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Pregnancy Outcome Following Exposure to Topical Retinoids: A Multicenter Prospective Study

Authors:

Abstract

Concerns have been raised about the use of topical retinoids since the publication of isolated cases of characteristic retinoid embryopathy, originally described after oral use. A collaborative study of the European Network of Teratology Information Services was carried out to evaluate the rate of congenital malformations following first-trimester topical retinoid exposure. A population of 235 exposed pregnant women was compared with 444 controls. No significant differences were observed between groups with regard to the rates of spontaneous abortion (odds ratio [95% confidence interval], 1.5 [0.8-2.7]), minor birth defects (1.3 [0.4-3.7]), and major birth defects (1.8 [0.6-5.4]). No child showed features of retinoid embryopathy. The rate of elective termination in the exposed group was increased 3-fold (3.4 [1.5-7.8]). In conclusion, these results do not suggest an increased risk of retinoid embryopathy. However, according to current knowledge, topical retinoids cannot be advised for use during pregnancy because their risk/benefit ratio remains questionable.
1844 J Clin Pharmacol 2012;52:1844-1851
Human teratogenicity of oral retinoids was clearly
established by the mid-1980s. Their use in preg-
nancy both increases the risk for spontaneous
abortion and leads to the characteristic retinoid
embryopathy, comprising anomalies of the ears,
facial and palate defects, micrognathia, cardiovas-
cular defects, and developmental impairment of
the thymus and the central nervous system.1 Mental
deficiencies have also been reported in children
with no notable physical anomaly exposed in utero
to isotretinoin.2 Consequently, retinoids are consid-
ered to date the most serious teratogenic threat since
thalidomide, and pregnancy prevention programs are
implemented worldwide (eg, iPLEDGE)3 to reduce
inadvertent exposures.4
Topical retinoids are used to treat a variety of
dermatologic conditions, from acne to sun damage.
They are also ingredients commonly found in cos-
meceuticals, making women of childbearing age prime
candidates for their use. Human and animal data
argue against plausible teratogenicity because of
minimal systemic absorption (values measured from
undetectable to a small fraction of the dose, not
exceeding endogenous levels) after topical application
in the absence of significant skin damage.5-10 However,
despite such reassuring considerations, several pub-
lished case reports described infants exposed in utero
Concerns have been raised about the use of topical retinoids
since the publication of isolated cases of characteristic
retinoid embryopathy, originally described after oral use. A
collaborative study of the European Network of Teratology
Information Services was carried out to evaluate the rate of
congenital malformations following first-trimester topical
retinoid exposure. A population of 235 exposed pregnant
women was compared with 444 controls. No significant
differences were observed between groups with regard to
the rates of spontaneous abortion (odds ratio [95% confi-
dence interval], 1.5 [0.8-2.7]), minor birth defects (1.3 [0.4-
3.7]), and major birth defects (1.8 [0.6-5.4]). No child
showed features of retinoid embryopathy. The rate of elec-
tive termination in the exposed group was increased 3-fold
(3.4 [1.5-7.8]). In conclusion, these results do not suggest
an increased risk of retinoid embryopathy. However,
according to current knowledge, topical retinoids can-
not be advised for use during pregnancy because their risk/
benefit ratio remains questionable.
Keywords: Clinical pharmacology; drug information; preg-
nancy; topical retinoid; birth defect
Journal of Clinical Pharmacology, 2012;52:1844-1851
© 2012 The Author(s)
From the Department of Swiss Teratogen Information Service and Division
of Clinical Pharmacology and Toxicology, University Hospital, Lausanne,
Switzerland (Dr Panchaud, Dr Rousso, Dr Winterfeld, Dr Rothuizen, Dr
Buclin); Department of Pharmaceutical Sciences, University of Geneva,
Geneva, Switzerland (Dr Csajka); BELTIS, Rabin Medical Center, Petah
Tikva, Israel (Dr Merlob, Dr Stahl); Pharmakovigilanz- und Beratungszentrum
Embryonaltoxikologie, Berlin, Germany (Dr Schaefer); Drug Consultation–
TIS, Zerifin, Israel (Dr Berlin); Telefono Rosso–TIS, Roma, Italia (Dr De
Santis); Pharmacovigilance, Lyon, France (Dr Vial); TIS AOU Careggi,
Florence, Italy (Dr Ieri); Teratology Information Service, Helsinki University
Central Hospital, Helsinki, Finland (Dr Malm); and Poison Control,
Bergamo, Italy (Dr Eleftheriou). Submitted for publication July 14, 2011;
revised version accepted October 18, 2011. Address for correspondence:
Alice Panchaud, Swiss Teratogen Information Service, STIS, Centre
Hospitalier Universitaire Vaudois, Beaumont-6ème étage, 1011 Lausanne,
Switzerland; e-mail: Alice.Panchaud@chuv.ch.
DOI: 10.1177/0091270011429566
Pregnancy Outcome Following Exposure
to Topical Retinoids: A Multicenter
Prospective Study
Alice Panchaud, PhD, Chantal Csajka, PhD, Paul Merlob, MD,
Christof Schaefer, MD, PhD, Maya Berlin, MMedSc,
Marco De Santis, MD, Thierry Vial, MD, Alessandra Ieri, MD,
Heli Malm, MD, PhD, Georgios Eleftheriou, MD, PhD, MSc,
Bracha Stahl, MPharm, Philippe Rousso, MD, Ursula Winterfeld, PhD,
Laura E. Rothuizen, MD, and Thierry Buclin, MD
Pharmacodynamics
PREGNANCY OUTCOME FOLLOWING EXPOSURE TO TOPICAL RETINOIDS
PHARMACODYNAMICS 1845
to topical tretinoin who exhibited structural abnor-
malities consistent with retinoic acid embryopathy.11-15
In contrast, 3 small epidemiological studies16-18 did
not identify a significantly increased risk associ-
ated with topical tretinoin, for either retinoic acid
embryopathy or major structural defects overall. One
case report on adapalene and 1 epidemiological study
involving tretinoin did not indicate an increased risk
of developmental disorders.19,20 Data on the safety of
several topical retinoids (motretinide, tazarotene,
adapalene) in pregnancy are still missing.
According to current knowledge, health care
practitioners remain reluctant to rule out a potential
for low-level teratogenicity of topical retinoids.21
This might consequently foster maternal fear and
lead to termination of healthy and otherwise wanted
pregnancies even though the risk of malformations
from topical retinoid exposure is not considered
significantly increased by many teratology informa-
tion specialists.22
The purpose of this study was to assess the fre-
quency of a spectrum of adverse birth outcomes
associated with first-trimester exposure to topical
retinoids, to enrich rather scarce human data avail-
able to date. We compared the overall prevalence of
major or minor birth defects at birth, the rate of spon-
taneous abortion, and the rate of elective termination
of pregnancy after first-trimester exposure to topical
retinoids with the baseline prevalence in pregnan-
cies exposed to no known teratogen.
METHOD
Our prospective, controlled, multicenter, observa-
tional study involved 11 teratology information ser-
vices (TIS). It enrolled pregnant women exposed
during the first trimester to topical retinoids, and
these women or their doctors contacted a TIS to seek
advice between 1992 and 2006. Patients were asked
for consent to further gather follow-up information.
The 11 TIS centers are members of the European
Network of Teratology Information Services (ENTIS),
an organization of services providing evidence-based
information on the safety and risks associated with
exposure to drugs during pregnancy and breastfeed-
ing, using similar methodology. Furthermore, ENTIS
members document prospectively the course of
exposed pregnancies to study drug safety with respect
to developmental toxicity.23 The study was approved
by the ENTIS investigational committee.
Women were exposed to adapalene, tretinoin,
isotretinoin, motretinide, retinol, or tazarotene; if
more than 1 topical retinoid was used, exposure was
classified as a combination. The exposed group was
compared with an ENTIS control group of women
who had used drugs known to be nonteratogenic
during pregnancy (eg, paracetamol, labetalol,
meclozine, loratadine, salbutamol, ranitidine, amox-
icillin, omeprazol, budesonide inhalation). Controls
were enrolled in the same TIS/country, in a similar
timeframe. Similar documentation and follow-up
methodology were used in both the exposed preg-
nancies and the controls. To strengthen the power of
our study, a 1:2 ratio was used between the size of
the cohort exposed to topical retinoids and of the
control group. Each case of topical retinoid exposure
was to be matched with 2 controls of the same center
for maternal age and gestational age at the time of
the call.
Using structured questionnaires or phone inter-
views, exposure details (drug, time of exposure,
dose), concomitant medication, maternal demograph-
ics, and medical and obstetric histories were col-
lected prospectively for each pregnant woman (ie,
topical retinoid use or control group).24
After the predicted date of birth, follow-up infor-
mation was requested through structured telephone
interviews and/or mailed questionnaires sent to the
mothers or physicians. Details on pregnancy out-
come, gestational age at delivery, birth weight, con-
genital anomalies, and neonatal complications were
obtained. In most cases, gathering of follow-up data
was performed during the neonatal period. Pregnant
women considered lost to follow-up were not included
in the analysis (overall rate of loss to follow-up in
the ENTIS group is known to range from 10% to 40%
and is expected to be similar in both groups). A
variable was not considered for analysis if more than
30% of the data were missing.
The primary outcome of interest was the rate of
major birth defects, defined as having serious medi-
cal, surgical, or cosmetic consequences,25 and minor
birth defects with special attention to anomalies
indicative of retinoid embryopathy. All reported
birth defects in exposed and control newborns were
sent to an ENTIS birth defect specialist, who blindly
classified them between major and minor. Secondary
end points were the rates of live births, spontaneous
abortions, pregnancy terminations (elective or ther-
apeutic), stillbirths, premature births (<37 weeks),
gestational age at term, and birth weight. Gestational
age in the present study is defined as the number of
weeks after the last menstrual period.
The proportion of major or minor birth defects,
spontaneous abortions, elective or therapeutic abor-
tions, and live births reported in the exposed group
1846 J Clin Pharmacol 2012;52:1844-1851
PANCHAUD ET AL
was compared with the control group using a χ2 test
or Fisher exact test when assumptions for χ2 were
not met. In addition, a 95% confidence interval (CI)
was defined using odds ratio (OR) calculation for
major and minor birth defect rates. All continuous
variables of interest, such as gestational age at birth
and birth weight, were compared between the
exposed and the control groups using the Student t
test or Wilcoxon test when assumptions for paramet-
ric tests were not met. The level of statistical signifi-
cance was set at P < .05 for the primary outcome. For
all other outcomes, P values were presented only for
exploratory comparisons. To assess the impact of
heterogeneity among retinoids, we applied an anal-
ysis of deviance in the framework of logistic regres-
sion analysis for categorical data and an analysis of
variance (ANOVA; with error sum of squares) for
continuous data.
We used a retrospective power calculation to esti-
mate the minimal detectable difference with the
available sample size (ie, estimation of the statistical
power of the study to detect an increase in birth
defects after topical retinoid exposure). This estima-
tion was performed assuming a significant level (α =
0.05) and a type II error rate (β = 0.2), as well as a
baseline incidence as the rate found in the control
group (1-tailed test).
The χ2 test, Student test, Wilcoxon test, logistic
regression, ANOVA, and power calculation were per-
formed using STATA version 9.2 (StataCorp, College
Station, Texas).
RESULTS
Eleven TIS of the European Network participated in
the study. Three centers could not provide controls
as requested. The Berlin TIS provided the missing
controls for Europe and Zerifin for Israel (Table I). A
total of 235 pregnancy outcomes were recorded fol-
lowing exposure to various topical retinoids (treti-
noin, n = 143; isotretinoin, n = 52; adapalene, n = 24;
retinoic acid, n = 10; motretinide, n = 1; combina-
tion, n = 5; Table II), and 444 matched outcomes in
controls exposed to drugs considered nonteratogens
were collected. Several descriptive variables were
not considered for analysis as they comprised more
than 30% of missing values (eg, street drug use,
detailed concomitant medication, gestity, parity,
social status).
Almost all patients treated with topical retinoids
were exposed from the beginning of pregnancy, with
the treatment having been started before conception.
The mean start time of exposure was 1.8 ± 3.2 gesta-
tional weeks. Most pregnant women stopped topi-
cal retinoids when pregnancy was confirmed, thus
yielding a mean time of exposure of 8.1 ± 5.8 gesta-
tional weeks. The most frequent treatment indica-
tion was acne (n = 174). Psoriasis, alopecia, bleaching,
dermatitis, and cellulitis were less often reported.
Maternal characteristics of patients in the topical
retinoids group and the control group are presented
in Table III. Except for a slight difference in maternal
age, there were no significant differences in any of
the maternal characteristics in both groups. Women
Table I Teratogen Information Services
Retinoids
(n = 235)
Controls
(n = 444)
Servicio de Información Telefónica
sobre Teratógenos Español
(Madrid, Spain)
19 0
Servizio di Tossicologica Perinatale
(Firenze, Italy)
19 21
Beilinson Teratology Information
Service (Tel Aviv, Israel)
13 28
Israel Teratogen Information service
(Jerusalem, Israel)
27 0
TIS-Helsinki (Finland) 8 16
Centre de Pharmacovigilance
(Lyon, France)
26 52
Poison Control Centre (Bergamo,
Italy)
6 16
TelefonoRosso (Rome, Italy) 27 56
Drug Consultation Information
Center (Zerifin, Israel)
4 64
Swiss Teratogen Information
Service (Lausanne, Switzerland)
13 0
Pharmakovigilanz- und
Beratungszentrum
Embryonaltoxikologie (Berlin,
Germany)
73 191
Table II Retinoids Identified
Retinoids (n = 235)
Tretinoin 143
Isotretinoin 52
Adapalene 24
Retinoic acid 10
Motretinide 1
Combination 5
PREGNANCY OUTCOME FOLLOWING EXPOSURE TO TOPICAL RETINOIDS
PHARMACODYNAMICS 1847
Table III Maternal Data
Retinoids Controls P Valuea
Maternal age 222 435
Median, y [range] 30 [21-42] 32 [17-48] .0024
<24, No. (%) 25 (11) 36 (8)
25-30, No. (%) 90 (40) 130 (30)
31-35, No. (%) 70 (32) 168 (39)
35, No. (%) 37 (17) 101 (23)
Gestational weeks at call
Median, wk [range] 7 [3-35] 8 [2-39] .23
Tobacco use, No. (%) 23 (12) 32 (7) .14
Alcohol use, No. (%) 10 (5) 13 (3) .38
a. χ2/Fisher exact or Student/Wilcoxon tests.
Table IV Pregnancy Outcomes and Newborn Data
Retinoids Controls P Valuea
Live born, No. (%) 200 (85) 410 (92)
Spontaneous abortion, No. (%) 19 (8) 26 (6) .19
Elective termination, No. (%) 15 (6) 7 (2) <.001
Therapeutic termination, No. (%) 1 (<1) 0 (0) .16
Fetal death, No. (%) 0 (0) 1 (<1) .65
Gestational age at term
Mean ± SD, wk 39.4 ± 1.9 39.4 ± 2.1 .43
<37 wk, No. (%) 9 (5) 29 (7) .32
Birth weight (n = 192) (n = 362)
Mean ± SD, g 3301 ± 495 3324 ± 567 .32
Sex (n = 193) (n = 349)
Male, No. (%) 94 (49) 178 (51) .55
a. χ2/Fisher exact or Student/Wilcoxon tests.
in both groups were enrolled in the study at a simi-
lar gestational timing, on average at the end of their
second month of pregnancy.
Pregnancy and newborn outcomes are detailed in
Table IV. A total of 200 live births, 19 spontaneous
abortions, 15 elective terminations, 1 therapeutic
termination, and no stillbirths were observed in
the group exposed to topical retinoids. None of the
children showed features of retinoid embryopathy.
The mean (SD) gestational age at delivery was 39.4
(1.9) weeks, and mean (SD) birth weight was 3301
(495) g. Pregnancy outcomes in the control group
included 410 live births, 26 spontaneous abortions,
7 elective terminations, 0 therapeutic terminations,
and 1 stillbirth. The mean (SD) gestational age at
delivery was 39.4 (2.1) weeks, and mean (SD) birth
weight was 3324 (567) g.
The proportion of mothers who spontaneously
aborted or had a therapeutic termination of preg-
nancy was not significantly different in the topical
retinoids group compared with the control group
(8% vs 6% for spontaneous abortion: P = .19; less
than 1% vs 0% for therapeutic termination: P = .16).
However, women in the exposed group were more
likely to undergo elective termination of their preg-
nancy (6% in the exposed group vs 2% in the control
group; P < .001). Gestational age at term, as calcu-
lated from the first day of the last menstrual period
1848 J Clin Pharmacol 2012;52:1844-1851
PANCHAUD ET AL
Table V Birth Defects in Retinoid and Control Group
Retinoids (n = 235) Controls (n = 444) Odds Ratio (95% Confidence Interval)
Major birth defects, No. (%) 8 (3.4) 9 (2.0) 1.8 (0.6-5.4)
Major birth defects in the retinoids group:
n = 1, congenital cerebral cysts (newborn with autism)
n = 1, bilateral polycystic kidneys (early termination of pregnancy at 21 weeks)
n = 1, hemangiomas (all body)
n = 1, angiomas (feet and back)
n = 1, congenital cataract (right eye)
n = 1, microphthalmia (right eye)
n = 1, cleft soft palate
n = 1, ventricular septal defect + congenital pulmonary valve stenosis + coarctation of
aorta + undescended testicle
Minor birth defects, No. (%) 7 (3.0) 11 (2.5) 1.3 (0.4-3.7)
Minor birth defects in the retinoids group:
n = 2, ankyloglossia
n = 1, ear lobe undeveloped
n = 1, blurred vision (hypermetropia)
n = 1, congenital nonneoplastic nevus
n = 1, metatarsus varus
n = 1, other misshapen ear (similar to mother’s ears)
or according to standard algorithms for uncertain
dates or discrepant ultrasound dating, was similar in
both groups (mean [SD], 39.4 [1.9] vs 39.4 [2.1] weeks;
P = .43). The proportion of preterm infants (<37 com-
pleted weeks’ gestation) did not significantly differ
between study groups (5% for the retinoids group vs
7% for the control group; P = .32). No statistical dif-
ference in birth weight was detected (P = .32).
Eight major and 7 minor birth defects among live-
born infants were observed in the retinoids group
compared with 9 and 11, respectively, in the control
group (Table V). One of the major birth defects (ie,
bilateral polycystic kidneys) was diagnosed at week
21 of pregnancy and led to therapeutic termination.
Other than this case, no elective termination or
spontaneous abortion is known to have been moti-
vated or shown by a major malformation. However,
no systematic histopathologic investigation was con-
ducted. There were no significant differences between
the exposed and control groups in the occurrence of
major birth defects (OR [CI], 1.8 [0.6-5.4]) and minor
birth defects (1.3 [0.4-3.7]). Furthermore, none of the
children showed features of retinoid embryopathy in
the retinoids group.
Based on 235 topical retinoid exposures and 444
controls, our study had sufficient power (80%) to
detect a 2.4 increase in the risk for major birth defects
and a 2.5 increase for minor birth defects (α = 0.05
and β = 0.2).
DISCUSSION
To our knowledge, this is the largest prospective
cohort study on reproductive safety of topical reti-
noids during pregnancy. Consistent with previously
published epidemiologic observations, we found no
significant differences in infants exposed to topi-
cal retinoids compared with controls on any out-
come measured, except for elective pregnancy
termination. Furthermore, we found no evidence
of an increase in anomalies consistent with reti-
noic acid embryopathy.
Our findings are also consistent with the lack of
biological plausibility for a teratogenic effect due to
limited systemic bioavailability of retinoids applied
by the transdermal route.6,26 Although appropriate
levels of retinol must be maintained for normal embry-
ogenesis, both deficiencies and excess levels may
be teratogenic. The exogenous application of topical
retinoids is not expected to significantly increase
endogenous levels. A physiologically based pharma-
cokinetic evaluation of topical retinoids predicted that
PREGNANCY OUTCOME FOLLOWING EXPOSURE TO TOPICAL RETINOIDS
PHARMACODYNAMICS 1849
systemic exposure to tretinoin through the skin results
in a 4 to 5 order of magnitude lower exposure than a
minimally teratogenic dose.5 Furthermore, the results
of various studies on the systemic absorption of
retinoids after topical use suggest very low plasmatic
levels. Neither single-dose nor long-term treatment
with topical 0.05% tretinoin cream affected endoge-
nous levels of tretinoin or its metabolites.7 After 42
days of an excessive application of 0.1% isotretinoin
cream, plasma concentrations indicated systemic
absorption but to a lesser extent than reported after
oral intake of 5000 IU of vitamin A supplementa-
tion.27 After topical treatment of the entire facial area
with adapalene 0.1% gel once daily for 12 weeks, no
adapalene could be detected in the plasma of exposed
patients.28 The systematic bioavailability of tazarotene
nears 1% of the dose after single or multiple applica-
tions to healthy skin but might increase up to 5%
under steady-state conditions in patients with psoria-
sis.8 In summary, under usual therapeutic use condi-
tions, an increase in plasma concentration resulting
from topical retinoid application is expected to be far
less than naturally occurring (endogenous) retinoid
plasma levels.
Several case reports of malformations compatible
with retinoid embryopathy after maternal use of topi-
cal tretinoin during the first trimester of pregnancy
nevertheless have been published.11-15 Although it is
certainly possible that these associations were coin-
cidental, a specific individual susceptibility to the
risk of embryopathy from topical retinoids use can-
not be completely ruled out.
The increased number of elective terminations of
pregnancy after inadvertent exposure to topical reti-
noids could not be attributed directly as a cause for
elective termination of pregnancy, as information on
factors influencing the patient’s decision to termi-
nate pregnancy was not reported. However, it is pos-
sible that patients’ or providers’ perceptions of fetal
risk might have contributed to this eventuality. Since
the thalidomide disaster, a high level of anxiety
among patients and physicians has been observed
regarding the use of drugs in general during preg-
nancy. For drugs associated with negative outcomes,
this anxiety can even become deleterious. Thus,
doubts on the safety of a drug can lead to potential
harmful effects such as psychological distress,
abrupt discontinuation of needed medication, and
even termination of healthy and otherwise wanted
pregnancies.29,30
In our study, different retinoids were pooled
together for the statistical analysis. Different com-
pounds, however, may have a different teratogenic
potential, depending on their pharmacotoxicological
activity or susceptibility to absorption in the sys-
temic circulation. The impact of this heterogeneity
on primary end points was explored by logistic
regression analysis, and no effect was observed.
It is well known that the prevalence of congenital
malformations is linked to maternal age. Yet, the dif-
ference observed (32 vs 30 years) is not expected to
significantly change the prevalence of overall con-
genital birth defects according to previous findings.31
This was confirmed by a regression analysis that
indicated that the slight age difference reported in
our study had no impact on the major and minor
birth defect rates (results not shown).
The limitations of this study involve in particular
the relatively small sample size, despite data col-
lected over 10 years and the contribution of 11 TIS
centers. Based on 235 topical retinoid exposure
cases, our study had the power to detect a 2 to 3
times increase in the risk of birth defects. Loureiro
et al17 calculated that their sample size (N = 106) was
sufficient to rule out a 4-fold risk for all major struc-
tural defects combined. Even if the absence of fea-
tures compatible with retinoid embryopathy is
clearly reassuring, smaller effects may not have been
detected. Thus, it is important that more research
is conducted to increase sample size and allow for
detection of infrequent outcomes. Although the
response rate was not 100%, it is important to note
that the rate of loss to follow-up is expected to be the
same in the exposed group and control group as the
cases lost to follow-up are mostly due to technical
reasons (eg, change of address), which should ran-
domly occur, and not because of a refusal to fill in the
questionnaire. We therefore believe that this does not
introduce a significant selection bias. Another limita-
tion was that some factors considered potential con-
founders were not fully documented (ie, street drug
use, concomitant medication, gestity, parity, social
status) for analysis. The effects of potent teratogens
are likely to outweigh concerns surrounding adjust-
ment for confounders. Additional data on potential
confounders, however, would contribute to quantify
moderate increases in risk. Teratogen information
services are likely to provide the most accurate infor-
mation because most cases are reviewed by an expert
in teratology, and the reporter is usually the obstetri-
cian attending the birth. Such centers encourage
follow-up by minimizing the effort for the physician
in terms of paperwork and time, though, thus leading
to a lack of completeness of outcome data. Finally,
other limitations of the study are as follows: recruit-
ment not early enough to assess risk for early first-
trimester miscarriage; reliance on maternal interview
as a source for outcome data in a large proportion of
1850 J Clin Pharmacol 2012;52:1844-1851
PANCHAUD ET AL
cases; variation in timing of follow-up; combining
data from 11 TIS, including 3 centers without control
data (a subanalysis showed no significant difference
on primary end points); and a nonrandomized design
with no blindness to exposure. However, applying
the same procedure to both groups and the prospec-
tive nature of data collected minimize potential biases
(eg, no significant difference on primary end points
observed between recruitment centers; P = .8 for
major birth defects and P = .1 for minor birth defects).
Although not ideal compared with prospective, ran-
domized control trials, such epidemiological sur-
veys have the advantage of easier feasibility and the
merit of providing rapidly useful information.
In summary, women exposed to topical retinoids
during the first trimester of pregnancy do not seem at
higher risk for major birth defects in neonates, above
the baseline rate of 1% to 3%. Furthermore, this study
found no evidence of an increase in anomalies consist-
ent with retinoic acid embryopathy. This evidence-
based information can be helpful to women and health
care professionals who are facing a pregnancy diagno-
sis after maternal exposure to topical retinoids. These
results, together with the previous epidemiologic
observations, allow for reassurance in cases of inad-
vertent exposure during pregnancy. However, accord-
ing to the current knowledge, topical retinoids certainly
cannot be advised for use during pregnancy, as their
risk/benefit ratio remains uncertain.
The authors thank the members of the TIS Madrid (Spain) and
TIS Jerusalem (Israel) who have completed the first part of the
study providing 46 exposed cases.
Financial disclosure: None declared.
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... 20,31 However, a multicenter prospective study revealed no evidence of an increase in anomalies consistent with retinoic acid embryopathy. 32 US FDA classi ed retinoic acid with category C. 5 Until more data are available, it is recommended to avoid using retinoic acid during pregnancy. 20 Alpha hydroxy acid (AHA) has been used in hyperpigmentation with good e cacy. ...
... No evidence of an increase in anomalies consistent with retinoic acid embryopathy was found. 32 -Until more data are available, the safest course is to avoid the use of retinoic acid during pregnancy, especially in the rst trimester. But if inadvertent exposure does occur during early pregnancy, the fetal risk, if any, appears to be very low. ...
Article
Objective: We sought to know the efficacy and safety profile of topical products for use during pregnancy. Methods: We used PubMed, Embase, and Cochrane Library to review literature on topical products and pregnancy. Results: A majority of pregnant women develop skin changes, including physiological or hormonal changes, worsening of preexisting skin conditions, or the appearance of new dermatoses during pregnancy. Most pregnant women are concerned about the availability of treatments options with good safety profiles, especially for skin and hair treatments, to maintain their appearance and health. Although most of the treatments are recommended to be used after delivery, there are some alternatives to prevent and treat skin lesions during pregnancy. Conclusion: The most current and comprehensive information about the efficacy and safety profile of topical products in pregnancy are necessary.
... These reports highlighted the occurrence of holoprosencephaly (a defect in development of the forebrain) in infants whose mothers had been exposed to topical retinoids; however, a subsequent investigation using the European network of population-based registries for the epidemiologic surveillance of congenital anomalies (EUROCAT) did not confirm this suspected association (De Wals et al., 1991). More contemporary case series and observational cohorts also have not corroborated the initial reported finding (Carlier, Choulika, & Dally, 1998;Jick, Terris, & Jick, 1993;Loureiro et al., 2005;Panchaud et al., 2012;Shapiro, Pastuszak, Curto, & Koren, 1997). ...
... Among the third-generational retinoids (bexarotene, tazarotene, and adapalene), only adapalene use in pregnancy has been examined (Panchaud et al., 2012). Panchaud and colleagues conducted a large observational cohort study; however, only 24 pregnant women reported using adapalene, which precluded examination of the risks associated with this exposure separately from that of other topical retinoids. ...
Article
The first pharmaceutical retinoids approved by the U.S. Food and Drug Administration were given black‐box warnings against their use in pregnancy due to potential teratogenic effects. These first‐ and second‐generation retinoids were initially formulated for oral dosing and are structurally very similar to vitamin A, which has beneficial effects on skin as well as plays a vital role in driving healthy embryogenesis. Some of these early retinoids have since been reformulated for topical application, which has resulted in their diminished potential for systemic exposures. Additionally, rational drug design has been applied to create today's third‐generation retinoids (adapalene, tazarotene, and bexarotene). These compounds include aromatic rings within their molecular cores to provide structural rigidity that contrasts with the flexible aliphatic backbone of vitamin A and the earlier generations of retinoids, and thus limits their off‐target activity. As a result of these design features, the teratogenic potential in animals of the third‐generation retinoids and those reformulated for topical use is generally less than seen with oral administration of earlier generations of retinoids. The available, but limited, epidemiologic data further show little‐to‐no teratogenic potential associated with real‐life use of these compounds in humans. Given the paucity of epidemiologic data available at this time, however, it is recommended that the use of topical retinoids during pregnancy be avoided. However, in circumstances when inadvertent exposure in pregnancy may occur, the available data provide some reassurance that adverse pregnancy outcomes are unlikely.
... There have been reports of congenital malformations associated with first-trimester use (31). Some studies found no difference in minor malformations between patients exposed to tretinoin in the first trimester and controls (32)(33)(34). A recent meta-analysis ruled out a major increase in the rates of major congenital malformations, spontaneous abortions, low birthweight, and prematurity (35); however, topical retinoid use in pregnancy is not recommended, because their risk/benefit ratio is questionable. ...
... There is a case report of maternal exposure to adapalene in early pregnancy with fetal anophthalmia and agenesis of the optic chiasma (39). A study including 24 pregnant patients exposed to adapalene in the first trimester did not find any fetal risks from adapalene (32). ...
... However, RA treatment can cause retinoic acid syndrome in many patients, a syndrome characterized by symptoms that include fever, weight gain, respiratory distress, hypotension, and acute renal failure (32). Moreover, RA treatment is associated with developmental anomalies (33). Due to these potential severe side effects, the commonly used dosage of RA has been reduced from 45 to 25 mg/m 2 per day (34); however, the dosage reduction reduces treatment efficacy. ...
Article
Curcumin, the yellow pigment derived from turmeric rhizomes, exhibits antioxidant, anti-inflammatory, antimicrobial, and anticancer properties. We have previously reported in a study that curcumin could induce differentiation in embryonal carcinoma cell (EC). EC cells are the primary constituents of teratocarcinoma tumors, and hence differentiating them to a non-proliferative cell type may be useful in anticancer therapies. Here, we conducted a detailed study using various molecular approaches to characterize this differentiation at the cellular and molecular levels. The cells were treated with 20 µM curcumin, which was the optimal concentration to produce the highest amount of differentiated cells. Changes in protein and RNA expression, membrane dynamics, and migration of these cells after treatment with curcumin were then studied in a time-dependent manner. The differentiated cells were morphologically distinct from the precursor cells, and gene expression profiles were altered in curcumin-treated cells. Curcumin promoted cell motility and cell adhesion. Curcumin also induced changes in membrane fluidity and the lateral mobility of lipids in the plasma membrane. The findings of this study suggest that curcumin might have therapeutic potential in differentiation therapy for the treatment of teratocarcinomas or germ cell tumors (GCTs) such as testicular and ovarian GCTs.
... Although the risk of embryopathies associated to topical retinoids is considered low, Clinical Photograph of 47 years old male patient with oral leukoplakia before and after treatment with topical calcipotriol Clinical photograph showing a case of 49 years male patient with oral leukoplakia before and after treatment with topical tretinoin their use during pregnancy is not recommended because their risk/benefit ratio remains questionable. Therefore, Pregnancy and lactation were also excluded (54) . ...
Chapter
The integumentary system undergoes significant changes during pregnancy. This may lead to new or worsening of dermatological conditions for which the pregnant or postpartum woman may seek over-the-counter remedies or the advice of the health care provider to resolve. Deciding upon an appropriate pharmacological approach is complex and often hazed by the dearth of evidence to guide clinical management. As a result, health care providers are seemingly perplexed concerning the safest course of action for this population. While there are a number of dermatological conditions, clinical guidance regarding common conditions, such as acne, psoriasis, dermatoses, bacterial infections, viral infections, fungal infection, and parasitic infections, can help to provide the much needed direction health care providers often seek.
Article
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The retinoids are a group of compounds including vitamin A and its active metabolite all-trans-retinoic acid (ATRA). Retinoids regulate a variety of physiological functions in multiple organ systems, are essential for normal immune competence, and are involved in the regulation of cell growth and differentiation. Vitamin A derivatives have held promise in cancer treatment and ATRA is used in differentiation therapy of acute promyelocytic leukemia (APL). ATRA and other retinoids have also been successfully applied in a variety of dermatological conditions such as skin cancer, psoriasis, acne, and ichthyosis. Moreover, modulation of retinoic acid receptors and retinoid X (or rexinoid) receptors function may affect dermal cells. The studies using complex genetic models with various combinations of retinoic acid receptors (RARs) and retinoid X (or rexinoid) receptors (RXRs) indicate that retinoic acid and its derivatives have therapeutic potential for a variety of serious dermatological disorders including some malignant conditions. Here, we provide a synopsis of the main advances in understanding the role of ATRA and its receptors in dermatology.
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Introduction: Acne vulgaris is a widespread skin disease. Topical therapy is a standard treatment for mild to moderate acne. Given the complex pathophysiology of acne, various agents with complementary action are nowadays frequently combined to increase the efficacy of therapy. Area covered: This review focus on safety profile of topical agents used for the treatment of acne vulgaris, including topical retinoids, benzyl peroxide, azelaic acid, topical antibiotic, and combined agents. Data from clinical trials but also metanalyses, systematic reviews, and other secondary analyses are presented. Expert opinion: In general, topical agents used for acne vulgaris have a favorable safety profile. The most commonly reported AEs were associated with local skin irritation, usually mild to moderate in intensity, intermittent, and rarely led to the cessation of therapy. Irritative potential seems to be highest for BPO and topical retinoids. Due to the possibility of development of Cutibacterium acnes resistance, topical antibiotics should not be used in monotherapy but as a part of combination therapy. In female adolescent and adults of childbearing potential, topical retinoids should be used with caution, because they are contraindicated in pregnant females (FDA Pregnancy category) C (adapalene, tretinoin) and X (tazarotene).
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Perception of risk may impact a woman's decision to take a needed drug during pregnancy. There is a paucity of research on this topic in the literature. (1) To evaluate the perception of risk of 17 commonly used drugs and other substances by pregnant women. (2) To investigate which sources of information regarding exposures during pregnancy were most commonly used by women. A questionnaire was developed through the University of Oslo's website for Internet surveys and posted on four Web pages used by pregnant women and mothers, from mid-September 2008 through October 2008. The inclusion criteria included women who were (1) pregnant or 2) a mother of a child less than 5 years old. A total of 1,793 eligible women completed the questionnaire. Most women overestimated the teratogenic risk associated with all the drugs during pregnancy. Characteristics of the women that were associated with a high perception of risk were primiparity, higher age, higher education, and choosing not to use a drug during pregnancy. More than 80% of the women had used drugs during pregnancy, mostly paracetamol, penicillins and reflux medications. The physician, the product information leaflet and the pharmacist were the three most frequently used sources of information. Women overestimate the risk of drug use and other exposures during pregnancy. Therefore, it is important for health care providers to use evidence-based information, to reduce unnecessary anxiety, and to ensure safe and appropriate treatment during pregnancy.
Article
Retinoids have a high teratogenicily for all species when administered orally. After topical use, derivatives available on French market (tretinoide, isotretinoide, adapalene) have been tested on animals. Results depend on the species and are sometimes contradictory. A small risk cannot be excluded but a high risk, of congenital anomalies, in the children of women treated with topical preparations during pregnancy is unlikely. Three isolated, différents and discussible malformations have been published. Nevertheless, French Medicine Agency asked for this survey. 132 cases have been collected and prospectively followed up. They come from Centres Régionaux de Pharmacovigilance and Centre de Renseignements sur les Agents Tératogènes. Women have a mean age of 29.5 (14-41). Exposure generally occurs within organogenesis (94 cases). 94 follows up are consistent and are normal in 76 cases (pregnancy, outcome and child). 8 miscarriages and 4 elective abortions are reported. One medical abortion for malformations is notified after adapalene applications (published case). Two fetal deaths occurred, one by cordonal link, the other one by oligoamnios. One neonatal death happened on one premature twin presenting hyaline membrane disease. Two malformations are described, one unilateral punctiform cataract and one congenital hydrocele associated to bilateral equinovarus. So, rates of miscarriages (8/94) and malformations (3/94) are those expected in general population. The legal mentions actually on use for these products (strict precaution with informative data) remain justified (considering the teratogenicily after oral administration) and are sufficient (in regard to contradictory anormal data, poor published human data and not worry results of this evaluation).
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Tazarotene (AGN 190168) is a new acetylenic retinoid which is effective for the topical treatment of patients with stable plaque psoriasis and mild to moderate acne vulgaris. Topical gel application provides direct delivery of tazarotene into the skin. At 10 hours after a topical application of 0.1% tazarotene gel to the skin of healthy individuals and patients with psoriasis, approximately 4 to 6% of the dose resided in the stratum corneum and 2% of the dose distributed to the viable epidermis and dermis. Tazarotene is rapidly hydrolysed by esterases to its active metabolite, tazarotenic acid. Tazarotenic acid does not accumulate in adipose tissue, but undergoes further metabolism to its sulfoxide and to other polar metabolites and is rapidly eliminated via both urinary and faecal pathways with a terminal half-life of about 18 hours. Percutaneous absorption is similar between healthy individuals and patients with facial acne, leading to plasma concentrations below 1 μ.g/L. The systemic bioavailability of tazarotene (measured as tazarotenic acid) is low, approximately 1% after single and multiple topical applications to healthy skin. In patients with psoriasis under typical conditions of use, systemic bioavailability increased during the initial 2 weeks of treatment from 1% (single dose) to 5% or less (steady state). The increased bioavailability is probably related to decreases in plaque elevation and scaling due to successful treatment, resulting in a less effective skin penetration barrier to tazarotene. Steady-state concentrations of tazarotenic acid are achieved within 2 weeks of topical treatment in both healthy and psoriatic skin types. The large variability in plasma concentrations observed in patients with psoriasis is probably because of the large differences in lesional skin condition, the amount of drug applied and the surface area of application. There was no significant drug accumulation in the body with long term treatment of patients with psoriasis. Topical administration of tazarotene requires dosages much smaller than those usually required for oral retinoids, such as isotretinoin, acitretin and etretinate, and it delivers the drug directly into the target skin tissues. The low systemic absorption and rapid systemic elimination of tazarotene and tazarotenic acid results in limited systemic exposure. Thus, topical tazarotene has a low potential for systemic adverse effects and is effective in the treatment of patients with acne and psoriasis.
Article
A single application of 17 g/kg or 8.7 mg/kg all-trans- [10,11-3H2]-retinoic acid dissolved in acetone to shaved dorsal hamster skin resulted in rapid absorption and dose-dependent rates of elimination. An equation describing a two-compartment open model with a very brief lag time and first-order uptake and elimination was used to describe the central plasma compartment kinetics. Unchanged all-trans-retinoic acid represented 4% of the total circulating radioactivity. Peak circulating concentrations of parent all-trans-retinoic acid were less than those observed after an equivalent oral dose, but prolonged absorption from the skin appears to contribute to high total bioavailability of topical retinoid. Topical administration to intact skin of up to three consecutive doses of 10.5 mg/kg/d all-trans-retinoic acid or a single 5 mg/kg dose of etretinate (Ro 10-9359) during a critical stage of embryogenesis in hamsters caused erythema and/or dose-dependent epidermal hyperplasia at the site of application, but failed to induce a significant teratogenic response. Topical application of 0.01–1.0 mg/kg arotinoid Ro 13- 6298 resulted in dose-dependent mucocutaneous toxicity and an increase in the numbers of dead embryos and malformed offspring. The marked skin toxicity and attenuated concentrations in maternal blood, compared to the oral route, limit the amounts of retinoid that can reach the hamster embryo. It is thus more important to compare the retinoid systemic values (absorbed dose) than it is to compare the oral or topical (applied) dose, when interpreting the results of conventional teratogenicity bioassays. The data suggest that in the human it is skin toxicity that limits the amounts of retinoid that can be applied and subsequently reach the embryo. In the rodent, overt skin toxicity under continued dosing could increase the amounts of retinoid penetrating the skin and reaching the embryo.
Article
The percutaneous absorption of clindamycin was studied in healthy male volunteers, comparing two investigative clindamycin (% w/v)/tretinoin (0.025% w/v) gels, containing clindamycin phosphate ester and clindamycin HCl, respectively, relative to a clindamycin phosphate lotion (1% clindamycin; Dalacin T®). Formulations were applied daily for 5 days on the face, according to a balanced complete block design. Redness of the skin was scored visually, and blood and urine were collected. Clindamycin plasma levels did not exceed the limit of quantification (5 ng mL−1) with the clindamycin phosphate formulations, but one volunteer who received the clindamycin HCl/tretinoin gel showed plasma levels of up to 13 ng mL−1. Clindamycin urinary excretion for 12 h after application of the clindamycin phosphate/tretinoin gel was comparable to the values of the reference lotion, whereas the clindamycin HCl/tretinoin gel gave significantly higher values. Erythema appeared to be associated with increased urinary excretion. The formulations were tolerated well. In a separate clinical pilot study in acne patients, the transdermal uptake of tretinoin and clindamycin from the clindamycin phosphate/tretinoin gel was monitored. Plasma samples were collected after 4 and 12 weeks of daily treatment. None of the study plasma samples contained measurable tretinoin levels. Clindamycin levels were not quantifiable in the majority (87%) of samples, the highest plasma level was 11 ng mL−1. The chemical form of clindamycin proved to modulate skin irritation and percutaneous uptake of clindamycin from a gel formulation in healthy subjects. There was no indications for a notable transdermal uptake of tretinoin during daily application of the gel in patients, nor for an enhancing effect of tretinoin on clindamycin uptake. Copyright © 1998 John Wiley & Sons, Ltd.
Article
Question: Many of my female patients complain about acne, unwanted hair growth, and other skin problems that have only developed since they became pregnant. Are products used for these types of benign skin conditions safe to use in pregnancy, as it is understandable that women want to look their best at this important time in their lives? Answer: With the exception of hydroquinone, which has a relatively high systemic absorption rate, and tretinoin, for which the evidence is controversial, these products act locally and therefore produce minimal systemic levels. Consequently, in most cases women can deal with these cosmetically unappealing skin conditions without compromising the safety of their unborn children.
Article
The potential systemic availability of retinoids from topically applied isotretinoin was assessed in 12 men with acne vulgaris. Isotretinoin 0.05% gel was applied to patients at a daily dose of 20 gm (equivalent to 10 mg of isotretinoin) over a 1900 cm2 surface area of skin on the face, back, and chest for 30 days. Blood samples were collected throughout the study and up to 48 hours after the last topical application; they were assayed for isotretinoin, tretinoin, and 4-oxo-isotretinoin by specific high-performance liquid chromatography. Plasma concentrations of isotretinoin, tretinoin, and 4-oxo-isotretinoin were not measurable (less than 20 ng/ml) at any time. Most adverse experiences were cutaneous; a few systemic adverse experiences were judged to be remotely related to topical drug administration. The lack of measurable plasma concentrations of isotretinoin, tretinoin, or 4-oxo-isotretinoin and systemic adverse experiences indicates negligible systemic availability of retinoids even after multiple application of isotretinoin 0.05% gel at doses approximately 12 times greater than normal daily use.