Influence of aspirin on obstetric outcomes in women with pre-gestational diabetes mellitus: a South-Western Sydney cohort study

Abstract

Aim

To investigate the effect of aspirin on obstetric outcomes in women with pre-gestational diabetes mellitus (PGDM).

Method

Retrospective audit of pregnant women with PGDM from two centres in South-Western Sydney was conducted. Women were categorised into the aspirin group (prescribed aspirin before 16 weeks, gestation) and non-aspirin group (not prescribed aspirin or prescribed aspirin at or after 16 weeks, gestation). The outcomes examined were pre-eclampsia, pre-term delivery and birthweight percentile.

Results

Of 494 women, 52 (10.5%) were in the aspirin group. Pre-eclampsia developed in 57 (12.0%) women. There was no association between aspirin use and pre-eclampsia (8 (15.4%) vs 49 (11.1%), P = 0.2). Aspirin use was not associated with difference in birthweight percentile and rate of pre-term deliveries when adjusted for maternal age, gravidity and other comorbidities.

Conclusion

There was no difference in the rates of pre-eclampsia, pre-term delivery, or birthweight percentile between women with PGDM in aspirin group compared to women in non-aspirin group.

Keywords

Pre-gestational diabetes mellitus pre-eclampsia pre-term delivery aspirin

Introduction

Pre-gestational diabetes mellitus (PGDM) has been reported to increase the risk of pre-eclampsia by three-fold.^1–4 Australian studies have revealed that the prevalence of PGDM is approximately 0.4% with an increase of 9% annually.^5,6 Internationally, the prevalence of PGDM has been increasing in recent years with some studies reporting an increase of 10% over the last 30 years.⁷

The use of aspirin in prevention of pre-eclampsia amongst high-risk women has been studied for over 40 years with variable observed outcomes.^8–10 More recently, a large randomised controlled trial demonstrated a significant reduction in the risk of pre-eclampsia with a relative risk (RR) of 0.38 (95% confidence interval (CI): 0.20–0.74) when aspirin is commenced prior to 16 weeks of gestation.¹¹ Furthermore, the study by Hoffman et al. (2020) revealed that the rate of pre-term delivery was also reduced with RR 0.89 (95% CI: 0.81–0.98).¹² Even though the subjects in this study comprised of high-risk women, less than 2% of the participants had PGDM.¹² While the pharmacotherapeutic effect of aspirin in the prevention of pre-eclampsia remains under investigation, some studies have demonstrated a platelet inhibitory and anti-inflammatory effect of aspirin on placental development, which serves to subsequently minimise placental dysfunction.¹³

The benefit of aspirin in the prevention of pre-eclampsia, specifically in women with PGDM, remains largely unclear with conflicting data. The Maternal Fetal Medicine Units Network study (MFMU), which investigated the role of aspirin in the prevention of pre-eclampsia in high-risk women, included 471 women with PGDM and did not demonstrate a difference in the rate of pre-eclampsia with the use of aspirin. However, women in this study were commenced on aspirin in the 2nd trimester.¹⁴ Furthermore, a systematic review by Zen et al. that examined individual patient data from 930 women with PGDM (published and unpublished data) did not demonstrate a difference in the rate of pre-eclampsia in women treated with aspirin compared to placebo (odds ratio (OR) 0.58; 95% CI 0.20–1.71; P = 0.33). However, the systematic review was limited by heterogeneity in the dose and gestation at which aspirin was initiated in addition to inadequately reported outcomes specific to women with PGDM.¹⁵ Therefore, the aim of this study was to explore the association between aspirin use and pregnancy outcomes in our cohort of women with PGDM.

Method

We undertook a retrospective study of all pregnancies in women with PGDM (Types 1 and 2) from January 2005 to June 2020. Data was obtained from two separate prospectively collected databases, electronic medical records and hospital paper records. The databases included women with PGDM from two hospitals in the South-West Sydney region: Liverpool and Bankstown-Lidcombe Hospitals. Both were metropolitan tertiary hospitals with a combined annual delivery rate of approximately 6000 births per year.¹⁶

These databases contained prospectively collected data by endocrinology teams at both centres and included parity, date of last menstrual period (LMP), estimated due date (EDD), maternal age, pre-gestational weight, body mass index (BMI), gravidity, HbA1c at first review, date of delivery, infant birth weight and infant sex. EDD was calculated by adding 40 weeks to the LMP. Women's identification number and name in the database was then matched to the hospital records (integrated electronic medical records) and paper files to obtain information such as aspirin and/or calcium use, blood pressure (BP) readings and biochemical data. All women in the database had a diagnosis of PGDM. This was confirmed by whether the women were on treatment for diabetes or had a biochemical result supporting their diagnosis. Women with gestational diabetes were excluded. Women who attended both hospitals during their pregnancy were only recorded once for the purpose of this study. Women who had more than one pregnancy were included as separate entries. Once data matching was complete, all identifying information was removed prior to data analysis.

Women were categorised in the ‘aspirin group’ if they were prescribed aspirin before 16 weeks of gestation and ‘non-aspirin group’ if they were either not prescribed aspirin or prescribed aspirin at or after 16 weeks. There was no standard protocol at which aspirin was commenced in the centres. The prescription of aspirin was done at the clinician's discretion. BMI was based on the recorded weight and height in first trimester. In instances where several readings were available, the first recorded readings were used to calculate BMI. The BP data was recorded from measurements taken in clinic using manual BP readings. Two BP measurements were taken consecutively of which the second result was recorded. Pre-gestational kidney disease was defined as creatinine above 70 μmol/L in the first trimester or the presence of albuminuria prior to pregnancy, as this was the standard of care of our obstetric medical department. Pre-pregnancy values were not routinely available for the patients hence first trimester readings were used. HbA1c readings were obtained from the first trimester.

The outcomes examined were pre-eclampsia (early-onset pre-eclampsia (EOPE): <34 weeks of gestation), late-onset pre-eclampsia (LOPE): ≥34 weeks of gestation), pre-term delivery (<37 weeks of gestation) and birthweight percentile.¹⁷ Pre-eclampsia was defined as hypertension with BP greater than or equal to 140/90 mmHg after 20 weeks of gestation and maternal end-organ or fetal involvement.¹⁸ In women with pre-gestational hypertension, the presence of organ or fetal involvement in addition to worsening BP control was used to diagnose pre-eclampsia. The birthweight percentile was calculated using the gestation-related optimal weight (GROW) which takes maternal ethnicity, height, weight, parity, infant sex, infant birth weight and gestational age into consideration.¹⁷ A sensitivity analysis was also undertaken, excluding those who started aspirin after 16 weeks.

SPSS program (Version 22) was utilised for the statistical analysis.¹⁹ Chi-squared and one way ANOVA tests were used for the univariate associations. Median and interquartile range (IQR) were used to present the results given that they were non-parametric. Multivariate logistic regression analysis was conducted to adjust for potential confounding factors and a P-value of less than 0.05 was considered statistically significant. Variables for the multivariate logistic analysis were included if the variables had a significant association in the univariate analysis or were clinically significant. Furthermore, collinearity was checked prior to ensuring that multicollinearity was not an issue in the regression model. The study was approved by the Human Research Ethics Committee South-West Sydney Local Health District. Approval number: LNRSSA/14/LPOOL/75.

Results

A total of 520 women were identified of which 26 (5%) were excluded (10 women had duplicate results and 16 had incomplete information) (Figure 1), leaving a total of 494 women for analysis. Of these, 52 women (10.5%) were in the aspirin group and 442 (89.5%) were in the non-aspirin group. Thirty-five women (7.1%) were commenced on aspirin after 16 weeks of gestation and were considered to be in the non-aspirin group. Sixty-seven women (13.5%) were commenced on calcium before 16 weeks of gestation. The median maternal age was 33.8 years (IQR 7.7) and the median BMI was 29.5 kg/m² (IQR 10). Seventy-six (15.4%) women were primigravid and 10 (2%) conceived through in vitro fertilisation (IVF) (Table 1). Most women (n = 370 (75%)) had a diagnosis of type 2 diabetes mellitus and 64 (13%) women were smoking cigarettes during pregnancy. There were 24 (4.9%) women with pre-gestational kidney disease, 85 (17.2%) with pre-gestational hypertension and 35 (7%) had experienced pre-eclampsia in a previous pregnancy.

Figure 1.

Flow chart of women included in study.

Table 1.

Baseline characteristics of women on aspirin compared to those not on aspirin (Chi-squared and T-tests were used to calculate P-value).

	Aspirin group (N = 52)		Non-aspirin group (N = 442)
Comorbidity	Median (IQR)	N (%)	Median (IQR)	N (%)	P-Value
Age (years)	34.7 (7.99)		33.7 (7.59)		0.35
Body mass index (kg/m²)	31.8 (10.5)		29.0 (10.5)		0.63
Pre-gestational HbA1c (%)	7.15 (2) IFCC: 55 mmol/mol)		7.2 (3) IFCC: 55(mmol/mol)		0.99
Antenatal creatinine (μmol/L)	45.0 (14)		50.00 (15)		<0.05
Booking systolic BP (mmHg)	115 (16)		110 (20)		0.1
Booking diastolic BP (mmHg)	70 (14)		66 (12)		0.1
Mode of conception (IVF)		1 (1.9)		9 (2)	0.70
Ethnicity
African		1 (2)		8 (1.8)
South East Asians		7 (14)		67 (15.1)	0.19
South Asians		17 (34)		90 (20.3)
Pacific Islanders		5 (10)		65 (14.6)
Middle Eastern		15 (30)		103 (23.2)
Central/South Americans		0		9 (2)
Anglo-European		5 (10)		100 (22.5)
Aboriginal people		0		2 (0.5)
Previous pre-eclampsia		6 (11.5)		29 (6.6)	0.15
Pre-gestational hypertension		9 (20)		76 (17.5)	0.40
Pre-gestational kidney disease		3 (6)		21 (4.8)	0.45
Diabetes type 1		13 (25)		111 (25.1)	0.57
Diabetes type 2		39 (75)		331 (74.9)
Commenced on calcium		34 (69.4)		33 (8)	<0.05
Smoking during pregnancy		9 (17.3)		55 (12.5)	0.60
Primigravida		12 (23.1)		64 (14.5)	0.08
Metformin use during pregnancy		31 (60.8)		162 (37.2)	<0.05

When comparing women in the aspirin and non-aspirin groups, there were no statistically significant differences in the maternal median age (34.7 years (IQR: 7.99) vs 33.7 years (IQR: 7.59), P = 0.35), BMI (31.8 (IQR 10.5) kg/m² vs 29.0 (IQR 10.5) kg/m², P = 0.63), pre-gestational HbA1c (7.15% (IQR 2) vs (7.2% (IQR 3), P = 0.99), booking systolic BP (115 mmHg (IQR 16) vs (110 mmHg (IQR 20), P = 0.1) and booking diastolic BP (70 mmHg (IQR 14) vs (66 mmHg (IQR 12), P = 0.1) (Table 1). The number of women who conceived through IVF, women with previous pre-eclampsia, pre-gestational hypertension, pre-gestational kidney disease, smoked during pregnancy and gravidity were similar between the women in the aspirin and non-aspirin groups (Table 1). However, women in the aspirin group were observed to have a significantly higher proportion of oral calcium supplementation (34 (69.4%) vs 33 (8%), P < 0.05) as well as metformin use in pregnancy (31 (60.8%) vs 162 (37.2%), P < 0.05). Furthermore, median creatinine was also significantly lower in the aspirin group compared to the non-aspirin group (45.0 μmol/L (IQR 14) vs 50.0 μmol/L (IQR 15), P < 0.05) (Table 1) although this is of minimal clinical significance.

The overall number of women with pre-eclampsia in this cohort was 57 (11.5%), with pre-term delivery in 118 cases (23.9%) and median birth weight percentile of 62.6 (IQR 58.5). There was a similar number of women in the aspirin group with PGDM who developed pre-eclampsia compared to women in the non-aspirin group (13 (10.5%) vs 39 (10.5%), P = 0.5). The prevalence of pre-eclampsia across both groups was statistically similar, 8 (15.4%) in the aspirin group and 49 (11.1%) in the non-aspirin group (P = 0.2) (Table 2). Women who developed pre-eclampsia were further divided into EOPE (<34 weeks) and LOPE (≥34 weeks). There was no significant difference between the groups with 4 (50%) women in the aspirin group compared to 20 (40.8%) women in the non-aspirin group (P = 0.45) with EOPE (Table 2).

Table 2.

Aspirin use and pregnancy outcomes (Chi-squared and T-tests were used to calculate P-value).

	Aspirin group (N = 52)		Non-aspirin group (N = 442)
Outcomes	N (%)	Median (IQR)	N (%)	Median (IQR)	P-Value
Pre-eclampsia	8 (15.4)		49 (11.1)		0.2
Early pre-eclampsia (before 34 weeks)	4 (7.7)		20 (4.5)		0.24
Mean birthweight percentile		71.4 (58.8)		60.8 (58.4)	0.51
Pre-term delivery^a	21 (41.2)		97 (23.4%)		<0.05

^aThere was no association between aspirin use and pre-term delivery on multivariate analysis (adjusting for age, smoking history, history of hypertension, kidney disease, ethnicity, calcium use, insulin dose and metformin use): OR 0.81, P = 0.64.

The incidence of pre-term delivery was observed to be higher in the aspirin group compared to the non-aspirin group on univariate analysis (OR 2.29, 95% CI: 1.26–4.18). However, on multivariate analysis, after adjusting for maternal age, smoking, history of hypertension, kidney disease, ethnicity, insulin dose as well as calcium and metformin use during pregnancy, there was no statistically significant difference between aspirin use and pre-term delivery (OR 1.37, 95% CI 0.57–3.31). The median birth weight percentile for the cohort was 62.6 (IQR 58.53) with no significant difference between those in the aspirin and non-aspirin groups (71.4 (IQR 58.8) vs 60.8 (IQR 58.4), P = 0.51).

A sensitivity analysis was also performed by excluding women who were commenced on aspirin after 16 weeks gestation. There was still no association between aspirin use and pre-eclampsia (P = 0.22) or birthweight percentile (P = 0.29). On univariate analysis, there was a significant association between use of aspirin and pre-term delivery in the sensitivity analysis (P < 0.05). However, this was not appreciable on multivariate analysis after adjusting for age, history of hypertension, history of kidney disease, ethnicity, total insulin dose pre-pregnancy, metformin use pre-pregnancy, smoking history and calcium use in pregnancy (OR 2.1, P = 0.05).

Discussion

This study did not identify an association between the use of aspirin and the rate of pre-eclampsia and pre-term delivery in women with PGDM. The baseline characteristics were similar between both groups of women, except for antenatal calcium and metformin use which were significantly higher in the aspirin group. This was likely due to the recommended practice of prescribing aspirin and calcium in women who are at a high risk of pre-eclampsia. Therefore, high-risk women who were prescribed aspirin by their treating clinicians were also likely to have been prescribed calcium for pre-eclampsia risk minimisation.¹² While a statistically significant difference in the antenatal creatinine level was observed between both groups, the difference is not clinically significant as the creatinine level in both groups were within normal ranges. The lack of an association between aspirin, pre-eclampsia and pre-term delivery could be due to the relatively low number of women on aspirin in this study. Furthermore, we were unable to ascertain adherence to aspirin which could have affected the results.²⁰

The lack of association between prophylactic aspirin and the rate of pre-eclampsia and pre-term delivery in women with PGDM is consistent with other studies.^11,15,21 The systematic review by Zen et al. did not demonstrate a difference in the rate of pre-eclampsia with the use of aspirin in women with PGDM, however, there was significant heterogeneity in the dose of aspirin, ranging from 60 to 150 mg, and the gestational age at which aspirin was initiated in these studies.¹⁵ Recent studies on the effective use of prophylactic aspirin have demonstrated the importance of optimal dose and initiation on aspirin prior to 16 weeks of gestation.^11,21 Therefore, the dose, timing of initiation and formulation inconsistencies in the prescription of aspirin is likely to have contributed towards the lack of the desired prophylactic benefit of aspirin in these women.¹⁵ In comparison to the study by Zen et al., our study included women with aspirin dose of either 100 or 150 mg. Our study also limited the pharmacological effect by limiting the commencement of aspirin to 16 weeks of gestation. Furthermore, factors such as glycaemic control and other medications were not factored into the study by Zen et al. In addition, our study is more homogenous, from the same health district with uniform clinical practices.

On univariate analysis, aspirin was associated with increased rate of pre-term delivery. This could be due to the fact that the patient's prescribed aspirin could have been perceived by the treating clinician as being high risk for pre-eclampsia. Factors such as BP readings, family history or a new partner could have affected this association, which was not collected in this study. However, on multivariate analysis, our study did not demonstrate an association between aspirin use and pre-term delivery after adjusting for relevant maternal comorbidities. This was similar to a single centre retrospective study which did not demonstrate a difference in the rate of pre-term delivery in women with PGDM who were prescribed aspirin prior to 16 weeks of gestation. However, similar to our study, this retrospective analysis had a small sample size of 45 (27%) women on aspirin.²²

Our study also did not demonstrate an association between aspirin use and birthweight percentile of the newborn. This finding was in contrast to a secondary analysis of the cohort of diabetic women enrolled in the Maternal-Fetal Medicine Units High-Risk Aspirin trial.²³ Their aim was to assess the impact of aspirin on fetal growth in diabetic pregnancies. Aspirin was significantly associated with a higher birthweight Z-score (0.283; 95% CI, 0.023–0.544) in the overall cohort (P = 0.03). The study, however, utilised a lower dose of aspirin at 60 mg daily with a delayed onset of therapy at 13–26 weeks of gestation.

The study has several limitations. Firstly, this was a relatively small sample size with only 52 (10.2%) women in the aspirin group. The lower rate of aspirin prescription prior to 16 weeks of gestation could be due to delayed presentation to our high-risk pregnancy service. Furthermore, women with no documentation of prescription of aspirin on paper records were assumed to have not been on aspirin. As such, women without adequate documentation on aspirin use may not have been captured in our dataset. Additionally, given the retrospective nature of the study, adherence to the prescribed aspirin could not be verified. Previous studies have demonstrated that adherence to aspirin of at least 90% of the duration of pregnancy (from <16 weeks of gestation to 36 weeks of gestation) is required to observe its desired prophylactic benefit.²⁰ Therefore, verification of adequate adherence is required when assessing obstetric outcomes in relation to the use prophylactic aspirin. Moreover, the dose of aspirin in our study was not uniform across the group, ranging from 100 to 150 mg.

The strengths of this study include the use of two centres in the southwest region of Sydney for data collection. Further, the inclusion of data points such as parity, comorbidities, and medication inclusion such as calcium allowed us to evaluate potential confounders to the outcomes.

Large randomised controlled studies that examine the use of aspirin in the PGDM population with the current understanding of optimal prescription of prophylactic aspirin (commenced before 16 weeks at gestation at 150 mg nocte) would be beneficial, and indeed a large, randomised control study examining the effect of aspirin on pregnancy outcomes in women with PGDM is currently underway and is likely to provide better insights into the efficacy of aspirin in preventing pre-eclampsia in women with PGDM.²⁴

Conclusion

Prophylactic aspirin use in women with PGDM was not associated with a lower rate of pre-term delivery, pre-eclampsia or higher newborn birthweight in this patient cohort. However, a larger study with optimal prescription of prophylactic aspirin and verification of adherence would be beneficial in assessing this.

Footnotes

Contributorship

Research idea and design: Andrew Jeyaruban, Renuka Shanmugalingam, Jeff Flack, Tang Wong, Vincent Wong and Angela Makris. Data acquisition: Jeff Flack, Vincent Wong, Andrew Jeyaruban, Pamela Wu and Rena Cao. Data analysis: Andrew Jeyaruban, Renuka Shanmugalingam and Angela Makris. Supervision: Renuka Shanmugalingam and Angela Makris. Draft writing: Andrew Jeyaruban. All authors interpreted the results, revised the draft and approved the final version of the manuscript.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical approval

The study was approved by the Human Research Ethics Committee South- west Sydney local health district. Approval number: LNRSSA/14/LPOOL/75.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Guarantor

Andrew Jeyaruban is the guarantor of the present work.

Informed consent

Informed consent was not sought for the present study because this was a database based study and no identifiable information was used in the final database. A waiver of consent was obtained from the ethics committee.

Trial registration

Not applicable.

ORCID iDs

Andrew Jeyaruban

Angela Makris

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