Our study suggests that a long IPI is associated with an increased risk of GDM in the second pregnancy. As shown in Table 2, for women with an IPI of 24 months or greater, the adjusted odds ratio value of GDM risk increased from 1.590 to 2.581 when compared with the reference IPI (18–23 months). For those with an IPI of less than 24 months, no significant differences existed in the GDM risk in the second pregnancy. Therefore, within the range of IPI recommended by the WHO12, the risk of GDM in the second pregnancy is lowest when the IPI is 18–24 weeks. For women planning a second pregnancy, our findings will provide useful information to select an appropriate IPI.
Some previous reports have also supported the association between a long IPI and increased GDM risk in the second pregnancy. In Holmes et al.’s study20, the interval (2.9 years) between the first and second pregnancies with recurrent GDM was significantly higher than that (2.4 years) without recurrent GDM. Khambalia et al.21 also reported that a long interval from the previous pregnancy was a risk factor for recurrent GDM. The study of Hanley et al.14 showed that a long IPI was associated with a significant increase in GDM risk using unmatched (between-participant) analyses, whereas this association disappeared in the matched analyses, which was inconsistent with our study. GDM in the second pregnancy was the primary outcome in our study, and more risk factors for GDM were adjusted, different from Hanley et al.’s study. A nationwide data analysis from the United States found that a long IPI (36 months or greater) was associated with an increased risk of GDM15. However, that study included a very high proportion of participants with obesity (mean BMI greater than 26 kg/m2) and the odds ratio value was not corrected for GDM in previous pregnancies. Women with GDM in the previous pregnancy are at high risk of recurrent GDM in the second pregnancy5, and this should be adjusted as a confounding factor when investigating the independent effect of the IPI on the GDM risk.
In a large-sample study by Gebremedhin et al.16, the between-participant analysis also found that the adjusted odds ratio of GDM in a second pregnancy was 1.13 (95% CI, 1.06–1.21) for the IPI of 24–59 months and 1.51 (95% CI, 1.33–1.70) for the IPI of 120 months or greater when compared with the IPI of 18–23 months. The adjusted odds ratio values in our study were higher than those in Gebremedhin et al.’s study. These differences may be due to a high proportion of GDM in the first pregnancy (11.29% in this study and 1.6% in Gebremedhin et al.’s study) and the IPI being divided into seven intervals in our study. However, in the same study by Gebremedhin et al.16, the adjusted within-participant matched analysis showed no significant association between IPI and GDM. They suggested that the previously found association between IPI and GDM was the result of confounding factors. We only collected information on two consecutive pregnancies, so we could not perform a within-participant matched analysis. To reduce the influence of confounding factors on the results, the effects of factors such as age, BMI, parity, and complications in the previous pregnancy were adjusted in our study. However, BMI was not included as a confounding factor in the studies by Gebremedhin et al.16
In our study, no significant difference in GDM risk in the second pregnancy existed when the IPI was less than 24 months. Gebremedhin et al.16 found that, compared with an IPI of 18–23 months, the adjusted odds ratio of GDM risk for an IPI of 6–11 months and 12–17 months was 0.89 (95% CI: 0.82–0.97) and 0.92 (95% CI: 0.85–0.99), respectively. This indicates that an IPI of less than 18 months had a protective effect against GDM. However, Hanley et al.14 suggested that a short IPI was significantly associated with an increased risk of GDM. Major et al.22 suggested that an IPI of 24 months or less was also the most significant risk factor for a recurrence of GDM. A large-sample study from the United States suggested that intervals of less than 6, 6–11, and 12–17 months had a significant overall protective effect against GDM (aRR: 0.89–0.98)23. In a nationwide data analysis from the United States, a short IPI (6–17 months) was also associated with an increased risk of GDM15. These studies indicate that the association between a short IPI and GDM remains unclear. According to the recommendations of ACOG24 and the WHO12, the pregnancy interval should be at least 18 to 24 months because a short IPI increases the risk of preterm birth, spontaneous prematurity, smallness for gestational age, and other adverse pregnancy outcomes25. Therefore, a short IPI is not recommended even if it is a protective factor for GDM.
Our study suggests (as shown in Table 3) that the minimum IPI that significantly increased the GDM risk in the second pregnancy was 24–35 months for those with GDM in the first pregnancy and 36–47 months for those without GDM. Compared with participants who did not have GDM during the first pregnancy, those with GDM required a shorter IPI to avoid an increased GDM risk during the second pregnancy. However, our results are inconsistent with the study of Gebremedhin et al.26, in which the minimum IPI that significantly increased the risk of GDM during the second pregnancy was 48 months and 24 months for participants with and without GDM during the first pregnancy, respectively. In our study, women with deliveries before 28 weeks were excluded, whereas those delivering after 20 weeks were enrolled in the study of Gebremedhin et al.26 The differences between the two studies may be related to differences in demographic characteristics and dietary habits.
The mechanism by which a prolonged IPI increases the risk of GDM is still unknown. Some studies have speculated that this association is related to a gradual decline in maternal physiological functions27 (such as increased uterine blood flow and other physiological and anatomical adaptations of the reproductive system) after childbirth. In case of a long period after childbirth without another pregnancy, the mother’s physiological functions may become similar to those of a first-time mother. Another hypothesis is that unobserved metabolic or anatomic factors may contribute to delayed fertility and poor delivery outcomes28. It has been suggested that 18 to 23 months is the optimal IPI for preventing adverse perinatal outcomes28.
Our study has some limitations. First, since this was a retrospective single-center study, the inclusion of cases may be biased, and some participant information may not have been collected comprehensively, such as whether an abortion before 28 weeks occurred between the two included pregnancies. Second, some confounding factors were not considered in the analysis, such as the method of conception, smoking, diet, and exercise habits. Third, because this was an unmatched study, confounding factors are inevitable. Fourth, the small sample size of obese or older women may have biased the findings.
In conclusion, we investigated the effect of IPI on the risk of GDM in a single center in China. An IPI of longer than 24 months was associated with an increased risk of GDM in the second pregnancy. The risk of second-pregnancy GDM in the women who had GDM in the previous pregnancy was more significantly affected by IPI. The findings of this study may help women to modify an optimal IPI to reduce the GDM risk in second pregnancies.