Abstract
Objective
Increasing numbers of pregnancies are complicated by pregestational diabetes mellitus, especially type 2 diabetes (T2DM). Some studies have reported similar or greater risks of adverse pregnancy outcomes among women with T2DM relative to type 1 diabetes (T1DM). We aimed to compare the risk of four pregnancy complications: pre-eclampsia, preterm delivery, macrosomia, and perinatal mortality, in pregnant women with T2DM vs T1DM in high-income countries.
Design
Systematic review with meta-analyses.
Methods
Systematic literature searches in Medline and Embase were performed. We included observational studies with original data of outcome occurrence in both women with pregestational T2DM and T1DM. Two researchers independently evaluated full-text studies for inclusion and assessed the risk of bias using the Newcastle–Ottawa scale. Finally, we performed four meta-analyses.
Results
We included 35 publications in total. Meta-analyses demonstrated that, compared to T1DM, T2DM was associated with a lower risk of pre-eclampsia (risk ratio (RR): 0.76; 95% CI: 0.68–0.85), preterm delivery (RR: 0.69; 95% CI: 0.62–0.77), and macrosomia (RR: 0.75; 95% CI: 0.60–0.94). Perinatal mortality was more likely in pregnancies with T2DM (RR: 1.26; 95% CI: 1.06–1.50).
Conclusion
A summation of the research literature demonstrated that, compared to T1DM, women with T2DM had a lower risk of pre-eclampsia, preterm delivery, and macrosomia, but a higher risk of perinatal mortality.
Significance statement
Our review of pregnant women with diabetes suggests a higher risk of perinatal mortality for cases with maternal type 2 diabetes, even though the risks of pre-eclampsia, preterm delivery, and macrosomia were higher in cases with type 1 diabetes. Hence, the prevention of the development of type 2 diabetes and focus on improved gestational and diabetic care could be beneficial for fetal health.
Introduction
The prevalence of diabetes mellitus (DM) has increased globally, including among women of childbearing age (1, 2, 3, 4). Several countries report increasing numbers of pregnancies affected by pregestational diabetes (PDM), featuring predominantly type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), with a relatively higher increase in T2DM (5, 6, 7, 8, 9, 10). These conditions are associated with a higher risk of certain pregnancy complications (1, 3, 11, 12, 13). Therefore, they require a planned approach to pregnancy with pre-conceptional care, including optimization of glycemic values, and appropriate prenatal care and postnatal assistance (2, 14).
In the context of pregnancy, T2DM is often associated with better overall glycemic control (15, 16, 17, 18) and has been, and might still be, considered a less serious condition than T1DM (4, 16, 19). However, there are studies suggesting that T2DM could have similar or worse risk for perinatal deaths compared to T1DM (16, 20, 21, 22, 23). Increased knowledge about the risk of developing serious pregnancy outcomes can guide appropriate resource allocation for prenatal care for diabetes subtypes.
The aim of this systematic review is to evaluate how the risk of serious perinatal outcomes (prematurity, pre-eclampsia, macrosomia, and perinatal mortality) compares between women with pregestational T2DM and women with pregestational T1DM.
A systematic review on the same topic was published in 2009 (20). We consider it timely to undertake new analyses that include several relevant studies that have been published since. The focus on offering quality pre-pregnancy and prenatal care for women with PDM continues to increase (24, 25, 26). Also, the use of new technologies to optimize blood glucose control, such as modern insulin analogs, continuous glucose monitoring, and continuous subcutaneous insulin infusion therapy (CSII), has increased (3, 27, 28, 29). These factors in prenatal care could reduce the current risk of adverse pregnancy outcomes related to T1DM and T2DM. Therefore, this review will focus on a more contemporary perspective, with data from the year 2000 to 2021.
Even though the majority of pregnancies affected by hyperglycemia occur in low- and middle-income countries, we have chosen to include studies from high-income countries, where data regarding detection, prenatal resources, and the registering of pregnancies complicated by DM are assumed to have fewer inconsistencies (2, 30).
Materials and methods
Protocol and registration
This systematic review was conducted according to the PRISMA statement (31). The study protocol was registered in the Prospero database with registration number CRD42021257546 (32).
Eligibility criteria
Inclusion criteria:
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Observational studies providing relevant original data regarding at least one outcome of interest (premature delivery, pre-eclampsia, macrosomia, or perinatal mortality) in both pregestational T1DM and T2DM, separately. Macrosomia is defined as birthweight >4000 g. Other outcome definitions are stated in Supplementary Table 1 (see section on supplementary materials given at the end of this article).
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Studies must include at least 15 participants in each group of diabetics.
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Publication date between January 1st 2001 and June 1st 2021.
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The studies must specify that the data originates from January 1st 2000 or later.
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Publications must be written in English, Norwegian, Swedish, or Danish.
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Trials originating from high-income countries according to the World Bank (33), that also invest in diabetes treatment, i.e. countries demonstrating higher ‘Diabetes-related expenditure (USD) per person with diabetes (20–79 years)’ according to the International Diabetes Federation (2).
Exclusion criteria:
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Reviews, conference abstracts.
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Studies of women diagnosed with T2DM or T1DM during their index pregnancy.
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Studies looking exclusively at women with T2DM who were treated with insulin before planning their pregnancy.
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When different studies presented overlapping data regarding a specific outcome, meaning that they most likely included some of the same pregnant women or offspring, only the study with the highest series of data was included.
Information sources and search strategy
From January 15th 2021 to June 1st 2021, we performed systematic searches for relevant literature from the Medline and Embase databases. Additionally, we examined the reference list of each eligible study for other relevant publications. Search terms are described in Supplementary Tables 2 and 3.
Study selection
All publications identified from the literature search were exported to the EndNote X9 citation manager and duplicates were removed. Irrelevant studies were first excluded by one reviewer after title and abstract screening. We obtained a full-text version of potentially eligible articles, and two people independently reviewed these studies for inclusion. Disagreement was resolved by consensus. If necessary, a third reviewer was consulted.
Data collection process
Data required to calculate risk ratio (RR) regarding a specific outcome of interest was extracted. This included the number of women with a specific outcome (n) and the number of women exposed to the outcome (n) in each DM subgroup. One reviewer extracted data from eligible studies, while another controlled the extracted data. When additional data were required, we tried to obtain this by contacting the study authors.
The outcomes of interest are related to the second half of pregnancy; hence, pregnancies ending in miscarriages will not be included in our results. Therefore, when available, we based the data extraction for the outcome analyses on the number of pregnancies reaching 20–24 weeks, thereby excluding participants with early pregnancy loss. Otherwise, we used the direct information stated in published texts or tables.
If data on the following maternal characteristics were available, we summarized them for T2DM and T1DM cohort descriptions: age, body mass index (BMI), DM duration, nulliparity, hypertension, retinopathy, nephropathy or albuminuria, pre-pregnancy care (PPC), gestational age at booking, glycated hemoglobin (HbA1c) at the initial visit and in the first, second, and third trimesters.
Risk of bias in individual studies
Two authors individually assessed the quality of the included studies with the Newcastle–Ottawa Scale (NOS) for cohort studies (34). Disagreement on each study’s estimated risk of bias (RoB) was resolved through discussion and consensus. A third reviewer was consulted when needed. According to NOS, the studies are given stars which represent judgment in three categories: selection, comparability, and outcome. Studies with ≤3 stars were considered at high RoB, 4–6 as moderate, and ≥7 stars at low RoB.
Summary measures
We used Review Manager (RevMan) (version 5.4.1, Cochrane Collaboration) to calculate the RR along with the 95% CI for each outcome of interest in the individual studies. Results with a P-value <0.05 were considered statistically significant.
Synthesis of results
RevMan was used to perform data analyses. Where there was sufficient and similar data regarding population and outcomes, meta-analysis was performed for each of the outcomes of interest. The results were presented as a combined RR with 95% CI when comparing women with T2DM to women with T1DM. Random-effects models, with the Mantel–Haenszel method, were employed because we anticipated some heterogeneity among the included studies. Heterogeneity was assessed by I2 and a value >50–60% was considered substantial.
Publication bias
In meta-analyses with at least ten included studies, we assessed the risk of publication bias by inspecting funnel plots (35).
Results
Study selection
Figure 1 demonstrates the process of study selection. After removal of duplicates, 4307 publications remained. Of these, 4107 studies were excluded after title and abstract assessment. Thirty-five of the remaining 200 full-text studies were considered eligible for inclusion. These studies included a total of 62,531 baseline pregnancies, of which 31,686 were women with T2DM and 30,845 women with T1DM. Five large national studies were included, and 83% were published between 2011 and 2021. Table 1 and Supplementary Table 5 present characteristics of eligible studies, while Supplementary Table 4 presents reasons for exclusion of full-text articles.
Flowchart of study selection. Abbreviation: n, number of publications.
Citation: Endocrine Connections 13, 12; 10.1530/EC-24-0066
Overview of included studies.
Author, year (Study ID) | Country | T2DM, n | T1DM, n | Study design | Outcomes of interest | RoB assessment |
---|---|---|---|---|---|---|
Gualdani et al., 2021 (70) | Italy | 606 | 373 | R, Regional | PTB, M | Low (7a) |
Guarnotta et al., 2021 (37) | Italy | 62 | 73 | R, SC | PE, PTB | Moderate (5a) |
Murphy et al., 2021 (16) | UK | 8685 | 8690 | National | PNM, PTB | Low (7a) |
Newman et al., 2021 (65) | Ireland | 244 | 415 | R, MC | PTB, M | Low (7a) |
Seah et al., 2021 (71) | Australia | 106 | 92 | R, SC | PE, PTB | Low (7a) |
Ali et al., 2020 (72) | Ireland | 50 | 124 | R, SC | PE, M | Low (7a) |
Do et al., 2020 (39) | Denmark | 79 | 110 | P, MC | PE | Moderate (5a) |
Egan et al., 2020 (73) | Ireland | 56 | 122 | R, MC | PTB, M, PNM | Low (7a) |
Fischer et al., 2020 (40) | Denmark | 86 | 118 | P, SC | PTB | Moderate (5a) |
Lopez-De-andres et al., 2020 (7) | Spain | 4391 | 5561 | R, National | PE, PTB | Low (7a) |
Zen et al., 2019 (38) | Australia | 94 | 40 | P, MC | PE | Moderate (6a) |
Castelijn et al., 2018 (74) | The Netherlands | 59 | 117 | R, SC | PE, PTB | Low (7a) |
Billionnet et al., 2017 (45) | France | 1907 | 1291 | National | PE, PTB | Moderate (6a) |
Ladfors et al., 2017 (75) | Sweden | 87 | 221 | SC | PTB, M | Low (7a) |
Metcalfe et al., 2017 (10) | Canada | 11,028 | 7362 | National | PE, PTB, PNM | Moderate (6a) |
Egan et al., 2016 (25) | Ireland | 145 | 269 | P, MC | PNM, PE, PTB | Moderate (6a) |
Owens et al., 2015 (17) | Ireland | 108 | 215 | R, MC | M | Moderate (6a) |
Cohen et al., 2014 (48) | USA | 42 | 117 | SC | PE | Moderate (6a) |
Kothari et al., 2014 (76) | Australia | 19 | 34 | R, SC | PTB | Low (7a) |
Sato et al., 2014 (77) | Japan | 579 | 369 | R, MC | PNM, PE, PTB, M | Low (7a) |
Cundy et al., 2013 (43) | New Zealand | 335 | 181 | R, SC | PTB, M | Moderate (5a) |
Hammoud et al., 2013 (44) | The Netherlands | 68 | 77 | SC | PE, PTB | Moderate (6a) |
Wong et al., 2013 (78) | Australia | 117 | 44 | R, SC | PE, PTB | Low (7a) |
Anderson et al., 2012 (79) | New Zealand | 224 | 125 | P, SC | PE | Low (7a) |
Knight et al., 2012 (41) | USA | 64 | 64 | R, SC | PE, PTB | Moderate (5a) |
Handisurya et al., 2011 (80) | Austria | 51 | 75 | SC | PNM, PE, PTB, M | Low (7a) |
Holman et al., 2011 (18) | UK | 556 | 812 | MC | PNM, PTB, M | Moderate (6a) |
Murphy et al., 2011 (68) | UK | 274 | 408 | P, MC | PE | Low (7a) |
Tajima et al., 2011 (81) | Japan | 29 | 15 | R, MC | PTB | Low (7a) |
Lim et al., 2009 (36) | UK | 31 | 129 | P, SC | PTB, M | Moderate (6a) |
Peticca et al., 2009 (46) | Canada | 516 | 904 | R, MC | M | Moderate (6a) |
Gonzales-Gonzalez et al., 2008 (49) | Spain | 147 | 257 | R, MC | PNM, PTB, M | Low (7a) |
Simmons et al., 2007 (47) | Australia & New Zealand | 43 | 45 | MC | PNM, M | Moderate (6a) |
Macintosh et al., 2006 (21) | UK | 652 | 1707 | National | PNM | Low (7a) |
Boulot et al., 2003 (42) | France | 146 | 289 | P, MC | PE, PNM | Moderate (6a) |
aNumber of stars according to the Newcastle–Ottawa Scale.
MC, multiple centers; M, macrosomia; PE, pre-eclampsia; PNM, perinatal mortality; P, prospective; PTB, preterm birth; n, number of baseline pregnancies; R, retrospective; SC, single center.
Ultimately, 18 studies in pre-eclampsia, 24 in preterm delivery, 14 in macrosomia, and nine studies in perinatal mortality participated in the meta-analyses.
Maternal baseline characteristics
Baseline characteristics are presented in Table 2. Most studies presented some baseline data that represented average maternal characteristics in the T2DM and T1DM cohorts (Supplementary Table 5). The patients in the T2DM cohorts, compared to the corresponding T1DM cohorts, had higher average age, BMI, and gestational age at presentation to pregnancy care, and higher prevalence of hypertension. Women with T1DM had a higher average DM duration, and PPC were more common among women with T1DM in all studies with baseline data. Most publications presented a higher percentage of women with T1DM who were nulliparous, had retinopathy, nephropathy, or albuminuria, than in T2DM cohorts. Likewise, T1DM cohorts more often had higher average HbA1c at the initial visit and throughout pregnancy, compared to T2DM cohorts.
Ranges in percentages and mean or median values between studies with baseline data.
Baseline characteristic | Ranges in average values or percentages in T2DM cohorts | Ranges in average values or percentages in T1DM cohorts |
---|---|---|
Age (years) | ||
Mean | 30.1–36.0 | 26.8–33.8 |
Median | 34–35 | 29–33 |
BMI (kg/m2) | ||
Mean | 27.6–37.1 | 21.8–27.2 |
Median | 31.1–34 | 24–27.2 |
GA at booking (weeks) | ||
Mean | 7.8–14 | 6.0–10 |
Median | 7.9–13 | 7–9.1 |
Pre-existing hypertension | 9.6–21.7% | 3.3–10.9% |
DM duration (years) | ||
Mean | 2.8–6.8 | 8.5–15.7 |
Median | 2.5–6.0 | 10.0–16.8 |
Nulliparous | 18–55.0% | 40.0–59.4% |
Pre-pregnancy care | 9.5–50.0% | 20.0–70.3% |
Retinopathy | 0.7–20.7% | 9.1–53.2% |
Nephropathy or albuminuria | 1.4–30.4% | 0–36.1% |
HbA1c at initial visit (mmol/mol)a | ||
Mean | 44.6–73 | 54–61 |
Median | 46–51.9 | 47–60 |
HbA1c first trimester (mmol/mol)a | ||
Mean | 49.5–66 | 50–62 |
Median | 44–51.5 | 54–60 |
HbA1c second trimester (mmol/mol)a | ||
Mean | 39.3–52 | 40–51 |
Median | 39–42 | 46–50 |
HbA1c third trimester (mmol/mol)a | ||
Mean | 37–55 | 42–55 |
Median | 40–44 | 46–50 |
aSome HbA1c values were converted from % to mmol/mol, using a conversion calculator (82).
BMI, body mass index; DM, diabetes mellitus; GA, gestational age; HbA1c, glycated hemoglobin.
Risk of bias assessment
Table 1 and Supplementary Table 6 present the RoB assessments. Six studies were evaluated as inadequate in selection of cohorts (36, 37, 38, 39, 40, 41), e.g. by excluding women with T2DM on diet treatment, women with T1DM using CSII, women with insufficient language skills, or women with T2DM not using insulin during pregnancy. Five studies had insufficient descriptions of diagnoses of DM (18, 25, 42, 43) or outcomes of interest (44). The follow-up time when evaluating perinatal mortality was insufficient for one publication (10), in which the analysis of perinatal death was limited to gestational age above 30 weeks. The publications that only presented results in percentages had unclear follow-up rates (17, 43, 45, 46), while follow-up rates were inadequate (i.e. results indicating <80% follow-up) in two studies (47, 48).
None of the included studies received two stars in comparability because the outcomes (n/N) were unadjusted for confounders, and most of the studies had not performed analyses for confounders in the T1DM and T2DM cohorts. Therefore, our analyses were based on unadjusted data.
Ultimately, 18 studies were considered at low RoB, while 17 publications were considered at moderate RoB (Table 1).
Results of meta-analyses in each outcome
Table 3 presents results of our meta-analyses with RRs.
Risk ratio of outcomes of interest in T2DM vs T1DM.
Outcome | RR T2DM vs T1DM |
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Pre-eclampsia | RR: 0.76; 95% CI: 0.68–0.85; P < 0.00001 |
Preterm delivery | RR: 0.69; 95% CI: 0.62–0.77; P < 0.00001 |
Macrosomia | RR: 0.75; 95% CI: 0.60–0.94; P = 0.01 |
Perinatal mortality | RR: 1.26; 95% CI: 1.06–1.50; P = 0.010 |
RR, risk ratio.
Pre-eclampsia
We included all 18 publications in the meta-analysis of pre-eclampsia. A total of 1287 out of 19,242 (6.7%) T2DM pregnancies and 1476/16,123 (9.2%) of T1DM pregnancies had pre-eclampsia. Nine of the studies presented specific diagnostic criteria, including the development of hypertension and proteinuria. Five studies additionally included other signs of organ dysfunction.
The meta-analysis (Fig. 2) showed that women with T2DM had a lower risk of developing pre-eclampsia compared to women with T1DM (RR: 0.76; 95% CI: 0.68–0.85; P < 0.00001). The I 2 of 18% indicated low heterogeneity between the studies.
Preterm birth
For participants with T2DM, 6111/28,505 (21.4%) delivered prematurely, compared to 8391/25,748 (32.6%) with T1DM. Twenty-four of 25 potential studies contributed to the meta-analysis with data on preterm birth. Twenty-one of these used the definition of <37 weeks of gestation, while the three other publications gave no further definitions of the outcome.
Boulot et al. (42) only presented separate data for T2DM and T1DM women from 32 to 37 weeks (26.7% in T2DM vs 36.7% in T1DM) and did not participate in the meta-analysis.
The meta-analysis (Fig. 3) demonstrated that women with T2DM were less likely to deliver preterm than women with T1DM (RR: 0.69; 95% CI: 0.62–0.77; P < 0.00001). However, an I 2 of 82% indicated substantial heterogeneity for our finding.
Forest plot of preterm delivery.
Citation: Endocrine Connections 13, 12; 10.1530/EC-24-0066
Macrosomia
We performed a meta-analysis of all the included studies. The risk of macrosomia was 420/3302 (12.7%) in T2DM pregnancies and 787/4069 (19.3%) in T1DM pregnancies.
The results (Fig. 4) show that women with T2DM had a lower risk of delivering an infant >4.0 kg (RR: 0.75; 95% CI: 0.60–0.94; P = 0.01) than women with T1DM. The I 2 of 68% indicated a significant degree of heterogeneity.
Perinatal mortality
Nine out of 11 potential studies were included in the meta-analyses of perinatal mortality. The outcome occurred in 258/10,444 (2.5%) of pregnancies with T2DM and in 258/11,983 (2.2%) with T1DM. The contributing publications had available data on both stillbirths and neonatal deaths.
In Metcalfe et al. (10), in which perinatal death occurred in 1.74% of pregnancies in T2DM and 1.30% in T1DM, the analysis was limited to gestational age above 30 weeks. Simmons et al. (47) with 3% in T2DM and 0% in T1DM, could not be used to calculate extractable data, as the n was unclear in the presentation of results. Hence, these publications were not included in our meta-analysis.
The meta-analysis (Fig. 5) suggests that perinatal mortality is more likely in pregnancies with T2DM (RR: 1.26; 95% CI: 1.06–1.50; P = 0.010) compared to those with T1DM. An I 2 of 0% indicated low heterogeneity.
Forest plot of perinatal mortality.
Citation: Endocrine Connections 13, 12; 10.1530/EC-24-0066
Publication bias
The funnel plots of pre-eclampsia, preterm delivery, and macrosomia (Supplementary Figures 1, 2, and 3) were evaluated as sufficiently symmetrical, meaning that publication bias is unlikely. The analysis of perinatal death consisted of fewer than ten studies. Therefore, a funnel plot was not constructed (35).
Discussion
This systematic review demonstrated that pre-eclampsia, preterm delivery, and macrosomia were significantly more common in pregnant women with T1DM than women with T2DM. In contrast, women with T2DM had a higher risk of perinatal mortality. The data are representative of women birthing between 2001 and 2021, living in high-income countries.
These findings differ from those reported by Balsells et al., a systematic review reporting birth outcomes for women with T1DM and T2DM between 1988 and 2008, including middle and low economies (20). Our review included a higher number of pregnancies, which increases the statistical power of our analyses. Data from three publications in our review overlap with that of Balsells et al. (21, 42, 49). For both T2DM and T1DM in Balsells et al., gestational age at booking was typically in the second trimester, while booking was typically early in the first trimester in our population. Balsells et al. demonstrated no significant difference between T2DM and T1DM in the risk of pre-eclampsia, preterm delivery, and macrosomia, while perinatal mortality was significantly more common in women with T2DM than T1DM (odds ratio 1.50, 95% CI 1.15–1.96) (20). We speculate that, during the time period covered by our review, women with T2DM currently receive better prenatal and/or diabetes care, as well as an earlier diabetes diagnosis due to more liberal screening. Hence, women might present with an overall milder T2DM at booking.
Relative to women with T2DM, pre-eclampsia was more common among women with T1DM in our study. Though present in both groups, pre-eclampsia risk factors differ in their proportions between women with T1DM and T2DM. More challenging blood glucose control among women with T1DM can negatively affect trophoblast invasion and placentation (50, 51).
Nulliparity, retinopathy, and nephropathy are also more common among women with T1DM, who typically have a longer duration of diabetes diagnosis (13, 52, 53). In contrast, women with T2DM are often older, with higher rates of obesity and pregestational hypertension, and are more often of non-Caucasian ethnicities (13, 16, 21, 53, 54, 55).
A possible explanation for the higher risk of preterm birth among women with T1DM is the higher occurrence of pre-eclampsia, with its complications being mitigated by the induction of labor, both preterm and at term (56). Additionally, older age, more pregestational hypertension, or less access to PPC could negatively impact the risk of preterm birth in women with T2DM (54, 57, 58).
Even though relatively common factors for accelerated fetal growth, including obesity and multiparity (12, 54, 55), are more common among women with T2DM, the risk of macrosomia was higher in women with T1DM. These women had lower BMI, were younger, and more often nulliparous but had longer duration of maternal hyperglycemia. A more representative measure of fetal overgrowth, rather than birthweight >4 kg, would be to define macrosomia according to the 90th percentile for any given gestational age. This would have included all babies demonstrating accelerated intrauterine growth and therefore at risk of an earlier induction.
The higher risk of perinatal mortality found in women with T2DM could be a paradox, since women with T1DM had higher risks of pre-eclampsia, preterm birth, and macrosomia. Likewise, women with T1DM often have more challenging glycemic control and have a greater risk of maternal ketoacidosis (20). However, higher maternal age and mean BMI in T2DM, which are associated with more frequent metabolic disturbance and oxidative stress (59, 60), together with more hypertension and lower scores for PPC, could provide possible explanations for the continued risk of perinatal mortality in pregnancies affected by T2DM (57, 59, 61, 62). Earlier induction of labor, indicated by macrosomia or pre-eclampsia, may be favorable in mitigating the risk of perinatal mortality at term for women with T1DM (63). Furthermore, women with T2DM normally have less time in contact with specialist healthcare, with poorer access to health advice regarding fetal movements, and hence poorer compliance with such surveillance.
The heterogeneity among the studies may be due to inherent differences between the T1DM or T2DM cohorts, e.g. in maternal baseline characteristics, exclusion of women with multiple pregnancies in a few studies, differences in pre-pregnancy and prenatal care, different years of observation, and disparities in outcome definitions. There were significant degrees of heterogeneity in the analyses of preterm birth and macrosomia. In the meta-analysis of preterm birth, the effect estimates of the largest studies were all concentrated on the side indicating higher risk in T1DM, with an RR from 0.55 (16) to 0.73 (10). In macrosomia, the largest study with the greatest weighted result, although not significant, showed an effect estimate with higher risk in T2DM (RR: 1.20), which did not correlate to the overall finding of the meta-analysis.
We utilized the NOS, which is a widely used tool for the assessment of RoB in observational studies. However, there is so far no consensus on the most optimal tool for assessing RoB in studies testing exposures.
This systematic review has several strengths. First, a relatively large number of pregnancies were included, especially for pre-eclampsia and preterm delivery. Secondly, we have used relatively uniform definitions of preterm delivery, macrosomia, and perinatal mortality, making the outcomes comparable across studies. We only included women who had DM before pregnancy to ensure that the subjects are representative of women who have a high probability of receiving standard pre-pregnancy and early pregnancy care.
There are also study limitations. Studies with data from longer intervals, from the late 1990s until more recently, were excluded. In the pre-eclampsia analysis, unspecified or diverging definitions could result in diversity in the outcome assessment, e.g. for studies before and after the diagnostic criteria changed in 2013 (64). Another weakness is that most studies had not performed multivariate analyses for confounders in the T1DM and T2DM cohorts, such as, e.g. HbA1c and diabetes complications for pre-eclampsia risk. Assessment of confounding factors is challenging, as these factors could differ in the two groups because some maternal characteristics are intrinsic to the DM subtype. In women with T2DM, confounding factors could be older age, higher BMI, higher parity, pre-existing hypertension, higher prevalence of PCOS, lower rates of PPC, later booking for prenatal care, more use of teratogenic medications, and higher levels of socioeconomic deprivation (16, 21, 26, 65, 66, 67, 68). In T1DM, longer DM durations, higher rates of retinopathy and nephropathy, and higher glycemic values are possible confounders. As we do not have data from individual participants, we cannot assess the known and important associations of even small increases in average glucose or HbA1c levels and the resulting influence on adverse pregnancy outcomes (69). Lastly, the findings of this systematic review represent the relative prevalence of the four pregnancy outcomes between women with T2DM and T1DM, but do not encompass the direct causality between different maternal risk factors such as HbA1c levels and the outcomes of interest.
Conclusion
Our analyses were from 35 observational studies of pregnant women from high-income countries in the last two decades. Women with T2DM had a lower risk of pre-eclampsia, preterm delivery, and macrosomia, but a higher risk of perinatal mortality compared to those with T1DM.
Supplementary materials
This is linked to the online version of the paper at https://doi.org/10.1530/EC-24-0066.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.
Data sharing/availability statement
Access can be provided upon reasonable request by contacting Mari Drabløs (mari.drablos@hotmail.com) or Elisabeth Qvigstad (eqwigsta@ous-hf.no).
Author contribution statement
MD screened abstracts, read the selected articles, performed analyses, and drafted the manuscript. EQ conceived the study and read the articles. HR advised on methodology and the structure of the results. All authors critically revised the draft.
Acknowledgements
The authors would like to thank librarian Marie Susanna Isachsen at Oslo University Hospital, who contributed to the work of creating a suitable search strategy.
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