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Full transcript:
[intro music]
Host — Dan Keller
Hello, and welcome to Episode Seventy-seven of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.
Pregnancy and the postpartum period present special pertains to to women along with MS. Dr. Annette Langer-Gould, a neurologist and epidemiologist at Kaiser Permanente in Los Angeles, investigates means to lessen the risk of relapses in these women. We discussed the effects of breastfeeding, among others topics, once we met at the ECTRIMS meeting last fall in Barcelona.
Interviewer – Dan Keller
In terms of pregnancy and breastfeeding in MS, exactly what are you looking at?
Interviewee – Annette Langer-Gould
We’re studying modifiable risk factors for postpartum relapses in women along with multiple sclerosis. And specifically, we are looking at starting therapy shortly after delivery, whether that can easily reduce the risk of postpartum relapses, whether breastfeeding, particularly breastfeeding exclusively, could reduce the risk of postpartum relapses, and whether vitamin D levels play any role in increasing or decreasing the risk of postpartum relapses.
MSDF
And are these women that are on disease-modifying therapy throughout pregnancy or not?
Dr. Langer-Gould
No. In our population, a little over 60% were treated prior to pregnancy. Yet we do have actually a decent number of women that had decided to never go on disease-modifying therapies before, and almost all of them stopped disease-modifying therapies either shortly prior to or once they locate out that they’re pregnant.
MSDF
In terms of each of those outcomes, exactly what are you finding?
Dr. Langer-Gould
We haven’t analyzed the data for the vitamin D yet, Yet in the German pregnancy registry, we merely published the data in exclusive breastfeeding, and once again showed that exclusive breastfeeding does protect versus postpartum relapses. In that population, actually 96% of the women had been on some sort of DMT prior to pregnancy, and none of them were treated throughout pregnancy. We likewise found that resuming DMTs does not seem to have actually a big effect on reducing the risk of relapses, particularly in the very first 6 months postpartum.
MSDF
Is that in women that are exclusively breastfeeding or not?
Dr. Langer-Gould
Ah, so that’s a good question. So there is no good safety data on taking the medications throughout breastfeeding. And therefore, several clinicians and most patients are concerned regarding potential theoretical risks. So behaviors are actually mutually exclusive. Women often will certainly either breastfeed or return to medications early in the postpartum course. The others thing we locate in the Kaiser population is that there are still a reasonable number of women that neither breastfeed exclusively or return to their medications, which presents sort of an interesting opportunity. If we could prove to that one or the others behaviors is protective, perhaps we could encourage either exclusive breastfeeding or resuming DMT.
MSDF
If women are not breastfeeding, do you have actually an pointer of the time course of resumption of risk for relapse?
Dr. Langer-Gould
Yes, so the concern regarding postpartum relapses actually is regarding having a relapse in the very first three to four months postpartum. If we look over at the whole pregnancy year, and that’s regarding 30% to 40% of women. So this is actually still the very best defined risk period for having a relapse and actually the only clear trigger—along with perhaps the exception of upper respiratory tract infections—of relapses. So we know that having merely had a baby or having an upper respiratory tract infection is a rather durable predictor of having a relapse. So it presents sort of a unique opportunity to likewise consider others biological factors, like vitamin D, which is why we’re interested in it, to see if any of these points have actually a durable role in relapses as well.
MSDF
If women are breastfeeding postpartum, exactly what is the hormonal profile like? Is this almost like an extension of pregnancy?
Dr. Langer-Gould
For women that breastfeed exclusively, meaning that they breastfeed to the point of suppressing their ovaries and not resuming menstruation—so that essentially there’s no regular meal that’s being replaced by formula or by table meals in the baby—they have actually rather higher prolactin levels. So it’s actually a little bit different compared to being postmenopausal, in the sense that they have actually rather higher prolactin levels. And they have actually incredibly reasonable nonpulsatile FSH and LH levels. In the postmenopausal period, there occurs a rather higher FSH and LH levels. The similarity, though, is that they both have actually bottomed-out estradiol and progesterone levels, in both women that are breastfeeding to the point of suppressing menses and likewise postmenopausal women. And of course the others similarity is that there’s no ovulation occurring, either throughout pregnancy, throughout exclusive breastfeeding, or after menopause.
MSDF
So it sounds like breastfeeding is actually a hypothalamic pituitary suppressant as opposed to in menopause, where you still have actually those cranking away, Yet merely no response from the ovaries.
Dr. Langer-Gould
Correct.
MSDF
Can this be used in any clinical sense? Do you see an application?
Dr. Langer-Gould
The most obvious direct method to translate these findings is that that, if you have actually a woman along with MS in front of you and she is pregnant and she tells you she’d like to breastfeed, we surely have actually no good necessity to discourage her. And that if anything, I would certainly suggest that the data we’ve already published would certainly point to the reality that we might wish to encourage exclusive breastfeeding, offer them along with lactation counseling, and likewise sort out exactly exactly what the optimal duration of exclusive breastfeeding might be for these women. Is it actually only eight weeks, which we had defined arbitrarily? Or does longer duration of exclusive breastfeeding have actually additional suppressive properties? And that would, of course, have actually implications in the United States for points like maternity leave and job accommodations to permit that to continue, if it has actually a durable therapeutic effect for the mother.
MSDF
What’s the relapse rate among postmenopausal women compared to postpartum women?
Dr. Langer-Gould
So relapse rate declines along with age. And so it often in postmenopausal women, despite the fact that there’s not terrific data, we would certainly expect them to have actually relapse rates of much less compared to 0.3 per year, Annualized relapse rates of much less compared to 0.3 per year. And in postpartum women, that very first three to four months, the annualized relapse rate exceeds one.
MSDF
But men likewise have actually a decline in relapse rate as they age, too. So you can’t attribute it to lower estradiol.
Dr. Langer-Gould
Exactly. Yeah, I believe it’s far a lot more complicated compared to merely a simple sex hormone effect. You know, that was sort of our very first instinct from pregnancy or the necessity pregnancy should be protective. It has actually to have actually something to do along with estradiol or the rather higher progesterone levels. And that’s exactly what prompted the postpartum study and likewise the estradiol randomized regulate trial. And both of those, of course, disappointingly have actually been negative. In isolation, the sex hormones associated along with the protective effect of pregnancy don’t actually have actually a protective effect on inflammation. It’s probably a lot more of a combination of factors that play in to modulating the immune response.
MSDF
Where do you go from here?
Dr. Langer-Gould
I believe that if we are able to reproduce the findings, looking at this population-based source, that early resumption of DMTs is not particularly helpful, Yet perhaps it might be later in the postpartum year, and that exclusive breastfeeding is, again, protective, then I believe the next step actually is to establish the safety of some of these medications throughout lactation. For several of them, there’s actually no biologically plausible necessity to believe that they would certainly have actually an effect on the baby, as they’re not most likely to be absorbed through the gut or enter in to the baby’s bloodstream.
Examples of that would certainly be the large molecules like Copaxone, the interferons, and likewise the infusion medications, Tysabri (natalizumab), and rituximab as well. despite the fact that you might be able to detect them in breast milk, they are such large molecules that they would certainly not diffuse across the baby’s stomach and in to the bloodstream. Consider it. If the mom has actually to take it as a pill, it is rather most likely to be transmitted to the baby. If the mom has actually to take it as an infusion or injection, rather unlikely that oral route through the baby would certainly have actually any effect.
MSDF
How sensitive is this effect to, as you said, exclusive breastfeeding? can easily you start introducing formula, or it’s all or none?
Dr. Langer-Gould
That’s a actually good question. So we did consider that likewise in the German pregnancy registry. So very first of all, women tend to have actually rather defined behavior. They tend to decide to supplemental feed along with formula very, rather early, prior to they’ve even established their full milk supply. So to spine up even further, a healthy and balanced woman gives birth to her child. Usually menstruation will certainly return to two months after delivery, not one month. So it does take the HPA gonadal axis a little opportunity to recover from those high-circulating hormones of pregnancy. And in women that introduce supplemental feedings, particularly early, we likewise see the rather same thing; that they will certainly return to their period at two months postpartum.
Actually, most of the job done in this field has actually been done by nutritionists that are in producing countries that are interested in knowing exactly what you need to do if you see a famished mother and a famished baby. that need to you feed?
It turns out that if you feed the baby, the mother’s ovarian function will certainly resume. So any regular supplemental feedings and rather quickly their prolactin levels will certainly drop. The pulsatility of the FSH and LH secretion will certainly return. Ovulation returns, and so does menses. It’s essentially sending the mother’s physique a signal that the baby no longer requires nourishment from the mom to survive, so she’s all set to have actually yet another child. So the right thing to do in that situation would certainly be feed the mom, and let her nurse the child. Biologically, it’s rather interesting. Although some breastfeeding is much better compared to none for the baby, in terms of the effect on the mother’s HP [hypothalamic-pituitary] ovarian axis, some supplemental feeding is merely like all supplemental feeding.
MSDF
Have we missed anything or anything interesting to add?
Dr. Langer-Gould
So I guess I would certainly say merely in general, women’s, and now even men’s, desire to have actually naturally-born kids has actually taken on a brand-new significance along with a lot of the small molecule agents, because we have to think of family preparation and discuss it much earlier, as small molecules are most likely to have actually an effect even if they get hold of pregnant accidentally on the producing fetus. This is a challenge we haven’t had before, because large molecules won’t cross the placenta in the very first trimester. And the very first trimester is the critical period for organ development.
So it’s sort of brand-new era for MS neurologists, where we really, actually have actually to believe carefully regarding which medication we put them on if they’re preparation on having kids soon. So I’d strongly encourage that you have actually that conversation rather early and have actually it along with every followup visit. I often will certainly ask them, are you preparation on having kids within the next two years? And if they say, no, I ask exactly what kind of birth regulate they’re on, or in some cases they’re in same-sex couples. That’s obviously an exception. And if they are not on a reliable form of birth control, I believe you have to believe two times regarding giving the small-molecule agents—so the pills, basically.
MSDF
Should MS neurologists job along with high-risk OB/GYNs?
Dr. Langer-Gould
I believe for the most portion it’s not necessary, because women along with MS, they don’t have actually abnormal complications at pregnancy. I believe there are surely situations that we’re operating in to now. If they get hold of pregnant accidentally on fingolimod, teriflunomide, or Tysabri, we do have to job along with them, mostly for the baby. So you might wish to do a lot more intense early screening if the mother is culturally open to the pointer of having an abortion. You might wish to do a lot more fetal ultrasounds, perhaps even a fetal MRI, if there’s suspicion of major malformations early on in pregnancy.
And likewise for the Tysabri, really, it’s not so much regarding organogenesis, Yet if they’ve had later exposure to Tysabri throughout pregnancy, which unfortunately on occasion has actually been essential to regulate rebound disease activity throughout pregnancy, that, you know, we have actually seen hematological abnormalities in some of these children, so far none along with clinical complications. Only one kid had a subclinical intraventricular hemorrhage that resolved. It’s still concerning. Our experience is rather small, and we would certainly surely highly recommend that those women provide birth in a hospital that has actually a neonatal intensive care unit available and a pediatrician on call to examine the kid and likewise ensure that the kid doesn’t have actually a severe thrombocytopenia or anemia at birth.
MSDF
Do the different drugs have actually different risks for fetal malformations or others dysfunctions?
Dr. Langer-Gould
Yes. So teriflunomide, or Aubagio, is the most concerning medication because if a woman gets pregnant on that accidentally, it is, you know, a category X drug because it can easily interfere along with neural tube development. And despite the fact that you can easily chelate to get hold of the medication out rather quickly, the safety data from others indications, you know, the rheumatoid arthritis and lupus literature, is not particularly reassuring in terms of fetal outcomes. So I believe that’s sort of the number one to prevent if a woman is preparation on getting pregnant. And it’s likewise one where, you know, there is some concern, despite the fact that not durable evidence, that it might likewise affect the offspring of men along with MS that are on the medication.
In terms of the others ones, of course, again, small molecules in fingolimod has actually regarding a 15% to 16% major fetal malformation risk along with early pregnancy exposure. It has actually a rather long half-life. So even if they stop the medicine the minute they locate out they’re pregnant, it takes over two months for it to be cleared, which means that the baby has actually seen it now through the entire very first trimester. That can easily have actually substantial effects, both on cardiac and brain development. And then along with dimethyl fumarate, we haven’t seen—now of course, this is a rather brand-new drug, so we don’t have actually nearly as much experience—we have actually not seen any major malformations, Yet there was concern in the animal models that it could interfere along with cognitive development. In particular, the rats had maze-finding difficulty.
MSDF
Is alemtuzumab indicated at all? It appears to have actually a long tail.
Dr. Langer-Gould
I’m not sure exactly what the half-life of alemtuzumab, Yet it’s probably similar to others monoclonal antibodies, which is usually about 15 to 20 days. So monoclonal antibodies don’t cross the placenta in the very first trimester, because it’s a rather large molecule. So large molecules only get hold of across if there’s an energetic transport system. For antibodies, there is an energetic transport system, because it’s rather crucial that the kid be born along with a higher dose of antibodies received from the mother to guidance protect them throughout the early portion of their infancy while their own immune system is still developing.
So we see maternal antibodies being transported, and of course, monoclonal antibody medications would certainly be dragged along along with that throughout second trimester. And it goes up in elliptical fashion, along with very, rather higher amounts being pumped across the placenta in third trimester. And they also, of course, have actually a rather delayed clearance mechanism, both the fetus actually has actually no clearance mechanism, and then even the neonate has actually a rather slow clearance mechanism. So in TNF alpha studies, if the drug is provided throughout third trimester, it’s often not cleared until regarding 6 to nine months postpartum.
So you likewise have actually to be concerned that a baby exposed would certainly have actually some of that medication hanging about throughout the early neonatal period and provide some believed to whether or not their immunization scheme would certainly have to be adjusted, as the cautionary tale there would certainly be TNF alpha exposure throughout pregnancy.
There was a case reported of a woman that had rather severe rheumatological disease, had discussed along with her rheumatologist the potential risks and benefits of taking it throughout pregnancy, opted to take it throughout pregnancy. And then living in an endemic area for tuberculosis, the baby got the BCG vaccine and got disseminated mycobacterium and died. And that, you know, was probably directly related to impaired immunity from the TNF alpha antagonist. And sure enough, the baby was born along with fairly higher cord levels and likewise had rather higher levels still remaining in the blood in the neonatal period.
So it’s not merely once the baby’s born, it’s like the drug is out. So drugs like alemtuzumab and rituximab, the method in which they work, Although the drug could be long gone, Yet the effect of the medication works rather long time. So those are actually good options for women along with highly energetic disease that are preparation on getting pregnant. And you have actually pertains to regarding rebound. I mean, we often use rituximab because it’s obviously much safer compared to alemtuzumab and appears to do a fairly good job. Yet you know, these aren’t medications we need to be giving while they’re pregnant, Yet probably not a big effect in crossing the placenta and on the baby if they’re used prior to pregnancy.
MSDF
If they can easily strategy that well and get hold of a pulse of that early, and then get hold of pregnant a few months later.
Dr. Langer-Gould
Yes. Yeah, that’s constantly the trick, right? And they do get hold of pregnant accidentally on merely regarding every little thing we put them on. So the infrequent infusion medications is the easiest because you can easily ask regarding last menstrual period. And you can easily ask regarding birth regulate use, and you can easily do a pregnancy test the day of, a quick urine dipstick and locate out so that you don’t accidentally infuse a pregnant woman. Of course along with Tysabri, once you’re giving them an infusion every month, it gets a little tricky. Usually people merely kind of get hold of tired of it. The nurses forget. The doctor forgets to order it, despite the fact that it’s not necessarily bad method if you know you have actually a patient that is not on a reliable form of birth control.
MSDF
Very good. I appreciate it. Thank you.
Dr. Langer-Gould
You’re welcome.
[transition music]
MSDF
Thank you for listening to Episode Seventy-seven of Multiple Sclerosis Discovery. This podcast was made by the MS Discovery Forum, MSDF, the premier source of independent news and short article on MS research. MSDF’s executive editor is Carol Cruzan Morton. Msdiscovery.org is portion of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.
Msdiscovery.org aims to focus attention on exactly what is known and not yet known regarding the triggers of MS and related conditions, their pathological mechanisms, and potential means to intervene. By communicating this short article in a method that builds bridges among different disciplines, we chance to open brand-new routes toward substantial clinical advances.
[outro music]
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For Multiple Sclerosis Discovery, I’m Dan Keller.