Tretinoin (Topical) in Pregnancy and Breastfeeding

Risk Factor: CM
Class: Vitamins

Contents of this page:
Fetal Risk Summary
Breast Feeding Summary
References
Questions and Answers

Fetal Risk Summary

Tretinoin (all-trans retinoic acid; retinoic acid; vitamin A acid) is a retinoid and vitamin A (retinol) metabolite used topically for the treatment of acne vulgaris and other skin disorders and systemically in the treatment of acute promyelocytic leukemia (see Tretinoin [Systemic]). Like other retinoids, the drug is a potent teratogen following exposure in early pregnancy (see also Etretinate, Isotretinoin, and Vitamin A), producing a pattern of birth defects termed retinoic acid embryopathy (central nervous system, craniofacial, cardiovascular, and thymic anomalies). The teratogenic effect of tretinoin is dose dependent in that an endogenous supply of retinoic acid is required for normal morphogenesis and differentiation of the embryo, including a role in physiologic developmental gene expression (1).

Low serum concentrations or frank deficiency of vitamin A and all-trans retinoic acid is also teratogenic. Recent studies have shown that inhibition of the conversion of retinol to retinoic acid or depletion of retinol may be involved in the teratogenic mechanisms of such agents as ethanol (2,3,4,5 and 6) and some anticonvulsants (7).

The extensive literature on the teratogenicity of tretinoin in various animal species has been summarized in a number of sources (8,9,10,11 and 12) . The latter Reference has particular application to the study of the teratogenic effects of tretinoin because it was an examination of the toxicity of very small doses of this compound at presomite stages in mouse embryos, thought to be the most sensitive period for retinoid-induced teratogenesis (12). An increasing incidence of severe microphthalmia, anophthalmia, and iridial colobomata was produced as the dose was increased from 0 to 1.25 mg/kg. These doses were much less than those typically used for reproductive toxicity testing at later gestational periods. Slightly higher threshold doses produced exencephaly (2.5 mg/kg) and marked craniofacial defects (7.5 mg/kg) representative of the holoprosencephaly-aprosencephaly spectrum (12).

When used topically, the teratogenic risk of tretinoin had been thought to be close to 0 (13). According to one source, no cases of toxicity had been reported after nearly 20 years of use (13). In support of this, it has been estimated that even if maximal absorption (approximately 33%) occurred from a 1-g daily application of a 0.1% preparation, this would only result in about one-seventh of the vitamin A activity received from a typical prenatal vitamin supplement (14). One Reference source stated that 80% of a 0.1% formulation in alcohol remained on the skin's surface, but when a 0.1% ointment was applied to the back with a 16-hour occlusive dressing, only 50% of the drug remained on the skin surface and 6% was excreted in the urine within 56 hours (15). Authors of a 1992 Reference reviewed the teratogenicity of vitamin A and its congeners, including tretinoin, but did not derive a conclusion on the safety of the drug following topical use (16), most likely because of the lack of studies with the drug in pregnancy.

In two brief reports, congenital malformations in newborns whose mother's were using tretinoin during the 1st trimester were described (17,18). The first case involved a woman who had used tretinoin cream 0.05% during the month before her last menstruation and during the first 11 weeks of pregnancy (17). Her term, growth-retarded (weight 2620 g, <3rd percentile; length 49 cm, 25th percentile; head circumference 32.5 cm, 3rd percentile), female infant had a crumpled right hypoplastic ear and atresia of the right external auditory meatus, a pattern of ear malformation identical with that observed with vitamin A congeners (17). The remainder of the examination was normal, including the eyes, cerebral computed tomography, and chromosomal analysis. The second report contained the description of the female infant of a woman who had used an over-the-counter alcohol-based liquid preparation of 0.05% tretinoin for severe facial acne (18). The infant had multiple congenital defects consisting of supraumbilical exomphalos, a diaphragmatic hernia, a pericardial defect, dextroposition of the heart, and a right-sided upper limb-reduction defect.

The results of a prospective survey involving 60 completed pregnancies exposed to tretinoin early in pregnancy were presented in a 1994 abstract (19). From these pregnancies there were 53 liveborns (1 set of twins), 3 lost to follow-up, 4 spontaneous abortions, and 1 elective termination. No major malformations characteristic of retinoic acid embryopathy were observed except for one case in which the mother had also taken isotretinoin.

Among 25 birth defect cases with 1st-trimester exposure to tretinoin reported to the FDA between 1969 and 1993, 5 were cases of holoprosencephaly (20). Six other cases of holoprosencephaly involved other vitamin A derivatives: isotretinoin (N=4), etretinate (N=1), and megadose vitamin A (N=1). In contrast, among 8,700 non-retinoid-exposed birth defect reports to the FDA, only 19 involved suspected holoprosencephalies (20). However, other data from 1,120 apparent 1st-trimester exposures to tretinoin were examined. Among the 49 birth defects observed (the expected incidence), no cases of holoprosencephaly were seen. Although it is speculation, the contrasting findings in the above two reports (19,20) on early pregnancy tretinoin exposure may reflect (a) fetal exposure to different doses of tretinoin at the critical times from the use of higher maternal doses or from enhanced systemic absorption, or (b) biased reporting of adverse pregnancy outcomes to the FDA.

A 1993 report summarized data gathered from the Group Health Cooperative of Puget Sound, Washington, involving 1st-trimester exposure to topical tretinoin and congenital malformations (21). A total of 215 women who had delivered live or stillborn infants and who were presumed to have been exposed to the drug in early pregnancy were compared with 430 age-matched nonexposed controls of live or stillborn infants delivered at the same hospitals. A total of 4 (1.9%) infants in the exposed group had major anomalies compared with 11 (2.6%) in the controls, a relative risk of 0.7 (0.22.3) (21). The defects observed in the exposed group of infants were hypospadias, undescended or absent testicles, metatarsus adductus, and esophageal reflux. The three stillborn infants in the exposed group were all associated with umbilical cord accidents. The authors concluded that these data provided no evidence for a relationship between topical tretinoin and the congenital abnormalities normally observed with other vitamin A congeners or for an increased incidence of defects compared with data from women not using tretinoin (21).

A brief 1997 report described a prospective, observational, controlled study that compared the pregnancy outcomes of 94 women who had used topical tretinoin during pregnancy with 133 women not exposed to topical tretinoin or other known human teratogens (22). Both groups were composed of pregnant women who had contacted a teratology information service between 1988 and 1996. No differences between the groups were found for the number of live births, miscarriages, elective terminations, major malformations, duration of pregnancy, cesarean sections, birth weight (after exclusion of one baby weighing 5396 g in the control group), and low birth weight. Two live-born infants from the tretinoin-exposed group had major birth defects: a bicuspid aortic valve in one and dysplastic kidneys in one. Neither of the defects is consistent with retinoic-acid embryopathy (22). Malformations in the four infants from the control group were congenitally dislocated hip in two, aortic valvular stenosis in one, and inperforate anus in one.

In summary, elevated serum concentrations of all-trans retinoic acid in early gestation are considered teratogenic in humans. Because of its relatively poor systemic absorption (if occlusive dressings are not used) after topical administration, however, tretinoin is not thought to present a significant fetal risk. Congenital malformations have been reported following topical use of this compound and, although a causal association has not been established, may reflect (a) greater-than-normal fetal exposure from higher-than-usual maternal doses or enhanced systemic absorption or (b) biased reporting of adverse outcomes. Most of the evidence, however, indicates that topical tretinoin does not increase the risk for congenital malformations.

Breast Feeding Summary

Vitamin A and, presumably, tretinoin (all-trans retinoic acid) are natural constituents of human milk. No data are available on the amount of all-trans retinoic acid excreted into milk following topical use. Although other retinoids are excreted (see Vitamin A), the minimal absorption that occurs after topical application of tretinoin probably precludes the detection of clinically significant amounts in breast milk from this source.

References

  1. Morriss-Kay G. Retinoic acid and development. Pathobiology 1992;60:26470.
  2. Keir WJ. Inhibition of retinoic acid synthesis and its implications in fetal alcohol syndrome. Alcohol Clin Exp Res 1991;15:5604.
  3. Pullarkat RK. Hypothesis: prenatal ethanol-induced birth defects and retinoic acid. Alcohol Clin Exp Res 1991;15:5657.
  4. Duester G. A hypothetical mechanism for fetal alcohol syndrome involving ethanol inhibition of retinoic acid synthesis at the alcohol dehydrogenase step. Alcohol Clin Exp Res 1991;15:56872.
  5. Dreosti IE. Nutritional factors underlying the expression of the fetal alcohol syndrome. Ann NT Acad Sci 1993;678:193204.
  6. DeJonge MH, Zachman RD. The effect of maternal ethanol ingestion on fetal rat heart vitamin A: a model for fetal alcohol syndrome. Pediatr Res 1995;37:41823.
  7. Fex G, Larsson K, Andersson A, Berggren-Sderlund M. Low serum concentration of all-trans and 13-cis retinoic acids in patients treated with phenytoin, carbamazepine and valproate. Possible relation to teratogenicity. Arch Toxicol 1995;69:5724.
  8. Schardein JL. Chemically Induced Birth Defects. 2nd ed. New York, NY: Marcel Dekker, 1993:55562.
  9. Shepard TH. Catalog of Teratogenic Agents. 8th ed. Baltimore, MD: Johns Hopkins University Press, 1995:3703.
  10. Sanders DD, Stephens TD. Review of drug-induced limb defects in mammals. Teratology 1991;44:33554.
  11. Apgar J, Kramer T, Smith JC. Retinoic acid and vitamin A: effect of low levels on outcome of pregnancy in guinea pigs. Nutr Res 1994;14:74151.
  12. Sulik KK, Dehart DB, Rogers JM, Chernoff N. Teratogenicity of low doses of all-trans retinoic acid in presomite mouse embryos. Teratology 1995;51:398403.
  13. Kligman AM. Question and answers: is topical tretinoin teratogenic? JAMA 1988;259:2918.
  14. Zbinden G. Investigations on the toxicity of tretinoin administered systemically to animals. Acta Derm Venereol (Stockh) 1975;Suppl 74:3640.
  15. American Hospital Formula Service. Drug Information 1996. Bethesda, MD: American Society of Health-System Pharmacists, 1996:260810.
  16. Pinnock CB, Alderman CP. The potential for teratogenicity of vitamin A and its congeners. Med J Aust 1992;157:8049.
  17. Camera G, Pregliasco P. Ear malformation in baby born to mother using tretinoin cream. Lancet 1992;339:687.
  18. Lipson AH, Collins F, Webster WS. Multiple congenital defects associated with maternal use of topical tretinoin. Lancet 1993;341:13523.
  19. Johnson KA, Chambers CD, Felix R, Dick L, Jones KL. Pregnancy outcome in women prospectively ascertained with Retin-A exposures: an ongoing study (abstract). Teratology 1994;49:375.
  20. Rosa F, Piazza-Hepp T, Goetsch R. Holoprosencephaly with 1st trimester topical tretinoin (abstract). Teratology 1994;49:4189.
  21. Jick SS, Terris BZ, Jick H. First trimester topical tretinoin and congenital disorders. Lancet 1993;341:11812.
  22. Shapiro L, Pastuszak A, Curto G, Koren G. Safety of first-trimester exposure to topical tretinoin: prospective cohort study. Lancet 1997;350:11434.

blog comments powered by Disqus

Questions and Answers

Is a topical tretinoin cream (Retin-A) safe to use while nursing?, I read that applying this after childbirth will diminish the appearance of stretchmarks, but is it safe to use while breastfeeding?

It is not known if this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when administered to a nursing woman. I would either talk to your doctor or even a pharmacist just to be sure.

when i should be using tretinoin and erythromycin topical?, my derm said it doesn't matter if i use either one at night or morning but he did say that if i use tretinoin during the day to use sunscreen. but i have been using the erythromycin during the night instead of the tretinoin because the eryhromycin makes my skin so dry and white and when i put my moisturizer on it still makes it look scaly and later in the day makes it look so oily. any opinoins? i use oil free neutrogena moisterizer with spf 30

well for you if your going to cont. .. your regimen.. the Tretinoin or Retina A should only be used at night.. or definately with a sunscreen .. cause.. will cause your to breakout more.. sunburn etc...and the emycin anytime day or night... emycin during the day.. and Retina A at night.... but here i wanna give you my story: THIS WORKS FAST & CHEAP!!! I used Tetracyclin, Proactive, Retina A and had many expensive facials with less than good results. This has worked for me and many many other happy people. Go to pharm.,Drug store, or Walmart, buy "PURPOSE" bar of soap - Blue box - Made by Johnson & Johnson - wash your face with this 2-3x's per day. Also pick up a LOW strength Benzoyl-peroxide cream, apply the cream by dabbing to the individual blemishes.... DONT rub it in works using a oxidation/reduction reaction...DONT over use this or put anywhere else on your face.. It will cause drying and make you look worse. Also, If need which probably will for moisture ASK FOR "NUTRADERM lotion" - the orginal not the new stuff, this works great and wont clog pores or leave a residue on your skin...Additonal TIPS: acne, pimples, etc are frequently cause by a bacteria or hormone issues.... DONT PICK POP POKE (your hands are the dirtiest part of your body) and will cause: infections, spreading of germs, more breakouts and scarring DONT EVER listen to people online who tell you to scrub your sensative skin or use harsh chemicals such as: Lemon juice, vinagar, alcohol, etc... DONT EVER use that APRICOT CRAP!!! DONT USE PROACTIVE- this is expensive and harsh it may kill the bacteria cause also Benzoyl based wash but will irritate skin and cause bleaching of face and neck.... Other similar treatments may work.. also things such as Accutane but have serious side effects.... THIS WORKS FAST AND CHEAP!!! I no longer get expensive facials, take oral antibiotics, or even NEED makeup... I am very happy - Have very good skin... and have many many other happy friends... THANKS again to my WONDERFUL DERMATOLOGIST... TRY THIS!! GOOD LUCK.... PS. "PURPOSE" costs about $3

tretinoin cream and clindaymcin phosphate topical lotion?, i just got 2 medicines from my doctor...its for my acne..
and it tells me to use the cream on the affected areas.
is it telling me to put it all over my face or just my pimples?

No just apply it on the pimples.I prefer Tretinoin cream.The ideal way is alternate the two treatments.
Treinoin makes your skin extremely sensitve to sunlight,and exposure to the sun after its application may give you a sunburn.Apply treatments a few hours before bedtime.
Drink a lot of water.Stay away from milk and shellfish.
Dont wash your face hundred timed a day.Over washing dries the skin out and your oil glands produce more oil to compensate for this dryness.Tretinoin will make your skin peel.It is one of the ways it works.Dont worry.Use a wash cloth to gently buff away the flaky skin.Good luck.

How long until acne disappears using tretinoin?, I am washing my face with a benzoyl peroxide topical wash 5% and then applying tretinoin gel 0.01% every night. Is this effective? and if it is, how long must i wait? (If it isn't, then what must i do to make it effective?)

I use Tretinoin cream (0.025%) and a 2% Benzoyl Peroxide wash. Don't worry about the percents of the products, i have sensitive-ish skin and i know that my face gets dry fast when using harsh products. I haven't been on my perscription for long, only about two weeks. The first few weeks you use tretinoin your face will be gross. I broke out some more the first week and my face started to peel. Right now my face is getting clearer and all the acne i had before is beginning to heal. The only sucky part is that my face still peels a bit, it still stings, and it is a little red. The reason this happens is because tretinoin cuases your skin to renew and flake off to reveal new clear skin. I wish i could tell you how long it takes for your acne to clear, but i really think it depends on each person's condition. I do think your regimen will work for you, you just have to give it some time. I think in a few months (hopefully) your skin will be used to the cream. Acne doesn't clear up over night, so it will probably take a while to clear. :/

how does erythromycin topical 2% work for acne?, how long does it take to see results. does it make ur face worse before getting better or does just kill existing bacteria? i use this in the evening and use tretinoin 0.05% in the morning with sunscreen.

Right now I am using benzemycin and it has erythromycin and benzate in it, my face is getting sligtly better I have been using it for one week now. It is making my face super dry though so I am using lotion to keep it less dry.

Changes in my skincare regimen, sublock, exfoliater, anti-biotics... help PLEASE!!?, Ok, so I have severe acne, whiteheads all over from my forehead to my neck and chest, to my back and shoulders.
Sorry to be gross but it's the truth.
It has been a problem for me since fourh grade and I am now a sophomore in high school.
Finally I went to my dermatologist because I have tried everything such as:
-Proactive
-Clean and Clear
-Neutrogena
-Proactive Gentle Formula
-SensiClear
-Clearisil Ultra, and many others.
So I was prescribed two treatments, one is an atibiotic, menacycline, and the other is a topical treatment tretinoin.
They are known to cause severe skin sensitivity and dryness. So my dermatologist recomended a sunblock. Also she recomended the neutrogena Oil-Free Acne Wash. So I need to drastically change my skincare regimen.

Here is my current regimen:
- Proactive Gentle Formula Facial Scrub
- Proactive Gentle Formula Toner
- Proactive Gentle Formula Night and Day Lotion
And on occassion when I get dry
- Proactive Green Tea Moisturizer

I hae extremely oily skin but these products are known to cause severe dryness and sunburns, so this is what I have to add to my regimen:

- Oil Free SPF 15 sunblock
- Neutrogena Oil Free Acne Wash
- Tretinoin (topical cream)
- Menacycline (antibiotic)

Now I am supposed to take the Menacycline twice a day, and apply the Tretinoin at night before bed.
I still want to exfoliate every once in a while or maybe every night, idk.
My dermatologist said to use a face wash with Salicylic Acid which both my current Cleanser and my new Neutrogena Acne Wash have. So idk if I should use my Proactive scrub at night or buy something new or what. Idk when to use these new things, should I still use the toner and lotions? I really don't know what to do.
Help, Please and Thank You.

Don't stress out about this, may cause more acne. When i stress i break out. Just ask your dermatologist what to do?

should i try accutane?, i have mild acne, but can't seem to find something that works for me. i have tried all over-the-counter (clean and clear, clearasil, neutrogena, etc.) washes, toners, pads, everything. and i also started using prescribed medications such as minocyclin (oral) and tretinoin (topical), which didnt do anything. i really want accutane, but i'm afraid they won't prescribe it to me because my acne won't be "severe" enough. however, i feel it's the easiest way, and i'm tired of waiting for the right answer. i know the side effects , and i think it's worth it, 100%. what should i do?

I developed mild acne case thru out my puberty. I tried many different acne medicine/ ointment and didnt get anywhere too far!
My doctor prescribed accutane when i was 19 and was told it will supress the acne for the next few years, and hopefully once i passed the puberty, i wont need it anymore.
It worked exactly as anticipated. Acne gone...
I wish i had taken accutane earlier and do not have to live with old scar now.
Just make sure you go over all the side effects with the doctor before you take them... it is a very strong medication!

Retinoids and cod liver oil?, I currently use a topical .05% tretinoin cream; would it be unwise/unsafe for me to take cod liver oil supplements as well? Do I risk a vitamin A overdose?

i would strongly suggest that you ask your pcp this question. because every1 person's body is different. Vitamin A overdose could mean something different for me than for you. what I'm trying to say is that every1's symptoms aren't always the same.

african americans who want to bleach there skin i found the answer plus its safe and very effective!?, Recent Study Shows Favorable Results of Solage(R) (mequinol 2%, tretinoin 0.01%) Topical Solution for the Treatment of Solar Lentigines in Dark Skin Types
Over 80% of Subjects Showed Significant Response to Treatment
PrintE-mailDisable live quotesRSSDigg itDel.icio.us

Last Update: 4:09 PM ET Jan 12, 2007


PRINCETON, NJ, Jan 12, 2007 (MARKET WIRE via COMTEX) -- Currently, Solage(R) (mequinol 2%, tretinoin 0.01%) Topical Solution is the only combination product approved in the United States for the treatment of solar lentigines, commonly known as "age spots," that contains two active ingredients, mequinol and tretinoin. Solar lentigines are localized, pigmented, macular lesions of the skin on the areas of the body that have been chronically exposed to sunlight and are a common dermatologic condition that affects all skin types. Often referred to as "age," "sun" or "liver" spots, solar lentigines commonly appear as medium to dark brown spots in areas on the face, hands, forearms

Come on are you serious????do you forget what the riches pop-star in the world some 10 to15 years back tried.all the money in the world still couldn't make Micheal Jackson a Caucasian man.Look at it this way!! If GOD ALMIGHTY wanted you to be born a white man or fair skinned,don't you think he would have made you that way.YOU know kid it doesn't matter what people say or think.it should only matter what number "1" thinksYOU.and when ever someone else tries and makes someone feel bad about ones self or feel like there the wrong color or they don't fit in ,,It's because this person that's trying to make someone else feel worthless,really feels worthless about themself.what better way to make themselves look good then too talk openly about another.So don't listen too lossers.Believe in yourself!!!!!!!!!!!!!!!!!!!!!!!!!!!!!