STAT E O F T H E A RT R E V I E W

Novel therapies for diabetes mellitus in

pregnancy
Maisa N Feghali,1 Christina M Scifres2
1
Department of Obstetrics,
Gynecology and Reproductive A B S T RAC T
Sciences, Magee-Womens
Research Institute, University of
Diabetes is a common complication of pregnancy, and the prevalence of all types of
Pittsburgh School of Medicine, the disease is increasing worldwide. Diabetes in pregnancy is associated with short
Pittsburgh, PA, USA
2
Department of Obstetrics and term and long term adverse effects for mother and child. The goal of treatment of
Gynecology, University of Oklahoma
College of Medicine, Oklahoma City,
diabetes in pregnancy is to minimize maternal and fetal adverse events related to
OK, USA hyperglycemia. Treatment options vary by type of diabetes, from a focus on lifestyle
Correspondence to: M Feghali
maisafeghali@gmail.com modifications in gestational diabetes to continuous glucose monitoring and insulin
Cite this as: BMJ 2018;362:k2034 pumps in pregestational diabetes. Nevertheless, given the commonality of hyper-
doi: 10.1136/bmj.k2034
glycemia, considerable overlap exists in the treatment of different types of diabetes
Series explanation: State of the
Art Reviews are commissioned in pregnancy. Also, despite ongoing research on treatment of diabetes in pregnancy
on the basis of their relevance to
academics and specialists in the US
for decades, changes in the characteristics of the patient population have high-
and internationally. For this reason lighted the limited effectiveness of different therapies. Specifically, despite the co-
they are written predominantly by
US authors occurrence of obesity and diabetes, treatment recommendations including glycemic
targets are not altered in such cases and a single optimal treatment strategy for each
type of diabetes in pregnancy does not seem to exist. Rather, the approach to treat-
ing pregnant women with diabetes likely needs to be individualized to maximize the
short term and long term health of mother and child. This article will review recent
clinical studies to summarize established treatment strategies and introduce novel
therapies for diabetes in pregnancy.

Introduction therapies for diabetes in pregnancy (table 1). We will

Diabetes affects 6-9% of pregnancies with approximately
99% of women having gestational diabetes, 0.5% having
type 2 diabetes, and 0.3% having type 1 diabetes.1‑4 In
particular, the prevalence of gestational diabetes varies
by population and diagnostic criteria.5 The prevalence of
both gestational and pregestational diabetes is increas-
ing, likely owing to the increasing obesity rates.2 3 6 7 All
types of diabetes are associated with increased risk for
hypertensive disorders of pregnancy, excessive fetal
growth, fetal demise, macrosomia, and neonatal morbid-
ity, along with long term risks for obesity and diabetes
in the offspring.8 9 Unique to pregestational diabetes is
the risk for early pregnancy loss and congenital anoma-
lies, which is directly linked to periconception glycemic
control.
The goal of diabetes treatment in pregnancy is to mini-
mize maternal and fetal adverse events related to hyper-
glycemia. Physiologic changes of pregnancy include
progressive increases in insulin resistance, weight gain,
and changes in body composition, and each of these
changes may affect the pharmacologic properties of dia-
betes treatment (fig 1). Treatment options vary by type
of diabetes, but given the considerable overlap we have
organized our review by treatment, summarizing est­
ablished treatment strategies and highlighting novel
focus on recent clinical studies that have evaluated vari-
ous lifestyle and therapeutic options for women with dia-
betes in pregnancy.
Sources and selection criteria
We obtained the references for this review from vari-
ous sources including PubMed, Clinicaltrials.gov, and
the Cochrane Database of Systematic Reviews (1990 to
April 2018) by using the following terms: “diabetes in
pregnancy”, “gestational diabetes”, “diet and diabetes
in pregnancy”, “lifestyle modifications and diabetes
in pregnancy”, “exercise and diabetes in pregnancy”,
“obesity and diabetes in pregnancy”, “glyburide in
pregnancy”, “metformin and pregnancy”, and “insulin
and pregnancy”. We prioritized articles on the basis of
study method (randomized controlled trials (RCTs) and
meta-analyses over longitudinal observational studies,
and cohort studies) and their date of publication. We
included only full text, English language, peer reviewed
publications. We used clinical guidelines from the Ameri-
can Congress of Obstetricians and Gynecologists (ACOG),
the Royal College of Obstetricians and Gynaecologists
(RCOG), the Royal Australian and New Zealand College of
Obstetricians and Gynaecologists (RANZCOG), the Inter-
national Association of the Diabetes and Pregnancy Study

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 STAT E O F T H E A RT R E V I E W

potential teratogenic effects. Preconception counseling

may also be useful in women at high risk for gestational
B,QVXOLQVHFUHWLRQ
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0HWIRUPLQ a strong family history of diabetes, or have impaired
$FDUERVH glucose tolerance (fig 3). One challenge is that many
pregnancies are unplanned, and novel interventions to
encourage family planning efforts in women with diabe-
?*OXFRQHRJHQHVLV tes are urgently needed.
B/LSRJHQHVLV
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Lifestyle modifications including diet, exercise, and
0\RLQRVLWRO B/LSRJHQHVLV weight management are first line treatment in women
DPSOLI\LQVXOLQVLJQDOLQJ ,QVXOLQ with gestational diabetes and important adjuncts to
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gain recommendations are based on the Institute of Medi-
,QVXOLQ ?,QVXOLQUHVLVWDQFH B*OXFRVHUHQDO cine’s guidelines for weight gain during pregnancy, which
B*OXFRVHFRQVXPSWLRQ H[FUHWLRQ account for maternal body mass index but are unchanged
([HUFLVH 6*/7LQKLELWRUV
by a diagnosis of diabetes in pregnancy.11 Exercise may
improve glucose tolerance during pregnancy in women
Fig 1 |  Potential treatments for diabetes in pregnancy and their proposed mechanism of action.
CPAP=continuous positive airway pressure
with gestational diabetes, and the ACOG and ADA have
endorsed exercise as a helpful adjunct therapy in the
treatment of diabetes.1 3 4
Groups (IADPSG), the National Institute for Health and Between a third and a half of women with gestational
Care Excellence (NICE), the Endocrine Society, and the diabetes are able to achieve glycemic control with diet
American Diabetes Association (ADA). We prioritized the alone,12 but the optimal diet in pregnant women with dia-
results of guidelines in this review for quality according betes is debated. The ACOG and the Endocrine Society
to the method outlined by the United States Preventive support a low carbohydrate diet, whereas the ADA and
Services Task Force. the Fifth International Workshop on Gestational Diabe-
tes have withdrawn specific recommendations on diet
Preconception care or macronutrients for women with diabetes because of
In women with pregestational diabetes, preconception the absence of adequate RCTs.3 4 13 14 A diet low in simple
care includes optimizing glycemic control before concep- carbohydrates (33-40% of calories) is thought to limit
tion with a hemoglobin A1c goal of 6.5% (48 mmol/mol) postprandial glucose excursions and the associated risk
to minimize the risk of congenital anomalies (fig 2).1 3 10 of excessive fetal growth.15 However, this approach neces-
Preconception counseling visits can also include assess- sitates an increase in dietary fat,15 which may promote
ment for comorbidities and a review of drugs to discuss insulin resistance in humans and has resulted in adipos-
ity, hepatic steatosis, and metabolic syndrome in off-
Table 1 | Summary of treatments for diabetes in pregnancy spring in animal models.16 Maternal triglyceride and free
Standard use Emerging use fatty acid concentrations are strong predictors of excess
Non-drug treatments fetal fat accretion, so a low carbohydrate, higher fat diet
Preconception Identify comorbidities, improve glycemic control, and – may have unintended consequences on fetal health.17‑19
care discontinue teratogenic drugs (T1DM and T2DM) Recent RCTs in women with gestational diabetes sug-
Lifestyle Low carbohydrate diet (GDM); exercise (GDM, T1DM, Diet high in complex carbohydrates (GDM) gest that a diet higher in complex carbohydrate and fiber,
changes and T2DM); limited gestational weight gain (GDM,
T1DM, and T2DM) low in simple sugar (low glycemic index), and lower in
Glucose Increase self monitored blood glucose (T1DM and CGM-CSII loop systems (T1DM and T2DM); saturated fat may be effective in blunting postprandial
monitoring T2DM); start self monitored blood glucose (GDM); flash glucose monitoring (T1DM and hyperglycemia, preventing worsened maternal insulin
continuous glucose monitoring (T1DM and T2DM) T2DM)
resistance and excess fetal growth.20 21 In a recent crosso-
Drug treatments
ver pilot study, 16 pregnant women with gestational dia-
Insulin Short and intermediate acting insulin treatment CGM-CSII loop systems (T1DM and T2DM);
(GDM, T1DM, and T2DM); long acting insulin ultralong acting insulin (T1DM and T2DM); betes were randomized to a higher complex carbohydrate
treatment; insulin pump (T1DM and T2DM) glargine U-300 (T1DM and T2DM) (60%), lower fat (25%) diet or a conventional low carbo-
Glyburide Glycemic control (GDM) Glycemic control (T2DM); combination hydrate (40% of calories), higher fat (45% of calories)
glyburide and metformin for glycemic diet at the time of diagnosis.22 The higher carbohydrate
control (GDM)
diet resulted in a slightly higher (by 6%; P=0.02), but well
Metformin Glycemic control (GDM) Glycemic control (T2DM); combination
glyburide and metformin for glycemic below current glycemic targets, area under the curve for
control (GDM); combination insulin and 24 hour glucose. However, in a separate pilot study of
metformin for glycemic control (T2DM); 12 women with gestational diabetes who followed the
prevention of hypertensive disorders
of pregnancy in overweight and obese complex carbohydrate and fiber diet for seven weeks,
women (GDM) postprandial free fatty acids were 20% lower (P=0.06)
CGM=continuous glucose monitoring; CSII=continuous subcutaneous insulin infusion; GDM=gestational diabetes mellitus; and measures of maternal insulin resistance and infant
T1DM=type 1 diabetes; T2DM=type 2 diabetes.
adiposity were improved, although these differences

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 STAT E O F T H E A RT R E V I E W

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Fig 2 |  Suggested treatment algorithm for pregestational diabetes in pregnancy. CGM=continuous glucose monitoring; CSII=continuous subcutaneous insulin
infusion

were not sugnificant.23 These findings suggest a possi-
ble benefit of eating more complex carbohydrates and
less fat. However, more definitive studies are needed to
better define the optimal diet for pregnant women with
diabetes, especially in obese women and in women with
pregestational diabetes.
Glucose monitoring
Blood glucose monitoring is a cornerstone of diabetes
management in pregnancy. Fasting and postprandial
blood glucose monitoring is recommended in all type of
diabetes, and preprandial testing is also recommended
for pregnant women with pre-existing diabetes who
are using insulin pumps or basal-bolus therapy.1 3 4 10
Although HbA1c assessment is less burdensome than fre-
quent daily testing, it is considered a secondary measure
of glycemic control in pregnancy because A1c concentra-
tions fall during normal pregnancy owing to red blood
cell turnover and HbA1c does not reflect variability in
glucose concentration.1 3 10
Continuous glucose monitoring (CGM) technology was
assessed in the CONCEPTT study, which randomized 325
pregnant women with type 1 diabetes to real time CGM
or capillary glucose monitoring.24 Real time CGM users

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 STAT E O F T H E A RT R E V I E W

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Fig 3 |  Suggested treatment algorithm for gestational diabetes in pregnancy. GDM=gestational diabetes mellitus

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 STAT E O F T H E A RT R E V I E W
spent more time in target (68% v 61%; P=0.003) and
had less hyperglycemia (27% v 32%; P=0.028) between
randomization and 34 weeks’ gestation.24 CGM use was
also associated with an approximately 50% reduction in
large for gestational age (LGA) births (odds ratio 0.50,
95% confidence interval 0.28 to 0.90), admission to a
neonatal intensive care unit (NICU) (0.48, 0.26 to 0.86),
and neonatal hypoglycemia (0.45, 0.22 to 0.89).24
In addition, an RCT that assigned 340 women with ges-
tational diabetes to either self monitored glucose or self
monitored glucose plus intermittent CGM use found that
CGM use was associated with lower mean birth weight
(3138 (SD 484) v 3345 (508) g; P<0.001), less macroso-
mia (4.1% v 10.8%; P=0.03), less pre-eclampsia (3.4%
v 10.1%; P=0.02), and fewer primary cesarean deliver-
ies (34.7% v 46.6%; P=0.03).25 By comparison, a recent
multicenter RCT found no significant difference in the risk
of macrosomia between CGM and self monitored glucose
in 300 pregnant women with gestational diabetes and
pregestational diabetes.26
More recent trials published in the past two years have
focused on devices that use flash glucose monitoring
(FGM) technology, which can be worn for a period of
time; users can obtain glucose measurements instantly by
scanning the glucose sensor with the reader, producing
real time data. Studies on the efficacy of FGM are limited
to non-pregnant adults. Two RCTs, one including 328
adults with type 1 diabetes and another in 224 adults
with type 2 diabetes, compared FGM with self monitor-
ing of blood glucose for six months. Both found that FGM
was associated with reduced rates of hypoglycemia (in
type 1 diabetes, time in hypoglycemia reduced by 0.14
hours on average per day (P<0.001); in type 2 diabetes, by
0.70 hours on average per day P<0.001) and high patient
satisfaction based on few adverse events attributed to
the device.27 28 However, in a pilot RCT in 40 adults with
type 1 diabetes and a history of severe hypoglycemia or
impaired awareness of glycemia, real time CGM use was
associated with less time spent below 59.4 mg/dL (3.3
mmol/L) compared with FGM (2.4% v 6.8%; P=0.006).29
Studies on FGM use in pregnancy are limited to a sin-
gle case report and a published abstract that noted good
agreement between FGM and capillary glucose monitor-
ing in 74 pregnant women (24 with type 1 diabetes, 11
with type 2 diabetes, and 39 with gestational diabetes).30
Further studies are needed to assess the utility of FGM
in pregnancy, but this technology has appeal given the
frequency of blood glucose monitoring in pregnancy.
Optimal glycemic targets
Fetal adiposity is strongly associated with elevated mater-
nal glucose, and approximately 15-20% of pregnant
women with diabetes whose glucose targets are within
current clinical targets still deliver macrosomic infants
who are at increased risk for long term metabolic dys-
function.31‑33
The Hyperglycemia and Pregnancy Outcomes (HAPO)
study better defined the relation between maternal gly-
cemia and fetal overgrowth, but current pregnancy gly-
cemic targets have not been rigorously defined or tested
in RCTs. In an observational study in pregnant women
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without diabetes, mean fasting (70.9 (SD 7.8) mg/dL (3.9
(0.4) mmol/L)) and one hour postprandial (108.9 (12.9)
mg/dL (6.1 (0.7) mmol/L)) blood sugars as assessed by
continuous glucose monitoring (CGM) were significantly
lower than the current fasting (<95 mg/dL (5.3 mmol/L))
and one hour postprandial (<140 mg/dL (7.8 mmol/L))
glucose targets in pregnancies with diabetes, suggest-
ing that current glycemic targets may be too high.34 In
particular, obese women with gestational diabetes are at
higher risk for adverse pregnancy outcomes than their
normal weight counterparts,35 and obese women also
have higher mean fasting and postprandial blood sugars
despite higher doses and more frequent use of drugs.12 In
a retrospective cohort of 1344 women with gestational
diabetes, obese women who had fasting blood glucose
above 88.7 mg/dL (4.9 mmol/L) or one hour postprandial
blood glucose above 123.8 mg/dL (6.9 mmol/L) were at
the highest risk for macrosomia, suggesting that tighter
glycemic control could help to optimize outcomes in
this high risk population.12 Lower glycemic targets may
require more intensive dietary modification and both ear-
lier and more aggressive dosing of drugs. This is the basis
for ongoing studies such as the GDM-MOMS study, which
is randomizing overweight and obese women with gesta-
tional diabetes to either standard glycemic targets (fasting
<95 mg/dL (5.3 mmol/L), one hour postprandial <140
mg/dL (7.8 mmol/L)) or more intensive glycemic control
(fasting <90 mg/dL (5 mmol/L), one hour postprandial
<120 mg/dL (6.9 mmol/L)) and is expected to report in
early 2009 (NCT02530866).
Insulin
Insulin is the preferred treatment for pregestational dia-
betes in pregnancy, and several professional societies
endorse it as a first line therapy in gestational diabe-
tes.3 4 The type of insulin, timing of administration, and
frequency are based on individual glycemic patterns. In
women with pregestational diabetes, insulin is tradition-
ally administered through multiple daily injections (MDI)
combining short acting insulin for mealtime excursion
and long acting insulin for basal glycemic control. The
safety and efficacy of long acting analogs such as glargine
and detemir have been demonstrated in pregnancy.36‑39
Although commonly used, most insulin analogs have not
been specifically tested in women with gestational dia-
betes, and few studies provide data specific to this popu-
lation. A comprehensive discussion of different insulin
formulations is beyond the scope of this review, and we
will limit the discussion to an overview of established for-
mulations followed by a focus on novel therapies. Data
are lacking on newer insulin analogs, with no published
reports on the use of Toujeo, Lispro-U200, or Basalgar
in pregnancy at the time of writing and a single report
of two pregnancies treated with degludec from the first
trimester of pregnancy.40 No malformations were seen
in the infants, but both needed admission to NICU due
to hypoglycemia.40 Given the lack of data, use of newer
insulin analogs in pregnancy should be further explored.
Recent technological advances have resulted in a pro-
grammable pump device that can manipulate the tim-
ing, quantity, and type of insulin through a continuous
 STAT E O F T H E A RT R E V I E W
subcutaneous insulin infusion (CSII). These devices can
be programmed to provide varying basal and bolus con-
centrations of insulin at differing times during the day,
without abrupt changes and additional injections. Out-
side of pregnancy, the benefits of CSII compared with MDI
include lower hemoglobin A1c levels, reduced variation
and blood glucose concentrations, fewer hypoglycemic
episodes, reduction in total daily insulin dose, and more
flexibility of lifestyle.41 However, the value of CSII in
improving pregnancy outcomes remains unclear.42‑44
A retrospective study assessed two comparable groups
of women with type 1 diabetes, of whom 100 were using
CSII and 44 were using MDI. Metabolic control deter-
mined by HbA1c measurements every trimester improved
during pregnancy in both groups, but control was
achieved earlier (second trimester compared with end of
pregnancy) among participants using CSII.45 At parturi-
tion, patients using CSII had lower HbA1c levels (6.2%
(SD 0.7%) v 6.5 (0.8%) (44 v 48 mmol/mol); P=0.02)
and needed less insulin (P<0.01). However, maternal
and neonatal outcomes did not differ.44 Similar find-
ings of improved HbA1c levels with CSII versus MDI were
reported in a case-control study in 99 pregnant women
with diabetes, again with no differences in maternal or
neonatal outcomes.46 A recent systematic review of six
RCTs that compared the use of multiple daily insulin
with CSII in 213 pregnant women found no significant
differences between groups, including the frequency of
maternal (odds ratio 1.35, 95% confidence interval 0.60
to 3.03) and neonatal hypoglycemia (1.31, 0.59 to 2.94)
and the rates of preterm birth (1.29, 0.45 to 3.71), cesar-
ean delivery (1.39, 0.76 to 2.55), stillbirth (2.5, 0.53 to
11.77), and LGA infants (1.04, 0.36 to 3.01).43
Subsequent studies have focused on the combination
of CSII with CGM. The CONCEPTT study, described earlier,
stratified women by insulin delivery (CSII or MDI) and
found that CGM reduced hyperglycemia, limited glycemic
variability, and improved HbA1c levels for CSII and MDI
users.24 Also, sensor augmented insulin pumps have been
developed to integrate real time CGM and insulin pump
technologies. A proof of principle crossover trial was
performed in 16 pregnant women with type 1 diabetes.47
Women were randomly assigned for a four week period
to using a CSII pump and a continuous glucose sensor
with or without tablet computer software that automati-
cally adjusted the pump basal insulin rate at night. After
four weeks, they switched to the other treatment group.47
Closed loop therapy resulted in a higher percentage of
time in the designated euglycemic range (63-140 mg/dL
(3.5-7.8 mmol/L)) than control therapy (74.7% v 59.5%;
95% confidence interval for the difference 6.1 to 24.2;
P=0.002), and the overnight mean glucose concentration
was lower with closed loop therapy than control therapy
(119 v 133 mg/dL (6.6 v 7.4 mmol/L); P=0.009).47 After
the initial eight week trial, 14 women continued to use
the closed loop system for approximately 15 additional
weeks, including time in labor and delivery. In these
women, glucose concentrations were in the target range
68.7% of the time with a mean concentration of 126 mg/
dL (7.0 mmol/L).47 However, no clear benefit of closed
loop therapy on adverse pregnancy outcomes was seen,
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as 13 of the 16 newborns in the study cohort had a birth
weight greater than the 90th centile.47
Two recent systematic reviews found no evidence to
recommend one type of insulin or insulin regimen over
another or continuous glucose monitoring over intermit-
tent monitoring.48 49 Although the findings from CON-
CEPTT are encouraging, and despite the advances in CSII
and CGM, rates of adverse pregnancy outcomes remain
high in women with type 1 diabetes. Further studies are
needed to explore combining CSII and CGM with other
treatment modalities to further reduce maternal and fetal
risks.
Metformin
Metformin is a biguanide that decreases hepatic glucose
output, decreases intestinal glucose absorption, and
increases peripheral glucose uptake in muscles and adi-
pocyte cells.50 Metformin is a hydrophilic compound with
low molecular weight and low binding capacity to plasma
proteins, and trans-placental passage occurs in a dose
dependent manner that is most likely carrier dependent.51
Observational studies have shown that concentrations
of metformin in cord blood range from 50% to 100% of
maternal concentrations, and fetal concentrations may
even be higher than maternal concentrations.52‑54 Met-
formin does not seem to affect human placental glucose
uptake or transport.55
Metformin to treat diabetes in pregnancy
Table 2 provides a summary of studies that have compared
metformin with either insulin or glyburide. The MiG study
remains the largest RCT comparing metformin plus insulin
if needed with insulin alone, and this study has played an
important role in recent recommendations that metformin
can be considered as an acceptable alternative to insulin
for treatment of gestational diabetes.56 We will discuss the
data that led to these recommendations and the ongoing
concerns about use of metformin in pregnancy.
In the MiG trial, glycemic control was similar between
the two groups, but 46% of women in the metformin
group needed supplemental insulin.56 Rates of neonatal
composite morbidity were similar between groups, but
metformin treatment was associated with fewer instances
of severe neonatal hypoglycemia.56 In contrast, met-
formin was associated with more preterm birth (12.1% v
7.6%; P=0.04).56 It was also associated with less weight
gain between study enrollment and 36-37 weeks’ gesta-
tion (0.4 (SD 2.9) kg in the metformin group versus 2.0
(3.3) kg in the insulin group; P<0.001).56 Importantly,
metformin had good patient acceptability, with 76.6% of
women suggesting that they would choose metformin in a
subsequent pregnancy compared with 27.2% of women
assigned to insulin who would choose that.56
Several systematic reviews and meta-analyses have
compared outcomes between women treated with met-
formin and either insulin or glyburide. These meta-anal-
yses have reached disparate conclusions, likely owing to
their varied approaches and whether unpublished studies
or those also enrolling women with type 2 diabetes were
included. The systematic review by Balsells et al found
that metformin was associated with less maternal weight
 STAT E O F T H E A RT R E V I E W

Table 2 | Summary of studies of metformin in pregnancy

Author Comparison
(year) Indication Study type Study population Intervention group Main findings
Rowan GDM RCT 751 women Metformin Insulin Neonatal composite morbidity: RR 0.99, 95% CI 0.80 to 1.23; preterm birth: RR
(2003)56 1.60, 1.02 to 2.52; insulin supplementation: 46.3% of metformin group
Balsells GDM Systematic review and meta- 15 RCTs, including Metformin Insulin or Versus insulin—weight gain: mean difference −1.14, 95% CI −2.22 to −0.06, kg;
(2015)57 analysis 2509 women glyburide preterm birth: RR 1.5, 1.04 to 2.16
Versus glyburide—weight gain: mean difference −2.06, 95% CI −3.98 to −0.14,
kg; birth weight: mean difference −209, −314 to −104, g; macrosomia: RR 0.33,
0.13 to 0.81; LGA: RR 0.44, 0.21 to 0.92
Farrar GDM Systematic review, meta- 42 RCTs Metformin Insulin or Versus insulin—NICU admission: RR 0.59, 95% CI 0.38 to 0.92
(2017)58 analysis, and network meta- glyburide Versus glyburide—LGA: RR 0.31, 95% CI 0.14 to 0.67; macrosomia: RR 0.33,
analysis 0.14 to 0.76; neonatal hypoglycemia: RR 0.38, 0.19 to 0.77
Butalia GDM Systematic review and meta- 16 RCTs and RCT Metformin Insulin Neonatal hypoglycemia: RR 0.63, 95% CI 0.45 to 0.87; LGA: RR 0.80, 0.64 to
(2017)59 analysis follow-up, including 0.99; pre-eclampsia: RR 0.56, 0.37 to 0.85; weight gain: mean difference −2.07,
2165 women 95% CI −2.88 to −1.27, kg; preterm birth: RR 1.18, 0.67 to 2.07
Ibrahim GDM or type RCT 90 women Metformin Insulin alone Adequate glycemic control: 76.1% v 100%, P=0.001; neonatal hypoglycemia:
(2014)60 2 diabetes and insulin 7% v 38.5%, P=0.001; NICU admission: 18.6% v 41%, P=0.026
Ainuddin Type 2 RCT 206 women Metformin Metformin Neonatal hypoglycemia: 25% v 7.8% v 30%, P<0.01; NICU admission: 43.8%
(2015)61 diabetes and insulin or v 23.3% v 69%, P<0.01; SGA: 31.2% v 14.4% v.2%, P<0.01; gestational age
insulin alone at delivery (weeks): 36.19 v 36.86 v 37.06, P=0.45; insulin supplementation:
84.9% of metformin group
Chiswick Obesity RCT 449 women with Metformin Placebo Birth weight: mean difference −0.03, 95% CI 0.22 to 0.16
(2015)62 BMI >30
Syngelaki Obesity RCT 400 women with Metformin Placebo Birth weight Z score: 0.05 v 0.17, P=0.660; pre-eclampsia: RR 0.24, 95% CI 0.10
(2016)63 BMI >35 to 0.61
BMI=body mass index; GDM=gestational diabetes mellitus; LGA=large for gestational age; NICU=neonatal intensive care unit; RCT=randomized clinical trial; RR=relative risk; SGA=small for gestational age.

gain, improved postprandial glycemic control, and fewer
cases of severe neonatal hypoglycemia but more preterm
birth.57 In contrast, a recent network meta-analysis that
included nine published and unpublished trials found
that the risk of most outcomes, including LGA (relative
risk 0.80, 95% confidence interval 0.64 to 0.99), mac-
rosomia (0.75, 0.57 to 0.98), admission to NICU (0.74,
0.57 to 0.97), neonatal hypoglycemia (0.68, 0.50 to
0.92), and pre-eclampsia (0.56, 0.37 to 0.85), was lower
in women randomized to metformin compared with insu-
lin.58 There authors did not find a difference in preterm
delivery (relative risk 1.37, 0.62 to 3.01) and concluded
that metformin had the highest probability of being the
most effective treatment when compared with insulin
or glyburide.58 Another meta-analysis that included
16 studies of women with gestational diabetes or type
2 diabetes found no differences in the rates of preterm
delivery (relative risk 1.18, 0.67 to 2.07).59 Although the
most common focus in gestational diabetes is the risk of
fetal overgrowth, the risk of increased preterm birth with
metformin has not been resolved, and preterm birth is
also associated with long term health consequences.64 65
The high rate of failure with metformin has raised ques-
tions about appropriate dosing of metformin during preg-
nancy, and the increased renal clearance of metformin
may necessitate dosing modifications.53 66
Metformin use is common in gestational diabetes, but
limited data exist regarding its use to treat type 2 diabe-
tes in pregnancy. The study by Ainuddin and colleagues
that used metformin to treat type 2 diabetes found that
a significant proportion of women needed insulin, but
metformin use was associated with less maternal insulin
use and lower weight gain.61 Metformin was associated
with fewer hypertensive disorders of pregnancy but more
small for gestational age infants.61 An additional study
by Ibrahim and colleagues of 90 women with gestational
diabetes or type 2 diabetes found that the addition of met-
formin to insulin reduced the risk of neonatal hypoglyce-
mia.60 Several ongoing RCTs comparing metformin with
placebo in women with either type 2 diabetes or early
onset gestational diabetes receiving insulin (Medical
Optimization of Management of Type 2 Diabetes Com-
plicating Pregnancy (MOMPOD), NCT02932475; and
Metformin in Women With Type 2 Diabetes in Pregnancy
Trial (MiTy), NCT01353391) will provide useful informa-
tion on the effect of metformin as adjuvant therapy in
this population, particularly with regard to the possible
reduction in pre-eclampsia rates.67
Metformin use in women without gestational diabetes
Several studies in obese women without diabetes have
explored the use of metformin to decrease the risk of fetal
overgrowth. The EmPOWaR study by Chiswick and col-
leagues randomized 449 obese pregnant women with
normal glucose tolerance to either metformin or placebo
and found no significant difference in birthweight cen-
tile between groups.62 Metformin was also evaluated
in a study of 400 obese women (body mass index >35)
without diabetes who were randomized to metformin or
placebo. Metformin did not affect birthweight Z scores,
but it was associated with less maternal weight gain and
a lower prevalence of pre-eclampsia.63 Metformin lowers
soluble fms-like tyrosine kinase 1 and soluble endoglin
secretion from primary human tissues. It may also reduce
endothelial dysfunction, increase vasodilation, and
induce angiogenesis, all of which show biologic plausi-
bility that metformin could have the potential to prevent
or treat pre-eclamspia.62
Potential long term effect of metformin on offspring
In addition to its glucose lowering properties, metformin
inhibits proliferation of cancer cells by suppressing the
production of mitochondrial dependent metabolic inter-
mediates needed for cell growth, and it also causes down-

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Table 3 | Summary of studies of glyburide in pregnancy

Comparison
Author (year) Study type Sample size Intervention group Main findings
Jacobson (2005)77 Retrospective 504 women with GDM Glyburide Insulin Birth weight: 3599 v 3661, P=0.28; LGA: OR 1.44, 95% CI 0.91 to 2.27; pre-eclampsia: OR 2.32,
and fasting glucose <140 1.17 to 4.63
mg/dL
Camelo Castillo Retrospective 9173 women with GDM Glyburide Insulin LGA: RR 1.43, 95% CI 1.16 to 1.76; NICU admission: RR 1.41, 1.23 to 1.62; respiratory distress:
(2015)78 cohort RR 1.63, 1.23 to 2.15
Langer (2000)79 RCT 404 women with GDM Glyburide Insulin Fasting glucose: 104 (5.8) v 108 mg/dL (6.0 mmol/L), P=0.12; postprandial glucose: 130
(7.2) v 129 mg/dL (7.2 mmol/L), P=0.69; no differences in neonatal outcomes; insulin
supplementation: 4% of glyburide group
Moore (2010)80 RCT 149 women with GDM Glyburide Metformin Fasting glucose: 90.9 (5.1) v 94.3 mg/dL (5.2 mmol/L), P=0.23; birth weight: 3330 v 3103 g,
P=0.02; insulin supplementation: RR 2.1, 95% CI 1.2 to 3.9
Silva (2012)81 RCT 200 women with GDM Glyburide Metformin Birth weight: 3387 v 3193 g, P=0.01; neonatal glucose: 54.1 (3.0) v 59.8 mg/dL (3.3 mmol/L),
P=0.01
Nachum (2017)82 RCT 104 women with GDM Glyburide Metformin Poor glycemic control with first line therapy: 34% v 29%, P=0.6; insulin supplementation: 17% v
4%, P=0.03
Dhulkotia (2010)83 Meta-analysis 6 RCTs, including 1388 Glyburide or Insulin Fasting glucose: mean difference 1.31 mg/dL (0.1 mmol/L), 95% CI −0.81 to 3.43 (0 to 0.2
women with GDM metformin mmol/L); postprandial glucose: mean difference 0.8 mg/dL (0 mmol/L), −3.26 to 4.86 (−0.2 to
0.3 mmol/L)
Poolsup (2014)84 Meta-analysis 13 RCTs, including 2151 Glyburide or Insulin Glyburide—macrosomia: RR 2.34, 95% CI 1.18 to 4.63; neonatal hypoglycemia: RR 2.06, 1.27
women with GDM metformin to 3.34
Metformin—preterm birth: RR 1.51, 95% CI 1.04 to 2.19; pre-eclampsia: RR 0.54, 0.31 to 0.91
Zeng (2014)85 Meta-analysis 5 RCTs, including 674 Glyburide Insulin Neonatal hypoglycemia: RR 1.98, 95% CI 1.17 to 3.36; macrosomia: RR 2.22, 1.07 to 4.61
women with GDM
Balsells (2015)57 Systematic review 15 RCTs, including 2509 Glyburide Insulin or Versus insulin—birth weight: mean difference 109, 95% CI 35.9 to 181, g; macrosomia: RR 2.62,
and meta-analysis women metformin 95% CI 1.35 to 5.08; neonatal hypoglycemia: RR 2.04, 1.30 to 3.20
Versus metformin—weight gain: mean difference 2.06, 95% CI 0.14 to 3.98, kg; birth weight:
mean difference 209, 104 to 314, g; macrosomia: RR 3.03, 95% CI 1.23 to 7.69; LGA: RR 2.27,
1.09 to 4.76
Brown (2017)86 Meta-analysis 4 RCTs, including 554 Glyburide Metformin Pre-eclampsia: RR 0.70, 95% CI 0.38 to 1.30; LGA: RR 0.67, 0.24 to 1.83; neonatal
women with GDM hypoglycemia: RR 0.86, 0.42 to 1.44
GDM=gestational diabetes mellitus; LGA=large for gestational age; NICU=neonatal intensive care unit; OR=odds ratio; RCT=randomized clinical trial; RR=relative risk; SGA=small for gestational age.

modulation of cell proliferation related proteins through
activation of AMPK and a decrease in mTOR.68 69 These
actions of metformin have raised interest in the poten-
tial short and long term effects of metformin on fetal
and childhood development. In a follow-up of the MiG
study, children aged 2 years whose mothers were treated
with metformin had significantly higher mid-upper arm
circumferences (17.2 (SD 1.5) v 16.7 (1.5) cm; P=0.002)
and higher subscapular (6.3 (1.9) v 6.0 (1.7) mm; P=0.02)
and biceps skinfolds (6.0 (1.9) v 5.6 (1.7) mm; P=0.04)
compared with infants whose mothers were treated with
insulin alone.70 However, no differences were seen in total
fat mass, percentage body fat, or waist circumference. The
authors speculated that metformin resulted in a more
favorable fat redistribution with more peripheral fat and
less visceral fat, but others have pointed out that only a
subset of children underwent DEXA testing and there were
no differences in waist circumference between groups.70 71
Longer term follow-up data are pending for these children.
Another follow-up of 211 children from the MiG study
found no significant differences in neurodevelopmental
and psychomotor outcomes between those who were or
were not exposed to metformin.72 Follow-up of a small
Finnish RCT comparing metformin and insulin found
that children exposed to metformin in pregnancy were
significantly heavier (10.47 (SD 1.49) v 9.85 (1.26) kg;
P=0.038) at 12 months and taller and heavier (12.05
(1.87) v 11.32 (1.45) kg; P=0.04) at 18 months despite
having similar birth weights.73 No differences existed
in motor, social, or linguistic development at 18 weeks
between the two groups, although the study was small
with only 93 children.73 Importantly, recently published
follow-up data from 4 year old offspring of women with
polycystic ovarian syndrome who were randomized to
metformin or placebo showed that antenatal exposure to
metformin resulted in higher weight and body mass index
Z scores in the offspring, and there were more overweight
and obese children in the group exposed to metformin.74
Glyburide
Sulfonylureas are insulin secretagogs that bind to the
sulfonylurea receptor 1 (SUR1) of ATP sensitive K+ chan-
nels of pancreatic β cells, which causes channel closure
and results in increased insulin secretion.75 Glyburide is
hepatically metabolized and effluxed from the fetal to the
maternal compartment against a concentration gradient
by placental breast cancer resistance protein.76
Glyburide to treat diabetes in pregnancy
Glyburide is predominantly used to treat women with
gestational diabetes. The largest trial evaluating use of
glyburide randomized 404 women with gestational dia-
betes to insulin or glyburide and found similar glycemic
control and neonatal outcomes for the two treatments
(table 3).79 One additional benefit was that only 4% of the
women who were treated with glyburide needed supple-
mental insulin. Although recent studies have shown that
concentrations of glyburide in cord blood are 50-70% of
maternal concentrations,76 87 at the time of the above
study glyburide transplacental transfer was thought to be
minimal.79 88 Likely as a result of these findings, glyburide
treatment in women with gestational diabetes dramati-
cally increased from 7% to 65% over the time period from
2000 to 2011.89

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The increased prevalence of glyburide use has
prompted multiple additional observational and ran-
domized clinical trials comparing outcomes in women
treated with glyburide with those treated with insulin. In
one “natural experiment” that arose in a US healthcare
system, the authors compared outcomes in 236 women
treated with glyburide with those in 268 historical con-
trols treated with insulin.77 More women in the glybur-
ide group achieved treatment goals, and no differences
were seen in birth weight or macrosomia.77 Glyburide was
associated with higher rates of pre-eclampsia and need
for phototherapy in infants, but fewer infants from the
glyburide group were admitted to NICU.77 In contrast,
a retrospective cohort study comparing outcomes in
4982 women treated with glyburide and 4191 women
treated with insulin found that glyburide treatment was
associated with increased risk of NICU admission, res-
piratory distress, hypoglycemia, birth injury, and LGA
birth weight.78 This study was limited by the lack of
information on glycemic control or maternal body mass
index. However, these data raised important questions
about whether the differences in outcomes between
women treated with glyburide and insulin were related
to unmeasured confounding or whether glyburide use
outside of a small, tightly regulated clinical trial was
associated with adverse perinatal outcomes due to either
suboptimal glycemic control or direct effects of the drug.
Several recent meta-analyses have also looked at out-
comes in women treated with glyburide compared with
insulin.80 83-85 The meta-analysis by Balsells et al found
that women treated with glyburide had higher birth-
weight infants, more macrosomia, and more neonatal
hypoglycemia than those treated with insulin.57 The
average rate of treatment failure among women treated
with glyburide was 6.4%. Both the observational stud-
ies and meta-analyses of RCTs raise questions about the
appropriate use of glyburide. The largest trial to date
suggests that as long as glycemic control is comparable,
outcomes are also similar between groups.79 The other
trials included in these meta-analyses have small sample
sizes and differ in their approach to glyburide dosing. In
addition, the observational studies showing increased
risk have methodological concerns including an inability
to account for the level of glycemic control. Beyond gesta-
tional diabetes, data on the use of glyburide to treat type 2
diabetes in pregnancy are scarce, but this is one potential
novel aspect of glyburide use. In one small cohort study,
outcomes were similar between women treated with oral
hypoglycemic agents (primarily glyburide) and insu-
lin, with less weight gain and similar glycemic control
between those receiving oral agents and insulin.90
Controversies in glyburide dosing
Several factors have been associated with a higher rate of
failure of glyburide treatment, including a fasting plasma
glucose above 110 mg/dL (6.1 mmol/L) on the oral glu-
cose tolerance test, older maternal age, multiparity, and
diagnosis of gestational diabetes before 25 weeks, but
data to ensure that providers can select the most appro-
priate candidates or dosing regimens for glyburide use
are limited.91‑93 Efficacy of glyburide in pregnancy may
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also be related to changes in drug metabolism, and the
dosing used in some studies may not be ideal. During
pregnancy, glyburide concentrations increase within
30-60 minutes, peak in two to three hours, and return
to baseline by eight hours.87 These data identify several
considerations for glyburide dosing. Firstly, glyburide
concentrations return to baseline within eight to 10 hours
of ingestion, so a pre-breakfast dose may not provide an
adequate insulin response for dinner.94 All of the glybur-
ide studies used either once or twice daily dosing, but
this could lead to inadequate glycemic control because
increasing the morning dose to control post-dinner
blood sugars may result in hypoglycemia earlier in the
day. Secondly, glyburide should be administered 30-60
minutes before a meal to ensure that glyburide concen-
trations increase before the rise in blood sugar seen after
a meal.94 In addition, plasma concentrations of glybur-
ide are lower in pregnancy than in the non-pregnancy
state.87 Such findings suggest a possible need to change
the dosing and administration schedule for glyburide in
pregnant women with diabetes to maximize the efficacy
of treatment.
Potential long term effect of glyburide on offspring
One important concern regarding glyburide use is the
lack of long term follow-up data on children who were
exposed to glyburide in utero, and these concerns have
become more pressing with the knowledge that glybur-
ide crosses the placenta. Recent data suggest that gly-
buride may also increase placental GLUT1 expression,
which could augment fetal glucose delivery.95 Whether
glyburide use increases the risk of fetal overgrowth inde-
pendently of glycemic control is unclear, but LGA birth
weight is thought to be a risk factor for adverse childhood
metabolic outcomes.96 97 Hypothetical concerns also exist
about long term β cell function in offspring exposed to
glyburide in utero, highlighting the importance of long
term studies of growth and metabolism in offspring.
Glyburide versus metformin
Several small studies have compared glyburide with
metformin. The meta-analysis by Balsells et al compared
glyburide with metformin,57 but it included only two stud-
ies.80 81 It found that metformin was associated with less
maternal weight gain, lower birth weight, less macroso-
mia, and fewer LGA births.57 Preterm birth was increased
in women who were treated with metformin. In contrast,
a recent systematic review compared outcomes between
women randomized to either glyburide or metformin from
several additional studies and found no differences in
maternal or neonatal outcomes.86 The authors noted that
most of the studies comparing glyburide with metformin
were of moderate to low quality, and they also stressed
that the benefits and potential harms of one oral antidia-
betic drug therapy compared with another are unclear.
Finally, a recent RCT of 104 women took a novel
approach and randomized patients to either glyburide
or metformin and then added the other drug if control was
inadequate.82 Treatment failure after first line treatment
because of poor glycemic control or adverse effects was
similar between glyburide and metformin (34% v 29%;
 STAT E O F T H E A RT R E V I E W
P=0.6), and treatment success after second line therapy
was higher in the metformin group than in the glyburide
group (87% v 50%; P=0.03).82 More patients in the gly-
buride group ultimately needed insulin compared with
those in the metformin group (17% v 4%; P=0.03). No dif-
ferences were seen in maternal weight gain, birth weight,
LGA births, or macrosomia.82 However, a trend was seen
toward more hypoglycemia in the metformin group. The
authors concluded that the combination of glyburide
and metformin may allow for a higher efficacy rate with
a significantly reduced need for insulin, and they also
postulated that the use of metformin first may have poten-
tiated the effect of glyburide when the latter was added.82
However, further studies are needed to assess whether
these drugs can be safely and efficaciously substituted for
insulin and would require the combination to be directly
compared with insulin alone. Using two drugs that cross
the placenta to avoid insulin raises concerns about the
potential long term programming effects of fetal hyperin-
sulinemia (glyburide) and altered hepatic gluconeogen-
esis, insulin sensitivity, mitochondrial function, and cell
cycle proliferation (metformin).98
Alternate oral agents
α glucosidase inhibitors inhibit the α glucosidase
enzymes present on the brush border of the small intes-
tine, which slows carbohydrate absorption and reduces
postprandial glucose concentrations. Only acarbose has
been studied in pregnancy. One small case series found
that postprandial glucose values normalized and infants
were healthy in six women treated with acarbose three
times a day.99 Another small RCT conducted in Brazil
compared insulin versus glyburide versus acarbose in 70
patients.100 No significant differences in LGA and cesar-
ean delivery rates among the three groups were seen, but
acarbose was associated with more gastrointestinal side
effects.100
Several other agents including DPP4 inhibitors, GLP-1
receptor agonists, SGLT-2 inhibitors, and thiazolidinedi-
ones are used outside of pregnancy, but minimal data are
available in pregnancy. DPP-4 inhibitors reduce DPP-4
mediated degradation of endogenous incretin hormones.
This leads to enhanced insulin synthesis and secretion as
well as suppressed glucagon secretion. GLP-1 receptor
agonists activate the GLP-1 receptor and enhance insulin
synthesis and secretion in a glucose dependent fashion.
SGLT-2 inhibitors inhibit activity of glucose transporters
in the proximal tubule, serving to increase renal glucose
excretion. Thiazolidinediones activate the PPAR family
of nuclear receptors and reduce insulin resistance. In
a mouse model, exposure to rosiglitazone resulted in
abnormal placental morphology and altered expression
of proteins implicated in placental development, raising
concerns about the therapeutic use of this class of drugs
during pregnancy.101
Emerging treatments
More than 200 studies are listed on Clinicaltrials.gov
under the heading of diabetes treatment in pregnancy.
The studies primarily focus on glyburide, metformin,
and insulin treatment to improve pregnancy outcomes,
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mostly in women with gestational diabetes. Nutrient
supplements such as myo-inositol are also being tested
to decrease the risk of adverse pregnancy outcomes in
women with gestational diabetes. Myo-inositol is hypoth-
esized to act through complex pathways that ultimately
shift glucose intracellularly and then into fatty acids
synthesis.102 103 Myo-inositol supplementation starting
at 12-13 weeks of pregnancy decreased the likelihood
of gestational diabetes in at risk groups such as obese
women and those with polycystic ovarian syndrome.104‑106
Trials in women with other risk factors for gestational dia-
betes showed mixed results, with a recent trial showing
no effect of myo-inositol supplementation in pregnant
women with a family history of diabetes.107 Furthermore,
evidence in support of myo-inositol as a treatment for
gestational diabetes is weak,108 but it is the subject of a
current investigation (NCT02149992).
Outside of pregnancy, obstructive sleep apnea (OSA)
has been linked to enhanced inflammatory and oxida-
tive stress responses, endothelial damage, and metabolic
derangements.109 110 Given the overlap between these bio-
logic pathways and adverse pregnancy outcomes, includ-
ing gestational diabetes, recent studies have focused on
evaluating the link between OSA and adverse pregnancy
outcomes. Rates of OSA increase with advancing gesta-
tion and may be even higher in women with gestational
diabetes.111 112 OSA was independently associated with
gestational diabetes (odds ratio 3.47, 1.95 to 6.19) after
adjustment for age, body mass index, chronic hyperten-
sion, and gestational weight gain.111 The study also noted
an increasing exposure-response relation between OSA
and gestational diabetes.111 Also, in women with ges-
tational diabetes, short sleep duration was associated
with worsened glucose control.113 These findings are the
basis for a pilot study assessing the effect of continuous
positive airway pressure treatment on glycemic control in
gestational diabetes (NCT02245659).
Lastly, ongoing studies are exploring the relation
between diabetes, obesity, and the gut microbiome. Evi-
dence that the gut microbiota might influence obesity
began with the observation that sterile, germ-free mice
have decreased capacity for energy utilization compared
with colonized counterparts.114 Data suggest that patients
with type 2 diabetes have a reduction in the Firmicutes
phylum, and the ratio of Bacteroides to Firmicutes cor-
relates with plasma glucose concentrations.115 Kuang et
al did a metagenome-wide association study comparing
fecal samples collected at 21-29 weeks from 43 women
with gestational diabetes and 81 healthy controls, and
they found changes in microbial composition that could
be used to identify women at risk of gestational diabe-
tes.116 Others found that the placental microbiota and
microbiome differed between women with and without
gestational diabetes.117 The stool microbiota of insulin
resistant women with a history of gestational diabetes has
been characterized postpartum, and women with former
gestational diabetes had relatively higher abundance of
the Prevotellaceae family as well as reduced abundance of
Firmicutes, similar to the situation in type 2 diabetes.118
Another cross sectional study of the gut microbiome in
women who had gestational diabetes and their offspring
 STAT E O F T H E A RT R E V I E W
Table 4 | Summary of guidelines on diabetes on pregnancy
Recommendation NICE10 ACOG1 4
Glucose targets Fasting <95mg/dL (5.3 mmol/L); 1 hour Fasting <95mg/dL (5.3 mmol/L);
postprandial <140 mg/dL (7.8 mmol/L); 2 hour 1 hour postprandial <140 mg/dL
postprandial <115 mg/dL (6.4 mmol/L) (7.8 mmol/L); 2 hour postprandial
<120 mg/dL (6.7 mmol/L)
HbA1c targets T1DM and T2DM in women with no T1DM and T2DM <6% (42 mmol/
hypoglycemia <6.5% (48 mmol/mol) mol)
Lifestyle changes GDM: dietary consultation; trial of diet and GDM: dietary consultation; limit
exercise in women with fasting glucose carbohydrate intake to 33-40%
<126mg/dL (7 mmol/L); focus on low glycemic of daily calories; focus on complex
index; regular exercise carbohydrates
Drug therapy T1DM, T2DM: NPH is first choice for long acting Insulin preferred agent for
insulin therapy; continue long acting insulin diabetes in pregnancy
analog if good pre-conceptional control
GDM: metformin first line; add insulin if blood
glucose targets are not met
Emerging therapies T1DM and T2DM: low dose aspirin for pre- – T1DM and T2DM: low dose aspirin for pre-
eclampsia prevention
ACOG=American College of Obstetricians and Gynecologists; ADA=American Diabetes Association; GDM=gestational diabetes; NICE=National Institute for Health and Care Excellence; NPH=neutral protamine
Hagedorn; RANZCOG=Royal Australian and New Zealand College of Obstetricians and Gynecologists; T1DM=type 1 diabetes; T2DM=type 2 diabetes.
five years postpartum found no significant differences in
gut microbiota between women who had gestational dia-
betes and controls, but some differences existed between
offspring of women who had gestational diabetes and
those who did not.119
A few RCTs have examined the effects of probiotics
administered during pregnancy with the aim of improv-
ing insulin sensitivity and reducing risk of gestational
diabetes. In one RCT, pregnant women were randomized
to either Bifidobacterium lactis alone or B lactis plus
Lactobacillus rhamnosus GG (LGG) probiotic 14 days
before a scheduled cesarean delivery.120 Both treatments
decreased the expression of toll-like receptor genes in the
placenta and meconium of neonates compared with pla-
cebo.120 A Finnish study randomized 256 women during
the first trimester to dietary counseling and either a daily
LGG and B lactis probiotic or placebo. Dietary counseling
and probiotics decreased the frequency of gestational dia-
betes from 36% to 13%, but no significant differences
in birth weight were seen.121 Of note, maternal central
adiposity at six months postpartum was lower in women
treated with diet and probiotics.121 In another RCT, 175
obese pregnant women were assigned to receive either
daily Lactobacillus salivarius probiotic or placebo from
24 to 28 weeks’ gestation, and the probiotic did not affect
maternal glycemia or birth weight.122
Guidelines
Guidelines for the management of diabetes in pregnancy
include those from NICE, ACOG, ADA, and RANZCOG
(table 4).1 3 4 10 123 All recommend treatment of all forms of
diabetes in pregnancy to decrease adverse maternal and
fetal outcomes. All agree that management of pregnancy
complicated by diabetes should include medical nutri-
tional therapy, counseling, and increased frequency of
glucose monitoring. Differences exist in specific glucose
targets, including the goal for fasting glucose below 90
mg/dL (5.0 mmol/L) by RANZCOG and a range of HbA1c
goals of 6-7% for women with pregestational diabetes.
Also, guidelines for treatment of gestational diabetes
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ADA3 RANZCOG123
Fasting <95mg/dL (5.3 mmol/L); 1 hour Fasting <90mg/dL (5.0 mmol/L); 1
postprandial <140 mg/dL (7.8 mmol/L); 2 hour hour postprandial <133 mg/dL (7.4
postprandial <120 mg/dL (6.7 mmol/L) mmol/L); 2 hour postprandial <120
mg/dL (6.7 mmol/L)
T1DM and T2DM: A1c target in pregnancy is –
6-6.5% (42-48 mmol/mol); <6% (42 mmol/mol)
if without significant hypoglycemia and <7% (53
mmol/mol) if necessary to prevent hypoglycemia
GDM: medical nutrition therapy, physical activity, GDM: consume ≥175 g
and weight management carbohydrate/day; spread
carbohydrates evenly throughout
the day; reduce intake of saturated
fats; limit excess weight gain
Insulin preferred agent for diabetes in pregnancy GDM: metformin and/or insulin
–
eclampsia prevention
differ, specifically regarding the use of oral agents. Both
SMFM and NICE have endorsed the use of metformin as
an alternative to insulin for treatment of gestational dia-
betes.10 124 However, we would argue that the available
data on oral agents are limited, especially regarding long
term effects after in utero exposure. Further research is
needed to fully support the use of oral agents as alternates
to insulin in gestational diabetes. All of the guidelines
recognize that recommendations for the management of
diabetes in pregnancy are largely based on studies with
small sample sizes and less than level A evidence.
Conclusions
Diabetes in pregnancy has significant short and long term
implications for affected mothers and their offspring.
Despite decades of research, complications rates are high,
particularly in pregestational diabetes, highlighting that
novel interventions are urgently needed. Future studies
are needed to clarify whether diets higher in complex
carbohydrates and lower in fat are more effective than
lower carbohydrate diets. Data on continuous subcu-
taneous insulin infusion suggest that this technology
may improve outcomes in women with type 1 diabetes,
and future studies are needed to assess whether it can
improve outcomes in women with type 2 diabetes and
even difficult to control gestational diabetes. Although
oral agents are not novel, robust debate continues about
the use of oral agents in gestational diabetes. We support
insulin as first line treatment for gestational diabetes and
hope that ongoing studies will clarify a potential role for
metformin in the treatment of gestational diabetes and
as an adjuvant to insulin in women with type 2 diabe-
tes. We would also suggest that the approach to clinical
trials in gestational diabetes would benefit from more
novel approaches. Studies on treatment of diabetes in
pregnancy have followed a traditional “simple parallel
arm” clinical trial design, but gestational diabetes is a
disease with a heterogeneous physiology characterized
by various levels of insulin resistance and insulin secre-
tion defects. Therapeutic studies outside of pregnancy
 STAT E O F T H E A RT R E V I E W
RESEARCH QUESTIONS
• What diet in pregnant women with diabetes optimizes
glycemic control and other metabolic characteristics and
ultimately results in the most favorable fetal growth profile?
• Are there different glycemic targets for subgroups of women
with diabetes in pregnancy (for example, pregestational
versus gestational diabetes or obese versus non-obese)?
• Are there alternative metabolic or nutritional targets in
pregnant women with diabetes to minimize maternal and
fetal adverse outcomes?
• What are the long term effects of diabetes treatment
options, specifically oral hypoglycemic agents, on the
offspring of pregnant women with diabetes?
recognize the heterogeneity of specific diseases and the
need for more tailored treatment regimens, and these
approaches could help us to better understand predic-
tors of treatment failure. Also, future studies should
engage patients to ensure access to novel therapies and
understand their preferences regarding various treatment
strategies.
Contributors: MNF and CMS both did the literature search, wrote the draft
article, and revised the manuscript. They are both guarantors.
Funding: MNF is supported by the National Institutes of Health through
grant number KL2 TR001856. The funding source had no involvement in
the preparation, analysis, and interpretation of the data or submission of
this review.
Competing interests: We have read and understood BMJ policy on
declaration of interests and declare the following interests: none.
Provenance and peer review: Commissioned; externally peer reviewed.
Patient involvement: No patients were asked for input in the creation of
this article.
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