Abstract

Objective

To compare the incidence of gestational diabetes mellitus (GDM) between pregnancies conceived spontaneously and pregnancies conceived following assisted reproductive technology (ART).

 

Study design

This cross-sectional study evaluated the medical records of 215 women who conceived spontaneously and 145 women who conceived following ART from September 2011 to October 2012. Exclusion criteria were: polycystic ovary syndrome, maternal age ≥40 years, family history of diabetes in first-degree relatives, pre-pregnancy diabetes, glucose intolerance treated with hypoglycaemic agent (e.g. metformin), history of GDM, history of stillbirth, recurrent miscarriage, history of baby with birth weight ≥4 kg (macrosomia), parity >3, Cushing syndrome, congenital adrenal hyperplasia and hypothyroidism. For better comparison of the incidence of GDM, the ART group was further subdivided into: (i) an in-vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) group (n = 95); and (ii) an intrauterine insemination (IUI) group (n = 50). The diagnosis of GDM was based on the criteria of the American Diabetes Association.

 

Results

The incidence of GDM was significantly higher in the IVF/ICSI and IUI groups (43% and 26%, respectively) compared with the spontaneous pregnancy group (10%). Age, pre-pregnancy body mass index (BMI) and weight gain in pregnancy were similar among women with GDM in all three groups. In addition, the incidence of pregnancy-induced hypertension was significantly higher in the IVF/ICSI group (21%) compared with the spontaneous pregnancy group (7%). Logistic regression analysis demonstrated four strong risk factors for GDM: age, BMI, mode of ART and progesterone use during pregnancy.

 

Conclusion

This study indicated that the risk of GDM is two-fold higher in women with singleton pregnancies conceived following ART compared with women who conceived spontaneously. In addition, progesterone use during pregnancy was found to be an important risk factor for GDM. This subject requires further study.

 

Keywords

Assisted reproductive techniques; Gestational diabetes mellitus; Risk factors

Introduction

Gestational diabetes mellitus (GDM) is a common endocrine disorder in pregnancy [1], where women without a previous diagnosis of diabetes exhibit high blood glucose levels and carbohydrate intolerance, especially during the third trimester [1]. The reported prevalence of GDM ranges between 1% and 14% of all pregnancies, depending on the population studied and the diagnostic tests used [1]. However, the incidence of diabetes during pregnancy has increased in recent years to approximately 40% [2]. GDM is associated with increased risk of maternal, fetal and neonatal complications, such as pre-eclampsia, caesarean delivery, macrosomia, shoulder dystocia, birth injuries, respiratory distress syndrome, hypoglycemia and jaundice [1] and [2]. Up to one-half of women with GDM will develop type 2 diabetes later in life [1] and [2].

 

It is important to understand the risk factors of GDM in order to provide timely diagnosis and appropriate care. The most important risk factors are: family history of diabetes, advanced maternal age, obesity, high parity, previous adverse pregnancy, non-white race, history of baby with birth weight >3800 g and hypothyroidism [1] and [3]. Recent studies have shown that in addition to the above risk factors, singleton and twin pregnancies resulting from assisted reproductive techniques (ART) have been associated with increased risk of GDM [4], [5], [6], [7], [8] and [9]. In addition, risk factors for GDM, such as age, multiple pregnancy, obesity and polycystic ovary syndrome (PCOS), are often seen among women undergoing in-vitro fertilization (IVF) [10]. The increasing number of pregnancies resulting from ART and increased awareness of GDM-related morbidity has led to research on possible differences in pregnancy outcomes between ART and non-ART pregnancies with GDM [10]. A recent study by Marchand et al. [11] found that the rate of GDM was lower among women who conceived following intracytoplasmic sperm injection (ICSI) compared with women who conceived spontaneously, following IVF or following simple ART. The higher rate of GDM in these patients, independent of age and parity, may be due to: (i) etiology of infertility; (ii) types of drugs used for ovulation induction and luteal phase support; (iii) changes in the hormonal environment due to increased hormone levels after ovulation induction and during early pregnancy; and (iv) presence of underlying metabolic and vascular factors exacerbated during ovulation induction and IVF/ICSI procedures [4], [5] and [6]. To increase knowledge in this field, this cross-sectional study was designed to compare the incidence of GDM in pregnancies conceived spontaneously and pregnancies conceived following ART.

 

Materials and methods

This cross-sectional study was performed at the Reproductive Biomedicine Research Centre of the Royan Institute, Tehran, Iran between September 2011 and October 2012. The ART group consisted of women with singleton pregnancies conceived following fresh IVF/ICSI or intrauterine insemination (IUI) at the Royan Institute. The control group consisted of women with singleton spontaneous pregnancies who were referred to Akbarabadi Women's Hospital, affiliated with Tehran University of Medical Science, over the same period of time. The exclusion criteria were: polycystic ovary syndrome, maternal age ≥40 years, family history of diabetes in first-degree relatives, pre-pregnancy diabetes, glucose intolerance treated with hypoglycemic agent (e.g. metformin), history of GDM, history of stillbirth, recurrent miscarriage, history of baby with birth weight ≥4 kg (macrosomia), parity >3, Cushing syndrome, congenital adrenal hyperplasia and hypothyroidism.

 

Fasting plasma glucose was measured in the first trimester for all participants. In accordance with the criteria of the American Diabetes Association (2005), pregnant women were screened at 24–28 weeks of gestation using a 50-g, 1-h oral glucose challenge test; if the result of this screening test was abnormal (glucose ≥7.8 mmol/l or 140 mg/dl), a 100-g, 3-h oral glucose tolerance test (OGTT) was performed in the following 1–2 weeks. Women were diagnosed with GDM if two or more of the 100-g OGTT glucose levels exceeded the following cut-off values based on the criteria of the American Diabetes Association: fasting, ≥5.3 mmol/l (≥95 mg/dl); 1 h, ≥10.0 mmol/l (≥180 mg/dl); 2 h ≥8.6 mmol/l (≥155 mg/dl); and 3 h, ≥7.8 mmol/l (≥140 mg/dl). Data concerning age, parity, history of diabetes during previous pregnancies and family history of diabetes were collected from the patients’ medical records. The study was approved by the Internal Review Board of the Royan Institute. All patients signed a consent form on their initial visit giving permission to use their results anonymously in future studies.

 

Statistical analysis

Data were analyzed using Statistical Package for the Social Sciences Version 16.0.0 (SPSS Inc., Chicago, IL, USA). Categorical and continuous variables were compared between the IVF/ICSI, IUI and spontaneous pregnancy groups using Chi-squared test and analysis of variance, respectively. Multiple comparisons were performed using Tukey's adjustment. Descriptive statistics are presented as mean ± standard deviation and percentage. Multivariate logistic regression using the Hosmer–Lemeshow algorithm was applied to evaluate the association between the mode of conception and the incidence of GDM after adjusting for potential confounding variables. Confounding variables were included if they satisfied the criteria of changing the −2 log likelihood by at least 3.84. This resulted in a final model that included age, pre-pregnancy BMI and progesterone support during the luteal phase. The anticipated difference in the incidence of GDM between spontaneous and ART pregnancies was 10%. At least 75 cycles were needed in each group to prove a difference of 10% with a power of 80%, assuming Type I error of 0.05.

 

Results

The medical records of 215 women who conceived spontaneously and 145 women who conceived following ART were evaluated from September 2011 to October 2012. The ART group was further subdivided into IVF/ICSI and IUI groups for better comparison of the incidence of GDM.

 

As expected, women's age, age at menarche and nulliparity were higher in the two ART groups compared with the spontaneous pregnancy group. More women had irregular menses in the IUI group (18%) compared with the IVF/ICSI (9.5%) and spontaneous pregnancy (4.7%) groups (p = 0.005). Significant differences in pre-pregnancy BMI and weight gain were found between the ART and spontaneous pregnancy groups ( Table 1). The incidence of GDM was significantly higher in the IVF/ICSI (43%) and IUI groups (26%) compared with the spontaneous pregnancy group (10%), and the incidence of pregnancy-induced hypertension was significantly higher in the IVF/ICSI group (21%) compared with the spontaneous pregnancy group (7%) ( Table 1).

 

          

        
 

Table 2 shows the characteristics of the women with GDM in the three groups. Age, pre-pregnancy BMI and weight gain in pregnancy were similar in all three groups, but the number of nulliparous cases was significantly higher in the IVF/ICSI (73%) and IUI (62%) groups compared with the spontaneous pregnancy group (25%). Insulin therapy was initiated in 20% of women with GDM in the spontaneous pregnancy group, 24% in the IVF/ICSI group and 23% in the IUI group, indicating that there is no significant difference in the severity of GDM between the three groups. Significant differences were found between the groups in terms of progestrone use during pregnancy, as most women with GDM (71%) in the IVF/ICSI group used progesterone after 12 weeks of pregnancy (p < 0.001) ( Table 2).

 

        

 

No significant differences in fasting glucose levels and OGTT results were found between the three groups (Table 3). 

 

        

 

Logistic regression was performed, and all risk factors were included in the initial model. Stepwise backward elimination was used to choose the final model for identification of the variables predictive of GDM in the study population. Age, BMI, ART conception mode and progesterone use during pregnancy were found to be strong risk factors for GDM (Table 4).

 

        

 

Comment

Previous studies have reported that pregnancies conceived following IVF are at higher risk of perinatal complications such as spontaneous preterm delivery, pre-eclampsia, GDM, perinatal mortality, low birth weight and small for gestational age [5], [6], [12], [13] and [14]. There are four hypotheses for the higher rate of GDM in women who conceive following ART [4], [5] and [6]: (i) etiology of infertility; (ii) types of drugs used for ovulation induction and luteal phase support; (iii) changes in the hormonal environment due to increased hormone levels after ovulation induction and during early pregnancy; and (iv) presence of underlying metabolic and vascular factors exacerbated during ART procedures. Among the different causes of infertility, woman with PCOS have shown higher physiological risk factors for pregnancy-induced peripheral insulin resistance [10] and [15]. Two meta-analyses of pregnancy outcomes in women with PCOS found a higher risk of developing GDM compared with the general population (odds ratio 2.94 vs 2.89) [16] and [17]. The authors decided to exclude PCOS and twin pregnancies, which are two strong risk factors for GDM, for more accurate examination of the effect of ART conception as an independent risk factor for GDM. The aim was to evaluate the relative risk factors associated with infertility, ovulation induction and progesterone use during pregnancy.

 

This study found that women with singleton pregnancies conceived following ART were at two-fold higher risk of GDM compared with women with singleton spontaneous pregnancies. Despite the higher BMI in the spontaneous pregnancy group, the prevalence of GDM was significantly lower compared with the ART groups. Therefore, it seems that ART treatment is an independent risk factor for GDM, although the effect of higher maternal age in the ART groups should not be ignored. In this study, the mean age of the women with GDM was similar in all three groups. It appears that ART (including ovulation induction medications, progesterone use for luteal phase support and continuation of progesterone after 12 weeks of pregnancy) significantly influenced the incidence of GDM in these patients.

 

This study compared the characteristics of women with GDM-complicated pregnancies who conceived following ART with women with GDM-complicated pregnancies who conceived spontaneously. In contrast to the study by Szymanska et al. [10], the course of GDM was similar in all three groups. Furthermore, no significant differences were seen in fasting glucose levels and OGTT between the three groups. These different results may be due to the small sample size in the present study. The primary objective of this study was to evaluate the incidence and risk factors of GDM in women undergoing ART, and the sample size was calculated on the basis of the main outcome.

 

This study found that the use of progesterone during pregnancy as luteal phase support and preterm labor prevention is an important risk factor for GDM in women who conceive following ART. To date, the diabetogenic effects of progesterone in pregnancy have been predominantly explained by increased insulin resistance, especially in skeletal muscle and adipose tissue, due to reduced expression of glucose transporter 4 [18] and [19]. Also, several studies have reported an increased risk of GDM in women treated with progesterone compounds [20], [21] and [22]. In one of these studies, Waters et al. [21] compared the incidence of impaired glucose tolerance during pregnancy between 110 women treated with 17-alpha-hydroxyprogestrone caproate and 330 control women; they found that that more women treated with 17-alpha-hydroxyprogestrone caproate showed impaired glucose tolerance during pregnancy compared with the control group (24% vs 11%), and this effect was not dependent on maternal race, age, BMI or parity [21].

 

The present study, in agreement with Jackson et al. [5], found a significantly higher risk of pre-eclampsia in the ART groups. The role of insulin resistance in the pathophysiology of pre-eclampsia has received much research attention [23], [24] and [25]. Further studies on insulin resistance in pregnant women following IVF are required.

 

In agreement with previous studies, the present study found that women with singleton pregnancies conceived following ART are at higher risk of GDM compared with women with singleton spontaneous pregnancies. In agreement with Szymanska et al. [10], the present authors believe that there is a need for precise evaluation of carbohydrate intolerance during early pregnancy for pregnancies conceived following ART.

 

In conclusion, the risk of GDM is two-fold higher in women with singleton pregnancies conceived following ART compared with women who conceived spontaneously. In addition, progesterone use during pregnancy was found to be an important risk factor for GDM: this subject requires further study. Early detection and treatment of carbohydrate intolerance in pregnancies conceived following ART, and timely commencement of dietary intervention and physical activity can prevent excessive weight gain during pregnancy, development of GDM and pre-eclampsia.

 

Condensation

Assisted reproductive techniques may be a risk factor for gestational diabetes mellitus, so infertile women undergoing ART should be considered as high-risk patients.

 

Conflict of interest statement

None declared.

 

Acknowledgements

The authors wish to thank all of the study participants, and Mrs. Zahra Zolfaghari for data entry.