A prospective study of fluconazole treatment for breast and nipple thrush.
Abstract: Background

Breastfeeding women with continuous burning nipple pain, often associated with post-feed radiating breast pain, may be diagnosed with nipple and breast Candida (thrush) infection. This project examined the efficacy of the three fluconazole capsule regime (one 150 mg capsule alternate days) and explored factors associated with longer courses of fluconazole.

Methods

Women diagnosed with nipple and breast Candida and treated with oral fluconazole at a tertiary hospital (n = 96) were followed up until pain resolution.

Results

Women took between 1 and 29 fluconazole capsules, mean = 7.3, median = 6. The number of capsules was not related to socio-demographic or health characteristics of mothers or babies; women with more severe breast pain were more likely to take > 3 capsules than women with less severe breast pain. Only minor side-effects were reported.

Discussion

Most women require more than three capsules of fluconazole, but two-thirds of women will require six or less.

Keywords: nipple pain, breast pain, treatment
Article Type: Report
Subject: Candidiasis (Care and treatment)
Breast diseases (Care and treatment)
Fluconazole (Dosage and administration)
Authors: Moorhead, Anita M.
Amir, Lisa H.
O'Brien, Paul W.
Wong, Swee
Pub Date: 11/01/2011
Publication: Name: Breastfeeding Review Publisher: Australian Breastfeeding Association Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2011 Australian Breastfeeding Association ISSN: 0729-2759
Issue: Date: Nov, 2011 Source Volume: 19 Source Issue: 3
Geographic: Geographic Scope: Australia Geographic Code: 8AUST Australia
Accession Number: 279262876
Full Text: Introduction

Breastfeeding women experiencing burning nipple pain associated with radiating breast pain may be diagnosed as having nipple and breast candida infection or thrush (Hoddinott,Tappin & Wright 2008). Diagnosis is based on clinical symptoms and signs (Brent 2001). In this condition, women describe a continuous burning nipple pain, usually associated with radiating breast pain after feeds; in comparison to mastitis, the appearance of the breast is normal (ie no redness, lumps, tenderness) and the woman has no fever (Amir 2003). Nipples appear pink and shiny (Francis-Morrill et al 2004), unlike dermatitis where the nipple/areola is erythematous, possibly flaky, with a well-demarcated edge (Barankin & Gross 2004). Damaged nipples may be colonised with Staphylococcus aureus, and may require antibiotic treatment (Livingstone & Stringer 1999).

One survey found that 9% (26/304) of women interviewed at six months postpartum said they had experienced 'nipple or breast thrush'(Amir 2002), whereas 22% (17/78) of women responding to a satisfaction survey of the Breastfeeding Education and Support Service (BESS) at the Royal Women's Hospital in 2005 had experienced nipple or breast thrush (Chin & Amir 2008).

Since 1995, oral fluconazole has been used to treat nipple and breast thrush with apparent success at the Royal Women's Hospital, Melbourne (The Royal Women's Hospital 2005). Women are prescribed one 150 mg fluconazole capsule on alternate days (x3), followed by nystatin 500,000U capsules, 2 caps tds (50 capsules). If breast pain persists, repeated courses of fluconazole may be prescribed. Concurrently, infants are treated with oral miconazole gel for at least one week, even if asymptomatic, and mothers apply miconazole oral gel (or cream) to nipples after feeds.

The prescribing regime of one 150 mg fluconazole capsule on alternate days (x 3) was based on clinical experience, but we were aware than some women required more than three capsules, and some women had purchased the treatment outside the hospital. We hypothesised that women with more than one predisposing factor for thrush would be more likely to need more than three capsules than women with one or less predisposing factors. This information would be useful in the process of guideline revision. In 2007, we designed this study to examine:

* if the current prescribing regime was effective in the management of breastfeeding women who have breast and/or nipple thrush;

* to identify the factors associated with women requiring more than the standard regime.

Secondary outcomes women's perceptions of safety of medicines taken and their satisfaction with the treatment experience.

Methods

Women who did not require an interpreter at the BESS services either in the day stay setting or the outpatient clinic with a diagnosis of breast or nipple thrush, were invited to be in the study. Following careful history and examination, the diagnosis was made by one of the hospital lactation consultants in consultation with a hospital medical officer in the usual way. The definition of clinical nipple candidiasis was based on the signs and symptoms found to have a high positive predictive value in the study by Francis-Morrill and colleagues (2004): nipple pain, associated with a shiny appearance of the nipple, and breast pain.

The recruitment questionnaire collected details about mother (parity and method of birth) and age of baby. Questions were asked about possible predisposing factors: history of candida infections (vaginal and elsewhere); history of long-term antibiotics or oral steroids; recent antibiotics (pregnancy, labour, postpartum). Women could answer yes, no or not sure to each of these. Also signs and symptoms of nipple and breast thrush including pain scoring; and any previous treatments used were documented. Nipple and breast pain were scored separately, each on a scale of 0 = 'no pain' and 10 = 'the worst pain possible'; women rated the worst pain in the previous 24 hours (Amir et al 1996).

Women completed a questionnaire (in person or by a hospital lactation consultant via telephone) approximately weekly (7-13 days) until their pain resolved (or was rated less than 2 out of 10). Women were asked at each contact: 'Did you notice any side-effects from the treatment(s) you have received?'. If women replied yes, they were asked to give more information. One of the lactation consultants conducted a final telephone follow-up interview one month after pain had resolved. This questionnaire also included questions about the women's satisfaction with various aspects of the treatment. Finally, women were given the opportunity to make any comments on their experience.

The study fell under the NHMRC guidelines for quality assurance/audit and did not need to considered by the hospital human ethics committee (Chair, RWH Human Research Committee, 12 July 2007). Women were advised that they were free to refuse participation and that their future treatment would not be affected by their decision to participate or not. Confidentiality was assured.

Using Epi-Info Version 6 (StatCalc) for an unmatched cross-sectional study with 95% confidence and 80% power, if 70% of women require three fluconazole (from RWH pharmacy data, June 2006 to May 2007, 108/152 women), and we estimated that 20% of women with three fluconazole had more than one predisposing factor for thrush and 50% of women requiring more than three fluconazole had more than one predisposing factor, then we would need 103 women in total. Descriptive statistics were reported, and the association between number of fluconazole capsules and socio-demographic and health characteristics of mothers and babies were investigated using non-parametric tests (chi-square and Fisher's exact, Stata 10.0). Women's comments at the final data collection were analysed using inductive content analysis, in which themes and constructs were derived from the data without imposing a prior framework (Holloway 2008). Women's comments are identified by their study ID number.

Results

All women attending BESS at the Royal Women's Hospital who were prescribed fluconazole between July 2007 and September 2008 participated in the study (n = 105). Ten women were lost to follow-up by either not taking the prescribed fluconazole or were unable to be contacted following recruitment (n = 96). In total, there were 391 contacts with women. Participant characteristics can be seen in Table 1.

Women took between 1 and 29 capsules of fluconazole (see Figure 1), mean = 7.3, median 6:

* 33% (32/96) women took one to three fluconazole in total;

* 46% (44/96) women took four to nine fluconazole in total;

* 21% (20/96) women took ten or more fluconazole in total.

Possible predisposing factors to Candida infections are shown in Table 2. The number of fluconazole capsules are also shown: mean (standard deviation) and median (Table 2). No relationship was found between the number of fluconazole capsules taken and the socio-demographic and health characteristics of mothers or babies. Analysis of the predisposing factors was conducted with the response 'not sure' being included with 'yes' and with 'no', there was no statistically significance difference either way. There was no relationship between the number of predisposing factors and number of fluconazole capsules taken; of the women who took three fluconazole or less, 63% (20/32) had more than one predisposing factor, and 66% (42/64) who took more than three fluconazole had more than one predisposing factor (chi-square = 0.09, p = 0.76). Post-hoc analysis indicated that if women had breast pain greater than 7 out of 10 at any time during our contacts they were more likely to take more than three fluconazole capsules (23/27, 85%, compared to 4/27, 15% who took three fluconazole or less, Fisher's exact p < 0.017)

Twelve women reported possible side-effects from fluconazole (12/96, 13%): seven gastro-intestinal symptoms (tummy ache; ?nausea; nausea, ?loss of appetite; nausea; nausea, dizzy [not really sure]; nausea and diarrhoea [mild]; diarrhoea--?due to onions). Five women reported central nervous system symptoms (?headache [x2]; slight headache; headaches; a little dizzy); no skin symptoms were reported. Seven possible side-effects for the baby were reported: flushed cheeks, upset tummy; runny poos; mucous faeces; tired baby; eczema--improving with change in detergent and maternal diet; and unsettled, but milk supply low at the time. Other side-effects were related to other medicines taken or used topically.

Most women were satisfied with information given and their management: 99% and 75% women agreed/strongly agreed that they were satisfied with the information received (93/94) and their management (70/94), respectively. Women were less satisfied with the cost of the treatment (35%, 33/94). Eighty three per cent of women (84/96) were continuing to breastfeed at the final contact; only one woman said that she had stopped breastfeeding because her pain had not resolved.

Two main themes emerged from women's comments at the last data collection point: Struggling to get help and Working on getting better. Each theme had three sub-themes. See Table 3 for examples of these.

[FIGURE 1 OMITTED]

Discussion

Currently, Candida infection of the nipple and breast is a contentious diagnosis (Graves et al. 2003), and there are no standard treatment regimes (Brent 2001). Topical antifungal treatments are often first-line treatments, but when breast pain occurs in the absence of signs of mastitis or nipple vasospasm (Amir 2003) fluconazole is widely used (Brent 2001). Recommended duration of treatment varies; one case study reported on a six week course of fluconazole for persistent breast pain (Bodley & Powers 1997).

Fluconazole has very good tissue penetration, oral bioavailability is > 90% and a half life of 24 hours (Chen & Sorrell 2007). The major excretion route is renal, with some metabolism by cytochrome P450 (Chen & Sorrell 2007). In Australia, fluconazole is not available on the Pharmaceutical Benefits Scheme for this condition, and the cost at community pharmacies is approximately $20 for one 150mg capsule of fluconazole. At the RWH, three 150 mg capsules of fluconazole are dispensed as a course of treatment for nipple and breast thrush, charged at the standard prescription contribution fee by patients. The gap in the drug costs are met by the hospital funds.

Although courses of 10 to 14 fluconazole are prescribed in North America (Hale 2004; Walker 2006), our experience is that some women will respond to shorter courses. However, from the data presented here, pain had resolved in only one third of women after our usual course of three fluconazole capsules. Sixty two per cent of women required up to six fluconazole.

Although our clinical impression was that women with predisposing factors such as recent antibiotic treatment required more antifungal treatment than women without any predisposing factors, this was not found in this study. Antibiotics are a known predisposing factor for vaginal candidiasis (Grigoriou et al 2006), and have been found to be associated with nipple and breast candidiasis (Amir 1991; Tanguay,McBean & Jain 1994; Dinsmoor et al 2005), yet we did not find an association with the number of fluconazole capsules taken. It is likely that there are a number of different factors involved including duration of antibiotic treatment and severity of pain reported by women.

As we asked women about any side-effects at every visit or phone call, a number of possible adverse effects were reported. However, in this series, no-one stopped treatment or had any serious adverse event. Reported side-effects of fluconazole include gastro-intestinal symptoms and skin rash (Hale 2004; Chen & Sorrell 2007). Fluconazole is regarded as a relative safe drug (Chen & Sorrell 2007); it is frequently used in preterm infants and is considered compatible with breastfeeding (Hale 2004).

This report is limited in that the patients were diagnosed and managed by different clinicians, but they were all seen within one setting and practice guidelines are in place. The diagnosis of Candida infection

of the nipple and breast is currently made on clinical grounds and is contentious. However, the overwhelming majority of patients made a full recovery, and were able to continue breastfeeding without pain.

As Candida infection of the nipple and breast is thought to be currently over-diagnosed, research is necessary to understand the pathogenesis and diagnosis of this condition. Clinicians should be careful to consider differential diagnoses, such as nipple trauma, bacterial infection, dermatitis or nipple vasospasm before commencing antifungal treatment.

References

Amir L 2002. Survey report: Breastfeeding survey of Frances Perry House and the Family Birth Centre. Melbourne, La Trobe University.

Amir LH 1991. Candida and the lactating breast: predisposing factors. J Hum Lact 7(4): 177-181.

Amir LH 2003. Breast pain in lactating women--mastitis or something else? Aust Fam Physician 32(3): 141-145.

Amir LH, Garland SM, Dennerstein L, Farish SJ 1996. Candida albicans: is it associated with nipple pain in lactating women? Gynecol Obstet Invest 41(1): 30-34.

Barankin B, Gross MS 2004. Nipple and areolar eczema in the breastfeeding woman. J Cutan Med Surg 8(2): 126-130.

Bodley V, Powers D 1997. Long-term treatment of a breastfeeding mother with fluconazole-resolved nipple pain caused by yeast: a case study. J Hum Lact 13(4): 307-311.

Brent NB 2001. Thrush in the breastfeeding dyad: results of a survey on diagnosis and treatment. Clin Pediatr (Phila) 40(9): 503-506.

Chen SCA, Sorrell TC 2007. Antifungal agents. Med J Aust 187(7): 404-409.

Chin LY, Amir LH 2008. Satisfaction survey of the Breastfeeding Education and Support Services, Royal Women's Hospital, Melbourne. BMC Health Serv Res 8: 83.

Dinsmoor MJ, Viloria R, Lief L, Elder S 2005. Use of intrapartum antibiotics and the incidence of postnatal maternal and neonatal yeast infections. Obstet Gynecol 106(1): 19-22.

Francis-Morrill J, Heinig MJ, Pappagianis D, Dewey KG 2004. Diagnostic value of signs and symptoms of mammary candidosis among lactating women. J Hum Lact 20(3): 288-295.

Graves S, Wright W, Harman R, Bailey S 2003. Painful nipples in nursing mothers: Fungal or staphylococcal? A preliminary study. Aust Fam Physician 32(7): 570-571.

Grigoriou O, Baka S, Makrakis E, Hassiakos D, Kapparos G, Kouskouni E 2006. Prevalence of clinical vaginal candidiasis in a university hospital and possible risk factors. Eur J Obstet Gynecol Reprod Biol 126(1): 121-125.

Hale T 2004. Medications and Mothers' Milk. Texas, Pharmasoft Medical Publishing.

Hoddinott P, Tappin D, Wright C 2008. Breast feeding. Br Med J 336(7649): 881-887.

Holloway I 2008. A-Z of Qualitative Research in Healthcare. Oxford, UK, Blackwell Publishing.

Livingstone V, Stringer LJ 1999. The treatment of Staphylococcus aureus infected sore nipples: A randomized comparative study. J Hum Lact 15(3): 241-246.

Tanguay KE, McBean MR, Jain E 1994. Nipple candidiasis among breastfeeding mothers. Can Fam Physician 40: 1407-1413.

The Royal Women's Hospital. (2005). Clinical Practice Guideline: Thrush in lactation. from http://www.thewomens.org.au/ThrushinLactation

Walker M 2006. Maternal pathology: Breast and nipple issues. Breastfeeding Management for the Clinician: Using the Evidence. Sudbury, Massachusetts, Jones and Bartlett Publishers: 365-409.

Anita M. Moorhead, RM, IBCLC

Lisa H Amir, MBBS, MMed, PhD, IBCLC

Paul W O'Brien, BPharm

Swee Wong, BPharm

The Authors

Anita M. Moorhead (1), RM, IBCLC Lisa H Amir (1,2,3) MBBS, MMed, PhD, IBCLC Paul W O'Brien (4), BPharm Swee Wong (2), BPharm

(1) Royal Women's Hospital, Parkville, Victoria

(2) Mother & Child Health Research, La Trobe University, Melbourne

(3) Centre for Women's Health, Gender and Society, University of Melbourne, Melbourne

(4) Bendigo Health Care Group, Bendigo
Table 1: Participant characteristics (n = 96)

Variables                                 (n = 96)     %

Mothers age: mean (range) years          33 (24-43)
Married or living with partner               92        96
Had private health insurance                 59        61
Completed secondary school to year 12        86        90
Highest education level
Completed a degree or higher                 64        67
Primiparous                                  62        65
Baby born by Caesarean section               29        30
                                          mean 7.2
Age of baby at first contact (weeks)    (range 1-42)
                                          median 5

Table 2: Predisposing factors--mother and baby

Variables                            n = 96   %   Number of
                                                  fluconazole
                                                  capsules
                                                  Mean (SD)   Median
Mother ever had frequent courses
of antibiotics?
  No                                  63     66   7.3 (5.4)     6
  Yes                                 31     32   7.4 (5.8)     6
  Unsure                               2      2   9.5 (0.7)     9.5

Mother ever had vaginal thrush?
  No                                  21     22   6.2 (3.1)     6
  Yes                                 75     78   7.5 (5.9)     6

Mother ever had other thrush/
candida infections?                   69     72   7.5 (5.6)     6
  No                                  21     22   6.9 (6.0)     6
  Yes                                  6      6   7.7 (2.5)     9
  Unsure

Mother ever had oral steroids in
the past?
  No                                  82     85   7.6 (5.8)     6
  Yes                                  8      8   5.3 (2.4)     5
  Unsure                               6      6   7.0 (3.6)     7.5

Mother had antibiotics in
pregnancy
  No                                  68     71   7.9 (6.0)     6
  Yes                                 24     25   6.0 (3.7)     6
  Unsure                               1      1     9 (-)       9
  Not answered                         3      3     5 (3.6)     6

Mother had antibiotics in labour
  No                                  65     68   6.9 (4.9)     6
  Yes                                 23     24   8.7 (6.9)     7
  Unsure                               6      6   8.7 (5.0)     7.5
  Not answered                         2      2     2 (1.4)     2

Mother had antibiotics since birth
  No                                  53     55   7.8 (5.6)     6
  Yes                                 42     44   6.7 (5.4)     6
  Not answered                         1      1      8 (-)      8

Baby had antibiotics?
  No                                  80     83   7.6 (5.6)     6
  Yes                                 16     17     6 (4.6)     3

SD: standard deviation

Table 3: Thematic analysis of women's comments at final data
collection

Main themes              Sub-themes and examples

Struggling to get help   Education is needed
                         '... Need to know about it--
                         heard about mastitis,
                         etc. Delayed treatment--
                         due to not knowing.'
                         [Study ID 1101]

                         '... Please get information to
                         GPs re prescribing and
                         treatment of thrush--
                         very frustrating' [1025]

                         Accessing help
                         If I have 3rd baby will
                         come straight to BESS if
                         any problems. Good to
                         know medications OK with
                         breastfeeding--otherwise
                         would have stopped
                         breastfeeding.' [1096]

                         Help from BESS very good-
                         -allayed my suffering--
                         step by step--correct
                         diagnosis.' [1069]

                         Diagnosis may be difficult
                         'Difficult to diagnose
                         and treat. Frustrating'
                         [1014] 'Not sure if pain
                         was thrush or vasospasm.
                         Difficult to diagnose
                         vasospasm.' [1069]

Working on getting       Treatment helps most women
better                   'Fluconazole worked well ...'
                         [1078] 'People great, but
                         treatment didn't work
                         [ceased breastfeeding]
                         [1055]

                         Need for persistence
                         Almost ready to give up
                         after two courses of
                         fluconazole--but took the
                         third course when it
                         finally worked. Thought
                         what the heck!--one more
                         try. Good to let other
                         women know this.' [1012]

                         'Very tough to get under
                         control. Needs
                         persistence. Natural
                         remedies help in
                         conjunction with
                         medications. Needed to
                         use all treatments in
                         combination.' [1075]

                         Negative emotions
                         'Nipple thrush impaired
                         ability to enjoy
                         motherhood' [1099]

BESS: Breastfeeding Education and Support Services
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