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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 focus on recent clinical studies that have evaluated vari-
99% of women having gestational diabetes, 0.5% having ous lifestyle and therapeutic options for women with dia-
type 2 diabetes, and 0.3% having type 1 diabetes.1‑4 In betes in pregnancy.
particular, the prevalence of gestational diabetes varies
by population and diagnostic criteria.5 The prevalence of Sources and selection criteria
both gestational and pregestational diabetes is increas- We obtained the references for this review from vari-
ing, likely owing to the increasing obesity rates.2 3 6 7 All ous sources including PubMed, Clinicaltrials.gov, and
types of diabetes are associated with increased risk for the Cochrane Database of Systematic Reviews (1990 to
hypertensive disorders of pregnancy, excessive fetal April 2018) by using the following terms: “diabetes in
growth, fetal demise, macrosomia, and neonatal morbid- pregnancy”, “gestational diabetes”, “diet and diabetes
ity, along with long term risks for obesity and diabetes in pregnancy”, “lifestyle modifications and diabetes
in the offspring.8 9 Unique to pregestational diabetes is in pregnancy”, “exercise and diabetes in pregnancy”,
the risk for early pregnancy loss and congenital anoma- “obesity and diabetes in pregnancy”, “glyburide in
lies, which is directly linked to periconception glycemic pregnancy”, “metformin and pregnancy”, and “insulin
control. and pregnancy”. We prioritized articles on the basis of
The goal of diabetes treatment in pregnancy is to mini- study method (randomized controlled trials (RCTs) and
mize maternal and fetal adverse events related to hyper- meta-analyses over longitudinal observational studies,
glycemia. Physiologic changes of pregnancy include and cohort studies) and their date of publication. We
progressive increases in insulin resistance, weight gain, included only full text, English language, peer reviewed
and changes in body composition, and each of these publications. We used clinical guidelines from the Ameri-
changes may affect the pharmacologic properties of dia- can Congress of Obstetricians and Gynecologists (ACOG),
betes treatment (fig 1). Treatment options vary by type the Royal College of Obstetricians and Gynaecologists
of diabetes, but given the considerable overlap we have (RCOG), the Royal Australian and New Zealand College of
organized our review by treatment, summarizing est­ Obstetricians and Gynaecologists (RANZCOG), the Inter-
ablished treatment strategies and highlighting novel 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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*O\EXULGH diabetes, including those who are overweight or obese,
'LHW
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,QFUHWLQPLPHWLFV have a history of previous gestational diabetes, have
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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7KLD]ROLGLQHGLRQHV
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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
B*OXFRVHXSWDNH &3$3
0HWIRUPLQ drug therapy in pregestational diabetes (fig 3). Weight
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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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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- for pregnant women with pre-existing diabetes who
ble benefit of eating more complex carbohydrates and are using insulin pumps or basal-bolus therapy.1 3 4 10
less fat. However, more definitive studies are needed to Although HbA1c assessment is less burdensome than fre-
better define the optimal diet for pregnant women with quent daily testing, it is considered a secondary measure
diabetes, especially in obese women and in women with of glycemic control in pregnancy because A1c concentra-
pregestational diabetes. tions fall during normal pregnancy owing to red blood
cell turnover and HbA1c does not reflect variability in
Glucose monitoring glucose concentration.1 3 10
Blood glucose monitoring is a cornerstone of diabetes Continuous glucose monitoring (CGM) technology was
management in pregnancy. Fasting and postprandial assessed in the CONCEPTT study, which randomized 325
blood glucose monitoring is recommended in all type of pregnant women with type 1 diabetes to real time CGM
diabetes, and preprandial testing is also recommended or capillary glucose monitoring.24 Real time CGM users

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

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spent more time in target (68% v 61%; P=0.003) and without diabetes, mean fasting (70.9 (SD 7.8) mg/dL (3.9
had less hyperglycemia (27% v 32%; P=0.028) between (0.4) mmol/L)) and one hour postprandial (108.9 (12.9)
randomization and 34 weeks’ gestation.24 CGM use was mg/dL (6.1 (0.7) mmol/L)) blood sugars as assessed by
also associated with an approximately 50% reduction in continuous glucose monitoring (CGM) were significantly
large for gestational age (LGA) births (odds ratio 0.50, lower than the current fasting (<95 mg/dL (5.3 mmol/L))
95% confidence interval 0.28 to 0.90), admission to a and one hour postprandial (<140 mg/dL (7.8 mmol/L))
neonatal intensive care unit (NICU) (0.48, 0.26 to 0.86), glucose targets in pregnancies with diabetes, suggest-
and neonatal hypoglycemia (0.45, 0.22 to 0.89).24 ing that current glycemic targets may be too high.34 In
In addition, an RCT that assigned 340 women with ges- particular, obese women with gestational diabetes are at
tational diabetes to either self monitored glucose or self higher risk for adverse pregnancy outcomes than their
monitored glucose plus intermittent CGM use found that normal weight counterparts,35 and obese women also
CGM use was associated with lower mean birth weight have higher mean fasting and postprandial blood sugars
(3138 (SD 484) v 3345 (508) g; P<0.001), less macroso- despite higher doses and more frequent use of drugs.12 In
mia (4.1% v 10.8%; P=0.03), less pre-eclampsia (3.4% a retrospective cohort of 1344 women with gestational
v 10.1%; P=0.02), and fewer primary cesarean deliver- diabetes, obese women who had fasting blood glucose
ies (34.7% v 46.6%; P=0.03).25 By comparison, a recent above 88.7 mg/dL (4.9 mmol/L) or one hour postprandial
multicenter RCT found no significant difference in the risk blood glucose above 123.8 mg/dL (6.9 mmol/L) were at
of macrosomia between CGM and self monitored glucose the highest risk for macrosomia, suggesting that tighter
in 300 pregnant women with gestational diabetes and glycemic control could help to optimize outcomes in
pregestational diabetes.26 this high risk population.12 Lower glycemic targets may
More recent trials published in the past two years have require more intensive dietary modification and both ear-
focused on devices that use flash glucose monitoring lier and more aggressive dosing of drugs. This is the basis
(FGM) technology, which can be worn for a period of for ongoing studies such as the GDM-MOMS study, which
time; users can obtain glucose measurements instantly by is randomizing overweight and obese women with gesta-
scanning the glucose sensor with the reader, producing tional diabetes to either standard glycemic targets (fasting
real time data. Studies on the efficacy of FGM are limited <95 mg/dL (5.3 mmol/L), one hour postprandial <140
to non-pregnant adults. Two RCTs, one including 328 mg/dL (7.8 mmol/L)) or more intensive glycemic control
adults with type 1 diabetes and another in 224 adults (fasting <90 mg/dL (5 mmol/L), one hour postprandial
with type 2 diabetes, compared FGM with self monitor- <120 mg/dL (6.9 mmol/L)) and is expected to report in
ing of blood glucose for six months. Both found that FGM early 2009 (NCT02530866).
was associated with reduced rates of hypoglycemia (in
type 1 diabetes, time in hypoglycemia reduced by 0.14 Insulin
hours on average per day (P<0.001); in type 2 diabetes, by Insulin is the preferred treatment for pregestational dia-
0.70 hours on average per day P<0.001) and high patient betes in pregnancy, and several professional societies
satisfaction based on few adverse events attributed to endorse it as a first line therapy in gestational diabe-
the device.27 28 However, in a pilot RCT in 40 adults with tes.3 4 The type of insulin, timing of administration, and
type 1 diabetes and a history of severe hypoglycemia or frequency are based on individual glycemic patterns. In
impaired awareness of glycemia, real time CGM use was women with pregestational diabetes, insulin is tradition-
associated with less time spent below 59.4 mg/dL (3.3 ally administered through multiple daily injections (MDI)
mmol/L) compared with FGM (2.4% v 6.8%; P=0.006).29 combining short acting insulin for mealtime excursion
Studies on FGM use in pregnancy are limited to a sin- and long acting insulin for basal glycemic control. The
gle case report and a published abstract that noted good safety and efficacy of long acting analogs such as glargine
agreement between FGM and capillary glucose monitor- and detemir have been demonstrated in pregnancy.36‑39
ing in 74 pregnant women (24 with type 1 diabetes, 11 Although commonly used, most insulin analogs have not
with type 2 diabetes, and 39 with gestational diabetes).30 been specifically tested in women with gestational dia-
Further studies are needed to assess the utility of FGM betes, and few studies provide data specific to this popu-
in pregnancy, but this technology has appeal given the lation. A comprehensive discussion of different insulin
frequency of blood glucose monitoring in pregnancy. formulations is beyond the scope of this review, and we
will limit the discussion to an overview of established for-
Optimal glycemic targets mulations followed by a focus on novel therapies. Data
Fetal adiposity is strongly associated with elevated mater- are lacking on newer insulin analogs, with no published
nal glucose, and approximately 15-20% of pregnant reports on the use of Toujeo, Lispro-U200, or Basalgar
women with diabetes whose glucose targets are within in pregnancy at the time of writing and a single report
current clinical targets still deliver macrosomic infants of two pregnancies treated with degludec from the first
who are at increased risk for long term metabolic dys- trimester of pregnancy.40 No malformations were seen
function.31‑33 in the infants, but both needed admission to NICU due
The Hyperglycemia and Pregnancy Outcomes (HAPO) to hypoglycemia.40 Given the lack of data, use of newer
study better defined the relation between maternal gly- insulin analogs in pregnancy should be further explored.
cemia and fetal overgrowth, but current pregnancy gly- Recent technological advances have resulted in a pro-
cemic targets have not been rigorously defined or tested grammable pump device that can manipulate the tim-
in RCTs. In an observational study in pregnant women ing, quantity, and type of insulin through a continuous

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subcutaneous insulin infusion (CSII). These devices can as 13 of the 16 newborns in the study cohort had a birth
be programmed to provide varying basal and bolus con- weight greater than the 90th centile.47
centrations of insulin at differing times during the day, Two recent systematic reviews found no evidence to
without abrupt changes and additional injections. Out- recommend one type of insulin or insulin regimen over
side of pregnancy, the benefits of CSII compared with MDI another or continuous glucose monitoring over intermit-
include lower hemoglobin A1c levels, reduced variation tent monitoring.48 49 Although the findings from CON-
and blood glucose concentrations, fewer hypoglycemic CEPTT are encouraging, and despite the advances in CSII
episodes, reduction in total daily insulin dose, and more and CGM, rates of adverse pregnancy outcomes remain
flexibility of lifestyle.41 However, the value of CSII in high in women with type 1 diabetes. Further studies are
improving pregnancy outcomes remains unclear.42‑44 needed to explore combining CSII and CGM with other
A retrospective study assessed two comparable groups treatment modalities to further reduce maternal and fetal
of women with type 1 diabetes, of whom 100 were using risks.
CSII and 44 were using MDI. Metabolic control deter-
mined by HbA1c measurements every trimester improved Metformin
during pregnancy in both groups, but control was Metformin is a biguanide that decreases hepatic glucose
achieved earlier (second trimester compared with end of output, decreases intestinal glucose absorption, and
pregnancy) among participants using CSII.45 At parturi- increases peripheral glucose uptake in muscles and adi-
tion, patients using CSII had lower HbA1c levels (6.2% pocyte cells.50 Metformin is a hydrophilic compound with
(SD 0.7%) v 6.5 (0.8%) (44 v 48 mmol/mol); P=0.02) low molecular weight and low binding capacity to plasma
and needed less insulin (P<0.01). However, maternal proteins, and trans-placental passage occurs in a dose
and neonatal outcomes did not differ.44 Similar find- dependent manner that is most likely carrier dependent.51
ings of improved HbA1c levels with CSII versus MDI were Observational studies have shown that concentrations
reported in a case-control study in 99 pregnant women of metformin in cord blood range from 50% to 100% of
with diabetes, again with no differences in maternal or maternal concentrations, and fetal concentrations may
neonatal outcomes.46 A recent systematic review of six even be higher than maternal concentrations.52‑54 Met-
RCTs that compared the use of multiple daily insulin formin does not seem to affect human placental glucose
with CSII in 213 pregnant women found no significant uptake or transport.55
differences between groups, including the frequency of
maternal (odds ratio 1.35, 95% confidence interval 0.60 Metformin to treat diabetes in pregnancy
to 3.03) and neonatal hypoglycemia (1.31, 0.59 to 2.94) Table 2 provides a summary of studies that have compared
and the rates of preterm birth (1.29, 0.45 to 3.71), cesar- metformin with either insulin or glyburide. The MiG study
ean delivery (1.39, 0.76 to 2.55), stillbirth (2.5, 0.53 to remains the largest RCT comparing metformin plus insulin
11.77), and LGA infants (1.04, 0.36 to 3.01).43 if needed with insulin alone, and this study has played an
Subsequent studies have focused on the combination important role in recent recommendations that metformin
of CSII with CGM. The CONCEPTT study, described earlier, can be considered as an acceptable alternative to insulin
stratified women by insulin delivery (CSII or MDI) and for treatment of gestational diabetes.56 We will discuss the
found that CGM reduced hyperglycemia, limited glycemic data that led to these recommendations and the ongoing
variability, and improved HbA1c levels for CSII and MDI concerns about use of metformin in pregnancy.
users.24 Also, sensor augmented insulin pumps have been In the MiG trial, glycemic control was similar between
developed to integrate real time CGM and insulin pump the two groups, but 46% of women in the metformin
technologies. A proof of principle crossover trial was group needed supplemental insulin.56 Rates of neonatal
performed in 16 pregnant women with type 1 diabetes.47 composite morbidity were similar between groups, but
Women were randomly assigned for a four week period metformin treatment was associated with fewer instances
to using a CSII pump and a continuous glucose sensor of severe neonatal hypoglycemia.56 In contrast, met-
with or without tablet computer software that automati- formin was associated with more preterm birth (12.1% v
cally adjusted the pump basal insulin rate at night. After 7.6%; P=0.04).56 It was also associated with less weight
four weeks, they switched to the other treatment group.47 gain between study enrollment and 36-37 weeks’ gesta-
Closed loop therapy resulted in a higher percentage of tion (0.4 (SD 2.9) kg in the metformin group versus 2.0
time in the designated euglycemic range (63-140 mg/dL (3.3) kg in the insulin group; P<0.001).56 Importantly,
(3.5-7.8 mmol/L)) than control therapy (74.7% v 59.5%; metformin had good patient acceptability, with 76.6% of
95% confidence interval for the difference 6.1 to 24.2; women suggesting that they would choose metformin in a
P=0.002), and the overnight mean glucose concentration subsequent pregnancy compared with 27.2% of women
was lower with closed loop therapy than control therapy assigned to insulin who would choose that.56
(119 v 133 mg/dL (6.6 v 7.4 mmol/L); P=0.009).47 After Several systematic reviews and meta-analyses have
the initial eight week trial, 14 women continued to use compared outcomes between women treated with met-
the closed loop system for approximately 15 additional formin and either insulin or glyburide. These meta-anal-
weeks, including time in labor and delivery. In these yses have reached disparate conclusions, likely owing to
women, glucose concentrations were in the target range their varied approaches and whether unpublished studies
68.7% of the time with a mean concentration of 126 mg/ or those also enrolling women with type 2 diabetes were
dL (7.0 mmol/L).47 However, no clear benefit of closed included. The systematic review by Balsells et al found
loop therapy on adverse pregnancy outcomes was seen, that metformin was associated with less maternal weight

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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 formin to insulin reduced the risk of neonatal hypoglyce-
cases of severe neonatal hypoglycemia but more preterm mia.60 Several ongoing RCTs comparing metformin with
birth.57 In contrast, a recent network meta-analysis that placebo in women with either type 2 diabetes or early
included nine published and unpublished trials found onset gestational diabetes receiving insulin (Medical
that the risk of most outcomes, including LGA (relative Optimization of Management of Type 2 Diabetes Com-
risk 0.80, 95% confidence interval 0.64 to 0.99), mac- plicating Pregnancy (MOMPOD), NCT02932475; and
rosomia (0.75, 0.57 to 0.98), admission to NICU (0.74, Metformin in Women With Type 2 Diabetes in Pregnancy
0.57 to 0.97), neonatal hypoglycemia (0.68, 0.50 to Trial (MiTy), NCT01353391) will provide useful informa-
0.92), and pre-eclampsia (0.56, 0.37 to 0.85), was lower tion on the effect of metformin as adjuvant therapy in
in women randomized to metformin compared with insu- this population, particularly with regard to the possible
lin.58 There authors did not find a difference in preterm reduction in pre-eclampsia rates.67
delivery (relative risk 1.37, 0.62 to 3.01) and concluded
that metformin had the highest probability of being the Metformin use in women without gestational diabetes
most effective treatment when compared with insulin Several studies in obese women without diabetes have
or glyburide.58 Another meta-analysis that included explored the use of metformin to decrease the risk of fetal
16 studies of women with gestational diabetes or type overgrowth. The EmPOWaR study by Chiswick and col-
2 diabetes found no differences in the rates of preterm leagues randomized 449 obese pregnant women with
delivery (relative risk 1.18, 0.67 to 2.07).59 Although the normal glucose tolerance to either metformin or placebo
most common focus in gestational diabetes is the risk of and found no significant difference in birthweight cen-
fetal overgrowth, the risk of increased preterm birth with tile between groups.62 Metformin was also evaluated
metformin has not been resolved, and preterm birth is in a study of 400 obese women (body mass index >35)
also associated with long term health consequences.64 65 without diabetes who were randomized to metformin or
The high rate of failure with metformin has raised ques- placebo. Metformin did not affect birthweight Z scores,
tions about appropriate dosing of metformin during preg- but it was associated with less maternal weight gain and
nancy, and the increased renal clearance of metformin a lower prevalence of pre-eclampsia.63 Metformin lowers
may necessitate dosing modifications.53 66 soluble fms-like tyrosine kinase 1 and soluble endoglin
Metformin use is common in gestational diabetes, but secretion from primary human tissues. It may also reduce
limited data exist regarding its use to treat type 2 diabe- endothelial dysfunction, increase vasodilation, and
tes in pregnancy. The study by Ainuddin and colleagues induce angiogenesis, all of which show biologic plausi-
that used metformin to treat type 2 diabetes found that bility that metformin could have the potential to prevent
a significant proportion of women needed insulin, but or treat pre-eclamspia.62
metformin use was associated with less maternal insulin
use and lower weight gain.61 Metformin was associated Potential long term effect of metformin on offspring
with fewer hypertensive disorders of pregnancy but more In addition to its glucose lowering properties, metformin
small for gestational age infants.61 An additional study inhibits proliferation of cancer cells by suppressing the
by Ibrahim and colleagues of 90 women with gestational production of mitochondrial dependent metabolic inter-
diabetes or type 2 diabetes found that the addition of met- 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 follow-up data from 4 year old offspring of women with
activation of AMPK and a decrease in mTOR.68 69 These polycystic ovarian syndrome who were randomized to
actions of metformin have raised interest in the poten- metformin or placebo showed that antenatal exposure to
tial short and long term effects of metformin on fetal metformin resulted in higher weight and body mass index
and childhood development. In a follow-up of the MiG Z scores in the offspring, and there were more overweight
study, children aged 2 years whose mothers were treated and obese children in the group exposed to metformin.74
with metformin had significantly higher mid-upper arm
circumferences (17.2 (SD 1.5) v 16.7 (1.5) cm; P=0.002) Glyburide
and higher subscapular (6.3 (1.9) v 6.0 (1.7) mm; P=0.02) Sulfonylureas are insulin secretagogs that bind to the
and biceps skinfolds (6.0 (1.9) v 5.6 (1.7) mm; P=0.04) sulfonylurea receptor 1 (SUR1) of ATP sensitive K+ chan-
compared with infants whose mothers were treated with nels of pancreatic β cells, which causes channel closure
insulin alone.70 However, no differences were seen in total and results in increased insulin secretion.75 Glyburide is
fat mass, percentage body fat, or waist circumference. The hepatically metabolized and effluxed from the fetal to the
authors speculated that metformin resulted in a more maternal compartment against a concentration gradient
favorable fat redistribution with more peripheral fat and by placental breast cancer resistance protein.76
less visceral fat, but others have pointed out that only a
subset of children underwent DEXA testing and there were Glyburide to treat diabetes in pregnancy
no differences in waist circumference between groups.70 71 Glyburide is predominantly used to treat women with
Longer term follow-up data are pending for these children. gestational diabetes. The largest trial evaluating use of
Another follow-up of 211 children from the MiG study glyburide randomized 404 women with gestational dia-
found no significant differences in neurodevelopmental betes to insulin or glyburide and found similar glycemic
and psychomotor outcomes between those who were or control and neonatal outcomes for the two treatments
were not exposed to metformin.72 Follow-up of a small (table 3).79 One additional benefit was that only 4% of the
Finnish RCT comparing metformin and insulin found women who were treated with glyburide needed supple-
that children exposed to metformin in pregnancy were mental insulin. Although recent studies have shown that
significantly heavier (10.47 (SD 1.49) v 9.85 (1.26) kg; concentrations of glyburide in cord blood are 50-70% of
P=0.038) at 12 months and taller and heavier (12.05 maternal concentrations,76 87 at the time of the above
(1.87) v 11.32 (1.45) kg; P=0.04) at 18 months despite study glyburide transplacental transfer was thought to be
having similar birth weights.73 No differences existed minimal.79 88 Likely as a result of these findings, glyburide
in motor, social, or linguistic development at 18 weeks treatment in women with gestational diabetes dramati-
between the two groups, although the study was small cally increased from 7% to 65% over the time period from
with only 93 children.73 Importantly, recently published 2000 to 2011.89

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The increased prevalence of glyburide use has also be related to changes in drug metabolism, and the
prompted multiple additional observational and ran- dosing used in some studies may not be ideal. During
domized clinical trials comparing outcomes in women pregnancy, glyburide concentrations increase within
treated with glyburide with those treated with insulin. In 30-60 minutes, peak in two to three hours, and return
one “natural experiment” that arose in a US healthcare to baseline by eight hours.87 These data identify several
system, the authors compared outcomes in 236 women considerations for glyburide dosing. Firstly, glyburide
treated with glyburide with those in 268 historical con- concentrations return to baseline within eight to 10 hours
trols treated with insulin.77 More women in the glybur- of ingestion, so a pre-breakfast dose may not provide an
ide group achieved treatment goals, and no differences adequate insulin response for dinner.94 All of the glybur-
were seen in birth weight or macrosomia.77 Glyburide was ide studies used either once or twice daily dosing, but
associated with higher rates of pre-eclampsia and need this could lead to inadequate glycemic control because
for phototherapy in infants, but fewer infants from the increasing the morning dose to control post-dinner
glyburide group were admitted to NICU.77 In contrast, blood sugars may result in hypoglycemia earlier in the
a retrospective cohort study comparing outcomes in day. Secondly, glyburide should be administered 30-60
4982 women treated with glyburide and 4191 women minutes before a meal to ensure that glyburide concen-
treated with insulin found that glyburide treatment was trations increase before the rise in blood sugar seen after
associated with increased risk of NICU admission, res- a meal.94 In addition, plasma concentrations of glybur-
piratory distress, hypoglycemia, birth injury, and LGA ide are lower in pregnancy than in the non-pregnancy
birth weight.78 This study was limited by the lack of state.87 Such findings suggest a possible need to change
information on glycemic control or maternal body mass the dosing and administration schedule for glyburide in
index. However, these data raised important questions pregnant women with diabetes to maximize the efficacy
about whether the differences in outcomes between of treatment.
women treated with glyburide and insulin were related
to unmeasured confounding or whether glyburide use Potential long term effect of glyburide on offspring
outside of a small, tightly regulated clinical trial was One important concern regarding glyburide use is the
associated with adverse perinatal outcomes due to either lack of long term follow-up data on children who were
suboptimal glycemic control or direct effects of the drug. exposed to glyburide in utero, and these concerns have
Several recent meta-analyses have also looked at out- become more pressing with the knowledge that glybur-
comes in women treated with glyburide compared with ide crosses the placenta. Recent data suggest that gly-
insulin.80 83-85 The meta-analysis by Balsells et al found buride may also increase placental GLUT1 expression,
that women treated with glyburide had higher birth- which could augment fetal glucose delivery.95 Whether
weight infants, more macrosomia, and more neonatal glyburide use increases the risk of fetal overgrowth inde-
hypoglycemia than those treated with insulin.57 The pendently of glycemic control is unclear, but LGA birth
average rate of treatment failure among women treated weight is thought to be a risk factor for adverse childhood
with glyburide was 6.4%. Both the observational stud- metabolic outcomes.96 97 Hypothetical concerns also exist
ies and meta-analyses of RCTs raise questions about the about long term β cell function in offspring exposed to
appropriate use of glyburide. The largest trial to date glyburide in utero, highlighting the importance of long
suggests that as long as glycemic control is comparable, term studies of growth and metabolism in offspring.
outcomes are also similar between groups.79 The other
trials included in these meta-analyses have small sample Glyburide versus metformin
sizes and differ in their approach to glyburide dosing. In Several small studies have compared glyburide with
addition, the observational studies showing increased metformin. The meta-analysis by Balsells et al compared
risk have methodological concerns including an inability glyburide with metformin,57 but it included only two stud-
to account for the level of glycemic control. Beyond gesta- ies.80 81 It found that metformin was associated with less
tional diabetes, data on the use of glyburide to treat type 2 maternal weight gain, lower birth weight, less macroso-
diabetes in pregnancy are scarce, but this is one potential mia, and fewer LGA births.57 Preterm birth was increased
novel aspect of glyburide use. In one small cohort study, in women who were treated with metformin. In contrast,
outcomes were similar between women treated with oral a recent systematic review compared outcomes between
hypoglycemic agents (primarily glyburide) and insu- women randomized to either glyburide or metformin from
lin, with less weight gain and similar glycemic control several additional studies and found no differences in
between those receiving oral agents and insulin.90 maternal or neonatal outcomes.86 The authors noted that
most of the studies comparing glyburide with metformin
Controversies in glyburide dosing were of moderate to low quality, and they also stressed
Several factors have been associated with a higher rate of that the benefits and potential harms of one oral antidia-
failure of glyburide treatment, including a fasting plasma betic drug therapy compared with another are unclear.
glucose above 110 mg/dL (6.1 mmol/L) on the oral glu- Finally, a recent RCT of 104 women took a novel
cose tolerance test, older maternal age, multiparity, and approach and randomized patients to either glyburide
diagnosis of gestational diabetes before 25 weeks, but or metformin and then added the other drug if control was
data to ensure that providers can select the most appro- inadequate.82 Treatment failure after first line treatment
priate candidates or dosing regimens for glyburide use because of poor glycemic control or adverse effects was
are limited.91‑93 Efficacy of glyburide in pregnancy may similar between glyburide and metformin (34% v 29%;

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P=0.6), and treatment success after second line therapy mostly in women with gestational diabetes. Nutrient
was higher in the metformin group than in the glyburide supplements such as myo-inositol are also being tested
group (87% v 50%; P=0.03).82 More patients in the gly- to decrease the risk of adverse pregnancy outcomes in
buride group ultimately needed insulin compared with women with gestational diabetes. Myo-inositol is hypoth-
those in the metformin group (17% v 4%; P=0.03). No dif- esized to act through complex pathways that ultimately
ferences were seen in maternal weight gain, birth weight, shift glucose intracellularly and then into fatty acids
LGA births, or macrosomia.82 However, a trend was seen synthesis.102 103 Myo-inositol supplementation starting
toward more hypoglycemia in the metformin group. The at 12-13 weeks of pregnancy decreased the likelihood
authors concluded that the combination of glyburide of gestational diabetes in at risk groups such as obese
and metformin may allow for a higher efficacy rate with women and those with polycystic ovarian syndrome.104‑106
a significantly reduced need for insulin, and they also Trials in women with other risk factors for gestational dia-
postulated that the use of metformin first may have poten- betes showed mixed results, with a recent trial showing
tiated the effect of glyburide when the latter was added.82 no effect of myo-inositol supplementation in pregnant
However, further studies are needed to assess whether women with a family history of diabetes.107 Furthermore,
these drugs can be safely and efficaciously substituted for evidence in support of myo-inositol as a treatment for
insulin and would require the combination to be directly gestational diabetes is weak,108 but it is the subject of a
compared with insulin alone. Using two drugs that cross current investigation (NCT02149992).
the placenta to avoid insulin raises concerns about the Outside of pregnancy, obstructive sleep apnea (OSA)
potential long term programming effects of fetal hyperin- has been linked to enhanced inflammatory and oxida-
sulinemia (glyburide) and altered hepatic gluconeogen- tive stress responses, endothelial damage, and metabolic
esis, insulin sensitivity, mitochondrial function, and cell derangements.109 110 Given the overlap between these bio-
cycle proliferation (metformin).98 logic pathways and adverse pregnancy outcomes, includ-
ing gestational diabetes, recent studies have focused on
Alternate oral agents evaluating the link between OSA and adverse pregnancy
α glucosidase inhibitors inhibit the α glucosidase outcomes. Rates of OSA increase with advancing gesta-
enzymes present on the brush border of the small intes- tion and may be even higher in women with gestational
tine, which slows carbohydrate absorption and reduces diabetes.111 112 OSA was independently associated with
postprandial glucose concentrations. Only acarbose has gestational diabetes (odds ratio 3.47, 1.95 to 6.19) after
been studied in pregnancy. One small case series found adjustment for age, body mass index, chronic hyperten-
that postprandial glucose values normalized and infants sion, and gestational weight gain.111 The study also noted
were healthy in six women treated with acarbose three an increasing exposure-response relation between OSA
times a day.99 Another small RCT conducted in Brazil and gestational diabetes.111 Also, in women with ges-
compared insulin versus glyburide versus acarbose in 70 tational diabetes, short sleep duration was associated
patients.100 No significant differences in LGA and cesar- with worsened glucose control.113 These findings are the
ean delivery rates among the three groups were seen, but basis for a pilot study assessing the effect of continuous
acarbose was associated with more gastrointestinal side positive airway pressure treatment on glycemic control in
effects.100 gestational diabetes (NCT02245659).
Several other agents including DPP4 inhibitors, GLP-1 Lastly, ongoing studies are exploring the relation
receptor agonists, SGLT-2 inhibitors, and thiazolidinedi- between diabetes, obesity, and the gut microbiome. Evi-
ones are used outside of pregnancy, but minimal data are dence that the gut microbiota might influence obesity
available in pregnancy. DPP-4 inhibitors reduce DPP-4 began with the observation that sterile, germ-free mice
mediated degradation of endogenous incretin hormones. have decreased capacity for energy utilization compared
This leads to enhanced insulin synthesis and secretion as with colonized counterparts.114 Data suggest that patients
well as suppressed glucagon secretion. GLP-1 receptor with type 2 diabetes have a reduction in the Firmicutes
agonists activate the GLP-1 receptor and enhance insulin phylum, and the ratio of Bacteroides to Firmicutes cor-
synthesis and secretion in a glucose dependent fashion. relates with plasma glucose concentrations.115 Kuang et
SGLT-2 inhibitors inhibit activity of glucose transporters al did a metagenome-wide association study comparing
in the proximal tubule, serving to increase renal glucose fecal samples collected at 21-29 weeks from 43 women
excretion. Thiazolidinediones activate the PPAR family with gestational diabetes and 81 healthy controls, and
of nuclear receptors and reduce insulin resistance. In they found changes in microbial composition that could
a mouse model, exposure to rosiglitazone resulted in be used to identify women at risk of gestational diabe-
abnormal placental morphology and altered expression tes.116 Others found that the placental microbiota and
of proteins implicated in placental development, raising microbiome differed between women with and without
concerns about the therapeutic use of this class of drugs gestational diabetes.117 The stool microbiota of insulin
during pregnancy.101 resistant women with a history of gestational diabetes has
been characterized postpartum, and women with former
Emerging treatments gestational diabetes had relatively higher abundance of
More than 200 studies are listed on Clinicaltrials.gov the Prevotellaceae family as well as reduced abundance of
under the heading of diabetes treatment in pregnancy. Firmicutes, similar to the situation in type 2 diabetes.118
The studies primarily focus on glyburide, metformin, Another cross sectional study of the gut microbiome in
and insulin treatment to improve pregnancy outcomes, women who had gestational diabetes and their offspring

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Table 4 | Summary of guidelines on diabetes on pregnancy


Recommendation NICE10 ACOG1 4 ADA3 RANZCOG123
Glucose targets Fasting <95mg/dL (5.3 mmol/L); 1 hour Fasting <95mg/dL (5.3 mmol/L); 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 1 hour postprandial <140 mg/dL postprandial <140 mg/dL (7.8 mmol/L); 2 hour hour postprandial <133 mg/dL (7.4
postprandial <115 mg/dL (6.4 mmol/L) (7.8 mmol/L); 2 hour postprandial postprandial <120 mg/dL (6.7 mmol/L) mmol/L); 2 hour postprandial <120
<120 mg/dL (6.7 mmol/L) mg/dL (6.7 mmol/L)
HbA1c targets T1DM and T2DM in women with no T1DM and T2DM <6% (42 mmol/ T1DM and T2DM: A1c target in pregnancy is –
hypoglycemia <6.5% (48 mmol/mol) mol) 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
Lifestyle changes GDM: dietary consultation; trial of diet and GDM: dietary consultation; limit GDM: medical nutrition therapy, physical activity, GDM: consume ≥175 g
exercise in women with fasting glucose carbohydrate intake to 33-40% and weight management carbohydrate/day; spread
<126mg/dL (7 mmol/L); focus on low glycemic of daily calories; focus on complex carbohydrates evenly throughout
index; regular exercise carbohydrates the day; reduce intake of saturated
fats; limit excess weight gain
Drug therapy T1DM, T2DM: NPH is first choice for long acting Insulin preferred agent for Insulin preferred agent for diabetes in pregnancy GDM: metformin and/or insulin
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 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 differ, specifically regarding the use of oral agents. Both
gut microbiota between women who had gestational dia- SMFM and NICE have endorsed the use of metformin as
betes and controls, but some differences existed between an alternative to insulin for treatment of gestational dia-
offspring of women who had gestational diabetes and betes.10 124 However, we would argue that the available
those who did not.119 data on oral agents are limited, especially regarding long
A few RCTs have examined the effects of probiotics term effects after in utero exposure. Further research is
administered during pregnancy with the aim of improv- needed to fully support the use of oral agents as alternates
ing insulin sensitivity and reducing risk of gestational to insulin in gestational diabetes. All of the guidelines
diabetes. In one RCT, pregnant women were randomized recognize that recommendations for the management of
to either Bifidobacterium lactis alone or B lactis plus diabetes in pregnancy are largely based on studies with
Lactobacillus rhamnosus GG (LGG) probiotic 14 days small sample sizes and less than level A evidence.
before a scheduled cesarean delivery.120 Both treatments
decreased the expression of toll-like receptor genes in the Conclusions
placenta and meconium of neonates compared with pla- Diabetes in pregnancy has significant short and long term
cebo.120 A Finnish study randomized 256 women during implications for affected mothers and their offspring.
the first trimester to dietary counseling and either a daily Despite decades of research, complications rates are high,
LGG and B lactis probiotic or placebo. Dietary counseling particularly in pregestational diabetes, highlighting that
and probiotics decreased the frequency of gestational dia- novel interventions are urgently needed. Future studies
betes from 36% to 13%, but no significant differences are needed to clarify whether diets higher in complex
in birth weight were seen.121 Of note, maternal central carbohydrates and lower in fat are more effective than
adiposity at six months postpartum was lower in women lower carbohydrate diets. Data on continuous subcu-
treated with diet and probiotics.121 In another RCT, 175 taneous insulin infusion suggest that this technology
obese pregnant women were assigned to receive either may improve outcomes in women with type 1 diabetes,
daily Lactobacillus salivarius probiotic or placebo from and future studies are needed to assess whether it can
24 to 28 weeks’ gestation, and the probiotic did not affect improve outcomes in women with type 2 diabetes and
maternal glycemia or birth weight.122 even difficult to control gestational diabetes. Although
oral agents are not novel, robust debate continues about
Guidelines the use of oral agents in gestational diabetes. We support
Guidelines for the management of diabetes in pregnancy insulin as first line treatment for gestational diabetes and
include those from NICE, ACOG, ADA, and RANZCOG hope that ongoing studies will clarify a potential role for
(table 4).1 3 4 10 123 All recommend treatment of all forms of metformin in the treatment of gestational diabetes and
diabetes in pregnancy to decrease adverse maternal and as an adjuvant to insulin in women with type 2 diabe-
fetal outcomes. All agree that management of pregnancy tes. We would also suggest that the approach to clinical
complicated by diabetes should include medical nutri- trials in gestational diabetes would benefit from more
tional therapy, counseling, and increased frequency of novel approaches. Studies on treatment of diabetes in
glucose monitoring. Differences exist in specific glucose pregnancy have followed a traditional “simple parallel
targets, including the goal for fasting glucose below 90 arm” clinical trial design, but gestational diabetes is a
mg/dL (5.0 mmol/L) by RANZCOG and a range of HbA1c disease with a heterogeneous physiology characterized
goals of 6-7% for women with pregestational diabetes. by various levels of insulin resistance and insulin secre-
Also, guidelines for treatment of gestational diabetes tion defects. Therapeutic studies outside of pregnancy

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RESEARCH QUESTIONS 13 Blumer I, Hadar E, Hadden DR, et al. Diabetes and pregnancy: an


endocrine society clinical practice guideline. J Clin Endocrinol Metab
• What diet in pregnant women with diabetes optimizes 2013;98:4227-49. 10.1210/jc.2013-2465  pmid:24194617.
glycemic control and other metabolic characteristics and 14 Metzger BE, Buchanan TA, Coustan DR, et al. Summary and
recommendations of the Fifth International Workshop-Conference on
ultimately results in the most favorable fetal growth profile? Gestational Diabetes Mellitus. Diabetes Care 2007;30(Suppl 2):S251-
• Are there different glycemic targets for subgroups of women 60. 10.2337/dc07-s225  pmid:17596481.
with diabetes in pregnancy (for example, pregestational 15 Hernandez TL, Anderson MA, Chartier-Logan C, Friedman JE, Barbour LA.
Strategies in the nutritional management of gestational
versus gestational diabetes or obese versus non-obese)? diabetes. Clin Obstet Gynecol 2013;56:803-15. 10.1097/
• Are there alternative metabolic or nutritional targets in GRF.0b013e3182a8e0e5  pmid:24047934.
pregnant women with diabetes to minimize maternal and 16 McCurdy CE, Bishop JM, Williams SM, et al. Maternal high-fat diet
triggers lipotoxicity in the fetal livers of nonhuman primates. J Clin Invest
fetal adverse outcomes? 2009;119:323-35.pmid:19147984.
• What are the long term effects of diabetes treatment 17 Harmon KA, Gerard L, Jensen DR, et al. Continuous glucose profiles
options, specifically oral hypoglycemic agents, on the in obese and normal-weight pregnant women on a controlled diet:
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understand their preferences regarding various treatment Favourable effects of the Dietary Approaches to Stop Hypertension
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Contributors: MNF and CMS both did the literature search, wrote the draft S0007114512004242  pmid:23148885.
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Funding: MNF is supported by the National Institutes of Health through diet for the treatment of gestational diabetes mellitus: a randomized
grant number KL2 TR001856. The funding source had no involvement in controlled trial. Diabetes Care 2013;36:2233-8. 10.2337/dc12-
the preparation, analysis, and interpretation of the data or submission of 2714  pmid:23564917.
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carbohydrate diet in gestational diabetes mellitus achieves
Competing interests: We have read and understood BMJ policy on glucose targets and lowers postprandial lipids: a randomized
declaration of interests and declare the following interests: none. crossover study. Diabetes Care 2014;37:1254-62. 10.2337/dc13-
Provenance and peer review: Commissioned; externally peer reviewed. 2411  pmid:24595632.
23 Hernandez TL, Van Pelt RE, Anderson MA, et al. Women With Gestational
Patient involvement: No patients were asked for input in the creation of Diabetes Mellitus Randomized to a Higher-Complex Carbohydrate/Low-
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