Oral Contraceptives and Neutropenia: A Population-Based Cohort Study

  • Yael Shalev Rosenthal
  • Gabi Chodick
  • Adam Rosenthal
  • Varda Shalev
  • Hila Shalev Ram
  • Gideon KorenEmail author
Original Research Article



Oral contraceptives (OCs) are one of the most commonly used classes of drugs worldwide. A case of neutropenia and associated infections in a young woman using OCs that settled after discontinuation and reappeared upon re-challenge, has led us to investigate a potential association between oral contraceptives and neutropenia.


To compare rates of neutropenia among women receiving OCs to a matched control group of women not exposed to the “pill”.

Patients and Methods

In this population-based cohort study we used a large computerized database of a health fund, comparing women prescribed OCs and a control group not using the pill. We selected a cohort of 51,394 OC users aged 16–40 years who purchased their first monthly pack of OCs between 2010 and 2018. Controls included all non-pregnant women aged 16–40 years for whom OC was not dispensed (n = 140,932). Neutrophil count before and during OC were compared.


Prior to OC exposure, 1.3% of the women were neutropenic, compared to 1.6% after exposure to OC (RR 1.22; 95% CI 1.1–1.35). Mean neutrophil count changed from 3.87 × 103 to 3.82 × 103 mm3 (p < 0.001). In the control group (n = 140,932) no difference was seen in the proportion of neutropenic women between the first complete blood count (1.7%) compared to the second (1.8%) count (p = 0.305). In all severity levels, neutropenia was significantly more common in the OC group. The relative risk was higher for severe (RR 1.63) than for mild neutropenia (RR 1.13) (p = 0.034 for trend).


There is a significant increase in the proportion of neutropenic women after initiating OCs. More research is needed in order to evaluate the effect of neutropenia in this group of women.


Authors Contributions

YR conceptualized the research, conducted the research and wrote the first draft of the paper. GC participated in overseeing the research, AR and HSR participated in data analysis, VS participated in critical appraisal, GK oversaw all stages of the research

Compliance with Ethical Standards

Ethical approval

The study was approved by Assuta Hospital Research Ethics Committee, Tel Aviv.


No sources of funding were used to conduct this research.

Conflict of interest

Yael Rosenthal, Gabi Chodick, Adam Rosenthal,Varda Shalev, Hila Shalev Ram and Gideon Koren have no potential conflicts of interest to report.

Data Availability

Anonymous data will be shared upon reasonable request from a qualified investigator, pending approval from Maccabi Health Services and the Assuta Research Ethics Committee.

Informed Consent

As this study is based on anonymous data, the ethics committee waived informed consent.


  1. 1.
    Mosher WD, Jones J. Use of contraception in the United States: 1982–2008. Vital and health statistics. Series 23, Data from the National Survey of Family Growth. 2010 Aug(29):1–44.Google Scholar
  2. 2.
    Lidegaard Ø, Løkkegaard E, Svendsen AL, Agger C. Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ. 2009;13(339):b2890.CrossRefGoogle Scholar
  3. 3.
    Vinogradova Y, Coupland C, Hippisley-Cox J. Use of combined oral contraceptives and risk of venous thromboembolism: nested case–control studies using the QResearch and CPRD databases. BMJ. 2015;26(350):h2135.CrossRefGoogle Scholar
  4. 4.
    de Bastos M, Stegeman BH, Rosendaal FR, Vlieg AV, Helmerhorst FM, Stijnen T, Dekkers OM. Combined oral contraceptives: venous thrombosis. Cochrane Database Syst Rev. 2014;2014:3.Google Scholar
  5. 5.
    van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP, Doggen CJ, Rosendaal FR. The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case–control study. BMJ. 2009;13(339):b2921.Google Scholar
  6. 6.
    Stampfer MJ, Willett WC, Colditz GA, Speizer FE, Hennekens CH. A prospective study of past use of oral contraceptive agents and risk of cardiovascular diseases. N Engl J Med. 1988;319(20):1313–7.CrossRefGoogle Scholar
  7. 7.
    Curtis KM. US medical eligibility criteria for contraceptive use, 2016. MMWR. Recommend Rep. 2016;2016:65.Google Scholar
  8. 8.
    Centers for Disease Control and Prevention. The United States Medical Eligibility Criteria for Contraceptive Use, 2016 (US MEC).Google Scholar
  9. 9.
    Jaisamrarn U, Santibenchakul S. A comparison of combined oral contraceptives containing chlormadinone acetate versus drospirenone for the treatment of acne and dysmenorrhea: a randomized trial. Contracept Reprod Med. 2018;3:5. (eCollection 2018).CrossRefGoogle Scholar
  10. 10.
    Alvir JM, Lieberman JA, Safferman AZ, Schwimmer JL, Schaaf JA. Clozapine-induced agranulocytosis–incidence and risk factors in the United States. New Engl J Med. 1993;329(3):162–7.CrossRefGoogle Scholar
  11. 11.
    Yunis JJ, Lieberman J, Yunis EJ. Major histocompatibility complex associations with clozapine-induced agranulocytosis. Drug Saf. 1992;7(1):7–9.CrossRefGoogle Scholar
  12. 12.
    van der Klauw MM, Goudsmit R, Halie MR, van’t Veer MB, Herings RM, Wilson JP, Stricker BH. A population-based case-cohort study of drug-associated agranulocytosis. Arch Int Med. 1999;159(4):369–74.CrossRefGoogle Scholar
  13. 13.
    Casato M, Pucillo LP, Leoni M, di Lullo L, Gabrielli A, Sansonno D, Dammacco F, Danieli G, Bonomo L. Granulocytopenia after combined therapy with interferon and angiotensin-converting enzyme inhibitors: evidence for a synergistic hematologic toxicity. Am J Med. 1995.Google Scholar
  14. 14.
    Giraldo E, Hinchado MD, Garcia JJ, Ortega E. Influence of gender and oral contraceptives intake on innate and inflammatory response. Role of neuroendocrine factors. Mol Cel Biochem. 2008;313(1–2):147.CrossRefGoogle Scholar
  15. 15.
    Spinillo A, Capuzzo E, Nicola S, Baltaro F, Ferrari A, Monaco A. The impact of oral contraception on Vulvovaginal candidiasis. Contraception. 1995;51(5):293–7.CrossRefGoogle Scholar
  16. 16.
    Schmidt A, Nöldechen CF, Mendling W, Hatzmann W, Wolff MH. Oral contraceptive use and vaginal candida colonization. Zentralbl Gynakol. 1997;119(11):545–9.Google Scholar
  17. 17.
    Goldshtein I, Shalev V, Zigman N, Chodick G, Levkovitch-Verbin H. The Maccabi Glaucoma Study: treatment patterns and persistence with glaucoma therapy in a large Israeli health maintenance organization. J Glaucoma. 2016;25(4):e386–91.CrossRefGoogle Scholar
  18. 18.
    Boxer LA. How to approach neutropenia. ASH Educ Program Book. 2012;2012(1):174–82.Google Scholar
  19. 19.
    Nieuweboer AJ, Smid M, de Graan AM, et al. Role of genetic variation in docetaxel-induced neutropenia and pharmacokinetics. Pharmacogenom J. 2016;16(6):519–24.CrossRefGoogle Scholar
  20. 20.
    Chowdhury NI, Remington G, Kennedy JL. Genetics of antipsychotic-induced side effects and agranulocytosis. Curr Psychiatry Rep. 2011;13(2):156–65.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Maccabi-Kahn Institute of Research and InnovationTel AvivIsrael
  2. 2.Sackler School of MedicineTel Aviv UniversityTel AvivIsrael
  3. 3.Adelson Faculty of MedicineAriel UniversityArielIsrael

Personalised recommendations