Summary of the Evidence
Seth C. Brody, M.D.a;
Russell Harris, M.D., M.P.H.b; Kathleen Lohr, Ph.D.c
The authors of this article
are responsible for its contents, including any clinical or treatment
recommendations. No statement in this article should be construed as an
official position from the Agency for Healthcare Research and Quality, or the
U.S. Department of Health and Human Services.
Address correspondence to:
Seth Brody, MD; Department of Obstetrics and Gynecology; University of North Carolina;
Wake Area Health Education Center; 3024 New Bern Avenue, Suite 306; Raleigh,
NC 27610-11255; E-mail: sbrody@med.unc.edu
Select for copyright information. The USPSTF recommendations based on this review are
online.
The summaries of the evidence briefly present evidence
of effectiveness for preventive health services used in primary care clinical
settings, including screening tests, counseling, and chemoprevention. They
summarize the more detailed Systematic Evidence Reviews, which are used by the U.S. Preventive
Services Task Force (USPSTF) to make recommendations.
Contents
Abstract
Epidemiology
Materials and Methods
Results
Discussion
Acknowledgments
References
Notes
Abstract
Objective: To systematically review the evidence for
screening for gestational diabetes mellitus (GDM).
Methods: We established eligibility criteria for
relevant studies. We systematically
searched MEDLINE® and the Cochrane Collaboration Library for studies meeting
eligibility criteria; we supplemented this search with further studies
identified from reference lists of reviews.
Two reviewers examined each article for eligibility. A single reviewer abstracted relevant data
from the included articles; a second reviewer checked the abstractions. We graded the quality of the articles
according to criteria developed by the U.S. Preventive Services Task Force
(USPSTF).
Results: No well-conducted randomized controlled
trial (RCT) provides direct evidence for the health benefits of screening for
GDM. The evidence is unclear about the
optimal screening and reference diagnostic test for GDM. The impact of hyperglycemia on adverse
maternal and neonatal health outcomes is probably continuous. Although insulin therapy decreases the
incidence of fetal macrosomia for those women with more severe degrees of
hyperglycemia, the magnitude of any effect on maternal and neonatal health
outcomes is not clear. The evidence is
insufficient to determine the magnitude of health benefit for any treatment
among the large number of women with GDM at milder degrees of hyperglycemia. We
found limited evidence about the potential adverse effects of screening for
GDM.
Conclusion: Because of the lack of high quality evidence
concerning critical issues, we are unable to determine the extent to which
screening has an important impact on maternal and neonatal health
outcomes. An RCT of screening is
necessary to answer the many remaining questions.
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Epidemiology
GDM is defined as glucose intolerance with the onset or first
detection during pregnancy.1,2 About 135,000 cases of GDM are diagnosed
annually in the United States.2 Important risk factors include higher
maternal age, family history of diabetes, and increased pregravid body mass
index (BMI).3 The prevalence of GDM in low-risk populations
ranges from 1.4 to 2.8 percent;4,5 in high-risk populations, prevalence ranges
from 3.3 to 6.1 percent.4
Markedly elevated
maternal glucose levels most often occur in women with pregestational
diabetes. Pregnant women with
pregestational diabetes are at higher risk for multiple complications affecting
both the mother and the fetus than those women without diabetes. Current therapy improves outcomes for both
mother and neonate.6
The additional risk for adverse
health outcomes attributable to the milder degrees of maternal hyperglycemia
associated with GDM and the magnitude of the benefit from treating that risk
are less certain. No well-designed and
conducted RCT of screening for GDM has been
completed, and thus the evidence for screening is indirect.
National groups disagree about
whether to recommend screening for GDM.2,7-11
Despite no strong recommendations in favor of
universal screening from the American College of Obstetricians and
Gynecologists (ACOG), 94 percent of Fellows
in office-based practices reported performing universal screening for GDM in
1996.12 Fellows performed this screening even though
ACOG acknowledged the weakness in the evidence in both 199413 and 2000.2
With continued
controversy around the advisability of GDM screening, the RTI-University of
North Carolina Evidence-based Practice Center (RTI-UNC EPC) conducted a
systematic evidence review to assist the USPSTF in reconsidering its 1996
review, which found insufficient evidence to recommend screening. We restricted this review to screening for
GDM after 24 weeks' gestation, thus excluding both women with known
pregestational diabetes and those who are discovered by symptoms earlier in
pregnancy.
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Materials and Methods
Sources
Our review of the literature was
guided by key questions and inclusion criteria we developed relevant to the
issue of screening for GDM (Table 1). We
required RCTs for direct evidence of the efficacy of treatment and the harms
associated with treatment. We examined the critical literature from the 1996
USPSTF review and searched MEDLINE® and the Cochrane Library for reviews and
relevant studies published in English between January 1, 1994, and August 30, 2002.
We supplemented this search by examining the reference lists of
pertinent articles and by contacting experts.
We also conducted focused searches of MEDLINE® from 1966 through 1994
to identify older articles of interest.
Study Selection
All searches began by
exploding the term "diabetes, gestational" and then proceeded by adding further
terms. We retrieved the full text of all
articles we thought were potentially eligible.
Two reviewers examined each article for eligibility. A single reviewer abstracted relevant data
from the included articles; a second reviewer checked the abstractions.
We abstracted all
included articles, entered the data into evidence tables, graded the quality of
all articles according to USPSTF criteria,14 and resolved disagreements by
discussion. We synthesized the evidence
into a systematic evidence review; this was subjected to extensive external
peer review and revised as appropriate.15 The final systematic evidence
review, including the evidence tables, is available on the Agency for
Healthcare Research and Quality (AHRQ) Web site (http://www.preventiveservices.ahrq.gov). This article summarizes the evidence from
that review.
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Results
For the USPSTF to
recommend screening for GDM, it must have either direct evidence from a
randomized controlled trial (RCT) of screening or indirect evidence that establishes
a complete linkage between screening and improved health outcomes. We found no well-conducted RCT that provides
direct evidence for the health benefits of screening for GDM. Given this, the USPSTF requires adequate
evidence that:
- Untreated GDM causes substantial maternal and/or neonatal adverse health outcomes.
- Available screening tests accurately and efficiently detect GDM.
- Available treatments improve health outcomes, with a magnitude that clearly justifies the harms and effort of screening and treatment.
These
issues will be examined in the sections that follow.
What Adverse Health Outcomes Occur with Untreated
GDM?
Determining the
existence and magnitude of a causal association between various degrees of GDM
and adverse health outcomes is complex.
We have only older studies of untreated GDM, at a time when obstetric
practice differed from current practice, or more recent studies in which women
received some treatment for GDM. Another
problem with many studies is that they consider GDM as a dichotomous variable,
yet we know that the risk for adverse health outcomes increases with the degree
of hyperglycemia among women with GDM; the impact of hyperglycemia on adverse
maternal and neonatal health outcomes is probably continuous.16-19 Few studies, however, stratify the risks of
GDM by severity of hyperglycemia.
Offspring Health Outcomes
Because the literature is
scant and mixed about whether untreated GDM, given optimal obstetric care
today, is associated with increased perinatal mortality,19-27 the extent to which GDM is truly associated
with perinatal mortality remains unclear.
Macrosomia is an
intermediate outcome of GDM. Three
recent studies of untreated women with GDM20,22,23 found that the percentage of infants
with macrosomia weighing more than 4,000 grams was between about 17 percent and
29 percent; the percentage in the general population is about 10 percent.26 Most infants with macrosomia are born to
women without GDM;28 maternal obesity is an
important potential confounding factor associated with both GDM and
(independently) with macrosomia.
Important adverse
neonatal health outcomes linked to macrosomia are brachial plexus injury and
clavicular fracture. The best (although
minimal) data on untreated women with GDM compared with the non-GDM population
reveal no difference in the rate of infant brachial plexus injury or clavicular
fracture.22 Recent data suggest that
women treated for GDM with more severe degrees of hyperglycemia may have a 2-percent absolute increase in having their infants develop a brachial plexus
injury and a 6 percent increase in having their infants develop a clavicular
fracture.26,29 While these adverse health outcomes are of
concern, the best studies show that 80-90 percent of brachial plexus injuries
resolve by 1 year of life,30-33 and more than 95 percent of clavicular
fractures heal within a few months without residual problems.34-39
GDM may also be a risk
factor for neonatal hypoglycemia. Studies
among untreated20 and treated women with GDM
have found higher rates of neonatal hypoglycemia among untreated women with
GDM. The magnitude of clinically
important neonatal hypoglycemia is less clear.
Also not clear is whether increased surveillance of infants whose mothers
have GDM contributes to the increased finding of hypoglycemia in their infants.
Likewise, the evidence
is limited and unclear as to whether GDM is associated with preterm birth or
neonatal hyperbilirubinemia, hypocalcemia, or polycythemia.1,20,38,40-44 Because of limited evidence and the increased
surveillance given to infants of women with GDM, the magnitude of any
associated adverse health effects is uncertain but is likely to be small.
Some have suggested
that the diagnosis of maternal GDM may have long-term implications for the
offspring, such as an increased risk for impaired glucose tolerance, childhood
obesity, and neuropsychological disturbances.
No large observational study has followed a group of children whose
mothers have GDM and a comparison group whose mothers do not have GDM long
enough to demonstrate whether any of these hypotheses are correct.45-48
Maternal Health Outcomes
The diagnosis of GDM can
also increase adverse health outcomes for the mother during her pregnancy. Limited data since 1980 reveal total cesarean
delivery rates of 22 percent49 to 30 percent22 for unrecognized or untreated
women with GDM, compared with a rate of about 17 percent for women without
GDM. Although the overall literature
suggests an association between GDM and higher cesarean delivery rates,31,50-54 some studies are limited by a lack of
adjustment for maternal obesity and by the impact of the diagnosis of GDM on
clinical decisionmaking.
Limited evidence is available on the rate of
third- or fourth-degree lacerations in women with GDM. Some studies have suggested an increase,30 but the only study that found
a substantial percentage of women with untreated GDM who had such lacerations
included only 16 subjects.26 Another study found equally
low rates among women with GDM and women without GDM.22
Overall, observational
studies have shown mixed results and are inconclusive as to whether women with
GDM have a higher risk for pre-eclampsia than women without GDM.1,39,55-57 Recent data from untreated women with GDM22 reveal a rate of
pre-eclampsia (about 9 percent) that is similar to that for treated women and
women without GDM.58-61
Mothers identified as
having gestational diabetes also have a higher risk for developing type 2
diabetes in the years after delivery.62 Studies investigating the rate of development
of type 2 diabetes after the onset of gestational diabetes have suffered from
low participation rates, retrospective design, short followup, and variation
in definition of both GDM and new diabetes.
Although nearly all studies show that women who have GDM face some
increased risk for developing diabetes, the degree of risk elevation they
experience and the degree of glucose abnormality they develop are uncertain.2 Further, the added benefit of
early detection of diabetes in young women with few cardiovascular risk factors
is uncertain.63
How Accurate and Reliable Are Screening Tests for GDM?
Reference Diagnostic Test
Before we can
determine the accuracy of a screening test, we need a reference diagnostic test
for comparison. Unfortunately, no
universally agreed on reference test for the diagnosis of GDM exists.
Three competing
criteria for diagnostic glucose tolerance tests (GTT) are available (Table 2). Criteria from the World Health
Organization (WHO)64 label twice as many women
with GDM as do criteria from the National Diabetes Data Group (NDDG).65 Criteria from the American Diabetes
Association (ADA)66 give an intermediate
prevalence.2,67-69
Abnormal values on any of the three tests are predictive of fetal macrosomia.11,23,70-72 This association is diminished or eliminated
when adjustments are made for such potential confounders as pregravid weight,
age, parity, and race.
The reliability of any
oral GTT is open to question. In 1 of the few studies on this issue, Harlass et
al. found that 23 percent of 64 unselected pregnant women who had had a
positive screening test for GDM had inconsistent results between two 100-gram
oral GTTs performed 1 week apart.73 Other studies have also raised concerns about the reproducibility of the oral GTT in nonpregnant
groups.74-76
Screening Tests
The thresholds for the reference diagnostic
tests do not clearly distinguish women at high risk from women at low risk for
adverse maternal or neonatal health outcomes from GDM. Thus, we can evaluate screening tests only
against imperfect standards. Most
studies on GDM screening strategies compare the results of one test with the results
of another test rather than examining how the test predicts adverse health
outcomes. Some studies assess the
association of the test with intermediate outcomes such as macrosomia rather
than health outcomes such as brachial plexus injury.
In the United States, the 50-gram, 1-hour glucose
challenge test (GCT) is most commonly used for screening (Table 2). Two groups have proposed different threshold
criteria to define a positive screening test.
If the GCT glucose value is above either 130 mg/dL77 or 140 mg/dL,65 then the patient is usually
given the 100-gram GTT for diagnosis.
Using the 130 mg/dl threshold, the GCT is positive for 20-25 percent of
all pregnant women, including 90 percent of women with GDM. Using the 140 mg/dl
threshold, the GCT is positive for 14-18 percent of all pregnant women, including
about 80 percent of women with GDM.67
In the general
population, false-positive results for the GCT are common. Fewer than 1 in 5 women with a positive GCT
will meet criteria for GDM on a full 100-gram GTT.78 The reliability of the GCT is also
problematic.16
In many countries
outside North America, clinicians use the WHO screening
approach: the 75-gram 2-hour oral GTT as
a single-step screening and diagnostic test.
As noted above, this approach identifies at least twice as many women as
having GDM as the two-step approach, although the evidence is sparse about
whether the one-step test is more or less predictive of adverse health outcomes
than the two-step approach.68,69
Because glucose
intolerance increases during pregnancy, screening for GDM is most commonly
conducted during the 24th to 28th week of gestation. However, this timing is not based on any
evidence that this is the optimal time to identify women who would benefit most
from treatment. Determining the best
time to screen involves examining the trade-off between the potential benefits
of early screening (i.e., finding fewer women at higher risk and treating them
for a longer time) and the potential benefits of later screening (i.e., finding
a larger number of women at lower risk and treating them for a shorter time).19 We found no study on this issue.
One suggested approach
to improve the efficiency of screening for GDM is to restrict screening to
women at higher risk ("selective screening") rather than screening all women
("universal screening"). In the most detailed
study of selective screening strategies, Naylor et al. developed a scoring
system that excluded nearly 35 percent of women from screening and actually
detected more cases of GDM than universal screening.61
In summary, the
evidence is unclear about the optimal screening and reference diagnostic test
for screening for GDM.
Does Treatment for GDM Improve Health Outcomes?
Glycemic Control
Three factors are important in considering
studies that evaluate the impact of tight glycemic control on health outcomes
for women with GDM:
- The first is the
degree of hyperglycemia in study participants.
As the risk for at least some adverse health events increases with an
increasing degree of hyperglycemia, the potential absolute risk reduction may
be larger with higher glycemic levels.
More than 70 percent of women diagnosed with GDM have mild hyperglycemia
and are usually treated with diet alone.24,41,79
- The second important
factor is the degree of separation of glycemic control between treatment
groups. If intensive treatment does not
produce a reasonable reduction in glycemic level compared with conventional
treatment (or no treatment), the hypothesis of improved glycemic control
leading to better health outcomes cannot be tested.
- The third factor in
considering these studies is assessment of outcomes: which ones to assess and
how to assess them. Most of these
studies focused on intermediate outcomes such as fetal macrosomia or chemical
findings such as neonatal hypoglycemia.
Intermediate outcomes are useful only insofar as they predict important
health outcomes that people care about.14 In the case of fetal macrosomia, an
intermediate outcome, only a small percentage of these cases lead to maternal
or neonatal trauma. In the case of
chemical findings (e.g., glucose or bilirubin level), few studies reported the
percentage of abnormalities that required treatment; no study was clearly
reassuring that differences attributed to improved glycemic control were not
associated instead with more intense surveillance of infants born to GDM
mothers. Finally, because few of these
studies masked the obstetricians,80,81 interventions or outcomes that depend on clinician judgment (e.g., cesarean
delivery rates) could be biased by knowledge of GDM status.22
Table 3 records data
from nine RCTs examining the impact of therapy on a variety of outcomes.20,29,58-60,80-83 The first four RCTs are of women with mild
hyperglycemia20,80,81,83 and the last five are of women with severe or
very severe hyperglycemia.29,58-60,82
Mild Hyperglycemia. Few studies have examined the effectiveness
of intensive compared with less intensive glycemic control among women with GDM
who have mild hyperglycemia. An overview
of 4 trials that included 612 women with mild hyperglycemia found no difference
in adverse health outcomes between the women treated with a modified diet and
the women receiving no therapy.84 The Li et al. RCT made a similar comparison
and had similar findings.81
Three RCTs compared
intensive with less intensive glycemic control (achieving some glycemic
separation) among women with GDM who had varying degrees of hyperglycemia but a
low mean entry fasting plasma glucose (FPG) or mean hemoglobin A1c (HbA1c).20,80,83 Two studies found statistically significant
improvements in intermediate outcomes for those women undergoing intensive
glycemic control (e.g., fewer large-for-gestational age [LGA] infants83; lower incidence of neonatal
hypocalcemia20); no study found clear differences in health outcomes
between glycemic control groups.
Severe Hyperglycemia. Four RCTs examined tight and less tight
glycemic control among women with GDM at more severe hyperglycemic levels
(Table 3).29,58,60,82 Of these trials, three achieved either small or no
difference in glycemic control between groups and found no difference in major
outcomes.29,58,60 One trial found a small absolute reduction in
chemical abnormalities in the neonate58; another found a reduction in
cesarean deliveries that was not explained by fetal size.29
One study achieved a
larger glycemic separation between groups (difference in mean glucose, 24
mg/dL).82 The infants of less
intensively treated women had a higher mean birth weight plus higher rates of
neonatal hypoglycemia and polycythemia. These differences were small and of
uncertain clinical importance.
Finally, de Veciana et
al. compared tight with less tight control among women with very severe
hyperglycemia, some of whom likely had frank diabetes (Table 3).59 They also achieved the
largest separation in glycemic control (HbA1c difference of 1.6 percent) and
found some of the larger reductions in fetal macrosomia and neonatal
hypoglycemia. Given the study population, however, this trial may have little
relevance for the great majority of women detected with GDM.
A major issue in all
of these trials is that they have too few participants to be able to detect
small differences among treatment groups in such uncommon adverse health
outcomes as perinatal mortality and brachial plexus injury. They have even less power to determine
whether the health benefit is different for women with GDM who have severe
hyperglycemia compared with those who have mild hyperglycemia. They provide insufficient evidence to confirm
or refute the hypothesis that glycemic control improves health outcomes for
women with GDM.
Several observational
studies without randomized controls have suggested improved intermediate or
health outcomes with more intensive treatment of women with GDM.22,71,85-91 The weakness in these studies is that women in
the treatment groups differ from women in the control groups in multiple ways
(some known and some unknown) other than glycemic control; most of the known
factors are also associated with health outcomes. Thus, observed improvements in health
outcomes may be attributable to factors other than glycemic control.
In summary, although
insulin therapy decreases the incidence of fetal macrosomia for those women
with more severe degrees of hyperglycemia, the magnitude of any effect on
maternal and neonatal health outcomes is not clear. The evidence is insufficient to determine the
magnitude of health benefit of tight glycemic control among the large number of
women with GDM at milder degrees of hyperglycemia.
Antepartum Surveillance
Various approaches to
antepartum surveillance might improve health outcomes among women with GDM. For
non-stress testing (NST) or biophysical profile (BPP) to constitute a rationale
for GDM screening, evidence would need to show that the use of these tests
reduces stillbirth among women with GDM who have no other indication for these
tests. This would require a large RCT,
as most women with GDM have a low risk for having a stillbirth. No completed study of women with GDM has
examined health outcomes among groups randomized to receive or not receive NST
or BPP. Observational studies have found
that using NSTs or BPPs in women with GDM is associated with either absent or
very low rates of stillbirth.92-95 Without appropriate control groups we do not
know whether the low rate of fetal death can be attributed to the additional
procedures.94 NSTs or BPPs have high
false-positive rates,92,95 and they lead to interventions94 that may, on occasion, be
unnecessary.
Ultrasound assessment
of abdominal circumference to allow improved targeting of insulin therapy in
order to decrease fetal macrosomia and birth trauma has been studied. Three RCTs have enrolled women with hyperglycemia
into insulin therapy triggered by ultrasound abdominal circumference.29,83,96 These studies have not found any important
differences in health outcomes; all three lacked power to detect differences in
health outcomes and in none were the obstetricians masked to the intervention
group.
What
are the Harms and Costs of Screening and Treatment?
Precise evidence on
the harms and costs of screening for GDM and early treatment is lacking. Although not well documented, the potential
for adverse psychological effects from screening is real; in the general
population, more than 80 percent of all positive GCT screening tests are false
positives.97 Limited and mixed data
suggest that labeling may negatively influence women's perceptions of their
health during pregnancy97-100 and that women diagnosed with GDM may have
long-term changes in their perception of their own health.98,101 The long-term impact of these changes in
perception of health is unclear.
Identification of GDM may also needlessly
increase the use of NSTs or BPPs (triggering unnecessary interventions due to
false positives) and rates of cesarean delivery (because of a lowered
intervention threshold).22,70 Furthermore, additional tests and
procedures increase the cost of
screening programs. Because of the lack
of evidence, the magnitude of other potential harms of aggressive
glycemic-lowering therapy, such as increased maternal starvation ketosis and
infants who are small for gestational age, is difficult to quantify.18,102
As the effectiveness
of screening in improving health outcomes is uncertain, so the
cost-effectiveness cannot be calculated with any precision. We do not have good information about the
differences in health care costs between screened and unscreened women.
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Discussion
Maternal and neonatal
morbidity increase with increasing levels of maternal hyperglycemia. Screening and intensive treatment for GDM aim
to reduce this morbidity. Various
screening strategies can detect women with different degrees of hyperglycemia,
but the threshold at which health outcomes begin to deteriorate to a clinically
important degree is uncertain.
The magnitude of any
benefit of intensive treatment at the various levels of hyperglycemia
associated with GDM is also uncertain, but it is likely to be small among the
many women with mild hyperglycemia. For
women with GDM who have more severe hyperglycemia, intensive treatment is
likely to reduce macrosomia. The extent
to which this translates into reductions in birth trauma is uncertain but
probably substantially less than reductions in macrosomia.
The evidence about the
health outcomes of intensive treatment of women with GDM at various levels of
maternal hyperglycemia is indirect. It
is also limited by a small number of studies, small number of participants,
lack of masking of obstetrical care, lack of control for important confounders,
and lack of emphasis on health outcomes rather than intermediate outcomes.
By making various
assumptions, we can calculate the number needed to screen (NNS) to prevent
various adverse health outcomes. Take,
for example, the number of women needed to screen to prevent one case of brachial
plexus injury (Table 4). Assume that 4
percent of pregnant women have GDM,2 that 30 percent of them will
have a high enough glycemic level to require insulin,79 and that, among these women,
the macrosomia rate is reduced to the degree seen in the most positive study.59 The NNS to prevent one
brachial plexus injury is about 8,900 (Case 1, Table 4).32,33,103 If we make more generous assumptions, the NNS
becomes 3,300 (best case scenario, shown in Case 3 and footnote, Table 4). Assumptions including a lesser reduction in
macrosomia, accounting for cesarean delivery rates, or using an outcome of
permanent brachial plexus injury, would give much higher NNS estimates.2
One potential benefit
of detecting women with GDM is the knowledge that they have a higher risk for
developing type 2 diabetes. The extent
to which this information can lead to a health benefit for younger women with
few cardiovascular risk factors, however, is uncertain.63
The evidence
concerning the harms and costs of screening and intensive treatment is even
more limited than the evidence about benefits, but several harms are of
concern. Many women may suffer anxiety
of uncertain duration because of a false-positive screening test. Labeling women with GDM as having an increased risk for future GDM and type 2 diabetes may have psychological
implications. Detection of GDM may
increase the probability of cesarean delivery; multiple antenatal tests may
increase the probability of a false-positive test leading to unnecessary
procedures. Costs may be increased with
little health benefit for many women, especially those many women with mild
hyperglycemia.
It is difficult to see
how the issue of screening for GDM can be clarified without large RCTs with an
untreated control arm, masked obstetrical care, and measurement of health (not
just intermediate) outcomes. These
studies should also monitor and report harms and costs associated with
screening and intensive treatment. The
National Institute for Child Health and Human Development is sponsoring one
such study—the Maternal-Fetal Medicine Network multicenter trial of treatment
of mild GDM, involving approximately 2,400 women—to be completed in 2004.
Screening for GDM is contentious. The reason for this controversy is largely a
lack of high-quality research addressing the central issues. Only good research can end the controversy
and inform us how to best serve our patients.
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Acknowledgments
This study was developed by the RTI-UNC Evidence-based Practice Center under
contract to the Agency for Healthcare Research and Quality (Contract
No. 290-97-0011), Rockville, MD.
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