Maternal disease and medication use in pregnancy

Medication use during pregnancy is common. Pregnant women may take medications for chronic conditions (such as asthma or epilepsy), as well as for acute conditions (such as an infection).

The safety of many medications for use in pregnancy is often not known at the moment that the medication is licensed because animal studies are seriously limited in their ability to predict human teratogenic effects, and pregnant women are excluded from pre-marketing clinical trials. In addition, teratogenic effects in humans cannot be predicted reliably from the class of a drug or from what is known about its pharmacology and toxicology.

Many medications are contraindicated in pregnancy or contain special warnings because they have not been sufficiently studied during pregnancy to know the possible risks. For women with chronic diseases where medication use is essential to their health and to the health of their fetus, uncertainty about medication safety particularly needs to be addressed.

Some maternal diseases increase the risk of congenital anomalies. It can often be difficult to differentiate the risk of a medication and the risk of the disease the medication is prescribed for.

EUROCAT and EUROmediCAT

EUROmediCAT is a European research consortium dedicated to improving medication safety in pregnancy. The EUROmediCAT consortium was established in 2011 as a daughter project of EUROCAT, with the aim of building a system for systematic identification of teratogenic effects of medication use in pregnancy. The EUROmediCAT Central Database consists of the 19 EUROCAT member registries who can provide data on medication use in pregnancy. In addition, EUROmediCAT performs analyses using their distributed databases including disease cohorts, population linked cohorts and electronic healthcare databases. To see information on the EUROmediCAT network access the EUROmediCAT website.

EUROCAT and ENCePP

The EUROCAT Central Registry with the University of Groningen were involved in the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) of the European Medicines Agency (EMA), an important forum for pharmacovigilance, to develop a code of conduct for scientific independence and transparency, particularly for industry funded pharmacovigilance studies.

EUROCAT and EUROmediCAT seeks to maintain the highest standards of scientific independence and transparency, in accordance with the ENCePP Code of Conduct

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What do EUROCAT and EUROmediCAT data tell us about disease and medication use during pregnancy?

Studies using EUROCAT and EUROmediCAT data have helped contribute to the scientific literature on risks and safety of maternal disease and medication use during pregnancy.

Diabetes in Pregnancy

Children of diabetic mothers have an increased incidence of congenital anomalies. EUROCAT studies have investigated the types of anomalies that are more likely to arise in pregnancies of mothers with pre-existing and gestational diabetes, such as congenital heart defects, laterality anomalies, neural tube defects, omphalocele, and renal anomalies1-3. EUROCAT data showed no increased risk of anomalies with the use of insulin analogues compared to human insulin4, and no increased risk with the use of metformin5.

Underweight and Overweight

Data from EUROCAT registries have added to the evidence that both obesity and underweight (as measured by body mass index (BMI) is associated with increased risk of congenital anomalies. EUROCAT data from Northern England and Italian registries found maternal underweight was associated with atrial septal defect, genital anomalies, urinary anomalies, and orofacial clefts while maternal overweight was associated with heart, eye, neural tube and nervous system anomalies 6,7. Data from the Northern Netherlands suggests the risk associated with maternal overweight is further increased when the mother also smokes during pregnancy8.

Zika

Zika is a virus transmitted by mosquitoes. Most people infected with Zika do not have any symptoms, but in those that do the infection is usually mild. However, Zika virus infection during pregnancy can cause microcephaly and other congenital anomalies, collectively referred to a Zika syndrome. In February 2016, the World Health Organization declared a public health emergency in relation to Zika-related microcephaly. By September 2016 EUROCAT had confirmed that it would be able to detect an outbreak of Zika in Europe resulting in similar increases in microcephaly to the magnitude observed in Brazil. The research also highlighted the need for consistent diagnostic criteria for microcephaly across Europe9.

Anti-epileptics

EUROCAT studies have added to the literature on the types of anomalies that are more likely to arise in pregnancies exposed to specific types of antiepileptics. For example, as well as the known increased risk of spina bifida with the use of Valproic acid, EUROCAT data has also found increased risks of atrial septal defect, cleft palate, hypospadias, and craniosynostosis10. Other than spina bifida, EUROCAT studies have found no additional anomalies associated with carbamazepine exposure11. No increased risk was found with the use of Lamotrigine12.

Selective Serotonin Reuptake Inhibitors (SSRIs)

SSRIs are a type of commonly used antidepressant. Examples include citalopram, fluoxetine, paroxetine, and sertraline. Several EUROCAT studies have reported associations between the use of SSRIs in the first trimester of pregnancy and an increased risk of congenital heart defects, including a dose-response relationship13-15.

Other Medications and Diseases

EUROCAT data has also contributed to the literature on several other medications and diseases including asthma medications16,17, methadone18, beta-blockers19, and more20-23. EUROCAT also frequently contributes to the literature on medication safety in pregnancy through the use of its classification system for congenital anomalies and prevalence statistics, by other international research groups.

European Signal Detection

Signal detection is the processes of identifying possible associations between medications and adverse outcomes, such as congenital anomalies. Identified signals are not evidence that the medication causes the congenital anomaly but indicate that any association should be investigated further to confirm or refute. Signal detection work may help identify possible harmful effects of medications earlier.

EUROmediCAT is continuing to work towards routine signal detection and has been investigating the best way to undertake signal detection within its datasets. Several studies using EUROmediCAT data have found signals that now require further investigation24-27.

References

 

  1. Lisowski LA, Verheijen P M, Copel J A, et. al. (2010). “Congenital heart disease in pregnancies complicated by maternal diabetes mellitus. An international clinical collaboration, literature review, and meta-analysis”. Herz, Vol 35, pp 19-26

  2. Bell R, Gliniannaia S V, Tennant P W G, et. al. (2012) “Peri-conception hyperglycaemia and nephropathy are associated with risk of congenital anomaly in women with pre-existing diabetes: a population-based cohort study”. Diabetologia.

  3. Garne E, Loane M, Dolk H, et. al. (2012) “Spectrum of congenital anomalies in pregnancies with pregestational diabetes”. Birth Defects Res A Clin Mol Teratol, Vol 94, pp 134-40

  4. Wang H, Wender-Ozegowska E, Garne E, et. al (2018) “Insulin analogues use in pregnancy among women with pregestational diabetes mellitus and the risk of congenital anomaly; a retrospective population-based cohort study”. BMJ Open, Vol 8, pp e014972

  5. Given J E, Loane M, Garne E, et. al. (2018) “Metformin exposure in first trimester of pregnancy and risk of all or specific congenital anomalies: exploratory case-control study”. BMJ, Vol 361, pp K2477

  6. Rankin J, Tennant PW, Stothard KJ, et. al. (2010) “Maternal body mass index and congenital anomaly risk: a cohort study". Int J Obes, Vol 34, pp 1371-80

  7. Mezzasalma L, Santoro M, Coi A, Perini A (2022) “Association between maternal body mass index and congenital anomalies: A case-control study in Tuscany (Italy)”. Birth Defects Res, Vol 114, pp 116-123

  8. Baardman ME, Kerstjens-Frederikse WS, Corpeleijn E, et. al. (2012) “Combined adverse effects of maternal smoking and high body mass index on heart development in offspring: evidence for interaction?” Heart, Vol 98, pp 474-9

  9. Morris JK, Rankin J, Garne E, et. al. “Prevalence of microcephaly in Europe: population based study”. BMJ, Vol 354, pp i4721

  10. Jentink J, Loane MA, Dolk H, et. al (2010). “Valproic acid monotherapy in pregnancy and major congenital malformations”. N Engl J Med, Vol 362, pp 2185-93

  11. Jentink J, Dolk H, Loane MA, et. al (2010) “Intrauterine exposure to carbamazepine and specific congenital malformations: systematic review and case-control study”. BMJ, Vol 341, pp c6581

  12. Dolk H, Wang H, Loane M, et. al. (2016) “Lamotrigine use in pregnancy and risk of orofacial cleft and other congenital anomalies”. Neurology, Vol 86, pp 1716-25

  13. Knudsen TM, Hansen AV, Garne E, Andersen AM (2014) “Increased risk of severe congenital heart defects in offspring exposed to selective serotonin-reuptake inhibitors in early pregnancy – an epidemiological study using validated EUROCAT data”. BMC Pregnancy Childbirth, Vol 14, pp 333

  14. Wemakor A, Casson K, Garne E, et. al. (2015) “Selective serotonin reuptake inhibitor antedepressant use in the first trimester of pregnancy and risk of specific congenital anomalies: a European register-based study”. Eur J Epidemiol, Vol 30, pp 1187-98

  15. Jordan S, Morris JK, Davies GI, et. al. (2016) “Selective Serotonin Reuptake Inhibitor (SSRI) Antidepressants in Pregnancy and Congenital Anomalies: Analysis of Linked Databases in Wales, Norway and Funen, Denmark". PLoS One, Vol 11, pp e0165122

  16. Garne E, Hansen AV, Morris J, et.al (2015) “Use of asthma medication during pregnancy and the risk of specific congenital anomalies: a European case-malformed control study”. J Allergy Clin Immunol, Vol 136, pp 1496-1502

  17. Garne E, Vinkel Hansen A, Morris J, et. al. (2016) “Risk of congenital anomalies after exposure to asthma medication in the first trimester of pregnancy – a cohort linkage study”. BJOG, Vol 123, pp 1609-18

  18. Cleary B, Loane M, Addor MC, et. al. (2020) “Methadone, Pierre Robin sequence and other congenital anomalies: a case-control study”. Arch Dis Child Fetal Neonatal Ed, Vol 105, pp 151-157

  19. Bergman JEH, Lutke LR, Gans ROB, et. al. (2018) “Beta-Blocker use in Pregnancy and Risk of Specific Congenital Anomalies: A European Case-Malformed Control study". Drug Saf, Vol 41, pp 415-427

  20. Leke AZ, Dolk H, Loane M, et. al. (2021) “Macrolide and lincosamide antibiotic exposure in the first trimester of pregnancy and risk of congenital anomaly: A European case-control study". Reprod Toxicol, Vol 100, pp 101-108

  21. Schurmann L, Hansen AV, Garne E. (2016) “Pregnancy outcomes after fetal exposure to antithyroid medications or levothyroxine”. Early Hum Dev, Vol 101, pp 73-7

  22. Van de Putte R, van Rooij I, Haanappel CP, et. al. (2010) “Maternal risk factors for VACTERL association: A EUROCAT case-control study”. Birth Defects Res, Vol 112, pp 688-698

  23. Given JE, Loane M, Garne E, et. al. (2017) “Gastroschisis in Europe – A Case-malformed-Control Study of Medication and Maternal Illness during Pregnancy and Risk Factors”. Paediatr Perinat Epidemiol, Vol 31, pp 549-559

  24. De Jonge L, Zestra-van de Woude PA, Bos HJ, et. al (2013) “Identifying associations between maternal medication use and birth defects using a case-population approach: an exploratory study on signal detection”. Drug Saf, Vol 36, pp 1069-78

  25. Luteijin JM, Morris J, Garne E, et. al (2016) “EUROmediCAT signal detection: a systematic method for identifying potential teratogenic medication”. Br J Clin Pharmacol, Vol 82, pp 1110-22

  26. Given, JE. Loane M, Luteijn JM, et. al (2016) “EUROmediCAT signal detection: an evaluation of selected congenital anomaly-medication associations. Br J Clin Pharmacol, Vol 82, pp 1094-109

  27. Cavadino A, Sandberg L, Ohman I, et al. (2021) “Signal detection in EUROmediCAT: Identification and Evaluation of Medication-Congenital Anomaly Associations and the Use of VigiBase as a Complementary Source of Reference”. Drug Saf, Vol 44, pp 765-785