U N I V E R S I T Ä T S M E D I Z I N B E R L I N

Herbal medicines in pregnancy – pharmacovigilance and risk communication

Dr. med. Wayan Philipps wayan.philipps@charite.de

Pharmakovigilanzzentrum

Embryonaltoxikologie, Institut für klinische Pharmakologie und

Toxikologie, Charité- Universitätsmedizin Berlin

PVZ Embryotox I

Publicly funded institution since 1988

Provides independent information to the safety and tolerance of drugs during pregnancy and lactation to healthcare professionals and pregnant women

Individual consultations are available drawing on the results from the institute‘s own database and other working groups

Multidisciplinary team, i.e. obstetrics/gynaecology, paediatrics, pharmacology,

human genetics, internal medicine, anaesthesiology

• Regularly updated information is also available via the open access database

www.embryotox.de covering 400 drugs

PVZ Embryotox II

PVZ Embryotox III

The aim is to provide a better evidence for medical safety through

• Identification of adverse drug reaction

• Transmission to responsible federal authorities

• Detection of signals • Conducting cohort studies or case control studies

→ To prevent prenatal development disorders → To reduce unnecessary invasive diagnostic and terminations of wanted

pregnancies due to overestimation of a risk of exposure to drugs

Embryotox: consultation combined with pregnancy outcome documentation

Embryotox data ascertainment from consultation to pregnancy follow-up

Risk communication

1. Recommendation on drugs of choice for a particular disease

2. A woman has already taken a suspect drug during pregancy (teratogen? Like MTX, thalidomide, valproate, tretinoin)

3. A baby is born with a birth defect suspected to be caused by a drug

%

chromosomal 16 - 25

intrauterine factors

2

Medicinal drugs, drugs of abuse, environmental pollution, hyperthermia, radioactivity

2 - 4

Maternal diseases

2 - 4

unknown, multifactorial ca. 60 Wilson JD. Embryotoxicity of drugs to man. In: JD Wilson, FC Frazer (eds), Handbook of Teratology, Vol. 1. New York: Plenum Press, 1977, pp. 309–55.

Causes of congenital malformations

Mean risk for major malformation: 3-5%

• 11.814 regarding an ongoing pregnancy (maternal exposure): 725 herbal medicines → 6% • most frequently used: Valerian, St. John´s Wort, Ivy, Thyme, Ginger, Cranberry

Use of Herbal medicinal products (HMP) regarding ongoing pregnancies PVZ Embryotox

• In Nigeria, Fekeye et al. recovered 67.5% of herbal medicine use among

pregnant women1

• German survey2 of 139 pregnant women, 96% took CAM (especially

phytotherapeutics) • The prevalence of HMP use during pregnancy in Middle East countries

ranges between 22-75%3,4

• American study5: 35.8% of 2673 women used also at least one form of CAM

Popularity of HMP in pregnancy

1 Fakeye et al., 2009 Attitude and use of herbal medicines among pregnant women in Nigeria. BMC Complement Altern Med. 2009 Dec 31;9:53. 2 Gut E, Melzer J, von Mandach U, et al. 2004 Natural remedies during pregnancy and lactation. Gynakol Geburtshilfliche Rundsch. 2004 Oct;44(4):233-7 3 Al-Ramahi, R., N. Jaradat, and D. Adawi, Use of herbal medicines during pregnancy in a group of Palestinian women. J Ethnopharmacol, 2013. 150(1): p. 79-84. 4 Sattari, M., et al., Self-reported Use and Attitudes Regarding Herbal Medicine Safety During Pregnancy in Iran. Jundishapur J Nat Pharm Prod, 2012. 7(2): p. 45-9. 5 Harrigan J.T, 2011 Patient disclosure of the use of complementary and alternative medicine to their obstetrician/gynaecologist. Journal of Obstetrics and Gynaecology, 31(1): 59–61

→ only 51.8% of these women had discussed it with their physician

Reasons for preference of HMP during pregnancy − Natural = safe1

− Desire for more „natural“ alternatives2 − To treat illnesses but also to enhance nutrition, to stay healthy3

− Studies4,5 have shown that HMP in pregnacy are most often used for ▪ Nausea and Vomiting ▪ Common Cold ▪ Anxiety ▪ Urinary tract problems ▪ Constipation ▪ Backpain ▪ Induction/ease of labour ➢ advice from midwives or family and friends 1 Adams C, Cannell S. Women’s beliefs about “natural” hormones and natural hormone replacement therapy. Menopause 2001;8:433–440 2 Kennedy et al. Safety classification of herbal medicines used in pregnancy in a multinational study 2016. BMC Complementary and Alternative Medicine 16:10 3 Bishop JL, Northstone JR, Green JR, Thompson EA The use of Complementary and Alternative Medicine in pregnancy: Data from the Avon Longitudinal Study of Parents and Children

(ALSPAC) Complementary Therapies in Medicine Volume 19, Issue 6, December 2011, Pages 303-310 4 Ranzini, A. Allen, Y. Use of complementary medicines and therapies among obstetric patients Obstetrics & Gynecology, Suppl. 4 (2001), p. pS4 5 Skouteris, Wertheim E.H., S. Rallis, S.J. Paxton, L. Kelly, J. Milgrom. Use of complementary and alternative medicines by a sample of Australian women during pregnancy Australian & New

Zealand Journal of Obstetrics & Gynaecology, 48 (2008), pp. 384-390

Objections concerning the use of HMP in pregnancy Little information about the possible risks in pregnancy

Limited standards for the preparation/ amounts of specific ingredients in

the products marketed1

May contain contaminants from the agricultural or manufacturing processes2

Certain herbs can affect the muscle tone of the uterus, abortifacients or

teratogens3

→ natural ≠ safe 1 Izzo, A.A., et al., A Critical Approach to Evaluating Clinical Efficacy, Adverse Events and Drug Interactions of Herbal Remedies. Phytother Res, 2016. 30(5): p. 691-70 2 Posadzki, P., L. Watson, and E. Ernst, Contamination and adulteration of herbal medicinal products (HMPs): an overview of systematic reviews. Eur J Clin Pharmacol, 2013. 69(3): p. 295-307. 3 Low Dog, T., The use of botanicals during pregnancy and lactation. Altern Ther Health Med, 2009. 15(1): p. 54-8.

Studies on HMP during pregnancy • 14 randomized controlled trials (RCT) related to herb efficacy in pregnancy1

→ Evaluating 5 different herbal medicines (Ginger, Cranberry, St. John´s wort, Rasberry and Garlic) → With the exception of ginger, no data support the use of any herbal supplement during pregnancy

• 9 RCTs2, very few or no additional side effects compared with placebo were observed for herbal remedies

• Norwegian study3: 39 % used possibly harmful herbal medicinal products or herbs, where information about safety in pregnancy was missing

• Multinational cross-sectional study4: Recommendation to take a contraindicated herbal medicine was 3times more likely to be from a health care professional than an informal source

1 Dante G, Pedrielli G, Annessi E, Facchinetti F. Herb remedies during pregnancy: a systematic review of controlled clinical trials. J Matern Fetal Neonatal Med 2013. 26: 306–12

2 Holst L, Wright D, Haavik S, Nordeng H, Safety and efficacy of herbal remedies in obstretics-review and clinical implications. Midwifery. 2011 Feb;27(1):80-6

3 Nordeng, H. and G.C. Havnen, Use of herbal drugs in pregnancy: a survey among 400 Norwegian women. Pharmacoepidemiol Drug Saf, 2004. 13(6): p. 371-80.

4 Kennedy et al. Safety classification of herbal medicines used in pregnancy in a multinational study BMC Complementary and Alternative Medicine 2016. 16:10

Ginger (Zingiber officinale) • Most widely used herbal therapy for Nause and vomiting in pregnancy (NVP)1 • NVP affects approximately 80–90% of pregnant women2

• 3 placebo-controlled trials addressed the safety and efficacy for morning sickness3,4,5

normal ranges of birth weight, gestational age, Apgar scores, and frequencies of congenital abnormalities compared to the general population

safe to use during pregnancy (up to 250 mg four times a day)

• Inhibition of thromboxane synthetase may affect testosterone binding in the fetus6

Not recommended by the Committee on Herbal medicinal products7

Conflicting recommendation 1 Kennedy DA, Lupattelli A, Koren G, Nordeng H. Safety classification of herbal medicines used in pregnancy in a multinational study. BMC Complement Altern Med. 2016;16:102

2Shawahna R, Taha A, Which potential harms and benefits of using ginger in the management of nausea and vomiting of pregnancy should be addressed? a consensual study among

pregnant women and gynecologists BMC Complementary and Alternative Medicine (2017) 17:204

3 Fischer-Rasmussen W. Ginger tratment of hyperemesis gravidarum . Eur J Obstet Gynecol Reprod Biol 1990; 38:19-24 4 Vutyavanich T, Kraisarint T. Ginger for Nausea and vomiting in pregnancy: randomized, double-masked, placebo-controlled trial. Ruangsrira Obstet Gynecol 2001; 97:577-82 5 Willets KE, Eskangahi A, Eden JA. Effect of a ginger extract on pregnancy- induced nausea: a randomised controlled trial. Aust NZ J Obstet Gynecol 2003; 43:139-44 6 Backon J Ginger in preventing nausea and vomiting of pregnancy; a caveat due to its thromboxane synthetase activity and effect on testosterone binding. Eur J Obstet Gynecol Reprod Biol.1991

Nov 26;42(2):163-4 7 Wiesner J, Knöss W Herbal medicinal products in pregnancy - which data are available? Reprod Toxicol. 2017 Sep;72:142-152

• Cranberry is frequently used for Urinary tract infections (UTI) prophylaxis and treatment3

• UTIs are the most common type of infection during pregnancy, affecting up to 10% of pregnant

women1

• UTIs may lead to serious maternal and fetal complications (premature birth, intrauterine growth restriction, increased neonatal mortality and pre-eclampsia)2

• Retrospective cohort study4 68522 women, 919 used cranberry in pregnancy → no negative fetal or pregnancy outcome • Randomised controlled study5 188 pregnant women, 125 with daily Cranberry-Juice

consumption → No negative effect on pregnancy outcome

→ Evidence to support its effectiveness in UTI treatment in pregnancy is weak Temporary use of cranberry preparation in food amounts is acceptable No use as alternative to conventional prescribed medication for UTI 1 Szweda H, Jozwik M.Urinary tract infections during pregnancy - an updated overview. Dev Period Med 2016;20(4):263-272 2 Aktuelle Leitlinien HWI, AWMF online 3 Dante G, Pedrielli G, Annessi E, Facchinetti F. herb remedies during pregnancy: a systematic reviewof controlled clinical trials . J Matern Fetal Neonatal med. 2013; 26(3):306-12 4 Heitmann K, Nordeng H, Holst L. Pregnancy outcome after use of cranberry in pregnancy-the Norwegian mother and child cohort study. BMC Complement Altern. Med. 2013; 13:345 5 Wing DA, Rumney PJ, Preslicka CW, Chung JH. Daily cranberry juice for the prevention of asymptomatic bacteriuria in pregnancy: a randomized, controlled pilot study. 2008;180(4):1367-72

Cranberry (Vaccinium macrocarpon)

• Is there evidence-based efficacy of the HMP?

• Does evidence-based information on the risk/safety in pregnancy exist?

• Is the drug licensed by the national drug authorities?

• What is the origin of the herbal preparation?

• Avoid alcoholic preparations!

Considerations for Pregnancy Part 1

• Is a uterine stimulating effect known? • Blue cohosh (Caulophyllum thalictroides), Black Cohosh (Cimicifuga racemosa), • Angelica root (Angelicae radix) • Senna, Aloe (Anthraquinone laxatives) • Lovage (Levisticum officinale)

• Is an estrogenic effect known? • Chaste tree (Vitex agnus-castus)

• Avoid plants with pyrrolizidine alkaloids (PA)1

• Coltsfood (Tussilago farfara) • Comfrey (Symphytum officinale)

• Consider potential interactions St John´s wort

1 Madge, I., et al., Pyrrolizidine alkaloids in herbal teas for infants, pregnant or lactating women. Food Chem, 2015. 187: p. 491-8. 2 Rasenack, R., et al., Veno-occlusive disease in a fetus caused by pyrrolizidine alkaloids of food origin. Fetal Diagn Ther, 2003. 18(4): p. 223-5. 3 Ernst, E., Serious adverse effects of unconventional therapies for children and adolescents: a systematic review of recent evidence. Eur J Pediatr, 2003. 162(2): p. 72-80.

Considerations for Pregnancy Part 2

Conclusion

• Very few/no side effects are generally observed for HMP • Long traditional clinical use during pregnancy

• Some HMP can cause harm in pregnancy

• There are little randomized controlled studies of safety or teratogenicity • Use of HMP is prevalent among pregnant women worldwide • More high quality research is needed

Thank you for your attention!

Embryotox: consultations 1997-2016

Embryotox: consultations for

Percentage of herbal medicines used and the number of women who used these herbal medicines by safety classification, overall and by region

Kennedy et al. Safety classification of herbal medicines used in pregnancy in a multinational study 2016. BMC Complementary and Alternative Medicine 16:10

• Valerian is recognized for its sedative and soothing medicinal properties and is frequently

used to ease symptoms of insomnia1

• Approximately 78-80% of pregnant women experience sleep disturbances2

• Long traditional clinical use

• Surveys3,4 in 2008-2013 indicated that valerian was one of the most commonly used herbal products during pregnancy

• Norwegian study3: data from Swedish Medical Birth Register, 98 pregnant women used valerian preparation (86 preparation with single ingredient) → No unfavourable effect on pregnancy outcome

• Hungarian study4: 2 cases after suicide dosage in early pregnancy → Children without congenital abnormalies or long-term damage

occasional use is safe, no alcoholic preparations! 1 Choi H., Ko BS, Kim HD et al. Effect of Valerian/Hop Mixture on Sleep-Related Behaviors in Drosophila melanogaster. Biol. Pharm. Bull. 40, 1101–1110 (2017) 2 Hung HM, Chiang HC Non-Pharmacological Interventions for Pregnancy-Related Sleep Disturbances. Hu Li Za Zhi 2017 Feb;64(1):112-119

3 Holst L, Nordeng H, Haavik S. Use of herbal drugs during early pregnancy in relation to maternal characteristics and pregnancy outcome 2008. Pharmacoepidemiol Drug Saf.;17(2):151-9 4 Czeizel AE, Tomcsik M, Tímár L. Teratologic evaluation of 178 infants born to mothers who attempted suicide by drugs during pregnancy.1997 Aug. Obstet Gynecol. 90(2):195-201

Valerian (Valeriana officinalis)