George Asimakopoulos, Panagiotis Antsaklis, Mariana Theodora, Michael Sindos, Alexandros Rodolakis, Dimitrios Loutradis, George Daskalakis
1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, “Alexandra” Hospital, Athens, Greece
Correspondence: 1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, “Alexandra” Hospital, Athens, Greece, e-mail: firstname.lastname@example.org
Gestational diabetes mellitus (GDM) is defined as impaired glucose tolerance with onset or first recognition during pregnancy, which is characterized by increased insulin resistance. GDM affects about 10% of pregnancies and its prevalence is rising worldwide mainly due to the advancing maternal age and the increased prevalence of obesity. GDM is associated with pregnancy-related maternal and fetal morbidity (both antenatal and perinatal). Traditional treatments for the GDM include diet and, if it is necessary, insulin. However, the percentage of macrosomic newborns does not appear to be significantly reduced. Safe and effective preventive interventions are therefore, needed in an attempt to lower the incidence of gestational diabetes. Myo-inositol has been suggested to improve insulin resistance in women with insulin resistant syndromes such as GDM, polycystic ovarian syndrome, type 2 diabetes and metabolic syndrome. Several studies report a significant decrease in GDM incidence in women at risk for GDM comparing to the placebo group. However, the option of myo-inositol supplementation needs to be further explored as the current evidence is relatively limited.
Keywords: Myo-inositol, Gestational diabetes mellitus, Insulin resistance, Review
Gestational diabetes mellitus (GDM) is defined as glucose intolerance with onset or first recognition during pregnancy, which is associated with increased insulin resistance1,2. This complication is associated with several risk factors such as advanced maternal age, increased body mass index (BMI) and family history or previous history of gestational diabetes2. The prevalence of GDM is rising worldwide mainly due to the advancing maternal age and the increased prevalence of obesity3. Although GDM is reported to affect about 10% of pregnancies, its prevalence is expected to be higher according to the newly proposed criteria for the diagnosis of GDM4.
Gestational diabetes mellitus is associated with higher risk of pregnancy complications. Perinatal morbidity is increased due to complications such as fetal macrosomia, shoulder dystocia, neonatal hypoglycemia and respiratory distress syndrome5. Maternal morbidity includes caesarean delivery, gestational hypertension, preeclampsia and predisposition to the development of type 2 diabetes (T2D) later in life6. Furthermore, the newborns with macrosomia are at increased risk for the onset of hypertension and diabetes later in life7.
Pregnancy is normally characterized by insulin resistance. Most women adjust during pregnancy and remain euglycemic by increasing insulin release. On the other hand, women who develop GDM are unable to counteract insulin resistance. Although insulin-sensitizing factors, such as metformin, were initially considered to be promising interventions for the prevention of GDM, they do not seem to be as efficacious as expected so far8. GDM is principally treated with diet and, if it is necessary, with insulin. The combination of intensive monitoring during pregnancy and the use of novel insulin regimens allows the effective regulation of blood glucose levels and improves the perinatal outcome. However, the percentage of macrosomic newborns does not appear to be significantly reduced (15-45%)9.
Inositol is a sixfold alcohol of cyclohexane which is present in animal and plant cells10. Myo-inositol and d-chiro inositol are the most common isoforms of inositol in eukaryotic cells with insulin-mimetic properties and potential therapeutic effects on insulin-mediated diseases11,12. Myo-inositol is an intracellular insulin mediator that provides more available phosphatidylinositol. Phosphatidylinositol seems to be important in the relation of insulin with its receptor leading to increased insulin sensitivity13. Myo-inositol is present in many foods, such as cereals, corn, legumes and meat. It is synthesized principally by the liver.
Preventive strategies are considered to be better than active response following the onset of a complication. Safe and effective interventions are therefore, needed in an attempt to lower the incidence of gestational diabetes. Such interventions could also decrease the economic burden of the disease and benefit health care systems.
In the last years, several clinical studies have been conducted to explore the efficacy and safety of myo-inositol use for the prevention of GDM.
Myo-inositol and Gestational Diabetes Mellitus
Several clinical studies have investigated the potential effect of dietary myo-inositol supplementation on the prevention of GDM in high-risk women.
In a retrospective study conducted in pregnant women affected by PCOS, D’Anna et al.14 observed that myo-inositol administration, throughout the pregnancy course, may reduce the prevalence of GDM. In particular, they demonstrated a lower prevalence of GDM in PCOS women who achieved conception on myo-inositol supplement and continued this regimen during pregnancy, compared with PCOS women who conceived on metformin and discontinued it after the diagnosis of pregnancy (17.4 vs. 54%, P = 0,001).
Another open-label RCT15 reported a significant decrease of GDM incidence in non-obese women, with a family history of T2D, treated with myo-inositol and folic acid from the end of the first trimester throughout the remainder of the pregnancy compared with similar control subjects treated with folic acid alone (6 vs. 15.3%, P = 0.04). Moreover, fetal macrosomia was significantly reduced (0 vs. 7%, P = 0.007) in the myo-inositol group and the mean birth weight was also significantly reduced in the treatment group (P = 0,018). The authors also reported a statistically significant decrease of fasting plasma glucose levels (P = 0.001) and 1-h plasma glucose levels on the 75gr oral glucose tolerance test (OGTT) (P = 0.02) in the myo-inositol group compared to the control group. The same authors16 reported a lower incidence of GDM (14 vs. 33.6%, P = 0.001) and a greater reduction in the homeostasis model assessment of insulin resistance (-1.0 ± 3.1 vs. 0.1 ± 1.8, P = 0.048) among 99 obese pregnant women treated with myo-inositol and folic acid from the first trimester to delivery compared to 107 obese pregnant women treated with folic acid alone.
Matarelli et al.17 demonstrated that myo-inositol supplementation in pregnancy reduces the incidence of GDM in women at high risk of this disorder accompanied by improved outcomes. In particular, women treated with myo-inositol showed a significantly lower prevalence of GDM in mid-pregnancy (RR = 0,127, 95% CI [0.032 – 0.502], P = 0,001), required less insulin therapy (RR = 0.136, 95% CI [0.018–1.031], P = 0.053), delivered at a later gestational age (95% CI [-2.578 to -0.948], P = 0.001) and had significantly smaller babies (birth weight is expressed as percentiles, 95% CI [10.807 – 30.116], P = 0.001) with fewer episodes of neonatal hypoglycemia (RR = 0.052, 95% CI [0.003 – 0.849], P = 0.038) compared to placebo.
In a randomized controlled trial, Santamaria et al.18 reported a significant decrease of GDM incidence in overweight non-obese women (pre-pregnancy BMI ≥ 25 and < 30) treated with myo-inositol and folic acid from the end of the first trimester until delivery compared with similar control subjects treated with folic acid alone (11,6 vs. 27,4%, P = 0.004).
In a meta-analysis of five trials containing 513 participants, Zheng et al.19 demonstrated that women treated with myo-inositol showed a significantly lower incidence of GDM ((RR 0.29; 95% CI, 0.19–0.44; P < 0.00001) and a statistically significant decrease of fasting plasma glucose levels (MD, –0.36; 95% CI, –0.51 to –0.21; P < 0.0001), 1-h plasma glucose levels (MD, –0.63; 95% CI, –1.01 to –0.26; P = 0.002) and 2-h plasma glucose levels (MD, –0.45; 95% CI, –0.75 to –0.16; P = 0.002) on the 75gr oral glucose tolerance test (OGTT) compared to placebo. Moreover, women treated with myo-inositol had significantly smaller babies (MD, –116.98; 95% CI, –208.87 to –25.09; P = 0.01) compared to placebo.
In a systematic review of Cochrane Database, Crawford et al.20 reported a significantly lower incidence of GDM (RR = 0.43, 95% CI [0.29 to 0.64]; three trials; n = 502 women) in women treated with myo-inositol compared to control subjects. However, no clear difference was reported in the risk of hypertensive disorders of pregnancy (average RR = 0.43, 95% CI [0.02 to 8.41]; two trials; n=398 women), caesarean section (RR = 0.95, 95% CI [0.76 to 1.19]; two trials; n = 398 women), macrosomia (average RR = 0.35, 95% CI [0.02 to 6.37]; two trials; n = 398 infants), neonatal hypoglycaemia (RR = 0.36, 95% CI [0.01 to 8.66]; two trials; n = 398 infants), shoulder dystocia (average RR = 2.33, 95% CI [0.12 to 44.30]; two trials; n = 398 infants). There were no maternal adverse effects of therapy in the two trials that reported on this outcome. The authors concluded that dietary supplementation with myo-inositol during pregnancy demonstrates a potential benefit for reducing the incidence of gestational diabetes. However, the current evidence is based on small trials conducted in Italy leading to concerns about the lack of generalizability of the evidence to other settings.
Another study conducted by Dell’ Edera at al.21 demonstrated that the supplementation with D-chiro-inositol and D-myo-inositol allows a better control of maternal glycemia resulting in a lower incidence of GDM (RR = 3.35; 95% CI = 1.37–8.17; P = 0.0028) and more favorable perinatal outcomes referring to the risk of macrosomia (RR = 5.12; 95% CI = 1.21–21.68; P = 0,0099) in women with an elevated fasting glucose value (glycemia ≥ 5.1 mmol/l or 92 mg/dl and ≤ 7.0 mmol/l or 126 mg/dl).
In a systematic review and meta-analysis of randomized controlled trials, Guo et al.22 reported that, compared with placebo, myo-inositol supplement is associated
with a reduced risk of developing GDM (RR = 0.44, 95% CI [0.32, 0.62], P < 0.0001), a significantly lower fasting OGTT (MD = -0.18, 95% CI [-0.24, -0.12], P < 0.00001), a lower 1h OGTT (MD = -0.55, 95% CI [-0.81, -0.28], P < 0.00001) and a lower 2h OGTT (MD = -0.58, 95% CI [-0.94, -0.23], P = 0.001). Furthermore, myo-inositol supplementation was associated with a significantly lower incidence of pre-term delivery (RR = 0.30, 95% CI [0.11, 0.79], P = 0.01). However, no significant differences were reported in the incidence of other complications, including distress respiratory syndrome, macrosomia, shoulder dystocia, and neonatal hypoglycemia.
A secondary analysis from three randomized controlled trials conducted by Santamaria et al.23 demonstrated that myo-inositol supplementation in early pregnancy is associated with a reduced incidence of GDM and a reduced risk of preterm birth and macrosomia in pregnant women who are at risk for GDM (obesity [pre-pregnancy body mass index ≥ 30 kg/m2], overweight [pre-pregnancy body mass index ≥ 25 to < 30 kg/m2], or parent affected by type 2 diabetes mellitus). In particular, myo-inositol treatment was associated with a significantly reduced GDM onset by 66% (OR = 0.34; P < 0.001) and improved fasting (OR = 0.37; P = 0.001) and 2-hour glucose values (OR = 0.44; P = 0.01). Moreover, women treated with myo-inositol showed a significantly decreased risk for preterm birth (OR = 0.44; P = 0.03) and macrosomia (OR = 0.38; P = 0.04), and border line decreased values for LGA (OR = 0.52; P = 0.05) and gestational hypertension (OR = 0.34; P = 0.06).
Myo-inositol supplementation seems to have some potential in preventing GDM. In particular, the daily administration of myo-inositol appears to improve the glycemic homeostasis and reduce GDM rate without the risk of side effects. Moreover myo-inositol offers an option with good tolerability and good compliance. However, further studies including pregnant women of different ethnicities with varying risk factors should be encouraged. Due to the poor quality of the available evidence, further good-quality RCTs are still needed to confirm the effectiveness and the optimal use (dose, frequency, timing of administration) of myo-inositol for GDM prevention.
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