM?
5. What is the association between a diagnosis of GDM and outcomes in women meeting lower versus higher diagnostic thresholds?
6  a. Does treatment of GDM reduce poor maternal, fetal/neonatal, and childhood health outcomes?
    b. Does treatment of GDM reduce poor maternal, fetal/neonatal, and childhood intermediate outcomes?
    c. Does the effectiveness of treatment of GDM differ for subpopulations defined by timing during pregnancy, diagnostic criteria, BMI, age, or ethnicity/race?
7.  What are the harms of treatment of GDM, including severe maternal and fetal/neonatal hypoglycemia and delivery of small for gestational age newborns?

Contextual questions will not be systematically reviewed and are not shown in the Analytic Framework.

  1. What is the association between measures of blood glucose (e.g., fasting and postload glucose concentration, percent hemoglobin A1c) and outcomes, and does it differ based on timing of diagnosis?
  2. What is the association between GDM diagnosis before 24 weeks of gestation and outcomes, and does it differ based on timing of diagnosis?
  3. How strongly do intermediate outcomes predict long-term or health outcomes in women who have had GDM or their children?
  4. Are postpartum interventions effective for reducing the incidence of long-term and health outcomes in women previously diagnosed with GDM, their children, or both?

The Proposed Research Approach identifies the study characteristics and criteria that the Evidence-based Practice Center will use to search for publications and to determine whether identified studies should be included or excluded from the Evidence Review. Criteria are overarching as well as specific to each of the key questions (KQs).

  Include Exclude
Population KQs 1–5: Pregnant women with no known history of pre-existing diabetes mellitus

KQs 6, 7: Pregnant women with GDM or hyperglycemia

KQs 1c, 3c, 6c: Subpopulations defined by pre-pregnancy BMI (i.e., <25 vs. ≥25 kg/m2, <30 vs. ≥30 kg/m2), age (<25 vs. ≥25 years, <35 vs. ≥35 years), timing during pregnancy, ethnicity/race (i.e., white vs. nonwhite), and severity of hyperglycemia (KQ 6c only)		 Populations in which ≥20% have pre-existing diabetes mellitus
Interventions/ Exposure KQs 1–3: Screening using two- or one-step strategies* followed by treatment of women diagnosed with GDM. In two-step strategies, the screening test must be FPG, 50-g OGCT, risk-based method (clinical or historical using ≥1 factors), or hemoglobin A1c; in one- and two-step strategies, the diagnostic test must be FPG or OGTT.

KQ 4: Screening tests (i.e., FPG, 50-g OGCT, risk-based method, or hemoglobin A1c).

KQ 5: Diagnosis of GDM but no treatment (e.g., criteria at lower threshold than that used by study site for initiating treatment).

KQs 6, 7: Any treatment for GDM, including, but not limited, to dietary advice, blood glucose monitoring, insulin therapy (all preparations), glucose-lowering medications, and combinations thereof.		 KQs 1–5: Alternative methods to delivering glucose (e.g., candy bars).
Comparators KQs 1, 2: No screening

KQ 3: Another screening strategy (i.e., one- vs. two-step screening, different diagnostic criteria and/or cut-offs, different timing in pregnancy, selective/risk-based vs. universal screening)

KQ 4: Any FPG or OGTT used for diagnosis of GDM

KQ 5: No GDM by any criteria applied in the study

KQs 6, 7: No treatment (i.e., no additional management or minimally active intervention, such as printed materials)		 KQs 1–5: Different methods to delivering glucose (e.g., candy bars, glucose loads) with same diagnostic criteria

KQs 6, 7: All active interventions
Outcomes KQs 1, 3, 5, 6:

Health Outcomes
Maternal and childhood: Mortality or major morbidity from type 2 diabetes mellitus (e.g., retinopathy, neuropathy) and/or cardiovascular disease; quality of life
Fetal/neonatal: Mortality (miscarriage, stillbirth, newborn death) or birth injury (fracture, permanent nerve injury)

Intermediate Outcomes
Maternal: Diagnosis of GDM, preeclampsia/maternal hypertension, cesarean delivery, induction of labor, and excessive gestational weight gain (as per guidance from the Institute of Medicine or author defined)
Fetal/neonatal: Fetal overgrowth (large for gestational age or macrosomia), shoulder dystocia, hypoglycemia, and acute major morbidity (e.g., hyperbilirubinemia, NICU admission, respiratory distress syndrome)

Long-Term Outcomes
Maternal: Development of metabolic impairment (IGT, type 2 diabetes mellitus), development of obesity, and cardiovascular health
Childhood: Development of obesity, development of metabolic impairment (IGT, type 2 diabetes mellitus), cardiovascular health, and neurocognitive outcomes

KQ 2: Adverse effects of screening tests (e.g., vomiting), anxiety or depression for the mother from screening tests or diagnosis, and consequences of labeling for the woman, fetus, or newborn (e.g., unnecessary delivery interventions, additional interventions with formula, separation of newborn and mother, breastfeeding challenges/failure)

KQ 4: Sensitivity, specificity, predictive values, accuracy, and yield (i.e., prevalence)

KQ 7: Severe maternal or neonatal hypoglycemia, delivery of small for gestational age newborns

 KQs 1, 3–6: Other outcomes
Outcome assessment timing Any duration of followup  
Setting KQs 1–3, 5–7: Settings applicable to primary care; countries not categorized as “Very High” on the Human Development Index (as defined by the United Nations Development Programme) will be subject to sensitivity analysis

KQ 4: Any setting

  
Study designs KQs 1, 2: RCTs, CCTs, and controlled observational studies

KQ 2: Studies in which all participants are screened but harms are assessed before (i.e., earlier in pregnancy) and after screening

KQ 3: RCTs and CCTs

KQ 4: Prospective cohort studies and single arms of trials

KQ 5: Observational studies and single-arm trials (i.e., arms not receiving treatment)

KQs 6, 7: RCTs, CCTs; controlled observational studies if no trials exist		 Systematic reviews,** abstracts, and conference proceedings
Publication language English  

* Two-step screening involves a screening test (e.g., 50-g OGCT) followed by a diagnostic test (i.e., OGTT), whereas one-step screening involves one test used for diagnosis in everyone.
** Systematic reviews, identified from a preliminary search for reviews on GDM and from searches for primary studies, will be scanned for potentially relevant studies but will not be included as the unit of analysis.

Abbreviations: BMI = body mass index; CCT = controlled clinical trial; FPG = fasting plasma glucose; GDM = gestational diabetes mellitus; IGT = impaired glucose tolerance; KQ = key question; OGCT = oral glucose challenge test; OGTT =oral glucose tolerance test; RCT = randomized, controlled trial.