DRUGS IN PREGNANCY

MOTHERISK ROUNDS

The Fetal Safety of Hydrocortisone-Pramoxine

(Proctofoam-HC) for the Treatment
of Hemorrhoids in Late Pregnancy
Neda Ebrahimi, BSc,1 Sabina Vohra, BSc,1 Christelle Gedeon PhD,1 Hani Akoury, MD,2
Paul Bernstein, MD,3 Nicholas Pairaudeau, MB, BS,4 Johanne Cormier, MD,5 Lorraine Dontigny, MD,5
Marc-Yvon Arsenault, MD,5 Claude Fortin, MD,5 Martine Goyet, MD,5 Chantal Lafortune, MD,5
Johanne Lalande, MD,5 Coralie Beauchamp, MD,5 Francis Engel, MD,5 Anne Fortin, MD,5
Anna Taddio PhD,1 Tom Einarson, PhD,1 Gideon Koren, MD1
1

Motherisk Program, Hospital for Sick Children, Toronto ON

Sunnybrook Health Sciences Centre, Toronto ON

Mount Sinai Hospital, Toronto ON

North York General Hospital, Toronto ON

LaSalle Clinic, Montreal QC

Abstract

Rsum

Objective: Fetal safety has never been studied for any drug used in
the treatment of hemorrhoids. Proctofoam-HC is a combination
of a corticosteroid and a local anaesthetic that is proven effective
for the treatment of hemorrhoids. The objective of this study
was to assess prospectively the fetal safety of third trimester
exposure to Proctofoam-HC.

Objectif : Linnocuit ftale na jamais fait lobjet dtudes pour

quelque mdicament que ce soit visant la prise en charge
des hmorrodes. Proctofoam-HC est une combinaison dun
corticostrode et dun anesthsique local qui sest avre
efficace pour la prise en charge des hmorrodes. Cette tude
avait pour objectif dvaluer de faon prospective linnocuit
ftale de lexposition Proctofoam-HC au cours du troisime
trimestre.

Methods: In a multicentre study, 240 women exposed to ProctofoamHC in the third trimester and a similar number of control pregnant
women were followed up postnatally.
Results: When compared to controls exposure to Proctofoam-HC
was not associated with any adverse fetal effects on birth
weight, gestational age, rates of prematurity, or pre- or postnatal
complications.
Conclusion: Proctofoam-HC is safe to use in the treatment of
hemorrhoids in late pregnancy.

Mthodes : Dans le cadre dune tude multicentrique, 240 femmes

exposes Proctofoam-HC au cours du troisime trimestre et un
nombre semblable de tmoins enceintes ont fait lobjet dun suivi
aprs laccouchement.
Rsultats : Par comparaison avec les tmoins, lexposition
Proctofoam-HC na t associe aucun effet ftal indsirable
sur le poids de naissance, lge gestationnel, les taux de
prmaturit ou les complications prnatales ou postnatales.
Conclusion : Lutilisation de Proctofoam-HC savre sre pour
la prise en charge des hmorrodes au cours des dernires
semaines de la grossesse.
J Obstet Gynaecol Can 2011;33(2):153158

BACKGROUND

Key Words: Pregnancy, hemorrhoids, hydrocortisone, pamoxine,

fetus, safety
Competing Interests: See Acknowledgements.

emorrhoids are much more prevalent in pregnancy

than before conception or after delivery.1 During
pregnancy, treatment of hemorrhoids is typically
conservative and primarily symptomatic, and surgical and
invasive treatments are usually avoided. The fetal safety of
treatments for hemorrhoids is largely unknown. Although
FEBRUARY JOGC FVRIER 2011 l 153

DRUGS IN PREGNANCY

the development of hemorrhoids is usually self-limiting, the

presence of hemorrhoids in pregnancy tends to be more
prolonged, and they do not usually resolve completely until
after delivery.2
Presently, there is no information on the fetal safety of any
of the commonly used anti-hemorrhoidal preparations. In a
recent review of PubMed and Medline we could not identify
any eligible studies on the fetal safety of any preparation
used for the treatment of hemorrhoids during pregnancy.
Since thalidomide caused widespread teratogenicity in the
1950s and 1960s, women and health care providers have
exercised extra caution with prenatal drug exposure; in fact,
many women are advised by their health care practitioners
to discontinue medications during pregnancy even if they
may not carry any additional risk for the fetus.3
Proctofoam-HC is a mucoadhesive analgesic and antiinflammatory foam used for the temporary relief of
anorectal inflammation and swelling associated with
hemorrhoids, pruritus ani, anal fissures, and other anorectal
discomforts.4 Each aerosol foam canister contains 18
g of a mixture of 1% hydrocortisone acetate and 1%
pramoxine hydrochloride in a hydrophilic base formulated
with cetyl alcohol, emulsifying wax, methylparaben,
polyoxyethylene-10 stearyl ether, propylene, glycol,
propylparaben, purified water, trolamine, and inert
propellants isobutene and propane. A canister contains
at least 36 applications; each application of 375 mg
mucoadhesive base provides 1% hydrocortisone acetate
(3.75 mg/dose) and 1% pramoxine hydrochloride
(3.75 mg/dose).4 Every canister contains a topical
applicator, thus avoiding direct touch to the inflamed area.
The foam is thought to adhere to the surface without
staining or leaking. The objective of the present study was
to assess the fetal safety of Proctofoam-HC.
METHODS

In this multicentre study we recruited pregnant women who

were prescribed Proctofoam-HC for hemorrhoids by their
physicians and who completed two telephone interviews
using two specially designed questionnaires. The first
questionnaire was completed at the time of enrolment and
prior to delivery when pregnancy outcome was unknown.
The second questionnaire was completed up to three
months after delivery. Fetal and maternal outcomes were
confirmed in a letter to the childs primary care physician
requesting corroboration of the mothers information.
Because exposure to Proctofoam-HC took place in the third
trimester of pregnancy, after malformations could have
developed, the primary endpoint of the study was birth

154 l FEBRUARY JOGC FVRIER 2011

weight, which is a sensitive measure of fetal development

in the third trimester. At 28 weeks the 50th percentile of
fetal weight is 1 kg; 10 weeks later it has typically gained
more than 2 kg.5 A variety of third trimester insults (e.g.,
cigarette smoking and placental insufficiency) have been
shown to have an adverse effect on this rapid and dynamic
process.68 Notably, repeated oral doses of corticosteroids
in pregnancy have been shown to cause a significant
decrease in birth weight.9
The secondary outcomes for the study included mode
of delivery, labour complications, fetal distress, and any
adverse event in the neonate.
A comparison group of women comprised Motherisk
patients who called to receive information on nonteratogenic drugs (e.g., hair dye, cold medications, and
herbal teas) or nausea and vomiting of pregnancy, and who
were not exposed to any teratogens during the course of the
pregnancy. This was further limited to women who had not
been exposed to Proctofoam-HC, any of its components,
or any other topical corticosteroids or local anaesthetics
during the course of their pregnancy. None of the women
in the comparison group suffered from hemorrhoids at
the time of the call. Each control subject was matched for
maternal age ( 2 years) and smoking status ( 2 cigarettes).
We compared gravidity, parity, alcohol use, smoking, adverse
pregnancy outcome, mode of delivery, prematurity, low
birth weight, major and minor malformations, fetal distress,
labour complications, and neonatal health between the
treatment and comparison groups using chi-square analysis
or Fisher exact test for dichotomous data. Maternal age,
gestational age at delivery, weight gain, and birth weight
were compared between the two groups using the Student
t test for normally distributed data or Mann-Whitney
rank sum test if the data were not normally distributed.
SigmaStat v 3.11.0 (Systat Software Inc., Point Richmond,
CA) was used to perform statistical analyses.
The multicentre study protocol was approved by the
Research Ethics Boards at the Hospital for Sick Children,
North York General Hospital, and Sunnybrook Health
Sciences Centre. Verbal informed consent was obtained
prior to enrolling women into the study.
RESULTS

In total, 204 pregnant women exposed to Proctofoam-HC

were recruited and matched to 204 control subjects. Seven
pairs of twin pregnancies were included, five of which
could not be matched with control subjects. While included
in most of the analyses, the twin pregnancies were omitted
from the comparison of birth weight.

The Fetal Safety of Hydrocortisone-Pramoxine (Proctofoam-HC) for the Treatment of Hemorrhoids in Late Pregnancy

Women in the study group received Proctofoam-HC in the

third trimester for a median of six weeks (Table 1).
There were no differences between women in the two
groups, except for more prevalent casual alcohol use and
smoking in the comparison group (Table 2). More women
in the comparison group had a Caesarean section (Table 3).
There was no difference between the groups in birth weight
or rates of prematurity. The Proctofoam-HCexposed
neonates did not differ from the comparison group in any
outcome (Table 4).

Table 1. Details of Proctofoam-HC use in the

treatment group
Mean (SD)

Median
(25% to 75% quartile)

Mean duration of treatment in

pregnancy, weeks

6.9 (5.1)

6.0 (3.0 to 10.0)

Frequency of treatment per day

2.6 (0.9)

2.5 (2.0 to 3.0)

Total number of canisters used

2.3 (1.3)

2.0 (1.0 to 3.0)

Treatment details

Table 2. Maternal characteristics of patients in the

treatment and comparison groups
Characteristics

DISCUSSION

No previous study has reported on the fetal safety of any

topical preparation for the treatment of hemorrhoids in
pregnancy. We selected birth weight as the primary end
point to evaluate exposure to Proctofoam-HC in the third
trimester of pregnancy because it is a very sensitive marker
of fetal distress, as shown in exposure to smoking, lead,
and drugs of abuse.9 Exposure to smoking in pregnancy
has been shown to cause an average reduction of 200 g
in birth weight.10 Hence, to detect a clinically significant
decrease of 200 g in birth weight at a power of 80% and
alpha of 5%, 200 women per group were required. Post
hoc power analysis of our cohort revealed that, in fact, we
had a 91.5% power to detect a 200 g difference in birth
weight between the two groups.
The local anaesthetic pramoxine hydrochloride, chemically
4-(3-[p-Butoxyphenoxy] propyl) morpholine hydrochloride,
does not belong to either of the two large classes of local
anaesthetics (amides and esters). Rather, it is classified as
an amino-ether. Pramoxine is less potent locally than other
commonly used topical anaesthetics, but is thought to
be as effective as benzocaine.11 Pramoxine appears to be
less irritating to tissue and possesses a considerably lower
systemic toxicity than amide and ester local anaesthetics.12
In addition, there is no cross-sensitivity with pramoxine
because of its unique molecular structure when compared
with other local anaesthetics.13

Treatment

Comparison

203

204

0.31*

32 (4.9)

31.5 (4.9)

Maternal age
N
Mean (SD)

Median
32.5
(25% to 75% quartile) (28.7 to 35.4)

32.0
(28.0 to 35.2)

Gravidity
N

206

198

2.0 (1.03.0)

2.0 (1.03.0)

202

199

1.0 (0.01.0)

0.5 (0.01.0)

Yes

6.0 (3.0%)

25.0 (17.4%)

No

198.0 (97%)

119.0 (82.6)

Yes

15 (7.4%)

31 (18.3%)

No

189 (92.6%)

138 (81.7%)

Median

0.2

Parity
N
Median

0.83

Casual alcohol use

< 0.001

Smoking
0.002

Pregnancy weight gain

N

199

123

14.8 (5.5)

14.5 (6.1)

14.7
(11.1 to 17.8)

14.0
(11.0 to 18.2)

Mean (SD)
Median
(25% to 75%)

0.68*

*Student t test
Mann-Whitney rank sum test
chi-square analysis

Peak effects are usually seen three to five minutes after

application.14 The duration of action is typically less than
one hour but may be up to five hours depending on the
amount of drug applied.15 The metabolism and clearance
of pramoxine is not fully understood. Another aminoether, fomocaine, which is a morphiline derivative similar
to pramoxine, is thought to undergo biotransformation
to hydrophilic metabolites via N-oxidation, and the
metabolites are then excreted by the kidney.16
FEBRUARY JOGC FVRIER 2011 l 155

DRUGS IN PREGNANCY

Table 3. Pregnancy outcomes for patients exposed to

Proctofoam-HC versus comparison group
Characteristics

Treatment

Comparison

Vaginal

173 (84.8%)

146 (72.6%)

0.003*

Caesarean section

31 (15.2%)

55 (27.4%)

204

194

39.4 (1.4)

39.1 (2.5)

39.6
(38.440.6)

40.0
(38.040.0)

Yes

8 (4.1%)

10 (5.3%)

No

193 (96.0%)

180 (94.7%)

201

201

Method of delivery

Gestational age at delivery

N
Mean (SD)
Median
(25%75% quartile)

0.16

Prematurity
0.55*

Birth weight, g
N
Mean (SD)

3406.9 (452.7) 3487.7 (491.4)

Median (25%75%)

3401.0
3409.0
(3100.03730) (3180.93770.5)

0.17

Low birth weight, < 2500 g

Yes

6 (3.0%)

3 (1.5%)

No

194 (97.0%)

198 (98.5%)

Yes

36 (18.1%)

31 (17.9%)

No

163 (81.9%)

142 (82.1%)

N = 199

N = 178

Yes

28 (14.1%)

24 (13.5%)

No

171 (85.9%)

154 (86.5%)

0.31*

Fetal distress

Neonatal health

*Chi-square analysis
Mann-Whitney rank sum test
Student t test.

156 l FEBRUARY JOGC FVRIER 2011

0.97*

0.87*

Typically, local anaesthesia has not been shown to increase

the risk of congenital malformations or other neonatal
adverse effects. Local anaesthetics are used for a variety of
indications in pregnancy, the most common being lumbar
epidural anaesthesia. Anaesthetics such as lidocaine are also
used systemically to treat ventricular arrhythmias.
Several animal studies investigating the safety of local
anaesthesia in pregnancy have been performed. In rats and
rabbits, studies with ropivacaine have found no teratogenic
effects.17 Similarly, in pregnant sheep given ropivacaine,
bupivacaine, or levobupivacaine, no adverse effects were
observed.18 Reproduction studies in rats receiving lidocaine
found no evidence of teratogenicity,19 and chronic exposure
to high doses of lidocaine in pregnant rats did not produce
any adverse reproductive or congenital anomalies.20,21 Several
animal models and sets of in vitro data have documented that
high concentrations of local anaesthetics can cause changes
in uterine blood flow22 and result in fetal convulsions.23
Another animal study has raised some concern by showing
changes in umbilical blood flow and fetal heart rate with
bupivacaine exposure in pregnant sheep.24 An in vitro study
identified a restriction in umbilical arteries and veins with high
concentrations of bupivacaine.25
Corticosteroid use in the first trimester of pregnancy has
been associated with an increased risk of oral cleft.26 More
relevant to our third trimester study, when no increased
malformation rate can be expected, corticosteroid use in
late gestation has been associated with intrauterine growth
restriction. One study by Schatz et al.27 found a significant
association between corticosteroid (oral and topical)
exposure and low birth weight (6% in the treatment group
vs. 3.3% in the control group) in women with asthma and
allergies. However, when the authors further analyzed
the risk by regrouping exposure to oral and topical, no
significant decrease in birth weight was observed in the
subgroup of women exposed to topical corticosteroids.
Similar results were observed by Mygind et al.,28 who
noted no differences in birth weight with topical use of
corticosteroids. One should also take into consideration
that the decrease in birth weight noted in most of these
studies was very small. Banks et al.29 quoted a decrease of
just 39 g, while Thorp et al.30 noted a decrease of 63 g in
the subjects receiving antenatal corticosteroids. To observe
such small decreases in birth weight, a sample size of 2500
participants would be required in each group. Obtaining
such a large group would not be feasible, considering the
issues of recruitment. Further, the clinical significance of
such small reductions in birth weight is questionable. In
our study, there was no difference in fetal distress or labour
complications between the exposed and non-exposed

The Fetal Safety of Hydrocortisone-Pramoxine (Proctofoam-HC) for the Treatment of Hemorrhoids in Late Pregnancy

groups, nor were there differences in neonatal health

outcomes.
The mean gestational age at delivery was not different
between the two groups. After correcting for gestational
age, birth weight in the exposed group was similar to that in
the comparison group. There were similar percentages of
low birth weight babies in the two groups, and in most cases
of low birth weight an objective etiology was identified
(e.g., multiple births, smoking). Both multiple pregnancies
and tobacco exposure in pregnancy have been associated
with low birth weight in babies.31,32 The birth weight in the
treatment group was also consistent with the expected birth
weight of full term babies in Canada, with a mean of 3394 g
(Statistics Canada, years 20002007).33 Pharmacologically,
the minimal quantity of the corticosteroid absorbed rectally
is not expected to induce any significant detrimental effects
on birth weight. Tromm et al.34 reported that only a very
small amount of rectally administered hydrocortisone
is absorbed, with the mean absolute bioavailability being
approximately 4%.
The fetal safety of late pregnancy exposure to ProctofoamHC is relevant only if this pharmaceutical product can be
shown to be effective for pregnancy-induced hemorrhoidal
disease. In a recent study we have shown Proctofoam-HC
to be highly effective, based on both objective evidence and
pregnant patients reported satisfaction.35
CONCLUSION

In the first ever study on the safety of an antihemorrhoidal

preparation in the third trimester of pregnancy,
Proctofoam-HC has been shown to be safe, empowering
health professionals and pregnant women to treat this
condition effectively.

Table 4. List of neonatal health concerns in the treatment

and comparison groups
Neonatal health

Treatment , %

Comparison, %

Cardiovascular

Heart murmur

Premature atrial
contraction

Total

Pulmonary
aspiration

Mild asthma

Tachypnea

Total

Urinary

Streptococcus B

Pneumonia

Leucocytosis

Total

Rash

Eczema

Acne

Total

0.35

Conjunctivitis

0.50

Myopia

0.47

Colic

0.22

Milk allergy

0.47

Hypoglycemia

0.50

Poor feeding

> 0.99

Poor weight gain

> 0.99

Anemia

0.47

Renal calculi

0.47

> 0.99

Respiratory

> 0.99

Infections

> 0.99

Skin

P values determined by Fisher exact test

ACKNOWLEDGEMENTS

This study was supported by a grant from Duchesnay Inc.,

Bainville, Quebec.
REFERENCES
1. Gordon PH, Nivatvongs S. Principles and practice of surgery for the
colon, rectum and anus. 2nd ed. St. Louis: Quality Medical Publishing;
1999:1936.
2. Dykes S, Bordeianou L. Hemorrhoids and incontinence. In: Kovac
SR, Zimmerman CW, eds. Advances in reconstructive vaginal surgery.
Philadelphia: Lippincott Williams & Wilkins; 2007:3203.
3. Hancock R, Koren G, Einarson A, Ungar W. The effectiveness of
teratology information services. Reprod Toxicol 2007;23:12532.

FEBRUARY JOGC FVRIER 2011 l 157

DRUGS IN PREGNANCY
4. Product information: Proctofoam-HC rectal anti-inflammatory foam,
hydrocortisone acetate, pramoxine HCI. Bainville, Quebec: Duchesnay
Inc; 1976.

23. Teramo K, Benowitz N, Heymann MA, Kahanp K, Siimes A,

Rudolph AM. Effects of lidocaine on heart rate, blood pressure and
electrocorticogram in fetal sheep. Am J Obstet Gynecol 1974;118:9439.

5. Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Rouse DJ,
Spong CY, eds. Williams obstetrics. 22nd ed. Chapter 4: Fetal growth
and development. New York: McGraw Hill; 2005: 91119.

24. Fleming JA , Lambert TF, Walker AM. The effects of bupivacaine on the
umbilical circulation and placental gas exchange in the fetal lamb. Anesth
Analg 1987;66(11):11216.

6. US Department of Health and Human Services. The health benefits

of smoking cessation. Rockville, MD: Office on Smoking and Health.
DHHS Publication No. (CDC) 908416; 1990.

25. Noren H, Kallfelt B, Lindblom B. Influence of bupivacaine and morphine

on human umbilical arteries and veins in vitro. Acta Obstet Gynecol
Scand 1990;69:8791.

7. Gagnon R. Placental insufficiency and its consequences. Eur J Obstet

Gynecol Reprod Biol 2003;110:S99107.

26. Park-Wyllie L, Mazzotta P, Pastuszak A, Moretti ME, Beique L, Hunnisett

L, et al. Birth defects after maternal exposure to corticosteroids:
prospective cohort study and meta-analysis of epidemiological studies.
Teratology 2000;62:38592.

8. Walsh RA, Lowe JB, Hopkins PJ. Quitting smoking in pregnancy.

Med J Aus 2001;175:3203.
9. Koren G. Medication safety in pregnancy and breastfeeding. New York:
McGraw Hill; 2007:213.
10. Butler NR, Goldstein H, Ross EM. Cigarette smoking in pregnancy: its
influence on birthweight and perinatal mortality. Br Med J 1972;15:12730.
11. Drugdex evaluations: pramoxine. In: Micromedex healthcare series
[Internet database]. Greenwood Village, CO: Thomson Reuters; 2008.
12. Noojin RO. Tronothande hydrochloride (pramoxine hydrochloride) in the
control of pruritus. Postgrad Med 1954;16:4535.
13. Peal L, Karp M. A new surface anesthetic agent: tronothane. Ill Med J
1953;104(5):299301.
14. Drug information for the health care professional (USP DI). 16th ed.
Rockville, MD: United States Pharmacopeial Convention, Inc; 1996.
15. Product information: tronolane, pramoxine. Columbus, OH: Ross Labs,
Consumer Products; 1996.
16. Ritchie JM, Greengard P. On the mode of action of local anesthetics.
Annu Rev Pharmacol 1966;6:40530.
17. Product information: naropin. AstraZeneca; 2001.
18. Santos AC, Karpel B, Noble G. The placental transfer and fetal effects of
levobupivacaine, racemic bupivacaine, and ropivacaine. Anesthesiology
1999;90:1698703.
19. Product information: xylocaine. AstraZeneca, 2000.
20. LaBorde JB. Developmental toxicity evaluation of lidocaine in CD rats.
Teratology 1988;37:472.
21. Fujinaga M, Mazze RI. Reproductive and teratogenic effects of lidocaine
in Sprague-Dawley rats. Anesthesiology 1986;65:62632.
22. Tuvemo T, Willdeck-Lund G. Smooth muscle effects of lidocaine,
prilocaine, bupivacaine and etiodocaine on the human umbilical artery.
Acta Anaesthesiol Scand 1982;26:1047.

158 l FEBRUARY JOGC FVRIER 2011

27. Schatz M, Zeiger RS, Harden K, Hoffman CC, Chilingar L, Petitti D. The
safety of asthma and allergy medications during pregnancy. J Allergy Clin
Immunol 1997;100:3016.
28. Mygind H, Thulstrup AM, Pedersen L, Larsen H. Risk of intrauterine
growth retardation, malformations and other birth outcomes in children
after topical use of corticosteroids in pregnancy. Acta Obstet Gynecol
Scand 2002;81:2349.
29. Banks BA, Cnaan A, Morgan MA, Parer JT, Merrill JD, Ballard PL, et al.
Multiple courses of antenatal corticosteroids and outcome of premature
neonates. North American Thyrotropin-Releasing Hormone Study Group.
Am J Obstet Gynecol 1999;181:70917.
30. Thorp JA, Jones PG, Knox E, Clark RHI. Does antenatal corticosteroid
therapy affect birth weight and head circumference? Obstet Gynecol
2002;99:1018.
31. Keith LG, Oleszczuk JJ, Keith DM. Multiple gestation: reflections on
epidemiology, causes, and consequences. Int J Fertil Womens Med
2000;45:20614.
32. Backe B. Maternal smoking and age: effect on birthweight and risk
for small-for-gestational age births. Acta Obstet Gynecol Scand
1993;72:1726.
33. Statistics Canada. Table 1024510. Mean and median birth weight (live
births), by sex, Canada, provinces and territories, annual. CANSIM
(database). Available at: http://cansim2.statcan.gc.ca/cgi-win/
cnsmcgi.exe?Lang=E&RootDir=CII/&ResultTemplate=CII/
CII_&Array_Pick=1&ArrayId=1024510. Accessed November 19, 2010.
34. Tromm A, Mllmann H, Barth J, Hochhaus G, Krieg M, Bigalke C, et al.
Pharmacokinetics and rectal bioavailability of hydrocortisone acetate after
single and multiple administration in healthy subjects and patients. J Clin
Pharmacol 2001;41:53641.
35. Vohra S, Akoury H, Bernstein P, Einarson TR, Pairaudeau N, Taddio A, et
al. The effectiveness of Proctofoam-HC for treatment of hemorrhoids in
late pregnancy. J Obstet Gynaecol Can 2009;31:6549.