REVIEW
Data on Safety of Intravaginal Boric Acid Use in
Pregnant and Nonpregnant Women: A
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Narrative Review
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Rachel Mittelstaedt, MD,* Alyssa Kretz, BA,† Michael Levine, MD,‡ Victoria L. Handa, MD, MHS,§
Khalil G. Ghanem, MD, PhD,¶ Jack D. Sobel, MD,|| Anna Powell, MD,§ and
Susan Tuddenham, MD, MPH¶
Abstract: Intravaginal boric acid (IBA) represents one of the only options
available to treat azole-resistant vulvovaginal candidiasis (VVC) and is
included as part of multiple national guidelines (including the United
Kingdom and the United States) for the treatment of VVC or recurrent
bacterial vaginosis. Novel products using IBA are under development
for treatment and suppression of VVC and bacterial vaginosis. Use of
over-the-counter or clinician-prescribed IBA in reproductive-aged women
is already widespread and may increase further if drug resistance in VVC
rises. However, IBA is not a Food and Drug Administration–approved
drug, and safety data are sparse. Given these factors, it is important to un-
derstand the currently available data on the safety of IBA use. Herein, we
set out to synthesize human and animal data (converting, where appropri-
ate, dose and serum values to standard units to facilitate comparison) to an-
swer 2 key questions: (1) What are the data on the safety of IBA use for
women? and (2) What are the data on the safety of IBA use in pregnancy?
We find that, despite gaps, available data suggest IBA use is safe, at least
when used in doses commonly described in the literature as being pre-
scribed by clinicians. Information on harms in pregnancy is limited, and
data remain insufficient to change current guidelines, which recommend
IBA avoidance in pregnancy.
I ntravaginal boric acid (IBA) has been used for decades to treat
vulvovaginal candidiasis (VVC) and bacterial vaginosis (BV).1–3
Intravaginal boric acid represents one of the few available options
From the *Department of Internal Medicine and †Medical School, Johns
Hopkins School of Medicine, Baltimore, MD; ‡Department of Emer-
gency Medicine, University of California Los Angeles School of Med-
icine, Los Angeles, CA; §Department of Gynecology and Obstetrics
and ¶Division of Infectious Disease, Johns Hopkins School of Medi-
cine, Baltimore, MD; and ||Division of Infectious Disease, Wayne State
University, Detroit, MI
Coauthors A.P. and S.T. contributed equally to this study.
Conflict of Interest and Sources of Funding: S.T. has been a consultant for
Biofire Diagnostics, Roche Molecular Diagnostics, and Luca Biologics;
receives royalties from UPTODATE; and has received speaker honoraria
from Roche Molecular Diagnostics and Medscape. S.T. is supported by the
National Institutes of Health (grant K23AI125715). A.P. receives royalties
from UPTODATE. J.D.S. has served as a consultant to Scynexis Pharma
and Mycovia Pharmaceuticals.
Correspondence: Susan Tuddenham, MD, MPH, 5200 Eastern Ave,
MFL Center Tower, Suite 381, Baltimore, MD 21224. E-mail: studden1@
jhmi.edu.
Received for publication April 26, 2021, and accepted September 14, 2021.
Supplemental digital content is available for this article. Direct URL
citations appear in the printed text, and links to the digital files are
provided in the HTML text of this article on the journal’s Web site
(http://www.stdjournal.com).
DOI: 10.1097/OLQ.0000000000001562
Copyright © 2021 American Sexually Transmitted Diseases Association.
All rights reserved.
Sexually Transmitted Diseases • Volume 48, Number 12, December 2021
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for azole-resistant Candida,4–6 is a treatment of last resort for
nitroimidazole-resistant trichomoniasis (TV; 4%–10% of TV
isolates show some nitroimidazole resistance6,7),5,8–10 and is in-
cluded as part of multiple national guidelines (Table 1) for infec-
tious vaginitis. Intravaginal boric acid is not a Food and Drug
Administration–approved drug; rather, it can be prescribed from
compounding pharmacies or is widely available over the counter
(OTC; often marketed as a “homeopathic” product). For example,
a search on a large Internet retailer reveals >20 brands of boric
acid (BA)–containing vaginal suppositories, marketed for indica-
tions ranging from vaginal odor, discharge, and dryness to VVC,
BV, and dyspareunia or “correcting” vaginal pH. Formulations
vary; commonly, BA powder is placed in a gelatin or vegetable-
based capsule for intravaginal use. Costs online range from $0.10
to $1.20 per capsule; costs at 2 compounding pharmacies were
$0.19 to $2.33 per capsule.
When described in the literature as prescribed by clini-
cians, IBA is most commonly used as a 600 mg suppository
for 14 days for acute VVC; 600 mg twice weekly used even
over years has been used for VVC or BV suppression,3 and
600 mg twice daily (BID) for up to 2 months for resistant TV8–10
(Table 1, footnote). A protocol for a randomized IBA trial for
BV treatment has been described,11 and a phase 2 trial of an
IBA-containing product for the treatment of BV and VVC was
recently published.12 Several trials of IBA-based products are
registered on ClinicalTrials.gov, including twice-weekly use for
BV suppression.13
Use of IBA is already widespread and may increase fur-
ther as drug resistance in VVC and TV rises, or if new trials12,13
prove efficacious. Most women with infectious vaginitis are of
reproductive age, and up to 50% of US pregnancies are un-
planned.14 However, safety data on IBA are relatively sparse.1
Given these factors, it is important to understand the available
data on the safety of IBA use. Herein, we reviewed the literature
to answer 2 key questions: (1) What are the data on the safety of
IBA use for women? and (2) What are the data on the safety of
IBA use in pregnancy?
MATERIALS AND METHODS
Searches were performed using keyword and controlled
vocabulary terms. Abstracts were reviewed, reference lists were
searched, and relevant articles were abstracted (Suppl. Table 1
[http://links.lww.com/OLQ/A752] and Suppl. Fig. 1 [http://
links.lww.com/OLQ/A753]). We considered data on borates and
elemental boron: BA (H3BO3) is a borate compound resulting
when boron combines with oxygen.15 For BA consumed orally
or applied topically, absorbed boron can be measured in the blood.
For selected articles, calculations were made to standardize mea-
sures for comparability (Suppl. Table 2, http://links.lww.com/
OLQ/A754).
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e242
TABLE 1. National and International Guideline Recommended Use of Intravaginal BA
Guideline Country Indication for BA Dosage/Duration BA Comments on Safety for Patient Comments on Pregnancy Other Comments
Mittelstaedt et al.

Centers for Disease United
Control STD States
Treatment Guidelines,
2015 and 20215,6
ACOG 2020 “Vaginitis United
in Nonpregnant States
Patients”107s
Canadian Guidelines on Canada
Sexually Transmitted
Infections 2010108s
Non-albicans VVC 600 mg IBA in gelatin capsule once None None Also mentions that
(if recurrence after daily for 2 wk (3 wk in 2021 clinical improvement
treatment with 7–14 d guidelines) for recalcitrant
nonfluconazole azole trichomonas has been
regimen) reported with
Recurrent BV† 600 mg IBA daily for 21 d (preceded by None None intravaginal BA*
oral nitroimidazole, followed by
metronidazole intravaginal gel twice
weekly for 4–6 mo)
Non-albicans VVC 600 mg IBA capsules daily for a “BA can be fatal if ingested orally “Patients should be
minimum of 14 d (no other options and patients should be well counseled…to use
recommended except topical counseled to use it only reliable contraception.”
flucytosine) intravaginally, to place it out of
the reach of children, and to use
reliable contraception.”
Recurrent VVC (4 or more Induction: 300–600 mg IBA gelatin None States “contraindicated in
episodes in capsule daily for 14 d. pregnancy”
12 mo). Recommend Maintenance: 300 mg IBA gelatin
induction and capsule 5 d each month on the first
maintenance therapy day of the menstrual cycle. Continue
6 mo then observe. If recurrence
occurs, treat the episode and
reintroduce maintenance regimen
Non-albicans VVC 600 mg IBA capsule daily for 14 d. Vaginal burning reported in <10% None
If symptoms recur, re-treat with
600 mg daily for 14 d followed by
“alternate day BA for several weeks”

Sexually Transmitted Diseases

BASHH guidelines United Non-albicans Candida BA vaginal suppositories 600 mg daily BA vaginal suppositories 600 mg “There may be a

•
vulvovaginal Kingdom species and azole for 14 d daily for 14 d are a “safe and teratogenic risk so BA
candidiasis 2019109s resistance-alternative effective alternative (grade 1B).” should be avoided in
regimen to nystatin If mucosal irritation occurs, dose pregnancy or risk of
can be reduced to 300 mg daily. pregnancy.”
Australian STI Australia Candida glabrata BA vaginal pessaries 600 mg daily for None None
management 14 d
guidelines for use in
primary care110s

*Muzny et al.9 and Backus et al.8 (600 mg intravaginal BID  60 days), Aggarwal et al.10 (first patient: vaginal clotrimazole alternating every other night with 600 mg BA intravaginally for 6 weeks, which failed,
but it was used for 5 months, which was successful; second patient: vaginal clotrimazole in the morning with 600 mg vaginal BA nightly for 3 weeks, which failed, but then 600 mg intravaginal BA twice daily with
weekly intravaginal gentian violet for 1 month was used, which was successful).
†
”Limited data indicate that for women with multiple recurrences an oral nitroimidazole (metronidazole or tinidazole 500 mg twice daily for 7 days) followed by intravaginal BA 600 mg daily for 21 days and
suppressive 0.75% metronidazole gel twice weekly for 4–6 months might be an option for women with recurrent BV.”
ACOG, American College of Obstetricians and Gynecologists; BASHH, British Association for Sexual Health and HIV.

Copyright © 2021 by the American Sexually Transmitted Diseases Association. Unauthorized reproduction of this article is prohibited.
Volume 48, Number 12, December 2021

RESULTS
What Are the Data on the Safety of IBA Use
for Women?
Toxicity From IBA Use in Humans
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We were able to identify >1100 individual patient uses based on
published literature of IBA use (primarily for VVC).3,7–10,12,16–29,31s–53s
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Most described 600 mg once daily or BID for 7 to 14 days,12,16,
20–27,29,31s,36s,37s,39s,41s,44s–51s
whereas others described BID for 1
to 2 months,7–10,43s,53s or extended or suppressive regimens.3,17,22,
23,25,26,29,35s,40s
Perhaps the greatest evidence for the safety of
IBA is that despite this literature, we were not able to find pub-
lished reports since the 1880s of serious toxicities. In 1888,
there was a report of toxicity in 3 women from IBA “packs.”52s
The author described treating chronic leucorrhoea (heavy vaginal
discharge) by packing 1 to 2 oz of BA into the upper one-third of
the vagina, tamponing it for 2 to 3 days “until liquefaction oc-
curred,” then using a moderately hot douche to clean it out, 1 to
2 times per week. These women exhibited formication, depres-
sion, corrosion of vaginal mucous membrane, sunken eyes, weak
voice, and skin swelling, charring, and skin exfoliation, which re-
solved on stopping the therapy, and were ascribed to BA toxicity.
Of note, the amount of BA used daily in these cases would appear
to be substantially larger (25–100 times) than the 600 mg daily or
BID commonly prescribed or advised in guidelines. Since 1888, the
only other documented adverse events have been sporadic and mild,
primarily limited to local irritation or watery vaginal discharge.3,17,42s,45s
Humans are routinely exposed to low levels of boron (B) in
food and water; indeed some level of intake is expected and may
even be important for health54s—“average” levels are 34 to 95 ng/mL
(0.04 μg/g whole blood [WB]).55s However, exposure to large
amounts of BA can cause toxicity and even death.56s–62s Given
limited data on IBA, it might be useful to compare (1) the amount
administered vaginally to “safe” or “toxic” exposures or (2) the
blood level observed as a result of vaginal absorption to “safe” or
“toxic” serum levels from the broader toxicity literature, accounting
for differential absorption.
Is There a Known “Toxic” or “Lethal” Dose of BA Based
on the Amount Administered or Measured in Blood?
Much of acute human toxicity data relates to case series
of reported accidental or purposeful oral ingestion, often in
children,56s–58s,61s of BA-containing insecticides or cleaning
products.57s,59s,61s Orally ingested BA seems to be nearly 100%
systemically absorbed,63s,64s although quickly renally excreted.
This was shown in one study in which 3 men drank 750 mg BA
dissolved in water; 3 more ate 740 to 1473 mg BA.63s Boric acid
was rapidly excreted in the urine, showing 100% oral bioavailabilty.
In another study, 562 to 611 mg BA was administered to human
males intravenously (IV) for 20 minutes.64s No volunteer in either
study experienced ill effects.
A full review of all case reports of oral toxicity is outside of
the scope of this article (see Hadrup et al.65s for additional details).
However, in a case series of large amounts of BA oral ingestion,
nausea, vomiting, abdominal pain, and diarrhea were common.57s,61s
In more severe cases, patients exhibited blue-green emesis, central
nervous system depression, fever, headache, an erythematous
“boiled lobster” desquamating skin rash, weakness, cyanosis,
and renal failure.57s–59s,61s,62s However, most (70%–80%) of
those with reported ingestions were asymptomatic.57s,61s Case
series have not reliably established a threshold blood boron
level or a threshold BA ingestion amount consistently leading
to toxicity or death (Table 2). Reported toxic or fatal ingestion
Sexually Transmitted Diseases • Volume 48, Number 12, December 2021
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IBA Use in Pregnant and Nonpregnant Women
amounts are also variable. Litovitz61s noted “potentially lethal
(oral) doses are…cited as 15 to 20 g for adults” but discuss that
they did not observe fatalities or severe manifestations despite
ingestions up to 88.8 g of BA. They do report on systemic symptoms
resulting from ingestion of 0.2 g/kg BA (14,000 mg in a 70-kg
adult).57s A clear limitation of these studies is variable reporting
on amount, concentration, and timing of ingestions and when after
ingestion blood levels were drawn, as well as patient size (many
children included).
In the animal literature, Weir et al.66s established an LD50
(the amount of material causing death of 50% of test animals) of
3450 mg BA/kg (603 mg B/kg) administered as an oral dose for
male Sprague-Dawley rats, and 4080 mg BA/kg (713 mg B/kg;
i.e., 285,600 mg BA in a 70-kg human) for females. No adverse
effects were seen in animals fed “350 ppm” boron equivalent daily
for 2 years, but conversion to B/kg is uncertain. Sprague-Dawley
rats are the most commonly used animal model given their rel-
ative sensitivity to BA.67s,68s (see reviews by Moore, Hadrup, and
Bolt65s,69s,70s).
Toxicity from topical BA has been reported.65s In the late
1800s, BA was included in skin ointments used for diaper rash
in infants.62s Unfortunately, this led to several cases of toxicity
and even death.56s,62s A number of controlled studies were per-
formed to assess the degree of systemic absorption from BA appli-
cation to skin.71s–74s These studies found that systemic absorption
was minimal through intact skin, but application of BA containing
aqueous jelly to severely damaged skin could lead to higher
absorption.73s,74s No clear toxic dose was defined (Suppl. Table
3, http://links.lww.com/OLQ/A753).
What Is the Systemic Absorption From IBA Use in
Women?
In 1974, Swate42s treated 40 women with symptomatic VVC
with 600 mg IBA twice daily, and 5% BA ointment to the vulva
3 times a day. Among 20 participants, none had detectable se-
rum BA levels after 14 days of IBA. However, contemporaries
raised concern that the detection threshold of 10 mg/100 mL
(16.55 μg B/g WB) was not sensitive enough to be relevant.75s
Van Slyke et al.44s performed a trial of IBA. They administered
600 mg IBA to 8 uninfected volunteers. Based on a single (unin-
fected) woman, they calculated 6% absorption systemically from
intravaginal use. Shinohara41s reported no detectable systemic
levels in a woman who used IBA 600 mg BID for 10 days; no in-
formation on detection threshold or time frame was provided.
Summary: Available information suggests low systemic ab-
sorption of IBA based on 600 mg suppositories. However, data are
limited, primarily to 8 uninfected volunteers, with an estimate of
6% absorption based on data from a single individual.44s Long
clinical experience (in the context of VVC, where inflammation
might be expected) would suggest little danger of toxicity at least
when 600 mg IBA is used daily or BID; however, the exact amount
of systemic absorption in women with inflamed vaginal mucosa or
mucosal ulceration is uncertain. Although there are reports of tox-
icity and increased absorption of BA from damaged skin, it is un-
known how applicable this is to the vaginal mucosa. In contrast to
IBA, BA ingested orally seems to be nearly 100% absorbed, al-
though it is quickly renally cleared. Doses of 15 to 20 g in adults
are considered “potentially lethal”; however, studies have not es-
tablished a clear oral dose limit in mg/kg or measured serum level
resulting in either toxicity or death. The absolute amounts con-
sumed orally in adults or the equivalent in animals associated with
adverse effects seem much larger than the individual 600-mg
IBA treatments used daily or BID (even if those were to be 100%
absorbed—IBA may not be), and indeed healthy volunteers who
e243
 Mittelstaedt et al.

TABLE 2. Selected Studies Reporting Acute BA Exposure, Measured Blood Levels, and Outcomes in Nonpregnant Humans and Animals
Range of Estimated Daily
Boron or BA Exposure Range of Boron
Study No. Patients (in Same Units Throughout) Mode of Exposure Levels (WB) Outcome
Rat oral exposure
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Weir et al., N/A LD50: 710 mg B/kg in a Data reported as g Death in 50% of rats
197266s single oral ingestion B/kg. Female rats
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Would be 285,600 mg BA weighed 206–248 g

ingestion in a 70-kg human in this study
Human oral exposure
Linden 4 (aged ~10,000–297,000 mg BA Oral 46–2196 μg B/g WB Toxicity, no deaths. 3
et al., 14 mo–65 y) (individual weights of patients, including those
198657s patients not reported) with the lowest and
highest blood levels, had
GI symptoms; 1 with a
blood level of 75.7 μg/g
WB was asymptomatic
Ishii et al., 1 (77 y old) ~30,000 mg BA Oral 35.7 μg B/g WB Death
199358s
Human IV exposure
Jansen et al., 8 (22–28 y) 570–620 mg BA IV 9.5–19 μg B/g WB* No toxicity
198464s
Human vaginal exposure
Van Slyke 8 600–1200 mg IBA daily Intravaginal 0.40 μg B/g WB average No toxicity
et al., (105–210 mg B daily) in those using
198144s 600–1200 mg IBA†
0.14 μg B/g WB at
1–18 h in 1 individual
after use of 600 mg IBA

Of note, blood boron levels were detected by spectrophotometry in older studies and by the more precise inductively coupled plasma mass or emission
spectrometry beginning in the mid-1980s. Across 2 large, retrospective case series of ingestion in children and adults,57s,61s the lowest blood boron level
reported in an adult with symptoms was 20 μg B/g WB. However, a patient with levels of 75.7 μg B/g WB was asymptomatic,57s and one with levels of
2196 μg B/g WB only had vomiting and facial flushing. A separate case58s reported a death from ingestion, with a blood boron level of 35.7 μg/g WB.
*Blood concentrations increased from <0.095–0.36 μg/g B to a peak of 9.5–19 μg/g B WB 25 minutes later. The estimated half-life was 21 hours.
†
Before the main study, they administered 600 mg IBA to 8 uninfected volunteers 1 to 2 times daily for 1 to 2 weeks and measured serum boron levels with
a detection limit of 0.04 μg B/g WB. They reported serum levels <1.0 μg B/mL (<0.95 μg B/g WB) with a mean level 0.42 μg B/mL (0.40 μg B/g WB) during
use and undetectable levels before and 48 hours after use. A single (uninfected) woman had a level of 0.15 μg/mL (0.14 μg B/g WB) at 1 to 18 hours and 0.1
(0.095 μg B/g WB) at 24 to 36 hours after using one 600 mg IBA, from which they calculated approximately 6% absorption systemically from intravaginal
use.
B indicates boron; N/A, not applicable; WB, whole blood.

ate or had comparable doses of around 600 mg BA injected IV ex-
perienced ill effects. How this may relate to individuals with poor
renal function or to extended IBA use is unclear. It seems that ex-
pected blood boron levels after use of IBA would be lower than
those reported to be associated with toxicity, but data are limited
(Table 2).
What Are the Data on the Safety of IBA Use
in Pregnancy?
Teratogenicity in Human Studies of IBA in Pregnant
Women
There are few studies of the impact of IBA use in human
pregnancy. Acs et al.28 reported data from the Hungarian Case
Control Surveillance of Congenital Abnormalities of 1980–1996.
A total of 22,843 infants with congenital abnormalities were com-
pared with 38,151 controls. Forty-three mothers of children with
abnormalities had used IBA during pregnancy, compared with
52 controls (prevalence odds ratio, 7.1 [95% confidence interval
{CI}, 1.7–29.5]). The authors report that most women used 60 mg
BA daily for 7 days (standard dosing is 600 mg). Two women treated
with IBA at some point in pregnancy had children with skeletal
abnormalities, compared with 0 controls (however, authors note
they used all population controls, not only matched control pairs
for this calculation). Two women using IBA in their second and
third months of pregnancy had children with neural tube defects
(prevalence odds ratio, 8.0 [95% CI, 1.7–37.8]). Overall, there
was a 2.8-fold (95% CI, 1.1–7.1) increase in the risk of congenital
abnormalities when women were exposed to IBA in months 2 to 3
of gestation and 1.6 (95% CI, 1.0–2.4) for the entire pregnancy.28
This study was significantly limited by its retrospective nature (re-
call bias); also, the absolute number of children with congenital
abnormalities born to women who used BA was low, and the indi-
cation for IBA use was not well defined.
Heinonen76s reported on a case series (conducted 1958–1965
in the United States) where >50,000 pregnancies were followed up
and women were queried about use of a large number of medications
during pregnancy, including “topical” BA. This study found 19
congenital abnormalities in the offspring of 253 mothers who used
BA in the first 16 weeks. There were 13 major malformations (vs.
7.4 expected), yielding a standardized relative risk ratio (SRR) of
1.75 (95% CI, 0.94–2.94). There were 5 minor malformations ob-
served versus 4.6 expected (SRR, 1.10 [95% CI, 0.36–2.53]). For
use of BA at any time during pregnancy, there were 15 abnormalities
observed versus 8.86 expected (SRR, 1.69 [95% CI, 0.95–2.76]).
None of these associations were statistically significant; the authors
noted that the association between BA use in the first 4 months
and major malformations might merit further investigation. De-
tails on dosage, duration, or indication of topical BA, or if it was
even intravaginal were not available.76s

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Copyright © 2021 by the American Sexually Transmitted Diseases Association. Unauthorized reproduction of this article is prohibited.

Data From Pregnant Women Exposed to Boron Other
Than IBA
Data from pregnant women exposed to boron in the water
supply have been published.70s In a study based in Argentina and
Chile, Harari77s reported no major differences in birth outcomes
between women living in San Antonio de los Cobres with a higher
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average maternal plasma level of boron as compared with a group
in Santiago. Igra reported that in 180 pregnant women living in the
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Andes,78s there was a statistically significant decrease in birth
length and weight when maternal blood boron levels increased.44s
One criticism, although the authors attempted to adjust for it, was
that the water supply also contained high levels of lithium, which
was independently associated with a decrease in birth weights.79s
Finally, Duydu79s found no differences in birth outcomes in boron
exposed women in Turkey comparing those with low, medium,
and high blood boron levels (Suppl. Table 4, http://links.lww.
com/OLQ/A753).
Boron Toxicity in Pregnant Animals
Dosing pregnant animals with very large amounts of oral
BA daily for an extended time can lead to significant fetal
problems.67s,68s,80s–83s Initial studies by Heindel68s in Sprague-
Dawley rats were refined by Price,80s who found no adverse effects
seen in the offspring of maternal rats (no-observable-adverse-effect
level [NOAEL]) fed 55.1 mg BA kg−1 d−1 or less from gestational
days 0 to 20 (Table 3). The lowest observed adverse effect level—
that is, the lowest dose at which an observed adverse effect level
was demonstrated on the fetuses—was 76 mg BA kg−1 d−1 or
13 mg B kg−1 d−1. Increased skeletal abnormalities were observed
in the offspring of pregnant rats treated with this amount or more.
An NOAEL of 55.1 mg BA kg−1 d−1 (10 mg B kg−1 d−1) corre-
lated with serum levels of 1.27 μg B/g WB in the maternal rats, al-
though67s these levels may be underestimated because there was a
time lag of up to 8 hours between BA administration and acquisi-
tion of blood samples. Subsequent studies reported fetal skeletal
abnormalities, decreased weight, and visceral abnormalities when
pregnant animals were given large amounts of BA.81s–83s The
Code of Federal Regulations (21 CFR 170.22) for food additive
TABLE 3. Selected Studies NOAEL and LOAEL for BA Toxicity Established in Sprague-Dawley Rats
Estimated Daily Boron or
BA Intake in Mother (in
Same Units Throughout)
Rat oral exposure
Price, 199767s NOAEL 10 mg B kg−1 d−1 orally
Price, 199767s LOAEL 13 mg B kg−1 d−1 orally
Human intravaginal
exposure
Van Slyke, 198144s 600–1200 mg IBA daily
(105–210 mg B intravaginally
daily)
1.6–3 mg B kg−1 d−1 in a 70-kg
human
LOAEL indicates lowest observed adverse effect level (i.e., the lowest dose at which an observed adverse effect level was demonstrated on the fetuses);
NOAEL, no-observable-adverse-effect level (i.e., no adverse effects seen in the offspring of maternal rates fed boric acid).
Sexually Transmitted Diseases • Volume 48, Number 12, December 2021
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IBA Use in Pregnant and Nonpregnant Women
procedural regulations typically necessitates a safety factor of 100
be applied to the NOAEL from animal data before extrapolating
to the human data for determining a tolerable daily intake (TDI)
in humans.84s The US Environmental Protection Agency has estab-
lished an oral reference dose of 0.2mg B kg−1 d−1, as a dose that is
presumed to pose no risk of adverse effects during a lifetime of ex-
posure.85s The World Health Organization has established a TDI
of 0.17 mg B/kg.86s,87s
Summary: Data from one28 and less clearly a second76s hu-
man study have raised concerns regarding the teratogenic potential
of IBA. These studies were limited by methodological concerns
and small absolute numbers of birth defects observed. No data
on other obstetric complications were available. Studies of birth
outcomes in women consuming boron in drinking water are mixed
and may be limited by confounders; it is unclear how well these
chronic daily exposures throughout pregnancy would relate to
the short-term or intermittent exposure resulting from IBA regi-
mens. High doses of oral BA given daily in pregnancy clearly have
teratogenic effects in animal models; data on other obstetric out-
comes are scarce. There are no studies specifically assessing
IBA in pregnant animals. The equivalent amounts of BA adminis-
tered orally in animals seem greater than the typical IBA dose pre-
scribed, even if IBA was 100% systemically absorbed, although
safety factors must be applied. If estimates of absorption by Van
Slyke et al. are accurate at 6%, the expected daily exposure from
IBA (0.096–0.18 mg B kg−1 d−1) might be similar to established
reference dose and TDI levels, but given the limitations of the data,
no definitive conclusions can be drawn.
DISCUSSION
Herein, we attempted to summarize relevant data on the safety
of IBA for women and in pregnancy. There were several limitations to
our article. This was a narrative rather than a systematic review, only
conducted through 2019. We abstracted data from all available articles
regarding use of IBA. However, because others have comprehen-
sively reviewed extensive literature relating to oral ingestion and
nonvaginal topical or environmental exposure to BA/boron,65s,69s,70s
we summarized only key articles on these topics. We did not find
Boron or
BA Levels
(WB) Reported Toxicity Comments
1.27 μg/g No toxicity at this level Reported in Rats fed BA
WB 55 mg BA kg−1 d−1 from
gestational day 0–20
(3850 mg in a 70 kg
individual). Absorption
expected to be 100%
1.53 μg/g At this level, the main toxicity Absorption expected to be
WB seen was decrease in fetal 100%
birth weight, in addition to
some skeletal defects
0.40 μg/g N/A Absorption expected to be
WB <100%. Per Van Slyke,
absorption estimated at 6%,
which might be estimated at
0.09–0.18 mg B kg−1 d−1
e245
 Mittelstaedt et al.
any literature regarding effects on fertility of IBA use. Data on
effects of oral BA or boron on female fertility70s in humans88s or
animals66s,89s were scant, difficult to disentangle from effects on
male fertility, and not extensively reviewed.69s,70s Finally, we re-
lied on published literature; it is possible that adverse events relat-
ing to IBA use have occurred but have not been reported.
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Overall, lack of reported toxicities despite use of IBA for
inflammatory conditions such as VVC is reassuring. Although
wCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 03/17/2023
limited, oral toxicity studies suggest that the amount of IBA re-
quired to induce significant toxicity in women would likely be
more than the intravaginal doses commonly described in the lit-
erature as being prescribed by clinicians to healthy adults with
normal renal function. Few data on the safety of longer-term or
suppressive regimens prescribed are available, although significant
toxicities have not been reported.3,8,9 Of note, the 600-mg dose of
IBA is largely arbitrary—no dose-range studies to evaluate safety
or efficacy have ever been performed; mechanisms of action are
uncertain, although under investigation90s–92s; and there are no ac-
cepted standardized susceptibility tests for vaginal pathogens such
as yeast or trichomonas.
Several guidelines advise (American College of Obstetri-
cians and Gynecologists, Canada, British Association for Sexual
Health and HIV) that IBA should be avoided in pregnancy. Human
data raise some concerns regarding teratogenic effects of IBA;
however, it is sparse and flawed. High-level oral exposure to BA
in animals is teratogenic. The level of exposure from IBA is likely
much lower; however, trying to relate animal data to the human
scenario is limited, in part, by uncertainty regarding systemic ab-
sorption of IBA under conditions of inflammation. Although preg-
nant and nonpregnant women93s and animals94s seem to clear boron
at similar rates, how else the physiology of pregnancy might impact
IBA effects is unknown. We were not able to find data addressing
maternal absorption of IBA, what amount of boron might cross
the placenta with IBA use, or the impact of IBA on obstetrical out-
comes other than teratogenicity. Therefore, it is not possible to rec-
ommend, based on existing data, changes to guidelines advising
against IBA use in pregnancy.
Forty-five percent of pregnancies in the United States are
unplanned14; half are diagnosed after the first 6 weeks.95s Thus,
women of reproductive potential are ideally informed about
possible adverse pregnancy-related effects of medications taken.
Isotretinoin96s is associated with birth defects in any amount—
prescribers and patients are held to special requirements to ensure
pregnancy avoidance. In comparison, although providers may rou-
tinely counsel women on risks of nonsteroidal anti-inflammatory
drugs, acetaminophen, or fluconazole (which have more robust
evidence for adverse pregnancy effects than IBA),97s–106s there
are no similar requirements to isotretinoin that all women using
these medications have antecedent pregnancy testing, repeated
testing during use, or sign a commitment to use effective contra-
ception. Such stringent measures would not seem appropriate for
IBA given available data. It may be reasonable to discuss the spar-
sity of data on pregnancy and the drug threshold of embryopathy
in IBA to facilitate a joint informed-consent process to consider
pregnancy avoidance while in use or defer if pregnancy is planned.
Also, women should be counseled to use the medication only
intravaginally and to keep it out of reach of children to avoid
accidental ingestions.
Our findings and analysis are focused on 600 mg IBA reg-
imens commonly described in the literature as prescribed by clini-
cians. However, given the ease of obtaining IBA OTC, women
may be self-medicating with nonrecommended regimens, with
products of uncertain dosage and purity, and may inadvertently
use IBA in early pregnancy. Toxicity and safety issues aside, given
widespread availability (and direct to consumer marketing for a
e246 Sexually Transmitted Diseases
Copyright © 2021 by the American Sexually Transmitted Diseases Association. Unauthorized reproduction of this article is prohibited.
variety of indications [some nonspecific or unsupported by studies]),
IBA may potentially be overused by healthy women for perceived
problems. Alternatively in those with true urogenital infections or
other pathology, IBA self-treatment may mask disease manifes-
tations, delaying needed medical care or making accurate clini-
cian diagnosis more difficult. Similarly, uninformed clinicians
may misdiagnose patients or overprescribe IBA for unsupported
indications or regimens.
Despite limitations, available evidence suggests IBA use at
dosages commonly described in the literature is likely safe for
women, at least those with normal renal function. However, we feel
IBA should be prescribed by a provider; given uncertainties, we
cannot recommend unregulated use of OTC products. Clinicians
should initiate a discussion for a joint informed-consent process
with patients on pregnancy avoidance with IBA use. Additional
public and clinician education regarding IBA is needed. In the
long term, additional regulation (e.g., of OTC availability, market-
ing claims, and product quality) may be needed.
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