Thursday, 6 November 2014

Month of birth effect is real

Month of birth effect is back on the MS agenda. #MSBlog #MSResearch

"Month of birth effect in MS is back on the agenda, big time. I don't think the Stephen Sawcer paper said it did not exist all they were saying is that there are potential confounders that need to be controlled for. This paper below does just that and demonstrates at a country level that more MSers are born in April than expected. I can't stress how important this finding is for MS prevention strategies and now needs to be confirmed in other countries."

"What this paper is saying that some environmental factor is probably acting in utero (inside the womb), and/or in early childhood, increase the risk of MS. Based on other findings this is likely to be low vitamin D levels. The current hypothesis is that if the immune system matures in a vitamin D deficient environment it increases one's chances of getting MS in later life. This means that vitamin D prevention studies may need to start in utero. This is why we have been recommending that all our patients with MS, who are planning to fall pregnant, make sure they are vitamin D replete before falling pregnant and whilst they are pregnant."

"What is needed however is a randomised international study of vitamin D supplementation during pregnancy to see if it reduces autoimmune disease in later life. Yes, autoimmune disease in general; the month of birth effect is not unique to MS and has been noted with other autoimmune diseases as well."


Torkildsen et al. Month of birth and risk of multiple sclerosis: confounding and adjustments. Ann Clin Transl Neurol. 2014 ;1(2):141-4.

Background: A month of birth effect on multiple sclerosis (MS) risk has been reported from different countries. Recent critics have suggested that this finding is caused by confounding and that adequately adjusting for year and place of birth would markedly reduce this effect. All inhabitants in Norway are registered in the Norwegian Population Registry (Statistics Norway), making this an ideal area for performing adjusted analyses. 


Methods: Using the entire Norwegian population born between 1930 and 1979 (n = 2,899,260), we calculated the excess between observed and expected number of births for each month for 6649 Norwegian MS patients, 5711 mothers, 5247 fathers, and 8956 unaffected siblings. The analyses were adjusted for year of birth and place of birth according to the 19 counties in Norway. 

Results: An unadjusted analysis revealed 13% fewer MS births than expected in February (P = 0.0015; Bonferroni corrected P = 0.018), 10% more in April (P = 0.0083; Bonferroni corrected P = 0.0996) and 15% more in December (P = 0.00058; Bonferroni corrected P = 0.007). Adjustments for both year and place of birth significantly altered our results for February and December, but even after these adjustments there were still 10% more MS births than expected in April (P = 0.00796; Bonferroni corrected P = 0.096). 

Conclusions: MS patients had a higher incidence of April births than their siblings (Fisher-exact test; P = 0.011), mothers (Fisher-exact test; P = 0.004), and fathers (Fisher-exact test; P = 0.011) without MS. Adjustments for confounding significantly affected our results. However, even after adjustments, there appears to be a persistent higher than expected frequency of April births in the MS population.

41 comments:

  1. Born on a 3rd of April - right in the eye of the storm!

    Would you go on to suggest that we (MSers) should give our offspring the best chances and perhaps plan for a birth date in Oct - Nov ?

    TOny

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  2. I have RRMS and was born in December.

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    1. I have P.R.MS and was born in September.

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  3. Read Stephen Sawcer's response to the paper; the study is still flawed.

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    1. Causality can be questioned all day long - but if the cost is a mere pregnancy control for people at risk (i.e. make sure you fall pregnant in the winter rather than summer)....then why not?

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    2. it's about whether the effect actually exists; Sawcer elegantly shows that it does not.

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    3. I don't think Sawcer shows that it does not exist; he simply stating he needs a more robust methodology.

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    4. which this present study does not address. So at the moment there is no evidence of a month of birth effect in MS.

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    5. Again - what does one have to lose?

      Obviously lots to gain....

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    6. Not lots- effect on MS risk is miniscule.

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    7. "Not lots- effect on MS risk is miniscule."

      How do you know? We need to do trials. Based on incidence rates in the pre-sunblock era moving from Tasmania to Queensland or England to South Africa would reduce the risk of MS in 2nd generation descendants by way over 50%.

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    8. confusing two things- the month of birth effect, if true, is negligible. so there wouldn't be much impact by telling people to give birth in a certain month.

      can do a trial, but all major trials for vitamin D for the last two years have been resoundingly negative for all outcomes

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    9. "can do a trial, but all major trials for vitamin D for the last two years have been resoundingly negative for all outcomes"

      Treatment trials or prevention trials? I am not aware of any vD prevention trials. You seem to be getting confused between the two.

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    10. prevention trials for respiratory tract infections; do some reading.

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    11. "prevention trials for respiratory tract infections; do some reading"

      Since when have respiratory tract infections become an autoimmune disease. If you know of any prevention trials done in utero to prevent autoimmunity we would be very interested in seeing the results.

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    12. Very curious as to what trials is meant, as a cursory look at recent trials with D3 for multiple sclerosis don't show 'resoundingly negative' outcomes to me. Must be missing something ...

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    13. Whether there is a month of birth effect or not we do know from diseases like sarcoidosis that vitamin d has a role in the immune system and that immune cells can convert none active 25(OH)D to active 1,25(OH)D.

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    14. There are a lot of vitamin d zealots here. If vit d did have a substantial immunomodulatory effects it would have protected against respiratory tract infections. The outcomes I was talking about are well powered randomised trials for many disorders but does not include MS. If vit D had an effect on MS risk in utero why did the Swedish blood spot study show no difference in vitamin D levels at birth between MS patients and controls. Wake up and see the evidence. There is no equipoise so no justification for a trial.

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    15. I'd love to see the trials you are referring to. Because I cannot find them. Before you call people zealots, where is your evidence? I'm sorry but you just come across as an angry troll to me.

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    16. A badly designed randomized trial gives you information that is poor, the study has to be well designed and randomized and some of the randomized trials have severe design limitations. As the function of vitamin d in the body is not fully understood the others may also be badly designed. However, studies in cellular biology show that vitamin d has a function in the immune system, while studies in genetics show that vitamin d is involved in programmed cell death. So a shortage is very likely to be damaging. If I raise my vitamin d intake and the effects are minor I have lost £10 a year and gained better calcium control. if it has a bigger effect then I have gained a great deal. So in terms of risk vs gain why would I not do it. This is not about raising the amount of vitamin d to abnormal levels just to where it would naturally be if we did not live the way we do. It is likely that the relationship between blood 25(OH)D levels or supplement intake and risk of illness is not going to be a simple relationship.

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    17. so these are the motions we are looking at:

      (i) Plan a birth in autumn with a potential upside and
      (ii) Plan a birth in spring with a potential downside.

      Outcome: highly speculative
      Financial Cost: None
      QoL Cost: None
      Annoyance Cost: Negligible.
      Public awareness (actual): Very low

      To all MSers planning to have children (at risk individuals): motion (i) is an obvious winner on a pure circumstantial cost/benefit approach.

      To public health official planning spendings on awakening campaigns: There is no clear cut winner.

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    18. http://www.ncbi.nlm.nih.gov/pubmed/22494826

      http://www.ncbi.nlm.nih.gov/pubmed/23032549

      http://www.ncbi.nlm.nih.gov/pubmed/24838406

      http://www.ncbi.nlm.nih.gov/pubmed/23939263

      http://www.ncbi.nlm.nih.gov/pubmed/23299607

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    19. Omg please tell me this isn't proof of how D3 doesn't work. Laughable! If I could be bothered I'd explain how NONE of these studies offer any proof vis MS but nope, somehow I don't think you'd listen.

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    20. http://www.ncbi.nlm.nih.gov/pubmed/22494826
      They gave babies (1 to 11 months) 100,000 IU (2·5 mg) vitamin D(3) every 3 months. Firstly 100,000IU is a massive dose for a baby (and may destabilise the blood calcium levels) and the half life of 25(OH)D in the blood is 20 to 30 days so the level of vitamin d is cycling over a very wide range. That looks very badly designed.

      http://www.ncbi.nlm.nih.gov/pubmed/23032549
      Initial dose of 200,000 IU oral vitamin D3, then 200,000 IU 1 month later, then 100,000 IU monthly. Again the blood levels will be cycling, due to the half life. The large doses may not be processed by the liver into 25(OH)D effectively. The body is not used to large infrequent doses of vitamin d.

      http://www.ncbi.nlm.nih.gov/pubmed/24838406
      Oral vitamin D3 (100,000 IU once, then 4000 IU/d for 28 weeks; n = 201) or placebo (n = 207) was added to inhaled ciclesonide (320 µg/d). They took first asthma treatment failure as the primary outcome but if it takes time for the vitamin d levels to rise that is a poor choice. They did see an overall reduction in the dose of ciclesonide required by the vitamin d group.

      http://www.ncbi.nlm.nih.gov/pubmed/23939263
      A total of 100,000 U of oral cholecalciferol or matching placebo every 3 months for 1 year.
      They saw no effect on blood pressure. Why would you expect one, You are more likely to see high blood calcium levels every time you give someone 100,000IU of vitamin d, especially if they have low 25(OH)D.

      http://www.ncbi.nlm.nih.gov/pubmed/23299607
      Participants were randomized to receive either placebo or oral cholecalciferol, 2000 IU/d, with dose escalation to elevate serum levels to more than 36 ng/mL. The is about knee pain of a damaged knee. Why would you expect vitamin d to repair a damaged knee?

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    21. Aw the knee trial was my favourite of these random and pointless links! Seriously thanks for taking the time to explain this - guess it shows we are just 'zealots' ;)

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    22. I have just realised that http://www.ncbi.nlm.nih.gov/pubmed/24838406 contains another flaw, if the group getting vitamin d improves and so reduces its use of ciclesonide it also reduces its intake of vitamin d because the vitamin d was in the inhaler.

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    23. To put http://www.ncbi.nlm.nih.gov/pubmed/22494826 in context, the Royal College of Paediatrics and Child Health recommend a daily dose of 400IU a day for babies in this age group, so 100,000IU is equivalent to 250 days. It is amazing how safe vitamin d is. It also shows how badly designed the study was. Also note the RDA for a new born (3.5Kg) is the same as a adult (say me at 100Kg). If you scale up the infant dose you get 5,000IU to 10,000IU a day for an adult.

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    24. "That looks very badly designed."
      Oh so giving too much vitamin D means it has no effect whatsoever? Awesome.

      "The body is not used to large infrequent doses of vitamin d."
      Where is the scientific evidence for this? All immunology studies use large doses of vitamin D to see effects. But I love that if you give 'too much' at once it has absolutely no effect.

      "but if it takes time for the vitamin d levels to rise that is a poor choice?"
      Do you have any idea about vitamin D biology? So here, now giving too a Prof G recommended dose is bad. Yet again no effect seen.


      "Why would you expect one?"
      read the literature

      Why would you expect vitamin d to repair a damaged knee?
      Sorry I thought vitamin D had a role in bone health? But you clearly know more.

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    25. AnonymousFriday, November 07, 2014 9:27:00 pm I think you are trolling but for the benefit of others I will explain.

      Taking too much vitamin d is bad for you at very high doses are toxic, it is used in very high doses in rat poison, rats being nocturnal and therefore very good at retaining vitamin d, it is especially toxic to them. It is toxic because very high levels of 25(OH)D stops 1,25(OH)D in the blood controlling the blood calcium levels. This said if you drank 250 days of water on one day it would kill but a dose of vitamin d equivalent to this does not.

      The body gets most of its vitamin d from sun exposure of the skin. Production is limited because the UV that start the process by breaking a chemical bond also breaks up the chemical formed, it is known as a dynamic equilibrium. The sun on an adult will on maximum exposure giving about 10,000IU at day, but then this would build slowly in spring and tail of in autumn (assuming you do not live on the equator). No food source would give you 100,000IU in a day. So single massive doses are not normal. Remember that vitamin d as taken is inert it must be converted to 25(OH)D in the liver and then into 1,25(OH)D by cells in the body before it is active and this takes time, any as taken vitamin d that is not converted to 25(OH)D is lost (also any vitamin d that enters fat cells appears to be lost to the body). The body uses 1,25(OH)D produced in the kidneys to control blood calcium levels, the required level is affected by the parathyroid and the 25(OH)D level in the blood. A sudden increase in 25(OH)D combined with high 1,25(OH)D gives a rise in blood calcium until the body readjusts the parathyroid hormones and 1,25(OH)D.

      The other problem with large single doses is that, as I have already stated, vitamin d has a half life, every 20 to 30 days half is consumed or lost, and so single large doses spread months apart cause the levels to rise and then fall.

      To sum up this section 100,000IU once every 3 months is not the same as 1,000IU a day. Name a drug or food where you would possibly think this sensible To save time I will eat all the dinners I would normally eat in 3 months in one sitting . So 5000Iu a day thought reasonable by Prof G is safe and sensible but 100,000IU every 3 months is not.

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    26. To consider you last two short phrases.

      Firstly not only have I read the abstracts on Pubmed I have also read the papers.

      With blood pressure there is no published mechanism by which vitamin d would either raise or drop blood pressure. There is little evidence either way, as the papers that reported a drop were underpowered and therefore need repeating. There is no evidence that 25(OH)D causes a dilation of the blood vessels or alters any narrowing, except that by avoiding excessive blood calcium levels and/or inflammation. However, this would occur over a lifetime and there is no mechanism by which vitamin d could reverse the pre existing damage.

      Vitamin d is important to bone health in that it is needed to absorb calcium through the gut and it is used to control blood calcium levels and to deposit calcium in the bones. There is no evidence that it controls the regeneration of tissue. The damage considered was mechanical damage to the knee and unless vitamin d can some how reconstruct the damaged bone back to its original shape it is not going to have an effect.

      You need to understand the differences between maintaining something and repairing it. You need to understand the difference between single large doses at infrequent intervals and small doses at frequent intervals.
      You need to understand that vitamin d is a nutrient that is needed for the correct function of the body but is not magical, there is no evidence that it can repair damage once it has occurred. It is used by the immune system, it is part of the innate immune system, it has a role in cell death and other genetic function and it is important to bone formation and maintenance.

      I guess you will not consider this before replying but I have tried.

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    27. But if you read the papers you will see that patients receiving the bolus vitamin d had higher levels of vitamin d at the end of the study as compared to people getting placebo. Why do you think this vitamin d won't work? Does the body only recognise vitamin d coming from a daily dose? If i eat lots today there will be immediate changes in my blood glucose which will then initiate glucose pathways. I guess vitamin d must act completely different.Can you cite some papers for your claims above-http://www.ncbi.nlm.nih.gov/pubmed/24246341 and many other papers refute your claims

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    28. Troll alert ( Friday, November 07, 2014 9:27:00 pm, 11.08 am etc etc) one can be that obtuse unless deliberately doing it.

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    29. No one is saying large bolus dosages (AnonymousFriday, November 07, 2014 9:27:00 pm) or as you appear to also be extrapolating, any Vitamin D3 at all, does not work. However I'd say far better to maintain a steady state by daily D3 supplements. I take 10,000 iu daily. I have, through this, got 'optimal' levels (measured on 25(OH)D test). Does this make a difference? Always difficult to judge as I do other things too (I don't use a DMT though) but as I rarely relapse (then it is only mild sensory symptoms lasting a few days) in 15 years diagnosed, subjectively I think it might.

      I have a little background in some biochemistry and while I can read clinical data to some extent, I'm far from in the loop and the mechanisms involved are incredibly complicated (what isn't, when it comes to the immune system) But I know enough to spot a troll:). Thanks for the explanations from the anonymous that has taken the trouble to explain more.

      PS I was born in April

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    30. The problem is that the dosing mechanism is designed for compliance not because it makes good dosing sense. It is assumed that only the level of vitamin d as 25(OH)D matters and not how it is changing. In the first case if you induce hypercalcemia in a few babies every time you give them the dose of vitamin d then you are increasing a risk of illness, they did not measure blood calcium levels so we do not know. If the change in vitamin d levels triggers a virus, like sun light triggers cold sores then the widely spaced doses will make thinks worse, this we do not know. The median 25(OH)D changes as you say but figure 3 shows that the low end is largely unchanged, is it these babies who get pneumonia, we don't know because they did not measure the vitamin d levels of those who got pneumonia. Thus my statement that it is badly designed, some of the design failure could have been mitigated by a daily dose but because of the location this would be difficult. Does 25(OH)D have an effect? From the medical evidence I would say the case is unproven, either way, mainly because the system is much more complex than glucose, with 25(OH)D being used by many cells for different things. From the science of cell biology, immune cell and animal studies and genetics it is certain that a lack of vitamin d is bad for humans.

      http://www.ncbi.nlm.nih.gov/pubmed/24246341 is a review not a primary source and it has a section on the side effects of large doses including hypercalcemia, which was observed, in a few of the papers they reviewed. However they considered papers on adults not babies. They considered doses greater than 100,000IU to about 500,000IU in adults, which is very different to babies up to 11 months. The paper does not compare the efficacy of large doses spread out over time vs a daily dose only whether the large dose leads to an increased 25(OH) level in the blood and the effect on the parathyroid gland. They conclude that "a single vitamin D3 dose of ≥100,000 IU offers a consistently efficient means of improving short-term vitamin D concentrations of >20 ng/mL, although vitamin D3 doses of ≥300,000 IU are necessary to achieve 25(OH)D concentrations >30 ng/mL and lowering of plasma PTH concentrations." Notice it says short term this is about fixing a serious short term shortage not a maintenance strategy.

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    31. http://www.ncbi.nlm.nih.gov/pubmed/24246341 also says "Although generally safe, bolus doses of >500,000 IU of vitamin D3 must be used with caution due to the potential for increased fracture risks, altered biochemical markers, and issues with tolerability, such as GI upset" If we assume a 6 month old child is 8 Kg and the average adult is 60Kg then 100,000IU is the equivalent of giving an adult 750,000IU and for a 1 month old it is equivalent to giving an average adult 1,000,000IU. Given that vitamin d is toxic in large doses is this sensible

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  4. How does this fit with you viral hypothesise. My bad case on mono was the cause of MS. I'm certainly not going to blame my mother for not getting out in the sun more when pregnant or conceiving at the wrong time of year.

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  5. I'll swim against the tide - born in UK in November, lived in India as a toddler (plenty of sun there), migrated to southern Australia as a 6yo - spent my childhood running around outside in the sun - no skin cancer campaigns back then! Now diagnosed in my mid-50's with MS after 8 years of symptoms which became progressively worse, but never a relapse in sight. Maybe there is some substance in the old practice of taking the baby outside in its pram for a while everyday, regardless of weather........

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  6. It appears that to conserve vitamin d the body can turn on and off different uses, the relationship between 25(OH)D level in the blood and supplement intake is not linear. So maybe to conserve vitamin d for calcium control and functions within the genes, which are critical, the body turns off its use by the immune system, when levels are low. The 25(OH)D blood level at which this occurs may be set before birth giving a month of birth effect. This would also mean that the 25(OH)D level in the blood is controlled both by supply and demand, and that a person with a higher 25(OH)D level may be more at risk of illness that one with a lower 25(OH)D level for the same intake, the equivalent of not being able to get the last bit out of the jar. This would complicate understanding the role of vitamin d, especially 25(OH)D levels.

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  7. Don't smoke, don't drink, exercise, low fat diet born October and still got MS and Cancer. I bet it's all about the Genes

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    Replies
    1. I think it's genes and a virus that acts on the HERV's when your immune system is low

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