www.impactjournals.com/oncotarget/ Oncotarget, 2017, Vol. 8, (No. 37), pp: 61048-61056 Research Paper Quantitative assessment of the effect of pre-gestational diabetes and risk of adverse maternal, perinatal and neonatal outcomes Lei Yu1,*, Xiao-Ling Zeng1,2,*, Ming-Liang Cheng3, Guo-Zhen Yang1, Bi Wang1,4, Zi-Wen Xiao1, Xin Luo2, Bao-Fang Zhang3, De-Wei Xiao4, Shuai Zhang5, Hua-Juan Liu3, Ya-Xin Hu3, Hou-Kang Lei1, Qin-Fen Li1 and Zheng-Rong Wang1 1Prenatal Diagnosis Center, Hospital Affiliated to Guizhou Medical University, Guiyang 550004, Guizhou, China 2The First Affiliated Hospital of Jinan University, Guangdong 510632, Guangzhou, China 3Department of Infectious Diseases, Hospital Affiliated to Guizhou Medical University, Guiyang 550004, Guizhou, China 4Department of Eugenics and Genetics, Guiyang Maternal and Child Health-Care Hospital, Guiyang 550003, Guizhou, China 5Department of Interventional Radiology, Cancer Hospital of Guizhou Medical University, Guiyang 550004, Guizhou, China *These authors have contributed equally to this work Correspondence to: Ming-Liang Cheng, email: [email protected] Guo-Zhen Yang, email: [email protected] Keywords: pre-gestational diabetes, adverse pregnancy outcomes, risk, meta-analysis Received: February 21, 2017 Accepted: April 05, 2017 Published: May 11, 2017 Copyright: Yu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Pregnancies complicated by pre-gestational diabetes (PGD) are associated with a higher rate of adverse outcomes, including an increased rage of preterm delivery, pregnancy-induced hypertension, pre-eclampsia, caesarean section, perinatal mortality, stillbirth, shoulder dystocia, macrosomia, small for gestational age, large for gestational age, low birth weight, neonatal hypoglycemia, neonatal death, low Apgar score, NICU admission, jaundice and respiratory distress. In the past two decades, numerous reports have been published regarding associations between PGD and risk of adverse outcomes. However, study results are inconsistent. To provide a synopsis of the current understanding of PGD for risk of adverse pregnancy outcomes, a random-effects meta-analysis over 40 million subjects from 100 studies was performed to calculate the pooled ORs. Potential sources of heterogeneity were systematically explored by multiple strata analyses and meta-regression. Overall, PGD were significantly associated with increased risk of preterm delivery (OR=3.48), LGA (OR=3.90), perinatal mortality (OR=3.39), stillbirth (OR=3.52), pre-eclampsia (OR=3.48), caesarean section (OR=3.52), NICU admission (OR=3.92), and neonatal hypoglycemia (OR=26.62). Significant results were also observed for 7 adverse outcomes with OR range from 1.54 to 2.82, while no association was found for SGA and respiratory distress after Bonferroni correction. We found that women with T1DM had higher risks for most of adverse pregnancy outcomes compared with women with T2DM. When stratified by study design, sample size, type of diabetes, geographic region, and study quality, significant associations remains. Our findings demonstrated that PGD is a strong risk- conferring factor for adverse maternal, perinatal and neonatal outcomes. INTRODUCTION diabetes (PGD) characterised by disturbance in glucose metabolism may be due to variable degrees of insulin Diabetes is one of the most common pre-existing resistance (type 2), or a consequence of autoimmune maternal disorders and complicated approximately 1.3% destruction of the pancreatic β-cells (type 1). With increasing of all pregnancies [1, 2]. Most women with pre-gestational numbers type 1 diabetes diagnosed among youth and high www.impactjournals.com/oncotarget 61048 Oncotarget prevalence of obesity among women of child-bearing age adverse pregnancy outcomes. Therefore, we conducted a [3–5], the demographic pattern of PGD is changing. Besides, comprehensive meta-analysis on all eligible studies to clarify the sex ratio of newly diagnosed type 2 diabetes among this inconsistency and to establish a comprehensive picture youth was remarkably skewed to female [6–8]. Therefore, of the relationship. continuous increase in diabetes rates in the global population will translate into higher prevalence of PGD eventually [9]. RESULTS Women with PGD are associated with adverse pregnancy outcomes. Unfortunately, the goal of the St. Characteristics of the included studies Vincent Declaration has not yet been achieved despite intensive maternal and neonatal care [10]. Furthermore, A detailed flowchart of literature search is shown PGD has also been associated with increased risk of maternal in Figure 1. We identified a total of 9650 citations from complications including shoulder dystocia, gestational the databases and 2 from reference lists. After exclusion hypertension, and pre-eclampsia [11–13], making pre- of duplicate reports and studies that did not meet our pregnancy care particularly glycaemic control and obstetrical inclusion criteria, a total of 100 publications were finally interventions of great importance. More recent studies on included in this study. Main characteristics of the included PGD have reported various results: preterm delivery and studies were summarised in Supplementary Table 1. These stillbirth were still significantly increased in some studies [2, eligible studies were published between 1993 and 2017, 14, 15] despite good metabolic control, while other studies and included a total of 304,144 women with PGD and > [16–18] reported that PGD was no longer a significant 40 million non-diabetic populations. Almost all included factor. These conflicting results may be partly due to ethnic studies were conducted in developed country, including diversity, insufficient power, phenotypic heterogeneity, and 28 studies in the North American, 48 in Europe, 3 in East even publication biases [19]. Until now, no quantitative Asian, 11 in Oceania, 3 in Africa and 7 with subjects assessment has focused on PGD with the risk various recruited from Middle East. 62 summarized results by two- Figure 1: Flow diagram for selection and inclusion of studies. www.impactjournals.com/oncotarget 61049 Oncotarget by-two tables, whereas 38 reported adjusted risk estimates. 4.02, P<10-5). Furthermore, PGD conferred much higher As for methodological quality assessment, 47 studies were risk of requiring caesarean section (OR=3.52; 95%CI: awarded ≥ 7 points, and 30 studies were awarded 5 to 6 2.91-4.25, P<10-5). In vaginal deliveries, the risk of points, indicating that the quality of included studies were shoulder dystocia occurred in infants delivered by pre- of median-to-high quality. Almost all included studies gestational diabetic mothers was much higher than control recruited women with singleton pregnancy, and only two infants with an OR of 2.73 (95%CI: 2.12-3.52, P<10-5). studies included women with twin pregnancy. As for perinatal outcomes including macrosomia, LGA, SGA, LBW, stillbirth, perinatal mortality, and low Quantitative data synthesis Apgar scores, the risk for women with PGD giving birth to LGA babies was significantly higher than for women Figure 2 shows the summary OR estimates for without diabetes (OR=3.90; 95%CI: 3.42-4.46, P<10-5). adverse pregnancy outcomes comparing women with PGD Similarly, women with PGD were more likely to have a with non-diabetic population. macrosomic infant (OR=1.91; 95%CI: 1.74-2.10, P<10-5) The adverse maternal outcomes were preterm and low birth weight babies than controls (OR=1.54; 95% delivery, very early preterm delivery, shoulder dystocia, CI: 1.45-1.64, P<10-5). In contrast, the risk of delivering caesarean section, pregnancy-induced hypertension an SGA infant was 0.86 (95%CI: 0.77-0.96, P=0.007). (PIH) and pre-eclampsia. The risk of preterm delivery at Women with PGD were more likely to have stillbirth or before 37 weeks was 3.48 (95%CI: 3.06-3.96, P<10- (OR=3.52; 95%CI: 3.19-3.88, P<10-5); thus, perinatal 5), whereas the risk was 2.55 (95%CI: 2.21-2.94, P<10- mortality (OR=3.39; 95%CI: 3.02-3.81, P<10-5) risks for 5) for very early preterm delivery in women with PGD. infants of PGD mothers were also significantly higher than There was significant difference in maternal hypertensive in the nondiabetic population (Table 1). complications. Using a random-effects model, the pooled As for secondary neonatal outcomes, women with OR of PIH was OR=2.56 (95%CI: 2.04-3.21, P<10-5). In PGD were more likely than those of women without addition, mother with PGD have statistically significant diabetes to have neonatal hypoglycaemia (OR=26.62; association with pre-eclampsia (OR=3.48; 95%CI: 3.01- 95%CI: 15.37-46.11, P<10-5), neonatal death (OR=2.26; Figure 2: Meta-analysis with a random-effect model for the association between pre-gestational diabetes and adverse pregnancy outcomes. www.impactjournals.com/oncotarget 61050 Oncotarget Table 1: Associations of pre-gestational diabetes and adverse pregnancy outcomes Overall Cohort based study Non-Cohort based study No. of No. of No. of Outcomes datasets datasets datasets OR (95%CI) P(Z) P(Q) OR (95%CI) P(Z) P(Q) OR (95%CI) P(Z) P(Q) Preterm delivery (< 37 weeks) 55 3.48 (3.06-3.96) <10-5 <10-5 21 3.69 (3.12-4.36) <10-5 <10-5 34 3.36 (2.85-3.96) <10-5 <10-5 Very early preterm delivery 4 2.55 (2.21-2.94) <10-5 0.22 4 2.55 (2.21-2.94) <10-5 0.22 NA NA NA NA (< 32 weeks)