1. Antifungal therapy in pregnancy and lactation
Felix Bongomin, M.B., Ch.B., M.Sc.

2. Intended Learning outcomes
To be able to recognise the complexity of treating fungal infections in pregnancy
To understand the pharmacokinetic changes of antifungal agents in pregnancy
To be aware of the teratogenic and/or embryotoxic effects of antifungals
To be aware of the FDA risk categorisation of antifungal agents in pregnancy

3. General principles
The great majority of drugs cross the placenta by “simple diffusion” from high to low concentration
Molecular weight of the drug i.e. M.W. <1500 pass ‘placental barrier” by simple diffusion,e.g. All antifungals (Amphotericin B (924.1g/mol), Fluconazole (306.3g/mol)
M.W. >1500 doesn’t pass “placental barrier e.g. Heparin.
Molecules not bound to protein are available for transfer
Molecules highly soluble in fat & in unionized state quickly pass to the fetus
Molecules low solubility in fat & in an ionized state slowly pass to the fetus

4. Physiological changes during pregnancy
 in plasma volume
 in cardiac output
 in renal blood flow and GFR
Altered liver enzyme activities
↑ 3A4 & 2C9 activity, ↓2C19 activity
 in plasma protein content
Delayed gastric emptying
William's Obstetrics, 24th edition

5. Resulting changes in pharmacokinetics
ABSORPTION ↓ GI motility causes ↑ drug absorption
DISTRIBUTION ↓ Protein binding causes ↑ free drug to be available
↑ in plasma volume causes ↑volume of distribution with ↓plasma concentration
METABOLISM ↑ Hepatic metabolism occurs for some drugs
EXCRETION ↑ Renal blood flow & GFR causes some drugs to clear the body faster.

6. The effect of a drug on the growing fetus
Depends on:-
1. The dose absorbed by the mother
2. The period of gestation
3. Exposure time (duration of therapy)
4. Degradation products (metabolites)

7. The periods of gestation
Pre-implantation – 2 weeks post conception
No teratogenicity (low dose)
Spontaneous abortions
After implantation
3-8 weeks (embryogenic period)
Teratogenicity (congenital foetal malformations)
9-40 weeks (foetal period)
Functional problems rather than gross anatomical anomalies
Injury to foetal organs and placenta
Learning and/or behavioural abnormalities

8. 1 2 3 4 5 6 7 8 9 16 32 38 Neural tube defects Mental retardation
Major congenital anomalies Functional & minor anomalies
Embryo Death
Highly sensitive period
Less sensitive period
TA, ASD, and VSD
Amelia/Meromelia
Cleft lip
CNS
TEETH
EARS
PALATE
GENITALIA
Early development Main embryonic period (weeks) Fetal period (weeks)
EYES
Masculinsation
Neural tube defects Mental retardation
HEART
LIMBS
UPPER LIP
Low-set malformed ears and deafness
Microphthalmia, cataracts,glaucoma
Enamel hypoplasia
Cleft palate
Common site(s) of action

9. Maternal benefit vs. foetal risk assessment
Benefits
- Foetal loss
- Congenital malformations
- Organ toxicity
- Prematurity
- Learning / behavioural abnormalities

10. How do you prove that a drug is a teratogen?
Three criteria must be met:
Drug must cause a characteristic set of malformations.
Exposure must be during a specific window of vulnerability (3-8 weeks) of gestation.
The incidence of malformations should increase with increased dosage and duration of exposure
Niebyl, J, Simpson, J, Glob. Libr. Women's Med.,(ISSN: ) 2008

11. FDA Classification of Drugs Risk to Foetus
Cat A
Controlled studies of women failed to demonstrate a risk to the foetus in the 1st trimester (and there is no evidence of risk in later pregnancy) and the possibility of foetal harm appears remote
Cat B
Either animal studies have not demonstrated a foetal risk but there are no controlled studies in women, or animal studies have shown an adverse effect but this has not been confirmed in controlled studies in women
Cat C
Either studies in animal have shown an adverse foetal effect and there are no controlled studies in women or studies in women and animals are not available
FDA: Federal Registry. 1980; 44: 37434–7.

12. FDA Classification of Drugs Risk to Fetus
Cat D
There is positive evidence of an adverse risk in the human foetus but the benefits from use in pregnant women may outweigh the risk
Cat X
Studies in animals or humans have demonstrated significant foetal abnormalities and the risk of the use of the drug in pregnant women clearly outweighs any potential benefit
FDA: Federal Registry. 1980; 44: 37434–7.

13. Antifungals in pregnancy: Considerations
Antifungal prescription remains a challenge in pregnant women
Gross uncertainties regarding foetal toxicity of most antifungals
Altered maternal pharmacokinetic parameters
Affects efficacy or increase maternal and foetal toxicity
Intrinsic activity of a given agent
Drug-Drug interactions
Pilmis et al. J Antimicrob Chemother. 2015; 70: 14–22.

14. Antifungal drugs and risk category in pregnancy
Polyenes
Amphotericin B
Nystatin* B A
FDA category
King et al. Clin Infect Dis. 1998; 27:1151 – 60
Pilmis et al. J. Antimicrob Chemother. 2015; 70: 14–22
* Topical only

15. Antifungal drugs and risk category in pregnancy
Azoles
FDA category C D
Ketoconazole
Fluconazole
Low-dose regimen (150 mg/day)
High-dose regimen (400–600 mg/day)
Itraconazole
Voriconazole
Posaconazole
Topical azoles C D
C (No human data) C
SLIDE TYPE: Template
Pilmis et al. J Antimicrob Chemother. 2015; 70: 14–22

16. Antifungal drugs and risk category in pregnancy
Echinocandins
#No human data
Caspofungin
Micafungin
Anidulafungin C#
FDA category
# no human data
Pilmis et al. J Antimicrob Chemother. 2015; 70: 14–22

17. Antifungal drugs and risk category in pregnancy
Other antifungals
Flucytosine
Terbinafine
Griseofulvin
Cotrimoxazole C B D
FDA category
Pilmis. et al J Antimicrob Chemother. 2015; 70: 14–22

18. Teratogenic profile of antifungals
Ketoconazole: Affects sex organ differentiation in the foetus
(Animal studies)
Fluconazole: Craniofacial and rib abnormalities, and congenital heart diseases
(Rodents & rabbits studies, case reports in humans).
Low dose is safe
Itraconazole: Craniofacial and rib abnormalities
(No evidence in clinical studies esp. in first trimester)
Voriconazole: Skeletal and visceral abnormalities
(No evidence in clinical studies )
Posaconazole: Skeletal malformations and rib abnormalities
(No published human data)
Sonino et al. N Eng J Med. 1987; 317: 812-8
Tiboni et al. Res Commun Chem Pathol Pharmacol. 1993; 79: 381–4.
Mølgaard-Nielsen et al. N Engl J Med. 2013;369:830-9

19. Teratogenic profile of antifungals
Ossification and rib malformations
Animal studies
Caspofungin
Visceral abnormalities and abortions
Animal studies
Micafungin
Skeletal abnormalities
Animal studies
Anidulafungin
Cancidas Package Insert
Cappelletty et al Pharmacotherapy 2007; 27: 369–88.
Eraxis Package Insert

20. Teratogenic profile of antifungals
Flucytosine
Bone and craniofacial malformations (reported from aborted foetuses)
Only in first trimester, no evidence of adverse outcomes in second and third trimester (limited case reports)
Amphotericin B
No teratogenicity in rodents or rabbits even in first trimester.
Case reports in humans (No foetal abnormalities)
Cotrimoxazole
Neural tube defects (spina bifida), congenital heart diseases, cleft lips and palates, club foot
Pilmis. et al J Antimicrob Chemother. 2015; 70: 14–22

21. Conclusion
Amphotericin B and its lipid derivatives are considered the cornerstone of treatment in any invasive fungal infection during pregnancy
Fluconazole could be considered after the first trimester in the absence of an alternative agent.
Effective contraception should be continued throughout treatment and for 2 months thereafter during itraconazole therapy
Voriconazole is contraindicated in pregnancy
Embryo-fetotoxic in rabbits, lack of human data
Superficial infections during pregnancy require topical treatment, which can be prescribed throughout pregnancy, including topical azoles.
Superficial fungal infections requiring systemic treatment, like dermatophytic onychomycosis, chromomycosis and mycetoma, should be treated after delivery.