The FDA has a new rating system for breastfeeding risks with medications. We look at what that changes for psychotropics.
Publication Date: 12/19/22
Duration: 18 mins, 20 seconds
Chris Aiken: In 2015 the FDA changed how they classify breastfeeding risks, but they gave pharmaceutical companies a few years to update their meds. Today, we look at how psychiatric medications fare in the new system.
Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the editor-in-chief of the Carlat Report.
Kellie Newsome: And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.
Last week we named the riskiest psych meds in pregnancy
- Paroxetine (Paxil), valproate (Depakote), lithium, carbamazepine, tricyclic antidepressants (particularly clomipramine), benzodiazepines, and stimulants like Ritalin and Adderall.
And reminded you that just because they are risky doesn’t mean you shouldn’t use them. Untreated psychiatric illness poses threats as well. But just because a medication is high risk in pregnancy doesn’t mean it is high risk for breastfeeding. Carbamazepine and valproate look much safer for the breastfeeding infant than they do in the womb.
When it comes to pregnancy, we worry about teratogenicity as the organs develop, but when it comes to breastfeeding the risks are very different. There we worry about how much the medication passes into the breast milk and what the risks of toxicity are. Those toxicity risks are similar for adults as they are for infants – so manly we’re worried about sedation and depressing respiration.
The safer drugs in breastfeeding are: Sertraline, bupropion, the atypical antipsychotics, buspirone, and – surprisingly – the z hypnotics, particularly zaleplon (Sonata) which has a favorable L2 rating – probably because of its short half life.
Chris Aiken: Kellie just dropped some terminology we best explain. On June 30, 2015 the FDA dropped the A B C D and the dreaded X grading system for medications in breastfeeding and switched to Lactation Risk Categories, which are rated L1 – the safest – to L5 – the riskiest. Wait a minute. They went from a 5 tiered letter system to a 5 tiered numeric system – what is really gained here?!?
Well, whether you use A B C D or 1 2 3 4 is arbitrary, but what is new is how medications are classified. The new system considers more detailed information when assigning risk level, and the descriptions of the L1 2 3 4 5 risks are more meaningful.
L1 Compatible. We have good studies and no harm was found.
L2 Probably Compatible. Here the studies are poorer in quality, but they show either no risk or a very remote possibility of risk. Zaleplon (Sonata), trazodone, paroxetine (Paxil) are L2. Olanzapine and haloperidol get an L2, but most other antipsychotics fall in L3 or below.L3 Probably Compatible, but largely unknown. This is where the FDA places new medications that we know nothing about. In the past they automatically received a deceptively safe rating of category B until we learned the real truth about them. This is one of the more meaningful changes of the system – I mean, I’m a humanist, and I believe people are innocent until proven guilty. But medications? They are guilty until proven innocent. This L3 category also includes medications where a risk is known, but it’s not a serious risk –it’s minimal and non threatening. Several sleep medications are L2, but a few made it into this riskier L3 category – namely zolpidem (Ambien), the benzos, and the newer untested sleep meds. There are several antidepressants in the L2 category, but a few fell down to L3, and that’s news – because most of these had the same rating in the FDA’s old system. Antidepressants with an L3 include bupropion, citalopram, escitalopram, fluoxetine, Mirtazapine, venlafaxine, and vortioxetine. Lamotrigine is also L3, which is controversial – there are lots of studies supporting its safety in pregnancy, but there is the possibility of an allergic rash in the infant. In theory, lamotrigine is probably safe if the baby was exposed to it in the womb, but if a new titration is started while breastfeeding there’s going to be a risk of a rash for the infant as well as the mother.
To pause and summarize, L1-L3 are categories where it might be safe to continue the medication. As we move toward L4 and L5, the hazards pile up and we start to worry more.
L4 Possibly Hazardous: Here there is a clear risk to a breastfed infant or to breastmilk production, but the risk is either low enough or non-serious enough that the FDA believes use of the medication is justified as long as it’s being used for a serious illness. Lithium, nefazodone, quetiapine, ziprasidone, and several older antipsychotics are L4.L5 Hazardous. Here the risk of significant damage to the infant is significant, and the drug is contraindicated during breastfeeding. We know of two psych meds in the L5 category: Doxepin, the tricyclic that is sometimes used for sleep, and the anti-alcohol med disulfiram (Antabuse), but bromocriptine falls there – and some people use this dopamine agonist to treat prolactinemia on antipsychotics. Kava-Kava, Kombucha Tea, and DHEA – which some women take over the counter – are also L5, as are most drugs of abuse including methamphetamine, cocaine, cannabis, and dextroamphetamine – that’s right Vyvanse/Dexedrine – when used in the high doses that it is abused in. In a few cases, the FDA adjusts the rating based on how old the breast feeding baby is, most notably with Fluoxetine (Prozac). This is considered relatively safe in infants (L2), but riskier in neonates – those less than one month old – where it gets an L3. This is a problem for Fluoxetine because women need to start breastfeeding right away for lactation to work.
The FDA has also discarded the A-X grading system for meds during pregnancy, replacing it instead with a more detailed description of the actual risks. However, most PDR sheets have not caught up and still include the pregnancy grade.
The final part of the FDA ruling added a new section to the prescribing information that details risks to Reproductive Potential. We expect more data to come here, but already see that paroxetine (Paxil) may decreased sperm quality, Fluvoxamine has been associated with blood in the semen, and several psych meds – most notably anticonvulsants – are associated with rare cases of inflammation of the tube that sperm pass through, epididymitis, and a few others like venlafaxine and quetiapine are associated with rare inflammation of the testicles, Orchitis.
Kellie Newsome: Back to breastfeeding. Here are some of the things we worry about with tThe riskier drugs in breastfeeding:
- Benzodiazepines: Sedation and, with anything that causes sedation, respiratory suppression
- The tricyclics: Constipation and – with doxepin – sedation
- Nefazodone and trazodone – sedation
- Sedating antipsychotics – particularly quetiapine (Seroquel) and ziprasidone (Geodon) – have an L4 rating, most likely due to sedation
- Lithium – we worry about lithium toxicity
- Valproate and carbamazepine: Potential hepatotoxicity or blood dyscrasias
- And a controversial one is lamotrigine. Dr. Clayton was concerned about the risk of a rash in the infant, but many women with epilepsy have breastfed on lamotrigine and we’ve found no cases of serious rash in the literature. We asked Dr. Clayton about this and she conjectured that lamotrigine is probably safe as long as the infant was exposed to it in the womb – because they are not likely to develop an allergic reaction if they are already accustomed to it – but that it could be risky to start lamotrigine in a breastfeeding mother. Lamotrigine levels do pass into the breastmilk, and in the baby lamotrigine reaches levels that are about 30% that of the mother.
Chris Aiken: And just as with pregnancy, we have to educate women that avoiding breastfeeding comes with risks of its own. Formula has not replaced the significant health benefits of breastfeeding, such as greater immunity, and protection against asthma, obesity, diabetes, and sudden infant death syndrome (SIDS). Breastfed babies also have higher IQs, which reminds me of one of my favorite studies: the Neurodevelopmental Effects of Antiepileptic Drugs study. This international study followed 177 women with epilepsy for 6 years after giving birth. The study was not randomized, but about half of the women chose to breastfeed while taking an anticonvulsant and the other half chose to bottle feed. They were taking a variety of antiepileptics - carbamazepine, lamotrigine, phenytoin, and valproate.
That last one scared me: valproate (Depakote), because it is probably the riskiest psych med during pregnancy. Not only can it cause neural tube defects, but children exposed to valproate in the womb grow up to have 10 points lower on their IQ. So I would not feel comfortable about giving a breastfeeding woman valproate. And this study did confirm that fetal exposure to valproate resulted in a lower IQ, but when it came to breastfeeding the results were flipped. At age 6, the children who were breastfed on valproate had higher IQs than those whose mothers bottle fed them while taking valproate to avoid any risks with the med.
The finding of greater development and IQ when breastfeeding on the meds was true for all the antiepileptics, and particularly significant for valproate.
Kellie Newsome: Managing meds in the peripartum is not about knowing which meds to use and which ones to avoid. There are risks on all sides in this business, and the hard part is in helping your patients understand that reality. Patients are often focused on the medications, as though each one is a jagged pill taking aim at their developing child. Not so. Babies are exposed to far more chemicals than what’s in their pill box – air pollution, caffeine, alcohol –the average package of processed foods has more chemicals on than your patients medlist – and most of them untested. The bottom line is that a healthy mother leads to a healthy baby – and mental health is part of that. Focus your patient on what they can do to improve their health during pregnancy. Are they taking a prenatal vitamin? Avoiding alcohol? Limiting caffeine? Are they keeping away from the kitty litter with its well-known risk of toxoplasmosis? Reducing stress and getting good sleep, exercise, and a healthy diet? Any one of those is going to make a bigger difference for the baby’s health than stopping or starting the average psych med. With the possible exception of the big 7 – the meds with known risks in pregnancy. Let’s call them out one more time:
•Paroxetine (Paxil), valproate (Depakote), lithium, carbamazepine, tricyclic antidepressants (particularly clomipramine), benzodiazepines, and stimulants like Ritalin and Adderall.
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Earn your CME for this episode through the link in the show notes, and we hope you will join us in a few weeks when we’ll pick up on the 10 Psychopharm Commandments with #6: Honor thy MAOI interactions. In the meantime, follow Dr. Aiken on twitter or LinkedIn – his handle is @chrisaikenmd - where he has posted a new finding every day for the past 6 months. Today’s study compares the cognitive effects of two popular treatments for bipolar depression: lurasidone and quetiapine.