Improved implementation of aspirin in pregnancy among Dutch gynecologists: Surveys in 2016 and 2021

Abstract

Objective

To evaluate the implementation of low-dose aspirin in pregnancy for the prevention of utero-placental complications among gynecologists in the Netherlands between 2016 and 2021. In this timeframe, a national guideline about aspirin in pregnancy was introduced by the Dutch Society of Obstetrics and Gynecology.

Materials and methods

A national online survey among Dutch gynecologists and residents was performed. An online questionnaire was distributed among the members of the Dutch Society of Obstetrics and Gynecology in April 2016 and April 2021. Main outcome measure was the proportion of gynecologists indicating prescription of aspirin in pregnancy for high and moderate risk indications.

Results

In 2016, 133 respondents completed the survey, and in 2021 231. For all indications mentioned in the guideline there was an increase in prescribing aspirin in 2021 in comparison to 2016. More specifically, the percentage of gynecologists prescribing aspirin for a history of preeclampsia before 34 weeks, between 34 and 37 weeks and at term increased from respectively 94% to 100%, 39% to 98%, and 15% to 97%. Consultant obstetricians and respondents working in an university hospital did not more often indicate the prescription of aspirin for tertiary care indications in 2021. Future use of a prediction model was suggested in the narrative comments.

Conclusion

Implementation of aspirin in pregnancy among Dutch gynecologists substantially improved after a five year timeframe in which the national guideline on aspirin during pregnancy was introduced and trials confirming the effect of aspirin were published.

Introduction

The efficacy of low-dose aspirin for the prevention of obstetrical complications has been an important research question for several decades [1]. Numerous studies have determined the effect of low-dose aspirin on the incidence of preeclampsia (PE) and other obstetric complications including fetal growth restriction (FGR) and preterm birth, with conflicting results [2–8]. In 2010, a meta-analysis showed that early initiation with aspirin before sixteen weeks of gestation resulted in risk reduction of obstetrical complications, in contrast to a later start after sixteen weeks of gestation [9]. After this meta-analysis in 2010, international guidelines had to be created for the translation to clinical practice [10]. It took three to eight years before international guidelines were published [11–14]. Initially, additions to the guidelines concerning hypertensive disorders of pregnancy (HDP) were made. Later, separate modules and/or guidelines on aspirin in pregnancy were created. In the Netherlands, aspirin as risk reducing therapy was added to the national guideline on HDP in 2018 [15]. In 2019, a separate module about aspirin in pregnancy was published [16].

The next step in implementation is the use of guidelines in clinical practice. Evidence based clinical guidelines are sometimes unmanageable because of the high volume of evidence and the poor translation to clinical practice [17]. Limited use of guidelines hinders reduction of adverse outcomes due to suboptimal treatment or prevention [18]. Multiple factors, so-called barriers in the implementation literature, are described as explanation for the challenge of implementation of guidelines [19]. These barriers include for instance characteristics of the caregiver and patient, and methods of information distribution.

We investigated the implementation in clinical practice over time. We hypothesized that the implementation of aspirin would have improved over time, for instance as a result of the introduction of the national guideline, module, and several published trials and meta-analyses confirming the effect of aspirin [15, 16, 20–26]. Therefore we performed a survey using questionnaires among gynecologists and residents on indications for which they prescribed aspirin in pregnancy in 2016 and repeated the questionnaire in 2021.

Materials and methods

In April 2016 and April 2021 a survey was distributed among members of the Dutch Society of Obstetrics and Gynecology. In 2016, the survey was sent to the 979 gynecologists registered at the Dutch Society of Obstetrics and Gynecology. In 2021, the survey was distributed among the 1511 registered gynecologists and residents, since we wished to explore the implementation among residents as well. Hereafter, gynecologists and residents will be mentioned as gynecologists. Members were invited by e-mail to conduct a questionnaire through a provided link. In 2016, the questionnaire was designed in Google forms. In 2021, the questionnaire was designed in Castor Electronic Data Capture [27] due to stricter rules on privacy. The study was approved by the medical ethical committee of the Amsterdam UMC location VUmc (2020.0712). No informed consent was obtained, since for an anonymous survey it is not required. The survey consisted of selected responses and open questions. An overview of the survey is available in S1 Table. Respondents were also invited to provide narrative suggestions to prescribe aspirin for other indications than mentioned in the survey. No personal identifying information was collected to maintain confidentially. Participation was voluntary and no incentives for participating were provided. Gynecologists could participate in 2016 and 2021.

Statistical analyses

Descriptive statistics were performed to present the raw data of the survey. Median with interquartile ranges (IQR) were reported for non-normally distributed variables and proportions were reported for categorical variables. To analyze the difference between 2016 and 2021, measurements were considered unpaired since it was unknown if and which percentage of the respondents answered the questionnaire both in 2016 and 2021. Chi Square Test or Fisher’s Exact Test were performed for categorical variables, and Mann Whitney U Test for numerical variables. In addition, we performed subgroup analyses investigating the influence of being a consultant obstetrician or working in an university hospital in prescribing aspirin for tertiary care indications (SLE, APS, other auto immune diseases and kidney disease). We expected that consultant obstetricians and respondents working in an university hospital more often prescribe aspirin for the tertiary care indications, because of higher awareness elicited by a population at risk for more severe illness. For the categorical variable of type of hospital, a dummy variable was created. The associations between the respondents characteristics and the above mentioned indications to prescribe aspirin were analyzed using logistic regression. SPSS version 26.0 (SPSS Inc., Chicago, IL, USA) was used to perform the statistical analyses. Results were considered significant at the two-sided 5% level.

Results

Respondents

In 2016, 133 out of the 979 invited gynecologists completed the survey, resulting in a response rate of 13.6%. In 2021, 231 out of the 1511 invited gynecologists completed the survey, resulting in a response rate of 15.3%. Characteristics revealed that in 2016, almost a quarter (24.1%) of the respondents reported to be a consultant obstetrician, and in 2021 18.1%. Characteristics of the respondents are depicted in Table 1.

[Figure omitted. See PDF.]

Indications

A significant rise over time in the percentage of gynecologists indicating prescription of aspirin for all indications described in the guideline, except for APS for which the percentage was already high in 2016, is illustrated in Fig 1. In the S2 Table an overview of the results of all questions is given.

[Figure omitted. See PDF.]

PE, preeclampsia; HELLP, hemolysis elevated liver enzymes low platelets; GA, gestational age; SLE, systemic lupus erythematosus; APS, antiphospholipid syndrome. * Statistically significant; p = 0.000. **Statistically not significant; p = 0.250.

Prescription

Details about the advices on the dose, time of administering, gestational age of start and stop of aspirin are depicted in Table 2.

[Figure omitted. See PDF.]

Subgroup analyses

Being a consultant obstetrician or working in an university or teaching hospital was not significantly related to prescribing aspirin for the tertiary care indications SLE, APS, other auto-immune diseases and kidney disease, see Table 3.

[Figure omitted. See PDF.]

Narrative suggestions

In 2021, twelve gynecologists responded to advice aspirin for other risk populations. Five respondents used a prediction tool for setting the indication for aspirin use during pregnancy. The other suggestions were: unexplained stillbirths (n = 2), smoking cigarettes or using cocaine (n = 1), atherosclerosis such as a history of myocardial infarction or transient ischemic attack (n = 1), other auto-immune diseases (n = 1), fetal growth restriction with or without histologically confirmed utero-placental insufficiency (n = 2).

Discussion

Main findings

This national survey among gynecologists revealed a significant rise of gynecologists indicating prescription of aspirin for all moderate and high risk populations. Consultant obstetricians and respondents working in an university hospital did not more often indicate the prescription of aspirin for tertiary care indications.

Interpretation in the light of other evidence

A significant rise in indicating prescription of aspirin over time was seen in the group with a history of HDP, with the highest indication rates for preterm PE or hemolysis elevated liver enzymes low platelets (HELLP) syndrome. This can probably be explained by the higher recurrence risk in case of preterm PE and the stronger risk reducing effect of aspirin on preterm PE in comparison to term PE [23, 28]. Moreover, aspirin as risk-reducing therapy in this population is already implemented in the Dutch clinical practice since the publications of Dekker et al in 1993 and Wallenburg in 1995 [29, 30]. The rise in indicating to prescribe aspirin for auto-immune diseases was statistically significant, except for APS. The most likely explanation is that the awareness of APS was already high in 2016 and further increased in 2021. Since 1997, there was already evidence on the beneficial effect of aspirin and low-molecular weight heparin on live births in pregnant women with APS [31]. Also in the group of maternal diseases a significant rise over time was shown. In a systematic review and meta-analysis of 2016 in which risk factors for developing PE were investigated, chronic hypertension showed a pooled relative risk of developing PE of 5.1 (4.0–6.5), pregestational diabetes of 3.7 (3.1–4.3) and chronic kidney disease of 1.8 (1.5–2.0) [32]. More insight in the elevated risk of women with maternal diseases probably have led to the increased prescription rates. At last, in the group of moderate risk factors also higher indication rates over time were seen, especially for a combination of ≥2 moderate risk factors. In the previous mentioned systematic review and meta-analysis of Bartsch et al, risk factors such as nulliparity, obesity, advanced maternal age and multifetal pregnancy showed an elevated pooled risk, suggesting that women with moderate risk factors may benefit from low-dose aspirin as well [32]. Screening only on maternal factors is a simplified risk calculation when compared to other screening methods in which in addition for instance Doppler measurements and serum placental growth factor and pregnancy-associated plasma protein A are determined [33, 34].

Around 10% of the gynecologists responded to advice aspirin in case of recurrent miscarriages, despite the fact that a systematic review revealed no evidence of a beneficial effect of low-dose aspirin in this group [35]. We did not investigate the motivation for this advice, but one could speculate that the methods to distribute the result of this systematic review have not been sufficient to reach some gynecologists, a known barrier of the implementation of new results.

In 2021, a small proportion of the respondents indicate prescription of aspirin to women with a history of spontaneous preterm birth <34 weeks of gestation. The evidence on the risk reducing effect of aspirin on spontaneous preterm birth varies [9, 36–40]. In addition, there is some evidence that aspirin may reduce preterm birth in nulliparous women without risk factors for hypertensive disorders of pregnancy [41]. If future studies can confirm the risk reducing effect in nulliparous women or women with a history of preterm birth, these indications may be added to the list of indications for aspirin during pregnancy.

The most frequently prescribed aspirin dose is stable over time, namely 80-100mg. Although in 2021, 14.3% of the respondents advised higher aspirin doses of 150-160mg. This might be explained by recent meta-analyses suggesting that aspirin doses above 100 mg may be more effective than lower doses [9, 23, 42]. However, this evidence is based on indirect comparisons. In 2021, the advice to take aspirin in the evening was considerably enhanced. This advice is based on the circadian rhythm of new platelets where the peak release is in the late night and early morning [43]. Since aspirin is quite rapidly absorbed with a time to maximal plasma level of 30 minutes to two hours, evening intake can inhibit this peak. In the cardiovascular population, evening intake is associated with a more stable platelet inhibition over 24 hours in comparison to morning intake [44]. Awareness of this pharmacologically explanation might stimulate further implementation and should therefore be emphasized in education about this topic.

Subgroup analyses showed that consultant obstetricians and respondents working in an university hospital did not more often indicate the prescription of aspirin for tertiary care indications. These promising results show the general awareness among gynecologists and residents among all type of hospitals. Although, awareness among clinical caregivers is no guarantee for awareness among and adherence in patients.

The improved implementation might be explained by the introduction of the national guideline in 2018 and module in 2019 [15, 16]. In addition, the Dutch Society of Obstetrics and Gynecology strives for improvement of implementation and overcoming barriers in the methods of information distribution. Therefore, in 2020 it published a document in Dutch with advice on optimizing the quality circle: the process from collecting evidence by trials to implementation in clinical practice [45]. In case of publication of a new guideline, the Dutch Society of Obstetrics and Gynecology communicates this by notifications to their members. As well as presenting updates in their newsletter, promoting discussions during congresses and other meetings, and/or teaching by e-learnings. These procedures probably have contributed to the improved implementation of aspirin in clinical practice. Moreover, awareness has been emphasized by large RCT’s and meta-analyses over the last years, confirming the risk-reducing effect of aspirin during pregnancy [20–26]. The studies probably created more assurance of the efficacy of aspirin and confirmed the lack of adverse events. The latter being specifically important when prescribing aspirin to women with a moderate risk profile.

Future

We showed that implementation of new therapy in clinical practice remains a challenge. Pathman et al described the process of implementation of clinical guidelines in the following four steps: 1) Awareness, 2) Agreement, 3) Adoption, and 4) Adherence [46]. In our study, we tested the adherence of the caregiver to the clinical guideline, in the study of Pathman et al described as ‘actually succeeding in following the guideline at appropriate times’. Research on implementation of new therapies and clinical guidelines should be more frequently be performed, since unsuccessful implementation could lead to harm of the patients. Our study shows that clinical caregivers are willing to expose to implementation testing, since a substantial part of the invited gynecologists and residents responded to the survey.

The use of a prediction model might be helpful in the successful implementation of aspirin in clinical practice. In the narrative suggestions, five gynecologists plead for the use of a prediction model to set the indication for aspirin during pregnancy. The Fetal Medicine Foundation provides a biomarkers, ultrasound and history based prediction tool to identify women at high-risk for preterm PE [47]. Such a prediction method was tested in the ASPRE trial, detecting 76% of the preterm PE cases [34]. A systematic review to prediction models for PE in 2019 concluded that there is a large variety of prediction models with great heterogeneity among the study methods [48]. In addition, most prediction tools were not validated. Therefore, no advice on the best performing prediction model could be given. Before implementing in clinical practice, model validation should be performed [48].

After adherence of the caregiver comes adherence of the patient. In 2020, we showed that the awareness about aspirin as risk-reducing therapy on HDP in women at risk was only present in 51.9% [49]. Low awareness could result in non-adherence. Previous research reported 21–46% of aspirin non-adherence during pregnancy [50]. In the ASPRE trial, a placebo-controlled trial studying the risk-reducing effect of aspirin on preterm PE, showed that in women with aspirin adherence ≥90%, aspirin had a higher risk-reducing effect in comparison to women with aspirin adherence <90% (OR 0.24; 95% CI 0.09–0.65 versus OR 0.59; 95% CI 0.23–1.53) [22]. Research to optimize aspirin adherence during pregnancy should be performed.

Strengths and limitations

As far as we know, we were the first who investigated the implementation of aspirin during pregnancy by gynecologists. The five-year evaluation on the change in implementation over time is an important strength of our study. By performing this survey, we completed the quality circle [45]. In addition, we investigated a homogeneous population with access to the same national guideline which is representative for the Dutch group of gynecologists. A limitation of our study is the relatively low response rates of 13.6% and 15.3% in 2016 and 2021, respectively. Secondly, a relatively large proportion of the respondents worked in an university hospital, which might give an overestimation of the implementation. At last, our survey might be not representative for all countries, although the attached survey in S1 Table facilitates reproduction of this study in other countries.

Conclusion

In conclusion, the implementation of aspirin in pregnancy for women at moderate or high risk among Dutch gynecologists is improved over time. The improved implementation can probably be explained by the introduction of the national guideline and published trials confirming the risk-reducing effect of aspirin. The next step in implementation is patients’ adherence. Future studies should focus on the optimization of screening tools for obstetrical complications and improvement of aspirin adherence of pregnant women.

Supporting information

S1 Table. Overview of the questions of the survey.

HDP, hypertensive disorders of pregnancy; PE, preeclampsia; HELLP, hemolysis elevated liver enzymes low platelets; GA, gestational age; PIH, pregnancy induced hypertension; FGR, fetal growth restriction; SPTB, spontaneous preterm birth; SLE, systemic lupus erythematosus; APS, antiphospholipid syndrome; BMI, body mass index.

https://doi.org/10.1371/journal.pone.0268673.s001

(DOCX)

S2 Table. Gynecologists and residents indicating prescription of aspirin during pregnancy: Comparison of 2016 and 2021.

Data are depicted as number (%). HDP, hypertensive disorders of pregnancy; PE, preeclampsia; HELLP, hemolysis elevated liver enzymes low platelets; GA, gestational age; PIH, pregnancy induced hypertension; FGR, fetal growth restriction; SPTB, spontaneous preterm birth; SLE, systemic lupus erythematosus; APS, antiphospholipid syndrome; BMI, body mass index; N/A, not available.

https://doi.org/10.1371/journal.pone.0268673.s002

(TIF)

Acknowledgments

We want to thank the Dutch Society of Obstetrics and Gynecology for their help with collecting our data by spreading the survey among their members. We also thank N. Schuster of the department of epidemiology and data science for her advice and help in performing the statistical analyses.

Citation: bij de Weg JM, Visser L, Oudijk MA, de Vries JIP, de Groot CJM, de Boer MA (2022) Improved implementation of aspirin in pregnancy among Dutch gynecologists: Surveys in 2016 and 2021. PLoS ONE 17(6): e0268673. https://doi.org/10.1371/journal.pone.0268673

About the Authors:

Jeske Milou bij de Weg

Roles: Data curation, Formal analysis, Project administration, Writing – original draft

E-mail: [email protected]

Affiliations Amsterdam UMC location Vrije Universiteit Amsterdam, Obstetrics and Gynecology, Amsterdam, Netherlands, Amsterdam Reproduction and Development Research Institute, Pregnancy and Birth, Amsterdam, Netherlands

https://orcid.org/0000-0002-9275-8825

Laura Visser

Roles: Data curation, Writing – review & editing

Affiliations Amsterdam UMC location Vrije Universiteit Amsterdam, Obstetrics and Gynecology, Amsterdam, Netherlands, Amsterdam Reproduction and Development Research Institute, Pregnancy and Birth, Amsterdam, Netherlands

Martijn Alexander Oudijk

Roles: Conceptualization, Supervision, Writing – review & editing

Affiliations Amsterdam UMC location Vrije Universiteit Amsterdam, Obstetrics and Gynecology, Amsterdam, Netherlands, Amsterdam Reproduction and Development Research Institute, Pregnancy and Birth, Amsterdam, Netherlands

Johanna Inge Petra de Vries

Roles: Supervision, Writing – review & editing

Affiliations Amsterdam UMC location Vrije Universiteit Amsterdam, Obstetrics and Gynecology, Amsterdam, Netherlands, Amsterdam Reproduction and Development Research Institute, Pregnancy and Birth, Amsterdam, Netherlands

Christianne Johanna Maria de Groot

Roles: Conceptualization, Supervision, Writing – review & editing

Affiliations Amsterdam UMC location Vrije Universiteit Amsterdam, Obstetrics and Gynecology, Amsterdam, Netherlands, Amsterdam Reproduction and Development Research Institute, Pregnancy and Birth, Amsterdam, Netherlands

Marjon Alina de Boer

Roles: Conceptualization, Supervision, Writing – review & editing

Affiliations Amsterdam UMC location Vrije Universiteit Amsterdam, Obstetrics and Gynecology, Amsterdam, Netherlands, Amsterdam Reproduction and Development Research Institute, Pregnancy and Birth, Amsterdam, Netherlands

References

1. Bujold E, Roberge S, Nicolaides KH. Low-dose aspirin for prevention of adverse outcomes related to abnormal placentation. Prenatal diagnosis. 2014;34(7):642–8. pmid:24799357

2. CLASP: a randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women. CLASP (Collaborative Low-dose Aspirin Study in Pregnancy) Collaborative Group. Lancet (London, England). 1994;343(8898):619–29. pmid:7906809

3. Askie LM, Duley L, Henderson-Smart DJ, Stewart LA. Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data. Lancet (London, England). 2007;369(9575):1791–8. pmid:17512048

4. Ayala DE, Ucieda R, Hermida RC. Chronotherapy with low-dose aspirin for prevention of complications in pregnancy. Chronobiology international. 2013;30(1–2):260–79. pmid:23004922

5. Beaufils M, Uzan S, Donsimoni R, Colau JC. Prevention of pre-eclampsia by early antiplatelet therapy. Lancet (London, England). 1985;1(8433):840–2. pmid:2858710

6. Caritis S, Sibai B, Hauth J, Lindheimer MD, Klebanoff M, Thom E, et al. Low-dose aspirin to prevent preeclampsia in women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. The New England journal of medicine. 1998;338(11):701–5. pmid:9494145

7. Roberge S, Nicolaides KH, Demers S, Villa P, Bujold E. Prevention of perinatal death and adverse perinatal outcome using low-dose aspirin: a meta-analysis. Ultrasound in obstetrics & gynecology: the official journal of the International Society of Ultrasound in Obstetrics and Gynecology. 2013;41(5):491–9. pmid:23362106

8. Uzan S, Beaufils M, Breart G, Bazin B, Capitant C, Paris J. Prevention of fetal growth retardation with low-dose aspirin: findings of the EPREDA trial. Lancet (London, England). 1991;337(8755):1427–31. pmid:1675315

9. Bujold E, Roberge S, Lacasse Y, Bureau M, Audibert F, Marcoux S, et al. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis. Obstetrics and gynecology. 2010;116(2 Pt 1):402–14. pmid:20664402

10. Io Medicine. Clinical Practice Guidelines We Can Trust. Washington DC: The National Academies Press; 2011.

11. ACOG Committee Opinion No. 743: Low-Dose Aspirin Use During Pregnancy. Obstetrics and gynecology. 2018;132(1):e44–e52. pmid:29939940

12. NICE Guideline: Hypertension in Pregnancy. 2019.

13. LeFevre ML. Low-dose aspirin use for the prevention of morbidity and mortality from preeclampsia: U.S. Preventive Services Task Force recommendation statement. Annals of internal medicine. 2014;161(11):819–26. pmid:25200125

14. Lowe SA, Bowyer L, Lust K, McMahon LP, Morton M, North RA, et al. SOMANZ guidelines for the management of hypertensive disorders of pregnancy 2014. The Australian & New Zealand journal of obstetrics & gynaecology. 2015;55(5):e1–29.

15. NVOG. NVOG richtlijn: Hypertensieve aandoeningen in de zwangerschap. 2018.

16. NVOG. NVOG Module: Acetylsalicylzuur. 2019.

17. Greenhalgh T, Howick J, Maskrey N. Evidence based medicine: a movement in crisis? BMJ (Clinical research ed). 2014;348:g3725. pmid:24927763

18. Pronovost PJ. Enhancing physicians’ use of clinical guidelines. Jama. 2013;310(23):2501–2. pmid:24310916

19. Mickan S, Burls A, Glasziou P. Patterns of ’leakage’ in the utilisation of clinical guidelines: a systematic review. Postgraduate medical journal. 2011;87(1032):670–9. pmid:21715571

20. Duley L, Meher S, Hunter KE, Seidler AL, Askie LM. Antiplatelet agents for preventing pre-eclampsia and its complications. The Cochrane database of systematic reviews. 2019;2019(10). pmid:31684684

21. Loussert L, Vidal F, Parant O, Hamdi SM, Vayssiere C, Guerby P. Aspirin for prevention of preeclampsia and fetal growth restriction. Prenatal diagnosis. 2020;40(5):519–27. pmid:31955436

22. Poon LC, Wright D, Rolnik DL, Syngelaki A, Delgado JL, Tsokaki T, et al. Aspirin for Evidence-Based Preeclampsia Prevention trial: effect of aspirin in prevention of preterm preeclampsia in subgroups of women according to their characteristics and medical and obstetrical history. American journal of obstetrics and gynecology. 2017;217(5):585.e1–.e5. pmid:28784417

23. Roberge S, Bujold E, Nicolaides KH. Aspirin for the prevention of preterm and term preeclampsia: systematic review and metaanalysis. American journal of obstetrics and gynecology. 2018;218(3):287–93.e1. pmid:29138036

24. Roberge S, Nicolaides K, Demers S, Hyett J, Chaillet N, Bujold E. The role of aspirin dose on the prevention of preeclampsia and fetal growth restriction: systematic review and meta-analysis. American journal of obstetrics and gynecology. 2017;216(2):110–20.e6. pmid:27640943

25. Rolnik DL, Nicolaides KH, Poon LC. Prevention of preeclampsia with aspirin. American journal of obstetrics and gynecology. 2020.

26. Rolnik DL, Wright D, Poon LC, O’Gorman N, Syngelaki A, de Paco Matallana C, et al. Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia. The New England journal of medicine. 2017;377(7):613–22. pmid:28657417

27. Castor Electronic Data Capture 2019 [27 Aug. 2019]. Available from: https://castoredc.com.

28. Ebbing C, Rasmussen S, Skjaerven R, Irgens LM. Risk factors for recurrence of hypertensive disorders of pregnancy, a population-based cohort study. Acta obstetricia et gynecologica Scandinavica. 2017;96(2):243–50. pmid:27874979

29. Dekker GA, Sibai BM. Low-dose aspirin in the prevention of preeclampsia and fetal growth retardation: rationale, mechanisms, and clinical trials. American journal of obstetrics and gynecology. 1993;168(1 Pt 1):214–27.

30. Wallenburg HC. Low-dose aspirin therapy in obstetrics. Curr Opin Obstet Gynecol. 1995;7(2):135–9. pmid:7787123

31. Rai R, Cohen H, Dave M, Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ (Clinical research ed). 1997;314(7076):253–7. pmid:9022487

32. Bartsch E, Medcalf KE, Park AL, Ray JG. Clinical risk factors for pre-eclampsia determined in early pregnancy: systematic review and meta-analysis of large cohort studies. BMJ (Clinical research ed). 2016;353:i1753. pmid:27094586

33. Akolekar R, Syngelaki A, Poon L, Wright D, Nicolaides KH. Competing risks model in early screening for preeclampsia by biophysical and biochemical markers. Fetal Diagn Ther. 2013;33(1):8–15. pmid:22906914

34. Rolnik DL, Wright D, Poon LCY, Syngelaki A, O’Gorman N, de Paco Matallana C, et al. ASPRE trial: performance of screening for preterm pre-eclampsia. Ultrasound in obstetrics & gynecology: the official journal of the International Society of Ultrasound in Obstetrics and Gynecology. 2017;50(4):492–5. pmid:28741785

35. de Jong PG, Kaandorp S, Di Nisio M, Goddijn M, Middeldorp S. Aspirin and/or heparin for women with unexplained recurrent miscarriage with or without inherited thrombophilia. The Cochrane database of systematic reviews. 2014;2014(7):Cd004734.

36. Groeneveld E, Lambers MJ, Lambalk CB, Broeze KA, Haapsamo M, de Sutter P, et al. Preconceptional low-dose aspirin for the prevention of hypertensive pregnancy complications and preterm delivery after IVF: a meta-analysis with individual patient data. Hum Reprod. 2013;28(6):1480–8. pmid:23528915

37. Kaandorp SP, Goddijn M, van der Post JA, Hutten BA, Verhoeve HR, Hamulyák K, et al. Aspirin plus heparin or aspirin alone in women with recurrent miscarriage. The New England journal of medicine. 2010;362(17):1586–96. pmid:20335572

38. Schisterman EF, Silver RM, Lesher LL, Faraggi D, Wactawski-Wende J, Townsend JM, et al. Preconception low-dose aspirin and pregnancy outcomes: results from the EAGeR randomised trial. Lancet (London, England). 2014;384(9937):29–36. pmid:24702835

39. Silver RM, Ahrens K, Wong LF, Perkins NJ, Galai N, Lesher LL, et al. Low-dose aspirin and preterm birth: a randomized controlled trial. Obstetrics and gynecology. 2015;125(4):876–84. pmid:25751215

40. Landman AJEMC, De Boer MA, Visser L, Nijman TAJ, Hemels MAC, Naaktgeboren C, et al. Evaluation of Low-dose Aspirin for the Prevention of Recurrent Spontaneous Preterm Labour (the APRIL study): a multicentre, randomised, double-blinded, placebo-controlled trial. PLoS Med, forthcoming. 2021.

41. Hoffman MK, Goudar SS, Kodkany BS, Metgud M, Somannavar M, Okitawutshu J, et al. Low-dose aspirin for the prevention of preterm delivery in nulliparous women with a singleton pregnancy (ASPIRIN): a randomised, double-blind, placebo-controlled trial. Lancet (London, England). 2020;395(10220):285–93. pmid:31982074

42. Seidler AL, Askie L, Ray JG. Optimal aspirin dosing for preeclampsia prevention. American journal of obstetrics and gynecology. 2018;219(1):117–8. pmid:29588190

43. Scheer FA, Michelson AD, Frelinger AL 3rd, Evoniuk H, Kelly EE, McCarthy M, et al. The human endogenous circadian system causes greatest platelet activation during the biological morning independent of behaviors. PloS one. 2011;6(9):e24549. pmid:21931750

44. van Diemen JJ, Fuijkschot WW, Wessels TJ, Veen G, Smulders YM, Thijs A. Evening intake of aspirin is associated with a more stable 24-h platelet inhibition compared to morning intake: a study in chronic aspirin users. Platelets. 2016;27(4):351–6. pmid:26599376

45. NVOG. Procedureboek Kwaliteitscirkel. 2020.

46. Pathman DE, Konrad TR, Freed GL, Freeman VA, Koch GG. The awareness-to-adherence model of the steps to clinical guideline compliance. The case of pediatric vaccine recommendations. Med Care. 1996;34(9):873–89. pmid:8792778

47. The Fetal Medicine Foundation [cited 2022 23rd of March]. Available from: https://fetalmedicine.org/.

48. De Kat AC, Hirst J, Woodward M, Kennedy S, Peters SA. Prediction models for preeclampsia: A systematic review. Pregnancy Hypertens. 2019;16:48–66. pmid:31056160

49. Bij de Weg JM, Abheiden CNH, de Boer MA, de Groot C, de Vries JIP. Patients’ perspective on aspirin during pregnancy: a survey. Hypertens Pregnancy. 2020;39(4):371–8. pmid:32564638

50. Abheiden CN, van Reuler AV, Fuijkschot WW, de Vries JI, Thijs A, de Boer MA. Aspirin adherence during high-risk pregnancies, a questionnaire study. Pregnancy Hypertens. 2016;6(4):350–5. pmid:27939481