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Review Article

The use of oral hypoglycaemic agents in pregnancy

R. I. G. Holt and K. D. Lambert

Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK

Accepted 29 November 2013

Abstract

While insulin has beenthe treatment of choice whenlifestylemeasuresdo not maintain glycaemiccontrol during pregnancy,

recent studies have suggested that certain oral hypoglycaemic agents may be safe and acceptable alternatives. With the

exception of metformin and glibenclamide (glyburide), there are insufficient data to recommend treatment with any other

oral hypoglycaemic agent during pregnancy. There are no serious safety concerns with metformin, despite it crossing the

placenta.Whenused in thefirst trimester, there is no increase in congenital abnormalities andthere appears to be a reduction

in miscarriage, pre-eclampsia and subsequent gestational diabetes. Studies of the use of metformin in gestational diabetes

show at least equivalent neonatal outcomes, while reporting reductions in neonatal hypoglycaemia, maternal

hypoglycaemia and weight gain and improved treatment satisfaction. Glibenclamide effectively lowers blood glucose in

women with gestational diabetes, possibly with a lower treatment failure rate than metformin. Although generally well

tolerated, some studies have reported higherrates of pre-eclampsia, neonatal jaundice, longerstay in theneonatal care unit,

macrosomia andneonatal hypoglycaemia.Thereis a paucity of long-termfollow-up data on children exposed to oral agents

in utero. The AmericanCollege of Obstetrics and Gynecology and the UK National Institute of Health and Care Excellence

(NICE) have recommended that either metformin or glibenclamide can be used to treat gestational diabetes. Metformin is

also recommended for use in the pre-conception period by NICE. By contrast, the American Diabetes Association

recommends that both drugs should only be used during pregnancy in the context of clinical trials.

Diabet. Med. 31, 282291 (2014)

IntroductionDiabetes is the commonest medical condition in pregnancy,

affecting 215% of pregnant women, depending on the

population and ethnic group studied [1,2]. Even with mild

hyperglycaemia, it is associated with increased rates of

miscarriage and congenital abnormalities in the first trimester

and abnormal fetal growth and development in the latter half

of pregnancy, characterized by macrosomia, which is in turn

associated with an increased risk of operative delivery,

shoulder dystocia and birth trauma. Offspring of mothers

with diabetes also experience increased rates of perinatal

hypoglycaemia, jaundice and respiratory distress and long

-term risk of diabetes and obesity.There is a linear relationship between maternal hyperglyca-

emia andadverse fetal outcomes [3]and twolargerandomized

controlled trials in women with gestational diabetes have

shown the benefit of treating mild maternal hyperglycaemia

[4,5]. The epidemiological data, coupled with these and other

trials, have led to recommendationsthat women with diabetes

should aim for normoglycaemia during pregnancy [1].

Traditionally, insulin is added if dietary and lifestyle

measures fail to maintain normoglycaemia [6]. However, thisapproach is demanding both for pregnant women and their

healthcare teams. Over the last decade, several studies have

challenged this strategy and suggested that the use of certain

oral hypoglycaemic agents may be safe and acceptable

alternatives to the use of insulin, at least for women with

gestational diabetes [7,8]. This review will examine the use of

oral agents in pregnancy, with a particular focus on

metformin and glibenclamide (glyburide).

Methods

PubMed, other electronic databases and relevant guidelines

were searched to identify articles that included the keywordspregnancy, diabetes and each individual oral hypoglycae-

mic agent name. The paper reference lists were searched

manually for further information. Oral hypoglycaemic agent

manufacturers were contacted for information and the

summaries of product characteristics consulted.

Metformin

Metformin is widely used to treat Type 2 diabetes and poly-

cystic ovary syndrome. It is an insulin sensitizer, inhibitingCorrespondence to: Richard I. G. Holt. E-mail: [email protected]

282 2013 The Authors.

Diabetic Medicine 2013 Diabetes UK

DIABETICMedicine

DOI: 10.1111/dme.12376


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gluconeogenesis and hepatic glucose output, while increasingmuscle glucose uptake. Metformin is excreted unchanged in

the urine. In pregnancy, as the glomerular filtration rate is

increased by 40%, there is potential for the drug to be

eliminated faster [9]. Metformin crosses the placenta, leading

to fetal concentrations that are at least half the maternal level

[7]. Metformin is not teratogenic in rats and rabbits at doses

of up to 600 mg kg1 day1, equivalent to 26 times the

maximum recommended human dose [7].

Human studies

Use in pre-conception period

Although metformin is not licensed for use during pregnancy,

increasing numbers of women have conceived (either acci-

dentally or purposefully) while taking metformin for Type 2

diabetes or polycystic ovary syndrome.

Retrospective studies. Retrospective cohort studies of the use

of metformin in the first trimester [10,11] and throughout

pregnancy [12,13] did not find major congenital malforma-

tions, although the total number of women studied was low.

Early pregnancy loss was reduced in one study (8.8 vs.

41.9%) [12] and neonatal hypoglycaemia was less common

in another (18.5 vs. 24.5%) [11]. One study showed amarginally reduced birthweight in neonates born to women

taking metformin [10], while another found no difference

[11].

The last retrospective study compared the use of metfor-

min with sulphonylureas and insulin in 105 women with

gestational diabetes and 55 women with Type 2 diabetes

[13]. There was a higher incidence of pre-eclampsia in

metformin-treated women [32% vs. 7% (sulphonylurea) vs.

10% (insulin), P < 0.001] and a higher incidence of perina-

tal mortality (11.6%) compared with women not treated

with metformin (1.3%, P < 0.02). The age and BMI of the

metformin-treated women (32 years, 31.2 kg/m2) were

significantly higher thanthe other groups (sulphonylurea group

28 years, 22.8 kg/m2, insulin group 29 years, 24.8 kg/m2),

making it unclear whether the differences reflect an indepen-

dent treatment effect, as obesity and increasing age are risk

factors for adverse pregnancy outcomes.

Prospective studies. Prospective cohort studies have also not

demonstrated significant adverse effects or congenital mal-

formations with metformin treatment and indeed have

shown some benefit [1420]. Most studies showed significant

reductions in miscarriage and fetal loss [14,15,19,20],

particularly when the women continued metformin through-

out pregnancy [16,17]. In one study, the spontaneous

abortion rate was reduced from 62% to 26% after the same

women began metformin treatment (P < 0.0001) [14].

A further important finding of these studies was an up to

tenfold reduction in incident gestational diabetes in metfor-

min-treated women [14

16,18,19]. The incidence ofpre-eclampsia was either unchanged [15,20] or reduced in

women taking metformin throughout pregnancy [16,18,19].

Birthweight and height of infants of metformin-treated

women was largely unchanged [14,20], but, in one study, the

incidence of intra-uterine growth restriction was lower in

women who continued treatment throughout pregnancy

compared with those who stopped metformin in the first

trimester (2.2 vs. 21.8%, P = 0.026) [16]. In another study

that followed the offspring for 18 months, there was no

evidence of motor or social developmental delays, although

male infants were thinner than the control group at 6 months

[15].

Randomized controlled trials. These observational studies led

onto a number of randomized controlled trials of the use of

metformin in early pregnancy [2124]. The first of these was

a pilot study that was subsequently extended into a larger

multi-centre study of 274 pregnant women with polycystic

ovary syndrome who were allocated to treatment with

metformin (n = 136) or placebo (n = 138) [21,22]. The pilot

study showed a reduction in adverse pregnancy outcomes,

but this was not replicated in the larger study. Furthermore,

there was no difference in the incidence of gestational

diabetes, pre-eclampsia or pre-term delivery in metfor-

min-treated women. The authors subsequently reported thepost-natal effects on offspring exposed to metformin during

pregnancy. Growth, body composition and metabolic mea-

surements were reported for 25 of the 37 children in the pilot

study when they were aged 79 years. There were no

differences in height, weight or body composition between

those exposed to metformin, but fasting glucose concentra-

tion was higher in the metformin group and there was also a

trend towards higher systolic blood pressure and lower LDL

cholesterol concentration [25]. In the larger study, at 1 year

after birth, infants in the metformin group were heavier than

Whats new?

Increasing numbers of women with polycystic ovary

syndrome or Type 2 diabetes are conceiving while

taking metformin.

Observational and experimental studies suggest that

metformin is safe throughout pregnancy and mayconvey specific benefits, including reduced pregnancy

loss, less maternal weight gain and less neonatal

hypoglycaemia.

Many women taking metformin for gestational diabetes

require supplementary insulin.

Glibenclamide is an effective alternative to insulin for

the treatment of gestational diabetes, but concerns

remain over its safety because of increased rates of

neonatal jaundice and hypoglycaemia.

2013 The Authors.Diabetic Medicine 2013 Diabetes UK 283

Review article DIABETICMedicine


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those in the placebo group (10.2 1.2 vs. 9.7 1.1 kg,

P = 0.003) [26].

There was a ninefold marked reduction in the incidence of

gestational diabetes in a further study of 29 women with

polycystic ovary syndrome who were randomized to con-

tinue metformin throughout the pregnancy compared with

30 who discontinued treatment during pregnancy (3.4 vs.

30%) [23].Thelast randomized study evaluatedthe effectof metformin

in 160 women with polycystic ovary syndrome and infertility

treated from conception to 12 weeks gestation [24].

Compared with the 160 women in the placebo group, the

metformin group experienced a higher pregnancy rate (53.6%

vs. 40.4%,P = 0.006) and live birth rate (41.9% vs. 28.8%,

P = 0.014).

Type 2 diabetes

At present there are no completed randomized controlled

trials of the use of metformin in women with Type 2 diabetes,butan ongoing trial of 500pregnantwomen recruitedfrom 25

centres in Canada will examine whether the addition of

metformin to standard treatment with insulin is beneficial

(Clinical Trials Registry No; NCT 01353391).

Gestational diabetes

Retrospective observational studies. The first study of

women with gestational diabetes included both metformin

and glibenclamide and as well as women with Type 2

diabetes. It reported that perinatal mortality was lower in

women treated with insulin compared with those in the oral

hypoglycaemic agent groups; however, this was explained by

differences in glycaemic control [27]. By contrast, the second

study found no significant differences in maternal outcomes

between the metformin and insulin groups [28]. Further-

more, there was no difference in mean birthweight, macros-

omia or gestational age at delivery. The incidence of neonatal

hypoglycaemia was higher in the offspring of insulin-treated

women (P = 0.03), but is probably explained by the higher

baseline glucose in insulin-treated women. The third retro-

spective study, which included 293 women treated with

metformin, found lower rates of macrosomia (8.2 vs. 14.3%,

odds ratio 0.56; 95% CI 0.330.99) and Caesarean delivery

and did not highlight any safety issues [29]. Fewer womentreated with metformin required insulin than women treated

with diet and lifestyle advice alone (21% vs. 37%, odds

ratio 0.46; 95% CI 0.320.66).

Prospective observational studies. In a study of 100 women

treated with metformin and 100 treated with insulin, there

was less maternal weight gain in the metformin group, while

neonates had less prematurity, neonatal jaundice and admis-

sion to the neonatal unit (P < 0.01) [30]. The benefits were

also seen in a study of 465 women treated with metformin,

either alone (n = 249) or with insulin (n = 216). These

women were compared with 371 women treated with diet

alone and 399 women treated with insulin alone [31].

Metformin-treated women had fewer pre-term births (19.2%

insulin, 12.5% metformin, 12.1% diet, P = 0.005) and

improved neonatal outcomes, including hypoglycaemia

requiring intravenous dextrose and neonatal intensive care

unit admission compared with women treated with insulin(11.1% insulin, 5.1% metformin, 7.4% diet,P = 0.004). No

difference in outcome was seen between the metformin and

diet group. Again, firm conclusions cannot be drawn because

of baseline differences between groups.

Randomized controlled trials. The largest and most influen-

tial study of the use of hypoglycaemic agents in pregnancy is

the Metformin in Gestational Diabetes (MiG), which eval-

uated the effectiveness and safety of metformin in the

treatment of gestational diabetes [32]. It recruited 751

women with gestational diabetes who were randomly allo-

cated to open-label treatment with metformin (1000

2000 mg daily) or to insulin alone. Strict glycaemic targets

were set and, if these were not met, women treated with

metformin were offered supplemental insulin. Of the 363

women in the metformin group, 168 (46.3%) required

insulin, but the median doses were lower than in women

treated with insulin alone (42 vs. 50 units). The women who

required supplemental insulin were more overweight, more

likely to have a past history of gestational diabetes and have

higher fasting glucose when they entered the trial. Consistent

with its use outside pregnancy, about 10% of women treated

with metformin developed gastrointestinal side effects, but

there were no serious adverse effects of metformin.

There was no significant difference in the primary out-

come, which was a composite of neonatal complications,

including hypoglycaemia, respiratory distress, phototherapy,

birth trauma, low APGAR and prematurity (metformin:

32.0%, insulin 32.2%). When the individual components of

the primary outcome were analysed, severe neonatal hypo-

glycaemia occurred more commonly in the insulin group (30/

370) than in the metformin group (12/363, P = 0.008). By

contrast, the number of preterm births was higher in the

metformin group (12.1% vs. 7.6%, P = 0.04); however, the

mean gestation was only 1.7 days shorter in the metformin

group. There was one perinatal death secondary to Budd

Chiari syndrome in the insulin-treated group. There were nodifferences in the number of congenital abnormalities

between groups.

The only significantly different secondary outcome mea-

sures were maternal weight gain (metformin 0.4 vs. insulin

2.0 kg, P = 0.001) and treatment satisfaction in favour of

metformin. Neonatal well-being and anthropometric mea-

surements were not different; however, 2-year-old children of

metformin-treated mothers had more subcutaneous upper

limb fat, but no difference in total body fat, implying a more

favourable pattern of fat distribution [33].



DIABETICMedicine Oral hypoglycaemic agents in pregnancy R. I. G. Holt and K. D. Lambert


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Seven more recent but smaller trials have largely confirmed

the safety and efficacy of metformin in gestational diabetes

compared with insulin [3439]. The first of these compared

50 women treated with metformin with 50 treated with

insulin [34]. There was no difference in neonatal outcomes,

but there was a non-significant doubling of Caesarean

delivery in metformin-treated women. Similarly, in another

trial of 160 women, of whom 80 were randomized tometformin treatment, there were no differences in obstetric

or neonatal outcomes, although maternal weight gain was

lower in women treated with metformin (11.3 vs. 13.7%,

P < 0.001) and the neonates were smaller (3.3 vs. 3.4 kg,

P = 0.005) [35]. Glycaemic control was similar with both

treatments. A further study of 47 women treated with

metformin found less maternal weight gain (P = 0.002) and

marginally improved maternal glycaemic control after dinner

compared with 47 women treated with insulin alone [36].

Hypoglycaemia was reduced in neonates in the metformin

group (P = 0.032).

Two further studies comparing the use of metformin withinsulin also found no difference in maternal and neonate

variables between groups, including Caesarean delivery,

birthweight, APGAR scores at 5 min, respiratory distress

syndrome, hyperbilirubinaemia, neonatal hypoglycaemia

and neonatal intensive care unit admission [37,39].

In the first of three trials comparing metformin with

glibenclamide, 75 women with gestational diabetes were

randomly assigned to treatment with metformin and 74 to

glibenclamide [38]. More women taking metformin were

switched to treatment with insulin (34.7 vs. 16.2%,

P = 0.01). In those women who achieved satisfactory

glycaemic control, there was no difference in fasting or

postprandial glucose between groups. There were more

Caesarean deliveries in the metformin group (15% vs. 3%,

P = 0.02), but no difference in pre-eclampsia. There was no

difference in neonatal hypoglycaemia or macrosomia rates,

but mean birthweight was 200 g greater in the glibenclamide

group (P = 0.02).

In the next trial, the main finding was that the 40

metformin-treated women experienced less weight gain than

the 32 treated with glibenclamide (10.3 vs. 7.6 kg, P = 0.02)

[40]. Similar numbers, 8% in the metformin group and 10%

in the glibenclamide group, required additional insulin

therapy. Although the numbers are small, there were no

differences in glycaemic control, birthweight, macrosomia orneonatal hypoglycaemia. A further report by the same group

described the use of metformin and glibenclamide in 104 and

96 women, respectively, again finding no differences in

adverse neonatal outcomes [41]. Birthweight was about

200 g lighter in the metformin group, while neonatal blood

glucose levels were significantly higher.

In most of the trials, a significant proportion of metfor-

min-treated womenup to 46.3%have required supple-

mental insulin. In general, these women had higher baseline

BMI, more marked hyperglycaemia and earlier diagnosis

and treatment of gestational diabetes, and tended to be

older.

Sulphonylureas

Sulphonylureas act by increasing insulin secretion from the

pancreaticb-cells. Glibenclamide clearance during pregnancy

is increased, leading to plasma concentrations that are about50% lower during pregnancy with equivalent doses [42].

Historical perspective

Early studies indicated that treatment with sulphonylureas

was associated with an increased incidence of congenital

abnormalities and neonatal hypoglycaemia, but this was

likely caused by maternal hyperglycaemia [27]. A more

recent systematic review and meta-analysis that examined

first-trimester exposure to oral hypoglycaemic agents, includ-

ing studies of chlorpropamide (n = 8), tolbutamide (n = 6)

and glibenclamide (n =

4), found no significant effect onmajor malformations after adjustment for maternal glycae-

mic control [43].

Nevertheless, the recognition that sulphonylureas readily

crossed the placenta and stimulated fetal insulin secretion

caused concern because many fetal complications of diabe-

tes, including macrosomia and neonatal hypoglycaemia, are

caused by fetal hyperinsulinaemia.

Preclinical studies

An interest in sulphonylureas was rekindled when it was

recognized that the degree to which sulphonylureas crossed

the placenta differed between individual drugs because of

differences in molecular weight, drug clearance and protein

binding [44]. These findings, and those of the subsequent

clinical trial [45] described below, have been contradicted by

a clinical study of 40 women with gestational diabetes and

40 healthy pregnant women, which found that glibenclamide

crossed the human placenta, leading to fetal plasma concen-

trations that are ~70% of maternal plasma levels [42].

Langer randomized controlled trial

Unlike metformin, where the major clinical trial was

preceded by several observational studies, the use of gliben-clamide was largely stimulated by the publication of a

randomized clinical trial by Langer and colleagues in 2000

[45]. Four hundred and four women with gestational

diabetes, defined by the Carpenter and Coustan criteria,

were randomly assigned to receive insulin or glibenclamide.

The starting dose of glibenclamide was 2.5 mg daily and was

increased by 5 mg per week to a maximum of 20 mg daily if

necessary. The primary outcome variable was achievement of

adequate glycaemic control, defined as a mean blood glucose

of 5.05.9 mmol/l, a fasting blood glucose of 3.45.0 mmol/l,




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age and parity [56]. It is interesting to note that, generally,

neonatal outcomes appear no worse in women who switched

to insulin [52,56], although, in one study, neonates were

more likely to require intravenous glucose to treat hypo-

glycaemia [54].

Randomized controlled trialsIn a Brazilian study, 27 women treated with insulin were

compared with 24 treated with glibenclamide and 19 treated

with acarbose [57]. Adequate glycaemic control was

achieved in 79% of the glibenclamide-treated women and

58% of women using acarbose. Large for gestational age

occurred in 3.7%, 25% and 10.5% of the neonates born to

mothers treated with insulin, glibenclamide and acarbose,

respectively. Six of the eight cases of neonatal hypoglycaemia

occurred in glibenclamide-treated women.

In a second smaller study from India, no differences in

glycaemia or birthweight were observed in 10 women treated

with glibenclamide and 13 treated with insulin [58].Following treatment commencement, there was no difference

in glycaemic measures or fetal outcomes. No hypoglycaemic

episodes were reported in either group.

In a further trial of 48 women with gestational diabetes

treated with glibenclamide and 49 treated with insulin, there

was no difference in maternal hypoglycaemia or Caesarean

delivery, but 28% of infants in the glibenclamide group were

more likely to experience an episode of hypoglycaemia (28

vs. 13%, P < 0.03) [59].

A randomized controlled trial examined neonatal body

composition in 82 infants born to 50 women treated with

insulin and 49 treated with glibenclamide [60]. Maternal

glycaemic control was similar between the groups, except after

dinner when glucose concentrations were lower in insu-

lin-treated women. There was no difference in neonatal fat

mass, BMI or ponderal index between groups. However,

macrosomia occurred more frequently in the glibenclamide

group (22% vs. 2.4%,P = 0.01). Furthermore, the glibencla-

mide group experienced a 4.9% increase in the rate of

intrauterine growth retardation (P < 0.01). There was no

difference in umbilical cord insulin and glucose concentration.

Thiazolidinediones

Thiazolidinediones are insulin sensitizers that activate thenuclear peroxisome proliferator activator receptor gamma

(PPARc), that in turn increases transcription of genes

regulating adipogenesis, glucose and lipid metabolism.

Several studies have shown that, similar to metformin,

thiazolidinediones improve insulin resistance and hyperan-

drogenism and are being used to treat polycystic ovary

syndrome [61].

PPARc plays a role in placental maturation and may

regulate placental fatty acid transport and storage and

hormone secretion [62]. Although thiazolinediones do not

appear to be teratogenic, they readily cross the placenta and

their use has been associated with fetal death and growth

retardation, secondary to placental dysfunction. There are

only limited data in human pregnancy [63 65] and so the use

of thiazolinediones is not recommended.

Alpha-glucosidase inhibitors

Alpha-glucosidase inhibitors reduce intestinal carbohydrate

absorption by inhibiting the cleavage of disaccharides and

oligosaccharides to monosaccharides in the small intestine.

As they reduce postprandial hyperglycaemia and less than

2% is absorbed (although drug metabolites may appear in

the maternal circulation), these agents may have potential

benefits in pregnancy. Animal studies have suggested no

harmful effects, but there are scanty data of its use in human

pregnancy [62]. There are theoretical concerns that the

reduced carbohydrate absorption may alter bowel flora and

alter inflammation or prostaglandin E secretion, with thepotential to induce labour.

Apart from the Brazilian study described above [57], two

other reports describe experience in 11 women [66,67]; in

one report, six women with gestational diabetes were

successfully treated [66], but the other reported that two of

the five women, who took acarbose early in pregnancy,

miscarried [67].

Although further studies are warranted, at present the use

of a-glucosidase inhibitors is not currently recommended

because of the lack of human pregnancy safety data.

Incretin-based treatmentsAt present, scant information exists for the use of incre-

tin-based therapies during pregnancy, but the available data

from animal studies suggest that these drugs should be

avoided. Although dideptidyl peptidase 4 (DPP-4) inhibitors

and glucagon-like peptide 1 (GLP-1) receptor agonists do

not appear teratogenic, there have been reports of growth

retardation and delayed ossification and other skeletal effects

in rats and rabbits.

SGLT-2 inhibitors

There are no human studies of the use of sodium-glucoseco-transporter 2 (SGLT-2) inhibitors in pregnancy, but

studies in rats have shown toxicity to the developing

kidney with an increased incidence and/or severity of renal

pelvic and tubular dilatations in the time period corre-

sponding to the second and third trimesters of human

pregnancy. At higher doses, the use of dapagliflozin was

associated with reductions in birthweight. As such, treat-

ment with SGLT-2 inhibitors during pregnancy is not

recommended.




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Recommendations

The US Food and Drug Administration (FDA) has classified

metformin and acarbose as category B drugs (does not

increase the risk of harm to the fetus) as animal studies have

failed to demonstrate a risk in pregnancy, but there are no

adequate well-controlled studies in pregnant women, while

all other oral hypoglycaemic agents are category C [eitherstudies in animals have revealed adverse effects on the fetus

(teratogenic or embryocidal or other) and there are no

controlled studies in women or studies in women and

animals are not available].

The American Diabetes Association (ADA) has cautioned

against the use of glibenclamide and metformin in preg-

nancy, but infers that, if a woman becomes pregnant while

taking either agent, she should continue this until insulin can

be initiated because of the known risk of hyperglycaemia

[68]. The guidelines currently recommend that both drugs

should only be used during pregnancy in the context of

controlled clinical trials. By contrast, the American Collegeof Obstetrics and Gynecology has recommended that either

drug may be considered to control hyperglycaemia in women

with gestational diabetes [6].

While acknowledging that there is no marketing authori-

zation specifically for pregnancy, the UK National Institute

of Health and Care Excellence (NICE) has recommended

that either metformin or glibenclamide can be used to treat

women with gestational diabetes. Metformin may also be

used in the pre-conception period and during pregnancy as

an adjunct or alternative to insulin, when the likely benefits

from improved glycaemic control outweigh the potential for

harm [1]. No other drugs are recommended.

Discussion

The aim of diabetes management in pregnancy is to achieve

normoglycaemia and meeting this goal is more importantthan the means by which it is achieved. However, with the

exception of metformin and glibenclamide, there are insuf-

ficient data to recommend treatment with any other currently

available oral hypoglycaemic agent during pregnancy. There

are also insufficient data about the use of glibenclamide

during the first trimester to recommend its use in women

with pre-existing Type 2 diabetes.

None of the studies of metformin in pregnancy have

highlighted any serious safety concerns, despite it crossing

the placenta. When used to treat women with polycystic

ovary syndrome, there is no increase in congenital abnor-

malities and there appears to be a reduction in miscarriageand pre-eclampsia. Most studies also suggest a reduction in

the later onset of gestational diabetes. While we await the

results of the use of metformin in women with Type 2

diabetes in pregnancy, these results should be reassuring to

women who conceive while taking metformin, and it seems

reasonable to continue metformin if a woman becomes

pregnant while taking the drug as it is likely that any

potential harm is outweighed by the risk of worsening

glycaemic control.

Table 1 Comparison of metformin and glibenclamide in pregnancy

Metformin Glibenclamide

Data available Observational and randomized controlled trial studiesin pre-conception period and during pregnancy

Observational and randomized controlledtrial studies during pregnancy

Maternal outcomesGlucose control Failure rate: up to 46% will require supplemental insulin

Less hypoglycaemia than insulinLess gestational diabetes in women treated throughout

pregnancy

Failure rate: 1621% will requiresupplemental insulin

Less hypoglycaemia than insulin

Pre-eclampsia Possibly reduced Possibly increasedWeight gain Less than insulin Similar to insulinTreatment satisfaction Better than insulin No data

Neonatal outcomesEarly pregnancy loss Possibly reduced No dataHypoglycaemia Less than insulin No difference from insulin

Timing of birth Discrepant findings but overall no effect No difference from insulinBirthweight No difference or marginally reducedNo difference or less intra-uterine growth restriction

No difference or lower rate of macrosomia

No differencePossible increase in intra-uterine growth

restrictionPossible increase in macrosomia

Jaundice No change Possibly increasedNeonatal unit admission Reduced Possibly longer stay

Long-term follow-up of infantsMotor or social development No evidence of delay No dataGrowth Thinner at 6 months

Heavier at 1 yearPossibly altered fat distribution at 2 yearsNo difference at 8 years

No data





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While many of the studies of the use of metformin in

gestational diabetes are limited by small numbers, they are

similarly encouraging, showing at least equivalent neonatal

outcomes for metformin compared with insulin, while

reporting reductions in maternal hypoglycaemia and weight

gain and improved treatment satisfaction. Neonatal hypo-

glycaemia also appears reduced. There are discrepant find-

ings regarding the timing of birth, but these differences maybe influenced by other factors apart from treatment. These

studies provide evidence that metformin is an effective and

safe alternative to the use of insulin.

At present there are few reports of the long-term effects of

metformin on offspring exposed to the drug in utero. There

may be early differences in growth patterns and one small

study has observed increased glucose concentrations. Larger

long-term follow-up of these children is needed.

Several experimental and observational studies have dem-

onstrated that glibenclamide can effectively lower blood

glucose in women with gestational diabetes, possibly with a

lower treatment failure rate than metformin. Glibenclamideis generally well tolerated with few experiencing significant

side effects [50,53]. While many studies have not shown

differences in fetal and maternal outcomes between gliben-

clamide and insulin, they are limited in their power to

demonstrate differences. One commentary suggested that,

had the number of participants been doubled in the Langer

trial with similar results, the observed differences in glycae-

mic control between groups may have been significant [49].

By contrast, other studies have reported higher rates of

pre-eclampsia, neonatal jaundice requiring phototherapy,

longer stay in the neonatal care unit, macrosomia and

neonatal hypoglycaemia in women who were treated with

glibenclamide. There are no reports of the long-term effects

of glibenclamide on offspring exposed to the drug in utero.

When making a choice between metformin and glibencla-

mide, the benefits of less maternal weight gain, lower

birthweight and treatment satisfaction favour the use of

metformin over glibenclamide (Table 1). Although a greater

proportion appears to require supplementary insulin, the

addition of insulin to metformin is more straightforward

than the switch from glibenclamide. Although both metfor-

min and glibenclamide appear safe, there are some residual

concerns about glibenclamide that need to be resolved before

this drug can be recommended unreservedly. Furthermore,

the very premise that glibenclamide does not cross theplacenta [45] has been challenged [42]. It is unclear why

there have been discrepant results, but, if indeed glibencla-

mide does cross the placenta in significant quantities, the

potential to stimulate fetal insulin production is of concern.

With both drugs, many women do not achieve adequate

glycaemic control and require insulin. It is important to

minimize the time of hyperglycaemia and so doses should be

rapidly escalated to the maximally tolerated doses, while

being mindful of the risk of side effects. Consideration should

therefore be given to starting insulin concurrently with

metformin in women with high BMI, prior history of

gestational diabetes and high baseline glucose who have a

high chance of missing their glycaemic targets with metfor-

min alone.

In conclusion, recent studies have suggested that metfor-

min and glibenclamide agents may be safe and acceptable

alternatives to insulin in the treatment of gestational diabe-

tes, with the evidence favouring the use of metformin.

Funding sources

This review was funded by the University of Southampton.

Competing interests

RIGH was a member of the National Institute for Health and

Clinical Excellence (NICE) diabetes and pregnancy guideline

development group.

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