Incidence of Adverse Drug Reactions in High-Risk Pregnancy: A Prospective Cohort Study in Obstetric Intensive Care

  • Tatiana Xavier da CostaEmail author
  • Marta Danielle de Almeida Pimenta Cunha
  • Priscilla Karilline do Vale Bezerra
  • Francine Johansson Azeredo
  • Rand Randall Martins
  • Antonio Gouveia Oliveira
Pharmacoepidemiology and Prescription



To estimate the cumulative incidence of adverse drug reactions (ADRs) in women with high-risk pregnancy hospitalized in an obstetric intensive care unit, then to describe the medicines involved and to identify major risk factors.


From June 2016 to December 2017, patients admitted to the ICU with high-risk pregnancy were considered eligible in this observational, longitudinal, prospective study. Patients were investigated daily for the occurrence of ADRs through pharmaceutical anamnesis, active search in medical records and questioning of the health team. Suspected ADRs were classified according to Naranjo’s algorithm. Written informed consent was obtained from all patients. Univariate and multivariate logistic regression were used to identify risk factors of ADR.


The study population consisted of 607 high-risk pregnancies from 851 women admitted to the ICU, of whom 244 admitted for non-obstetric conditions, with an ICU stay less than 24 h or readmitted to the ICU were excluded. The mean age was 27.0 ± 7.5 years-old, mean gestational age was 33.8 ± 6.3 weeks. ADR were observed in 165 women (27.2%). No severe ADR was observed and 29.7% were of moderate severity. The most often implicated medicine was magnesium sulphate (25.2%) with 44.5% of patients administered that substance experiencing ADRs consisting of somnolence (68.6%), absent patellar reflex (21.6%) and hypotension (9.8%). Risk factors of ADR were blood pressure (adjusted odds-ratio (aOR) 1.02), haemoglobin level (aOR 1.21) and body temperature (aOR 0.71).


ADRs affect about one third of high-risk pregnancies, mainly due to magnesium sulphate administrations. High blood pressure, lower body temperature, and high haemoglobin concentration on admission were associated with an increased risk of ADR.


High-risk pregnancy Adverse drug reactions Magnesium sulphate Intensive care 



The authors would like to thank the clinical team for assistance in data collection.

Contribution/responsibility of each author

• Conceived of or designed study and analysed data: Rand Randall Martins.

• Conceived of or designed study and analysed data: Antonio Gouveia Oliveira.

• Performed research and wrote paper: Tatiana Xavier da Costa.

• Performed research Francine Johansson Azeredo.

• Performed research: Marta Danielle de Almeida Pimenta Cunha.

• Performed research: Priscilla Karilline do Vale Bezerra.


This study was financed in part by Coordenação de Aperfeiçoamento de Pessoal de Nivel Superior – Brasil (CAPES) – Finance code 001.

Compliance with ethical standards

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee Comitê de Ética em Pesquisa do Hospital Universitário Onofre Lopes and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Stock SJE, Norman JE (2019) Medicines in pregnancy. F!000research 8:1–8. CrossRefGoogle Scholar
  2. 2.
    Daw JR, Hanley GE, Greyson DL, Morgan SG (2011) Prescription drug use during pregnancy in developed countries: a systematic review. Pharmacoepidemiol Drug Saf. 20:895–902. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Mitchell AA, Gilboa SM, Werler MM, Kelley KE, Louik C, Hernández-Díaz S (2011) Medication Use During Pregnancy, With Particular Focus On Prescription Drugs: 1976–2008. Am J Obstet Gynecol. 205:1–17. CrossRefGoogle Scholar
  4. 4.
    Lacroix I, Damase-Michel C, Lapeyre-Mestre M, Montastruc JL (2000) Prescription of drugs during pregnancy in France. The Lancet. 356:1735–1736. CrossRefGoogle Scholar
  5. 5.
    Lupattelli A, Spigset O, Twigg MJ, Zagorodnikova K, Mårdby AC, Moretti ME, Drozd M, Panchaud A, Hämeen-Anttila K, Rieutord A, Gjergja Juraski R, Odalovic M, Kennedy D, Rudolf G, Juch H, Passier A, Björnsdóttir I, Nordeng H (2014) Medication use in pregnancy: a cross-sectional, multinational web-based study. BMJ Open. 4:1–11. CrossRefGoogle Scholar
  6. 6.
    Costantine MM (2014) Physiologic and pharmacokinetic changes in pregnancy. Frontiers in Pharmacol. ;1–5.
  7. 7.
    Zieleskiewicz L, Chantry A, Duclos G, Bourgoin A, Mignon A, Deneux-Tharaux C, Marc L (2016) Intensive care and pregnancy: Epidemiology and general principles of management of obstetrics ICU patients during pregnancy. Anaesth Crit Care Pain Med. 35:S51–S57. CrossRefPubMedGoogle Scholar
  8. 8.
    Patil V, Jigajinni S, Wijayatilake DS (2015) Maternal critical care: One small step for woman, one giant leap for womankind. Curr Opin Anaesthesiol. 28:290–299. CrossRefPubMedGoogle Scholar
  9. 9.
    Zwart JJ, Dupuis JRO, Richters A, Ory F, Van Roosmalen J (2010) Obstetric intensive care unit admission: a 2-year nationwide population-based cohort study. Intensive Care Med. 36:256–263. CrossRefPubMedGoogle Scholar
  10. 10.
    Kattah AG, Garovic VD (2013) The management of hypertension in pregnancy. Adv Chronic Kidney Dis. 20:229–239. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Edwards Z, Lucas DN, Gauntlett R (2019) Is training in obstetric critical care adequate? An international comparison. International Journal of Obstetric Anesthesia. 37:96–105. CrossRefPubMedGoogle Scholar
  12. 12.
    WHO (2011) Recommendations for Prevention and treatment of pre-eclampsia and eclampsia. World Health Organization, GenevaGoogle Scholar
  13. 13.
    Smith JM, Lowe RF, Fullerton J, Currie SM, Harris L, Felker-kantor E (2013) An integrative review of the side effects related to the use of magnesium sulfate for pre-eclampsia and eclampsia management. BMC pregnancy childbirth. 5:13–34. CrossRefGoogle Scholar
  14. 14.
    Wilson MS, Ingersoll M, Meschter E, Bodea-Braescu AV, Edwards RK (2014) Evaluating the side effects of treatment for preterm labor in a center that uses high-dose magnesium sulfate. Am J Perinatol. 31:711–716. CrossRefPubMedGoogle Scholar
  15. 15.
    Omu AE, Al-Harmi J, Vedi HL, Mlechkova L, Sayed AF, Al-Ragum NS (2008) Magnesium sulfate therapy in women with pre-eclampsia and eclampsia in Kuwait. Med Princ Pract. 17:227–232. CrossRefPubMedGoogle Scholar
  16. 16.
    Bain ES, Middleton PF, Crowther CA (2013) Maternal adverse effects of different antenatal magnesium sulfate regimens for improving maternal and infant outcomes: a systematic review. BMC Pregnancy Childbirth. 13:195CrossRefGoogle Scholar
  17. 17.
    Oliveira-Filho AD, Vieira AES, Silva RC, Neves SJF, Gama TAB, Lima RV, Oliveira WR, Dias JMG (2017) Adverse drug reactions in high-risk pregnant women: A prospective study. Saudi Pharm J. 25:1073–1077. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Levy-Shiff R, Lerman M, Har-Even D, Hod M (2002) Maternal adjustment and infant outcome in medically defined high-risk pregnancy. Dev Psychol. 38:93–103. CrossRefPubMedGoogle Scholar
  19. 19.
    Schatz SN, Weber RJ (2015) Adverse drug reactions. Pharmacy Practice: 5–26Google Scholar
  20. 20.
    Naranjo CA, Busto U, Sellers MD, Sandor P, Ruiz I, Roberts EA, Janecek E, Domecq C, Greenblatt DJ (1981) A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 30:239–245. CrossRefPubMedGoogle Scholar
  21. 21.
    Lemeshow S, Teres D, Avrunin JS, Gage RW (1988) Refining intensive care unit outcome prediction by using changing probabilities of mortality. Crit Care Med 16:470–477 0090–3493/88/1965–0470$02.00/0CrossRefGoogle Scholar
  22. 22.
    Demotes-Maineard J, Canet E, Segard L (2006) Modèles de partenariats Public-Privé en France et en Europe. Therapie. 61:313–323. CrossRefGoogle Scholar
  23. 23.
    Johansen ET, Haustreis SM, Mowinckel AS, Ytrebø LM (2016) Effects of implementing a clinical pharmacist service in a mixed Norwegian ICU. Eur J Hosp Pharm. 23:197–202. CrossRefPubMedGoogle Scholar
  24. 24.
    Hart LA, Sibai BM (2013) Seizures in pregnancy : Epilepsy , eclampsia , and stroke. Seminars in Perinatology. 37:207–224. CrossRefPubMedGoogle Scholar
  25. 25.
    Sibai BM (2004) Magnesium sulfate prophylaxis in preeclampsia: Lessons learned from recent trials. Am J Obstet Gynecol. 190:1520–1526. CrossRefPubMedGoogle Scholar
  26. 26.
    Magpie Trial Follow-up Study Collaborative Group (2007) The Magpie trial: a randomised trial comparing magnesium sulfate with placebo for pre-eclampsia. Outcome for women at 2 years. BJOG 114:300–309. CrossRefGoogle Scholar
  27. 27.
    Begum R, Begum A, Johanson R, Ali MN, Akhter S (2001) A low dose (‘Dhaka’) magnesium sulfate regime for eclampsia: Clinical findings and serum magnesium levels. Acta Obstet Gynecol Scand. 80:998–1002. CrossRefPubMedGoogle Scholar
  28. 28.
    Smith JM, Lowe RF, Fullerton J, Currie SM, Harris L, Felker-Kantor E (2013) An integrative review of the side effects related to the use of magnesium sulfate for pre-eclampsia and eclampsia management. BMC Pregnancy Childbirth. 13:1–11. CrossRefGoogle Scholar
  29. 29.
    Mol BWJ, Roberts CT, Thangaratinam S, Magee LA, de Groot CJM, Hofmeyr GJ (2016) Pre-eclampsia. Lancet. 387:999–1011. CrossRefPubMedGoogle Scholar
  30. 30.
    Okusanya BO, Oladapo OT, Long Q, Lumbiganon P, Carroli G, Qureshi Z, Duley L, Souza JP, Gulmezoglu AM (2016) Clinical pharmacokinetic properties of magnesium sulfate in women with pre-eclampsia and eclampsia. BJOG. 123:356–366. CrossRefPubMedGoogle Scholar
  31. 31.
    Beloosesky R, Khatib N, Ginsberg Y, Anabosy S, Shalom-paz E, Dahis M, Ross MG, Weiner Z (2016) Maternal magnesium sulfate fetal neuroprotective effects to the fetus : inhibition of neuronal nitric oxide synthase and nuclear factor kappa-light-chain-enhancer of activated B cells activation in a rodent model. Am J Obstet Gynecol 125:1–6. CrossRefGoogle Scholar
  32. 32.
    Brookfield KF, Elkomy M, Su F, Drover DR, Carvalho B (2017) Optimization of Maternal Magnesium Sulfate Administration for Fetal Neuroprotection: Application of a Prospectively Constructed Pharmacokinetic Model to the BEAM Cohort. J Clin Pharmacol. 57:1419–1424. CrossRefPubMedGoogle Scholar
  33. 33.
    Gano D, Ho MR, Patridge JC, Glass HC, Xu D, Barkovich AJ, Ferriero DM (2016) Antenatal exposure to magnesium sulfate is associated with reduced cerebellar hemorrhags in preterm newborns. J Pediatr. 178:68–74. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Vilchez G, Dai J, Lagos M, Sokol RJ (2017) Maternal side effects & fetal neuroprotection according to body mass index after magnesium sulfate in a multicenter randomized controlled trial. J Maternal-Fetal Neonatal Med 31:178–183. CrossRefGoogle Scholar
  35. 35.
    Usman S, Foo L, Tay J, Bennett PR, Lees C (2017) Use of magnesium sulfate in preterm deliveries for neuroprotection of the neonate 19; 21–28. CrossRefGoogle Scholar
  36. 36.
    Chuan FS, Charles BG, Boyle RK, Rasiah L (2001) Population pharmacokinetics of magnesium in preeclampsia. Am J Obstet Gynecol.:593–599. CrossRefGoogle Scholar
  37. 37.
    Chaiworapongsa T, Chaemsaithong P, Korzeniewski SJ, Yeo L, Romero R (2014) Pre-eclampsia part 2: prediction, preventions and management. Nat Rev Nephrol 10:531–540. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Zuspan F (1966). Treatment of severe preeclampsia and eclampsia. Publishing in Clinical Obstetrics and gynecology. Acess in 22 jul 2019
  39. 39.
    Leape LL, Cullen DJ, Clapp MD, Burdick E, Demonaco HJ, Erikson JI, Bates WB (1999) Pharmacist participation on physician ward rounds and adverse drug events in intensive care unit. J Am Med Assoc. 282:267–270. CrossRefGoogle Scholar
  40. 40.
    Tedoldi CL, Freire CMV (2009) Diretriz da Sociedade Brasileira de Cardiologia para Gravidez na Mulher Portadora de Cardiopatia. Arq Bras Cardiol. 93:e110–e178. CrossRefGoogle Scholar
  41. 41.
    Aali BS, Khazaeli P, Ghasemi F (2007) Ionized and total magnesium concentration in patients with severe preeclampsia-eclampsia undergoing magnesium sulfate therapy. J. Obstet. Gynaecol. Res. 33:138–143. CrossRefPubMedGoogle Scholar
  42. 42.
    Rodis JF, Vintzileos AM, Campbell WA, Deaton JL, Nochimson DJ (1987) Maternal hypothermia: An unusual complication of magnesium sulfate therapy. Am J Obstet Gynecol. 156:435–436. CrossRefPubMedGoogle Scholar
  43. 43.
    Crozier TM, Wallace EM (2011) Obstetric admissions to an integrated general intensive care unit in a quaternary maternity facility. Austral New Zealand J Obstet Gynaecol 51:233–238. CrossRefGoogle Scholar
  44. 44.
    Al-Suleiman AS, Qutub HO, Rahman J, Rahman MS (2006) Obstetric admissions to the intensive care unit: a 12-year review. Arch Gynecol Obstet. 274:4–8. CrossRefPubMedGoogle Scholar
  45. 45.
    Kam EPY, Eslick GD, McLean AS (2004) Obstetric critical care admissions: a 10-year retrospective review in an intensive care unit. Anaesthesia Intens Care. 32(1):137–138Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Tatiana Xavier da Costa
    • 1
    • 2
    • 3
    Email author
  • Marta Danielle de Almeida Pimenta Cunha
    • 1
    • 2
  • Priscilla Karilline do Vale Bezerra
    • 1
  • Francine Johansson Azeredo
    • 4
  • Rand Randall Martins
    • 5
  • Antonio Gouveia Oliveira
    • 5
  1. 1.Postgraduate Program in Pharmaceutical Sciences, Centro de Ciências da SaúdeUniversidade Federal do Rio Grande do NorteNatalBrazil
  2. 2.Maternity School Januário Cicco, Centro de Ciências da SaúdeUniversidade Federal do Rio Grande do NorteNatalBrazil
  3. 3.Faculdade de Farmácia, Centro de Ciências da SaúdeUniversidade Federal do Rio Grande do NorteNatalBrazil
  4. 4.Department of Pharmacy, Faculdade de FarmáciaUniversidade Federal da BahiaSalvadorBrazil
  5. 5.Department of Pharmacy, Centro de Ciências da SaúdeUniversidade Federal do Rio Grande do NorteNatalBrazil

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