Pre-eclampsia/hypertensive complications
Glibenclamide versus insulin
One RCT by Langer (2005)68 reported no
difference in pre-eclampsia after treatment with glibenclamide versus insulin.
Four observational ones gave differing results (Figure 1). One cohort study (Jacobson 200575)
reported significantly higher pre-eclampsia rates with glibenclamide than with insulin (12% vs 6%), but no differences were found in the other observational studies (Ramos 200761 which
provided data as in Figure 1, and Duncan 200571
and Patterson 200877 which only reported no
differences). Taking both RCTs and observational studies together, there were between 6% and 12% of women with pre-eclampsia (where reported).
Acarbose versus insulin
Pre-eclampsia rates were not reported for acarbose versus insulin.
Metformin versus insulin
Two RCTs (Hague 200385 and Rowan 200888)
reported no difference in pre-eclampsia after treatment with metformin versus insulin (Figure 2). Nor did two cohort studies (Tertii 200856 and
Balani 200889) find any difference in pre-eclampsia
rates between metformin and insulin.
Overall, there were between 5.5% and 19% of women with pre-eclampsia. Balani (2008),89 Tertti
(2008),56 and Rowan (2008)88 found no significant
difference in pregnancy-induced hypertension rates between metformin and insulin groups.
Caesarean delivery
Glibenclamide versus insulin
Three RCTs reported no differences in
caesarean delivery rates for women treated with
Outcome Number of RCTs Significance of effect Comment
Number of observational studies (including
abstracts) Significance of effect Comment
Respiratory distress 2 NS 1 NS
5-minute Apgar score
< 7 1 NS 1 NS
1-minute Apgar score
Preterm delivery 1 Significant Higher with
metformin than with insulin (12.1% vs 7.6%, p = 0.04). Favours insulin 2 NS Direct of effect opposite to RCTs in both cohort studies Gestational age at
delivery 3 Significant Mean difference of
–0.21 weeks (95% CI –0.40 to –0.02) (p = 0.03) lower gestational age with metformin. Favours insulin 1 NS In opposite direction to RCTs
n.a., not appropriate to combine studies; NS, not significant. Values are mean ± SD unless indicated otherwise.
29 glibenclamide versus insulin (Figure 3). The RR was
0.91 (95% CI –0.71 to 1.16).
Five observational studies (Figure 3 and Patterson 200877) published as full papers reported no
significant differences between treatment groups. However, Duncan (2005),71 published as an
abstract, reported a significant difference in caesarean sections in favour of glibenclamide for non-morbidly obese women but not for morbidly obese women. The RR was 1.04 (95% CI 0.84 to 1.28) for cohort studies published in full, and 0.53 (95% CI 0.36 to 0.77, p = 0.001) for cohort studies published as abstracts. However, when combining the observational cohort studies published in full with those published as abstracts the RR was not significant, i.e. 0.82 (95% CI 0.59 to 1.14). Overall, between 14% and 56% of women had caesarean deliveries.
Five per cent of women in the glibenclamide group and 6% of women in the insulin group had an operative vaginal delivery (no significant
difference); 7% of deliveries in the glibenclamide group and 9% in the insulin group were assisted vaginal deliveries.
Acarbose versus insulin
Bertini (2005)67 did not report any significant
difference in caesarean delivery rates between women receiving acarbose or insulin (53% and 44%), RR 1.18 (95% CI 0.65 to 2.16) (Figure 4).
Metformin versus insulin
Three RCTs (Hague 2003,85 Moore 200786 and
Rowan 200888) reported on caesarean delivery
rates for women treated with metformin versus insulin (Figure 5). Significant heterogeneity was noted. However, the largest study (Rowan 200888)
did not demonstrate any appreciable or significant difference between women treated with insulin and those treated with metformin. Between 21% and 63% of women had caesarean deliveries. The overall RR for the RCTs was 1.41 (95% CI 0.77 to 2.58) (but with significant heterogeneity). Rowan (2008)88 reported that 15% of the metformin group
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FIGURE 1 Pre-eclampsia: glibenclamide versus insulin.
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and 17% of the insulin group had an emergency caesarean delivery (no significant difference). Two observational studies (Tertti 200856 and Balani
200889) reported no significant difference.
Glycaemic control during pregnancy
Glibenclamide versus insulin
For mean BG, 2-hour PPG and HbA1c, none of the studies found a significant difference between the glibenclamide groups and the insulin groups.
With respect to FBG one cohort study found significantly lower values among women receiving glibenclamide compared with insulin (mean difference –0.41 mmol/l in the study by Jacobson 200575) (Figure 6). However, the RCT by Langer
(2000)68 did not find any significant difference
among women receiving glibenclamide or insulin. FBG values in the different studies after treatment were between 5.01 and 5.44 mmol/l, 2-hour post-prandial values were between 5.16 and 6.59 mmol/l, mean BG values were between 5.78 and 5.83 mmol/l and HbA1c was between 5.3% and 5.5%.
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FIGURE 3 Caesarean delivery: glibenclamide versus insulin.
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Acarbose versus insulin
Maternal glycaemic control was not reported for acarbose versus insulin.
Metformin versus insulin
Two RCTs reported on maternal glycaemic control with metformin compared with insulin. Neither of the trials by Moore (2007)86 or Rowan (2008)88
found any significant difference in maternal FBG between metformin and insulin (FBG values between 5.09 and 5.37 mmol/l).
There was no significant difference in 2-hour post-prandial values in Moore (2007).86 However,
Rowan (2008)88 found significantly lower 2-hour
postprandial glucose values in the metformin group 1 week after randomisation and overall (mean difference –0.20 mmol/l for both
measurements, p < 0.01) but not during the last 2 weeks before delivery. Mean 2-hour post-prandial values were between 5.9 and 6.69 mmol/l in the two studies. Rowan (2008)88 reported no significant
difference between treatment groups with respect to HbA1c values.
Hypoglycaemia
Glibenclamide versus insulin
Three RCTs reported on maternal hypoglycaemia (Figure 7).
The trials by Anjalakshi (2007)66 and Bertini
(2005)67 reported no maternal hypoglycaemia in
either the glibenclamide or the insulin groups
(hypoglycaemia requiring hospital admission in Bertini 2005;67 not defined in Anjalakshi 200766).
However, Langer (2000)68 found significantly
less hypoglycaemia (BG < 2.2 mmol/l) in the glibenclamide group than in the insulin group [20% vs 2%, RR 0.10 (95% CI 0.04 to 0.27), p = 0.03]; none of the women reported severe symptoms.
Two observational studies reported different outcomes. Jacobson (2005)75 found slightly
but significantly more hypoglycaemia (values < 3.3 mmol/l) in the glibenclamide group than in the insulin group [0.20% vs 0.08%, RR 2.40 (95% CI 1.41 to 4.07), p < 0.001]. Yogev (2004),78 however, found significantly less
asymptomatic hypoglycaemia (BG ≤ 4.0 mmol/l) with glibenclamide than with insulin (in 28% vs 63% of women with 242 vs 46 episodes, p = 0.04); no symptomatic hypoglycaemic episodes were reported.
Acarbose versus insulin
Bertini (2005)67 found no maternal hypoglycaemia
requiring hospitalisation for acarbose versus insulin.
Metformin versus insulin
Only the RCT by Moore (2007)86 reported
maternal hypoglycaemia after treatment with metformin versus insulin. No cases of maternal hypoglycaemia were seen (hypoglycaemia not clearly defined).
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