+ (234) 703 809 0032

info@pipsickletrial.com

Follow Us on Social:

The Presentation

Low dose aspirin for preventing intrauterine growth restriction and preeclampsia in sickle cell pregnancy (PIPSICKLE): a randomised controlled trial

About

This is the first randomised controlled trial of its kind to be carried out in women with sickle cell disorder.

We will be working with a skilled and qualified team of doctors and nurses who will be the site coordinators across selected study sites in Lagos state.

Nigeria has the highest number of people living with sickle cell disease (SCD) in the world, amounting to 2-3% of the population. SCD is a debilitating illness and in the past, very few people with the condition survived till adulthood. In the past 60 years, with improved care, more people have been surviving. Over 50% of females with SCD now achieve pregnancy due to this increased survival but they have a high incidence of complications during pregnancy including hypertensive disease called preeclampsia, growth restriction of their babies, severe illness that almost results in death (which we call near miss), and actual deaths of the women and their babies during pregnancy and delivery. There clinical course is also variable and although most women have complications, some women have fewer than others and a very small percentage actually have no problems during pregnancy and delivery.

 

My team and I have done a lot of work in this area, including a major doctoral thesis. During these studies, we found an abnormality in the ratio of certain hormones or chemicals in the body of these women, known as prostacyclin-thromboxane ratio. This same situation has been found in non-sickle pregnancies with preeclampsia and unexplained IUGR but we were the first to report it in sickle cell pregnancy+.

 

Aspirin was originally conceived as a painkiller but in a lower dose, it has been found to be very useful in many clinical conditions when taken daily e.g. for stroke and heart disease. Over the last 25-30 years, it has also been found useful in pregnancy – to prevent IUGR and preeclampsia due to its correction of the reversed prostacyclin thromboxane ratio,

 

Aspirin is safe in pregnancy and is recommended in many guidelines for this use – this here is the guideline of the National Institute for Health and Care Excellence in the UK for the Management of Hypertension in Pregnancy and aspirin is being advocated.

 

See the NICE guideline on antenatal care for advice on risk factors and symptoms of pre-eclampsia. [2010, amended 2019]

Anti-platelet Agents

1.1.2.
Advise pregnant women at high risk of pre-eclampsia to take 75-150 mg of aspirin daily from 12 weeks until birth of the baby. Women at high risk are those with any of the following:

  • Hypertensive disease during a previous pregnancy
  • Chronic kidney disease
  • Auto immune disease such as systemic lupus erythematosus  or antiphospholipid syndrome
  • Type 1 or Type 2 diabetes
  • Chronic hypertension [2010, amended 2019]

 

1.1.3
Advise pregnant women with more than 1 moderate risk factor for pre-eclampsia to take 75-150 mg of aspirin daily from 12 weeks until birth of the baby. Factors indication moderate risk are:

  • First Pregnancy
  • Age 40 years or older
  • Pregnancy interval of more than 10 years
  • Body mass index (BMI) of 35kg/m or more at first visit
  • Family history of pre-eclampsia
  • Multi-fetal pregnancy [2010, amended 2019]

 

Severity and Variability of Sickle Cell Pregnancy

MOTHER

  • crises, urinary and respiratory infectons, malaria
  • Generally increased morbidity and mortality.

FETUS

  • Prematurity
  • Intra-uterine growth restriction
  • Increased perinatal mortality

There is a great deal of variability in their clinical course. Also many near miss events in the mothers.

Expected Outcomes and Impact

Potential to save maternal and newborn lives – SDG3

Early warning, risk reduction & management of sickle cell pregnancy

Promote capacity building of health workers - SDG 4

Reduce deaths thus improve economy - SDG 8

International collaboration from published research SDG-17 (improving global partnerships)

To determine whether daily administration of 100mg LDA reduces the risk of IUGR, preeclampsia, perinatal deaths or miscarriages and other complications in pregnant sickle cell women compared with the use of placebo

Specific Objectives

  1. To determine the effect of the use of LDA during pregnancy in HbSS and HbSC women on the risk of intrauterine growth restriction (IUGR), perinatal death or miscarriage.
  2. To determine the effect of the use of LDA during pregnancy in HbSS and HbSC women on the risk of other maternal complications including preeclampsia, preterm delivery, number of vaso-occlusive crises, need for blood transfusion, urinary tract infections, respiratory tract infections, acute chest syndrome, retained placenta, placental abruption and vaginal bleeding.
  3. To collect data in order to develop a predictive model for severe maternal outcomes using machine learning which will be used to build a mobile phone application in future.
  4. To build capacity in conducting Randomized Controlled Clinical Trials especially for the junior faculties who will be involved in the research.
A multi-centre parallel, double blind, superiority randomized controlled trial, in 15 study sites
Primary and secondary outcomes will be analysed by intention to treat using STATA statistical software

METHODOLOGY

Statistics: Sample size

476 women in total would be required to have a 90% power of detecting a decrease in IUGR at the 5% significance level (assuming incidence of IUGR of 20% in SCD (35) and expecting a 50% IUGR reduction with the use of LDA as detected by Bujold et al (36))

ETHICAL CONSIDERATIONS

  • Registered in PACTR
  • Has ethical approval from LUTH
  • Participants’ consent  prior to recruitment
  • The personal data of each participant will be kept strictly confidential
  • None of the women will be made to pay for any aspect of the study
  • Aspirin is safe in pregnancy and in sickle cell; low dose of 100mg, about 1/3 or normal dose
  • Participants will enjoy equal rights and quality care all through the duration of the research

Presentation at conferences

Publication in high impact peer reviewed journals

Development of standard operating care manuals for sickle cell pregnancy

Pertinent References

    1. Afolabi B. Plasma volume in normal and sickle cell pregnancy. United Kingdom: University of Nottingham; 2011.
    2. Afolabi B. Plasma volume in normal and sickle cell pregnancy. United Kingdom: University of Nottingham; 2011.
    3. Afolabi BB, Iwuala NC, Iwuala IC, Ogedengbe OK. Morbidity and mortality in sickle cell pregnancies in Lagos, Nigeria: a case control study. J Obstet Gynaecol. 2009;29(2):104-6.
    4. Afolabi BB, Iwuala NC, Iwuala IC, Ogedengbe OK. Morbidity and mortality in sickle cell pregnancies in Lagos, Nigeria: a case control study. J Obstet Gynaecol. 2009;29(2):104-6.
    5. Afolabi BB, Oladipo OO, Akanmu AS, Abudu OO, Sofola OA, Broughton Pipkin F. Volume regulatory hormones and plasma volume in pregnant women with sickle cell disorder. J Renin Angiotensin Aldosterone Syst. 2016;17(3).
    6. Afolabi BB, Oladipo OO, Akanmu AS, Abudu OO, Sofola OA, Broughton Pipkin F. Volume regulatory hormones and plasma volume in pregnant women with sickle cell disorder. J Renin Angiotensin Aldosterone Syst. 2016;17(3).
    7. Ahrens KA, Silver RM, Mumford SL, Sjaarda LA, Perkins NJ, Wactawski-Wende J, et al. Complications and Safety of Preconception Low-Dose Aspirin Among Women With Prior Pregnancy Losses. Obstet Gynecol. 2016;127(4):689-98.
    8. Ajibola SO, Adeyemo TA, Afolabi BB, Akanmu AS (2016). Utility of a single mid-trimester measurement of plasminogen activator Type 1 and fibronectin to predict preeclampsia in pregnancy. Niger Med J. 57(4):213-6.
    9. Al Jama FE, Gasem T, Burshaid S, Rahman J, Al Suleiman SA, Rahman MS. Pregnancy outcome in patients with homozygous sickle cell disease in a university hospital, Eastern Saudi Arabia. Arch Gynecol Obstet. 2009;280(5):793-7.
    10. Al-Farsi SH, Al-Riyami NM, Al-Khabori MK, Al-Hunaini MN. Maternal complications and the association with baseline variables in pregnant women with sickle cell disease. Hemoglobin. 2013;37(3):219-26. doi: 10.3109/03630269.2013.780249. Epub 2013 Apr 17.
    11. Babah OA, Aderolu MB, Oluwole AA, Afolabi BB. Towards zero mortality in sickle cell pregnancy: a prospective study comparing Haemoglobin SS and AA women in Lagos, Nigeria. Nigerian Postgrad Med J. 2019;26:1-7.
    12. Babah OA, Aderolu MB, Oluwole AA, Afolabi BB. Towards zero mortality in sickle cell pregnancy: a prospective study comparing Haemoglobin SS and AA women in Lagos, Nigeria. Nigerian Postgrad Med J. 2019;26:1-7.
    13. Boafor TK, Olayemi E, Galadanci N, Hayfron-Benjamin C, Dei-Adomakoh Y, Segbefia C, et al. Pregnancy outcomes in women with sickle-cell disease in low and high income countries: a systematic review and meta-analysis. BJOG. 2016;123(5):691-8.
    14. Brown MA, Lindheimer MD, de Swiet M, Assche AV, Moutquin J-M. The classification and diagnosis of the hypertensive disorders of pregnancy: statement from the international society for the study of hypertension in pregnancy (ISSHP). Hypertens Pregnancy 2001;20(1):ix–xiv.
    15. 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. Obstet Gynecol. 2010;116(2 Pt 1):402-14.
    16. Capone ML, Tacconelli S, Sciulli MG, Grana M, Ricciotti E, Minuz P, et al. Clinical pharmacology of platelet, monocyte, and vascular cyclooxygenase inhibition by naproxen and low-dose aspirin in healthy subjects. Circulation. 2004;109(12):1468-71.
    17. Chakravorty S, Williams TN. Sickle cell disease: a neglected chronic disease of increasing global health importance. Arch Dis Child. 2015;100(1):48-53.
    18. Duley L, Henderson-Smart DJ, Meher S, King JF. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database of Systematic Reviews. 2007.
    19. Ellis RJ, Wang Z, Genes N, Ma’ayan A. Predicting opioid dependence from electronic health records with machine learning. BioData Min. 2019 Jan 29;12:3.doi: 10.1186/s13040-019-0193-0. eCollection 2019.
    20. Henderson JT, Whitlock EP, O’Connor E, Senger CA, Thompson JH, Rowland MG. Low-dose aspirin for prevention of morbidity and mortality from preeclampsia: a systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2014;160(10):695-703.
    21. Jhee JH, Lee S, Park Y, Lee SE, Kim YA, Kang SW, Kwon JY, Park JT. Prediction  model development of late-onset preeclampsia using machine learning-based methods. PLoS One. 2019 Aug 23;14(8):e0221202. doi: 10.1371/journal.pone.0221202.
    22. Lewis DF, Canzoneri BJ, Gu Y, Zhao S, Wang Y. Maternal levels of prostacyclin, thromboxane, ICAM, and VCAM in normal and preeclamptic pregnancies. Am J Reprod Immunol. 2010;64(6):376-83.
    23. Mone F, Mulcahy C, McParland P, McAuliffe FM. Should we recommend universal aspirin for all pregnant women? Am J Obstet Gynecol. 2017;216(2):141 e1- e5.
    24. Moore GS, Allshouse AA, Post AL, Galan HL, Heyborne KD. Early initiation of low-dose aspirin for reduction in preeclampsia risk in high-risk women: a secondary analysis of the MFMU High-Risk Aspirin Study. J Perinatol. 2015;35(5):328-31.
    25. NICE. Hypertension in pregnancy: the management of hypertensive disorders during pregnancy. National Institute for Health and Clinical Excellence Clinical Guideline. 2010;107:1-47.
    26.  Nwabuko OC, Okoh DA, Iyalla C, Omunakwe H. Prevalence of sickle cell disease among pregnant women in a tertiary health center in south-south Nigeria. Sub-Saharan Afr J Med. 2016; 3:132-6.
    27. Obilade OA, Akanmu AS, Broughton Pipkin F, Afolabi BB. Prostacyclin, thromboxane and glomerular filtration rate are abnormal in sickle cell pregnancy. PLoS One. 2017;12(9):e0184345
    28. Obilade OA, Akanmu AS, Broughton Pipkin F, Afolabi BB. Prostacyclin, thromboxane and glomerular filtration rate are abnormal in sickle cell pregnancy. PLoS One. 2017;12(9):e0184345.
    29. Olugbenga AO. Managing sickle cell disease in pregnancy, the success and the challenges: Our experience in a semi-urban tertiary health-care facility, Southwest, Nigeria. Trop J Obstet Gynaecol 2018; 35:342-7.
    30. Oteng-Ntim E, Ayensah B, Knight M, Howard J. Pregnancy outcome in patients with sickle cell disease in the UK-a national cohort study comparing sickle cell anaemia (HbSS) with HbSC disease. Br J Haematol. 2015;169(1):129-37.
    31. RCOG. Management of Sickle Cell Disease in Pregnancy. Royal College of Obstetricians and Gynaecologists Green-top Guideline. 2011:1-20.
    32. Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet. 2010;376(9757):2018-31.
    33. Resende Cardoso PS, Lopes Pessoa de Aguiar RA, Viana MB. Clinical complications in pregnant women with sickle cell disease: prospective study of factors predicting maternal death or near miss. Rev Bras Hematol Hemoter. 2014 Jul-Aug;36(4):256-63. doi: 10.1016/j.bjhh.2014.05.007.
    34. 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. N Engl J Med. 2017;377(7):613-22.
    35. Say L, Souza JP, Pattinson RC (2009) Maternal near miss–towards a standard tool for monitoring quality of maternal health care. Best Pract Res Clin Obstet Gynaecol 23: 287–296.
    36. Sealed Envelope Ltd. Power calculator for binary outcome equivalence trial. [Online]. 2012. Available from: https://www.sealedenvelope.com/power/binary-equivalence
    37. Tohgi H, Konno S, Tamura K, Kimura B, Kawano K. Effects of low-to-high doses of aspirin on platelet aggregability and metabolites of thromboxane A2 and prostacyclin. Stroke. 1992;23(10):1400-3.
    38. United Nations, Department of Economic and Social Affairs, Population Division (2018). World Urbanization Prospects: The 2018 Revision, Online Edition. https://population.un.org/wup/Download/
    39. Villers MS, Jamison MG, De Castro LM, James AH. Morbidity associated with sickle cell disease in pregnancy. Am J Obstet Gynecol. 2008;199(2):125 e1-5.
    40. WHO. Sickle-cell Anaemia Report by the Secretariat. World Health Organisation. Fifty-ninth World Health Assembly; 2006a. Report No.: A59/9 Contract No.: Provisional agenda item 11.4.
    41. Xu TT, Zhou F, Deng CY, Huang GQ, Li JK, Wang XD. Low-Dose Aspirin for Preventing Preeclampsia and Its Complications: A Meta-Analysis. J Clin Hypertens (Greenwich). 2015;17(7):567-73.
    42. Yang F, Banerjee T, Narine K, Shah N. Improving Pain Management in Patients with Sickle Cell Disease from Physiological Measures Using Machine Learning Techniques. Smart Health (Amst). 2018 Jun;7-8:48-59. doi:10.1016/j.smhl.2018.01.002. Epub 2018 Feb 2.
    43. Yawn BP, Buchanan GR, Afenyi-Annan AN, Ballas SK, Hassell KL, James AH, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014;312(10):1033-48.

Thanks for Reading

Click the button to see what we have on Recruitment