Preeclampsia and other hypertensive disorders in pregnancy

#Background

Preeclampsia is a pregnancy specific multi-organ condition characterised by impaired uteroplacental perfusion and defective trophoblast invasion with subsequent endothelial dysfunction and systemic vascular inflammation.¹ It is one of the leading causes and contributors to mortality and morbidity for māmā/people and pēpi worldwide. Wāhine/people with hypertension prior to pregnancy and those who develop gestational hypertension have a significantly higher chance of developing preeclampsia.

Approximately 10% of all pregnancies will be impacted by hypertension, the majority of which will be due to gestational hypertension, with 2.5-3% experiencing preeclampsia.^2,3 Although hypertension can usually be medically controlled, there are currently no proven therapeutic interventions to cure preeclampsia whilst maintaining pregnancy once it has occurred, and therefore, in its more severe forms, preterm birth may be required. In Aotearoa, preeclampsia contributes to approximately 15% of all births <37 weeks gestation³ and therefore is a major contributor to provider initiated preterm birth.

Identifying wāhine/people who have a high chance of preeclampsia allows for timely introduction of preventative therapy and planned surveillance. When preeclampsia occurs prior to term (37 weeks), an expectant approach should be taken with management focussed on close surveillance of māmā/person and pēpi wellbeing. Where there is concern for wellbeing before term, the risks and benefits of ongoing pregnancy against preterm birth must be considered and, when necessary timely preparation for early birth should be made. Guidance within this section is specific to the prevention and management of preeclampsia to reduce the chance of severe preeclampsia before 37 weeks gestation, as well as optimising the timing and planning when preterm birth is indicated. However, improved care prior to and early in pregnancy to reduce preterm birth secondary to preeclampsia will also have positive impacts on the incidence and severity of preeclampsia at term.

#Recommendations and Practice

Guideline Recommendations (pink boxes) and Good Practice (yellow boxes) are provided as recommendations of practice. Comprehensive clinical oversight of māmā/person and pēpi wellbeing is required, and this may influence how these recommendations of practice are used.

Each recommendation of practice should be considered in consultation with wāhine/people and whanāu, including clear explanations to allow informed decision-making. Wāhine/people have the right to decline a recommendation of practice. In these circumstances, healthcare providers should follow their professional responsibilities for ongoing care. ^29-32

Definitions and classifications for preeclampsia and other hypertensive disorders of pregnancy

Standardised and consistent definitions for hypertensive disorders of pregnancy are essential to support consistent and optimised care. Definitions used in the national preeclampsia guideline²⁰ are predominantly in line with the 2021 International Society for the Study of Hypertension in Pregnancy (ISSHP) statement.²² Definitions within the ISSHP statement are the most widely accepted internationally. They are endorsed by the International Federation of Gynecology and Obstetrics (FIGO)¹³ and used by the Society of Obstetric Medicine of Australia and New Zealand (SOMANZ).⁷

Identification and modification of risk for preeclampsia

Identification of wāhine/people with a higher chance of preeclampsia allows for timely introduction of preventative therapy and planned surveillance. A wide variety of approaches to screening for preeclampsia have been proposed and are currently recommended globally. These include clinical risk assessment, blood pressure, plasma biomarkers, uterine artery Doppler waveform assessments and combinations of these assessments.²⁰

All modalities and combinations of screening are more effective in detection of preterm preeclampsia than term preeclampsia.³³ However, the only large general population screening study including Aotearoa participants (the SCOPE Study) suggested that although the addition of placental growth factor (PlGF) to clinical risk assessment (but not uterine artery Doppler or other biomarkers) measured at 14-16 weeks improved the detection of preterm preeclampsia, the improved performance was not sufficient to justify introduction as a routine clinical test.³⁴ Aotearoa currently supports a clinical risk assessment only based approach to screening. Clinical risk assessment includes clinical history and demographic information, BMI and blood pressure assessment.

Surveillance and antenatal management

Indications and timing of preterm birth for preeclampsia and other hypertensive diseases of pregnancy

For all hypertensive diseases of pregnancy, a general approach for expectant management is recommended.

#Auditable Standards

To be developed.

#Included guidelines

The search identified 16 guidelines that met criteria for high-quality and/or were recommended for use or use with modifications by the Review Panel.^4-19 Five guidelines were assessed to be high-quality in Rigour of Development (score >60%) and Overall Assessment (score >60%) and recommended for use; these were all World Health Organization (WHO) guidelines.^8-12 One guideline was assessed to be high-quality in Rigour of Development (score >60) but not in Overall Assessment.⁴ Five guidelines were assessed to be high-quality in Overall Assessment (score >60%), but not in Rigour of Development (score >60).^6,13-16 The remaining five guidelines were recommended for use with or without modifications.^5,7,17-19

Three guidelines were national,^4-6 nine were international/bi-national (Aotearoa and Australian),^7-15 and four were district-specific.^16-19 Nine guidelines covered the overall management of preeclampsia and hypertensive disorders of pregnancy,^{4,7-9,14,16-19} three were specific to screening^6,13,15 and four were specific to drug treatments.^5,10-12

Recommendations in this section are primarily based on the Te Whatu Ora published ‘Diagnosis and Treatment of Hypertension and Pre-eclampsia in Pregnancy in Aotearoa New Zealand: Te Tautohu, Te Tumahu i te Toto Pōrutu me te Pēhanga Toto Kaha i te Hapūtanga ki Aotearoa: A clinical practice guideline’,²⁰ (ongoing referred to as ‘national preeclampsia guideline’). This 2022 guideline superseded the 2018 New Zealand Manatū Hauora ‘Diagnosis and Treatment of Hypertension and Pre-eclampsia in Pregnancy in New Zealand – a clinical practice guideline’⁴ that was identified as high-quality through the search and Review Panel assessment. The 2022 national preeclampsia guideline was contracted by Manatū Hauora and included a multidisciplinary project team, literature reviews, and a multidisciplinary and representative steering group with recommendations developed by expert consensus.²⁰ It provides definitions and classifications for hypertensive disorders of pregnancy and clinical practice recommendations and practice points covering preconception counselling; antenatal management including screening and risk assessment, monitoring requirements and treatment of hypertension; intrapartum management and; postpartum care.²⁰ The guideline is divided into documents including a summary of recommendations, evidence summaries and supporting management algorithms.

Recommendations from the 2022 national preeclampsia guideline²⁰ have been considered against the other guidelines meeting Review Panel quality and use recommendations. Where recommendations in this best practice guide differ to those in the national preeclampsia guideline, reference and justification is provided. Some recommendations and practice points have also been added, in particular, where there is relevance to preterm birth, and are referenced accordingly.

Two other guidelines that were identified for use have been updated since the search and Review Panel critical appraisal was performed. The Society of Obstetric Medicine of Australia and New Zealand (SOMANZ) ‘Guideline for the Management of Hypertensive Disorders of Pregnancy’, originally published in 2014⁷ was replaced by the SOMANZ ‘Hypertension in Pregnancy Guideline 2023’.²¹ The International Society for the Study of Hypertension in Pregnancy (ISSHP) ‘Classification, Diagnosis and Management Recommendations for International Practice’ 2018¹⁴ was replaced by a guideline of the same name in 2021,²² shortly after the guideline search was completed. The most recent versions of these guidelines have been used.

Since the search was undertaken, the RANZCOG ‘Screening in early pregnancy for adverse perinatal outcomes’ guideline (C-Obs 61) has been reviewed and adapted to become the ‘Screening in early pregnancy for the prevention of preterm preeclampsia and related complications’ guideline (C-Obs 61) (April 2024).²³ The original guideline was assessed to be high-quality in Rigour of Development (score >60%) and Overall Assessment (score >60%) and recommended for use. As the scope of the guideline is now specific to preeclampsia, its recommendations have been considered in this section.

#Impact on equity

The vision of the Carosika Collaborative is ‘Equity in preterm birth outcomes will be achieved in Aotearoa by lowering preterm birth rates and optimising preterm birth care’ ; Taonga Tuku Iho is a major tool to support this. Equity has been prioritised throughout the development process of Taonga Tuku Iho and will drive its implementation and measurement of impact.

During the identification, evaluation and selection of the clinical practice guidelines that inform Taonga Tuku Iho, the Review Panel considered the potential impact on equity of recommendations within each guideline ²⁴ and these are summarised here.

Within Aotearoa rates of preeclampsia and other hypertensive disorders of pregnancy and their impact on preterm birth are not well established at a population level or by factors such as ethnicity, region of residence and socio-economic status. The only Te Whatu Ora maternity clinical indicator relevant to hypertensive disorders of pregnancy is indicator 13 ‘diagnosis of eclampsia at birth admission’.²⁵ Eclampsia is at the most severe end of the spectrum with very few events occurring (e.g. only 24 episodes of eclampsia across the country in 2022, 0.04%) and therefore any analysis by equity factors is not meaningful. Data from Te Toka Tumai National Women’s Annual Clinical Report suggests that rates of preeclampsia may differ by ethnicity (in 2023 – 5.4% Māori, 6.6% Pacific and 4.3% European nulliparous wāhine/people)²⁶ however the proportion that required preterm birth is not reported and rates may be confounded by transfers in for tertiary level care amongst other factors. International literature identifies that disparities in rates of preeclampsia by ethnicity exist. These may be partly explained by contributing factors such as obesity, diabetes and chronic hypertension and potential genetic influencers on pathophysiology, but also importantly implicit bias and systemic racism.²⁷

Review Panel guideline assessments identified that the recommendations in five of the 16 guidelines^4,8,9,17,28 meeting criteria for consideration of inclusion in this guide had potential to increase differences by equity factors.

Differences were noted by region including access to lead maternity carers, general practitioners, ultrasound services, ward capacity for in-patient stays and 24 hour laboratory testing. More specifically for rural regions the lack of lead maternity carers and access to tertiary care, appropriate medical knowledge and expertise in screening were noted.

Insufficient funding and education for lead maternity carers to implement effective screening protocols were identified as a factor that may impact on equity of access to care, as well as the lack of appropriate funding for lead maternity carers to undertake frequent blood pressure surveillance in the community.

Recommendations on healthy lifestyle, use of medications and accessing early pregnancy care to allow preventative interventions to be instigated were highlighted to have potential to increase differences by socioeconomic status. A lack of recommendations on culturally targeted initiatives to promote early pregnancy screening and preventative therapies in the 2018 national preeclampsia guideline⁴ was noted, this has been addressed in the 2022 version.²⁰

#Current research

None identified

#Statement on rationale for any differing recommendations from the high-quality guidelines

Recommendations in this section are based on the 2022 national guideline and evidence statements ‘Diagnosis and Treatment of Hypertension and Pre-eclampsia in Pregnancy in Aotearoa New Zealand: Te Tautohu, Te Tumahu i te Toto Pōrutu me te Pēhanga Toto Kaha i te Hapūtanga ki Aotearoa: A clinical practice guideline’.²⁰ Each of the other guidelines meeting Review Panel quality and use recommendations have also been reviewed and considered. Significant discrepancies include some modifications to definitions, screening approaches and recommended aspirin dose. For these discrepancies this guide has followed the recommendations used in the 2022 national guideline and provided some justification (see relevant sections with references and links). Some recommendations in addition to those 2022 national guideline are highlighted below with rationale for these additions.

The 2022 national guideline recommends commencing 100 mg aspirin for wāhine/people with ≥1 major risk factor for preeclampsia between 12 and 16 weeks gestation. In this guide we have included a further recommendation ‘For wāhine/people seen after 16⁺⁶ weeks and before 20⁺⁰ weeks, aspirin should be recommended as there may still be some benefit (preeclampsia prevention not FGR prevention)’. This addition is made based on evidence from two large studies published in 2017; a secondary analysis of the meta-analysis of the PARIS Collaboration, an individual participant data from 31 randomised trials (32 819 participants),⁴⁴ and a systematic review and meta-analysis of 45 randomised controlled trials (20 909 participants).⁴⁵ In the PARIS Collaboration individual participant data meta-analysis aspirin commenced <16 or ≥16 weeks had similar effects on rates of preeclampsia and preterm birth <34 weeks (p=0.98).⁴⁴ In the trial level aggregate data meta-analysis study, the impact of aspirin was greatest when commenced <16 weeks (preeclampsia relative risk 0.57, 95% CI 0.43–0.75, severe preeclampsia relative risk 0.47, 95% CI 0.26–0.83, FGR relative risk 0.56, 95% CI 0.44-0.71).⁴⁵ When aspirin was commenced ≥16 weeks a significant reduction in preeclampsia was still seen (relative risk 0.81, 95% CI 0.66–0.99) although this effect was not significant for more severe disease (relative risk 0.85, 95% CI 0.64–1.14) or FGR (relative risk 0.95, 95% CI 0.86–1.05).⁴⁵ Recommendations to only commence aspirin <16 weeks often refer to this trial level aggregate data meta-analysis. However, in view of discrepancies in results between the two studies, some benefit still seen on overall rates of preeclampsia even after a delayed start, and relative safety of aspirin in pregnancy we have included this additional recommendation.

The 2022 national guideline recommends commencing treatment for hypertension in pregnancy for persistently sBP ≥140 mmHg and/or dBP ≥90 mmHg. It does not provide recommendations for target blood pressure with antihypertensive therapy. We have added this recommendation (sBP ≤135 and dBP ≤85 mmHg) as included for sBP and dBP from SOMANZ 2023 guidance²¹ and for dBP from ISSHP 2021 guidance²² and in consultation with local specialist obstetric physician service.

For pragmatic reasons we have reduced the recommended frequency of routine blood tests for wāhine/people with non-severe preeclampsia from ‘twice weekly’ to ‘at least’ weekly.

The 2022 national guideline recommends that for wāhine/people with severe preeclampsia after 34 weeks, birth should be recommended once the wahine/person is stabilised in a centre with resource to care for māmā/person and pēpi. As severe preeclampsia includes severe hypertension which may be controlled by increasing dose and/or number of antihypertensive therapies, in this guide we have included an option to continue with an expectant approach. This includes clear direction in which scenarios this may be considered appropriate. This additional recommendation is consistent with the World Health Organization (WHO) recommendations in ‘Policy of interventionist versus expectant management of severe pre-eclampsia before term’.⁸ Furthermore, where severe preeclampsia is diagnosed by fetal growth restriction (associated with oligohydramnios and/or abnormal Doppler waveforms) alone, we have recommended timing of birth to be guided by fetal indications.⁴¹

The SOMANZ ‘Hypertension in Pregnancy Guideline 2023’,²¹ the International Society for the Study of Hypertension in Pregnancy (ISSHP)²² and the International Federation of Gynecology and Obstetrics (FIGO)¹³ recommend a 150mg dose of aspirin for the prevention of preeclampsia. We have remained consistent with the 2022 national guideline²⁰ for a 100mg dose. The rationale and justification to continue to recommend 100mg dose in Aotearoa can be viewed here.

We have included additional recommendations regarding termination of pregnancy when severe preeclampsia, eclampsia and HELLP syndrome occur at gestational ages before and at the limits of survival. This is very uncommon, and many units will rarely care for wāhine/people in these situations however, as the risk of major morbidity and mortality for the wahine/person is high, we have elected to highlight consideration of termination of pregnancy and a recommendation to plan birth when survival of the pēpi is not considered possible and unlikely to be achieved within 1-2 weeks.^8,14 These recommendations are included in ISSHP guidelines (discussion of termination of pregnancy)²² and WHO guideline ‘Policy of interventionist versus expectant management of severe pre-eclampsia before term’ (recommendation to plan birth).⁸

In the recommendation on the use of uterine artery Doppler screening at 20 weeks for those meeting criteria, we have included a recommendation that uterine artery Doppler waveform measurement should be repeated at 24 weeks. This recommendation is made in the New Zealand Obstetric Ultrasound Guide.⁶

#References

1. Dimitriadis E, Rolnik DL, Zhou W, Estrada-Gutierrez G, Koga K, Francisco RPV, et al. Pre-eclampsia. Nature Reviews Disease Primers. 2023;9(1):8. DOI: 10.1038/s41572-023-00417-6.

2. Anderson NH, Sadler LC, Stewart AW, Fyfe EM, McCowan LM. Ethnicity, body mass index and risk of pre-eclampsia in a multiethnic New Zealand population. Aust N Z J Obstet Gynaecol. 2012;52(6):552-8. DOI: 10.1111/j.1479-828X.2012.01475.x.

3. Groom KM, North RA, Poppe KK, Sadler L, McCowan LM. The association between customised small for gestational age infants and pre-eclampsia or gestational hypertension varies with gestation at delivery. BJOG. 2007;114(4):478-84. DOI: 10.1111/j.1471-0528.2007.01277.x.

4. Ministry of Health. Diagnosis and Treatment of Hypertension and Pre-eclampsia in Pregnancy in New Zealand: A clinical practice guideline. Wellington: Ministry of Health; 2018. Available from: https://www.health.govt.nz/system/files/documents/publications/diagnosis-and-treatment-of-hypertension-and-pre-eclampsia-in-pregnancy-in-new-zealand-v3.pdf.

5. New Zealand College of Midwives, Royal College of Obstetricians and Gynaecologists. Guidance regarding the use of low-dose aspirin in the prevention of pre-eclampsia in high risk women 2015. Available from: https://thinkhauorawebsite.blob.core.windows.net/websitepublished/CCP/Resources/Womens Health/Early Pregnancy/Low-dose aspirin for treating pre-eclampsia 2015.pdf.

6. Ministry of Health. New Zealand Obstetric Ultrasound Guidelines. Wellington: Ministry of Health; 2019. Available from: https://www.tewhatuora.govt.nz/publications/new-zealand-obstetric-ultrasound-guidelines.

7. Lowe SA, Bowyer L, Lust K, McMahon LP, Morton MR, North RA, et al. Guideline for the Management of Hypertensive Disorders of Pregnancy: Society of Obstetric Medicine of Australia and New Zealand; 2014. Available from: https://www.somanz.org/content/uploads/2020/07/HTguidelineupdatedJune2015.pdf.

8. World Health Organisation. WHO recommendations: policy of interventionist versus expectant management of severe pre-eclampsia before term. Geneva: World Health Organisation; 2018. Available from: https://www.who.int/publications/i/item/9789241550444.

9. World Health Organisation. WHO recommendations for prevention and treatment of pre-eclampsia and eclampsia. Geneva: World Health Organisation; 2011 (updated 2021). Available from: https://apps.who.int/iris/bitstream/handle/10665/44703/9789241548335\_eng.pdf?sequence=1.

10. World Health Organisation. WHO recommendations on drug treatment for non-severe hypertension in pregnancy. Geneva: World Health Organisation; 2020. Available from: https://www.who.int/publications/i/item/9789240008793.

11. World Health Organisation. WHO recommendations: drug treatment for severe hypertension in pregnancy. Geneva: World Health Organisation; 2018. Available from: https://www.who.int/publications/i/item/9789241550437.

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14. Brown MA, Magee LA, Kenny LC, Karumanchi SA, McCarthy FP, Saito S, et al. Hypertensive Disorders of Pregnancy: ISSHP Classification, Diagnosis, and Management Recommendations for International Practice. Hypertension. 2018;72(1):24-43. DOI: 10.1161/hypertensionaha.117.10803.

15. Sotiriadis A, Hernandez-Andrade E, da Silva Costa F, Ghi T, Glanc P, Khalil A, et al. ISUOG Practice Guidelines: role of ultrasound in screening for and follow-up of pre-eclampsia. Ultrasound Obstet Gynecol. 2019;53(1):7-22. DOI: 10.1002/uog.20105.

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21. Society of Obstetric Medicine Australia and New Zealand. Hypertension in Pregnancy Guideline. 2023. Available from: https://www.somanz.org/content/uploads/2024/01/SOMANZ\_Hypertension\_in\_Pregnancy\_Guideline\_2023.pdf.

22. Magee LA, Brown MA, Hall DR, Gupte S, Hennessy A, Karumanchi SA, et al. The 2021 International Society for the Study of Hypertension in Pregnancy classification, diagnosis & management recommendations for international practice. Pregnancy Hypertens. 2021;27:148-69. DOI: 10.1016/j.preghy.2021.09.008.

23. The Royal Australian and New Zealand College of Obstetricians and Gynaecologists. Early pregnancy screening and prevention of preterm preeclampsia and related complications (C-Obs 61). 2024. Available from: https://ranzcog.edu.au/wp-content/uploads/Screening-Prevention-Preterm-PET.pdf.

24. Hunter B, Dawes L, Wadsworth M, Sadler L, Edmonds L, McAra-Couper J, et al. An evaluation of the quality, suitability and impact on equity of clinical practice guidelines relevant to preterm birth for use in Aotearoa New Zealand. BMC Pregnancy Childbirth. 2024;24(1):234. DOI: 10.1186/s12884-024-06415-0.

25. Te Whatu Ora - Health New Zealand. Maternity clinical indicator trends: Te Whatu Ora Health New Zealand. Wellington: Health New Zealand; 2022. Available from: https://tewhatuora.shinyapps.io/maternity-clinical-indicator-trends/.

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27. Johnson JD, Louis JM. Does race or ethnicity play a role in the origin, pathophysiology, and outcomes of preeclampsia? An expert review of the literature. Am J Obstet Gynecol. 2022;226(2):S876-S85. DOI: 10.1016/j.ajog.2020.07.038.

28. New Zealand Committee of the Royal Australian and New Zealand College of Obstetricians & Gynaecologists, New Zealand College of Midwives. Guidance regarding the use of low-dose aspirin in the prevention of pre-eclampsia in high-risk women. 2018.

29. New Zealand College of Midwives. Consensus Statement: Informed Consent and Decision Making. 2016. Available from: https://www.midwife.org.nz/wp-content/uploads/2019/05/Informed-Consent-and-Decision-Making.pdf.

30. Medical Council of New Zealand. Good Medical Practice. 2021. Available from: https://www.mcnz.org.nz/assets/standards/b3ad8bfba4/Good-Medical-Practice.pdf.

31. The Royal Australian and New Zealand College of Obstetricians and Gynaecologists. Consent and provision of information to patients in New Zealand regarding proposed treatment. 2019. Available from: https://ranzcog.edu.au/wp-content/uploads/Consent-Provision-Information-to-Patients-New-Zealand.pdf.

32. Te Whatu Ora - Health New Zealand. Guidelines for Consultation with Obstetric and Related Medical Services (Referral Guidelines). Wellington: Health New Zealand; 2023. Available from: https://www.tewhatuora.govt.nz/publications/guidelines-for-consultation-with-obstetric-and-related-medical-services-referral-guidelines/.

33. Tan MY, Wright D, Syngelaki A, Akolekar R, Cicero S, Janga D, et al. Comparison of diagnostic accuracy of early screening for pre-eclampsia by NICE guidelines and a method combining maternal factors and biomarkers: results of SPREE. Ultrasound Obstet Gynecol. 2018;51(6):743-50. DOI: 10.1002/uog.19039.

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35. New Zealand Maternal Fetal Medicine Network. New Zealand Obstetric Doppler Guideline. 2014. Available from: https://www.tewhatuora.govt.nz/assets/For-the-health-sector/Maternity-Services/NZMFMN-Obstetric-Doppler-Guideline-2015.pdf.

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37. Roberge S, Bujold E, Nicolaides KH. Aspirin for the prevention of preterm and term preeclampsia: systematic review and metaanalysis. Am J Obstet Gynecol. 2018;218(3):287-93.e1. DOI: 10.1016/j.ajog.2017.11.561.

38. Hofmeyr GJ, Lawrie TA, Atallah Á, Duley L, Torloni MR. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database of Systematic Reviews. 2014(6). DOI:10.1002/14651858.CD001059.pub4.

39. Wright D, Wright A, Magee LA, Von Dadelszen P, Nicolaides KH. Calcium supplementation for the prevention of pre-eclampsia: Challenging the evidence from meta-analyses. BJOG. 2024;131(11):1524-9. DOI:10.1111/1471-0528.17769.

40. Ministry of Health. Guidance for Healthy Weight Gain in Pregnancy2014. Available from: https://www.tewhatuora.govt.nz/publications/guidance-for-healthy-weight-gain-in-pregnancy.

41. Te Whatu Ora - Health New Zealand. Small for Gestational Age and Fetal Growth Restriction in Aotearoa New Zealand He Aratohu Ritenga Haumanu mō te Tōhuatanga Kōpiri me te Pakupaku Rawa. A clinical practice guideline2023. Available from: https://www.tewhatuora.govt.nz/publications/small-for-gestational-age-fetal-growth-restriction-guidelines/.

42. Magee LA, Yong PJ, Espinosa V, Côté AM, Chen I, von Dadelszen P. Expectant Management of Severe Preeclampsia Remote from Term: A Structured Systematic Review. Hypertension in Pregnancy. 2009;28(3):312-47. DOI:10.1080/10641950802601252.

43. Khong TY, Mooney EE, Ariel I, Balmus NC, Boyd TK, Brundler MA, Derricott H, Evans MJ, Faye-Petersen OM, Gillan JE, Heazell AE, Heller DS, Jacques SM, Keating S, Kelehan P, Maes A, McKay EM, Morgan TK, Nikkels PG, Parks WT, Redline RW, Scheimberg I, Schoots MH, Sebire NJ, Timmer A, Turowski G, van der Voorn JP, van Lijnschoten I, Gordijn SJ. Sampling and Definitions of Placental Lesions: Amsterdam Placental Workshop Group Consensus Statement. Arch Pathol Lab Med. 2016;140(7):698-713. DOI:10.5858/arpa.2015-0225-CC.

44. Meher S, Duley L, Hunter K, Askie L. Antiplatelet therapy before or after 16 weeks’ gestation for preventing preeclampsia: an individual participant data meta-analysis. American Journal of Obstetrics & Gynecology. 2017;216(2):121-8.e2. DOI:10.1016/j.ajog.2016.10.016.

45. 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 & Gynecology. 2017;216(2):110-20.e6. DOI:10.1016/j.ajog.2016.09.076.