Vitamin B3 and miscarriage

By , 13 August 2017

This week, media outlets widely reported findings of an Australian study linking vitamin B3 to birth defects and miscarriages.  The study, published in the New England Journal of Medicine, was undertaken by an Australian research team headed by Professor Sally Dunwoodie.  The study findings have even been compared to the discovery of the link between folate and neural tubes defects such as spina bifida.

Unfortunately, though perhaps not surprisingly, media enthusiasm has allowed a good headline to get in the way of responsible journalism.  While the discovery of an association between vitamin B3 and birth defects (in mice) is interesting, important, and creates many questions for further research, it is a far, far cry from "preventing millions of women from suffering miscarriage".  

In a nutshell, the researchers of this study:

  • Tried to identify random genes that might be associated with the occurrence of multiple congenital abnormalities (that is, more than one birth defect occurring in the same person, suggesting something more than just random chance at work).
  • Found a couple of possible genes, among four families that included such individuals.
  • Determined that these genes were associated with NAD metabolism - mutations in these genes meant less NAD produced.
  • Created "knockout" mice (that is, mice that were genetically engineered to make zero NAD by completely removing all function of these genes - as opposed to these families, that had the genes, but some mutation in them that reduced their function).  That is to say, they created mice with significantly warped metabolisms.
  • Determined that these mice had babies with lots of congenital abnormalities (and early abortions – probably related to the lethality of multiple congenital abnormalities).
  • Acknowledged that NAD is synthesised using ether niacin (B3) or tryptophan (found in cheese).
  • Fed the mummy mice niacin and fixed the problem (which they created….)
  • Concluded that:
    • NAD is important to embryogenesis (like many other things….) -- this seems reasonable. 
    • Removing it – entirely – creates problems, in a mouse model at least. -- interesting. 
    • Removing it and replacing it prevents these problems. -- also interesting, perhaps not surprising given the first two points.
    • Theorised that niacin supplementation may be useful in these families with recognised gene mutations affecting NAD pathways-- MAYBE, but remains to be answered.

Importantly (and curiously left out by the media):

  • They didn’t actually conclude (nor should they), that niacin supplementation reduces birth defects in “normal” families.
  • NOWHERE in their study is the word “miscarriage” or phrase “first trimester loss” used (even though the entire media reports focus on B3 reducing miscarriage).
  • There are no trials (“intervention trials”) looking at the effect of NAD/niacin/B3 on low-risk women (or low-risk/non-mutant mice, for that matter).
  • Likewise, there are no intervention trials looking at supplementation in HIGH risk women, such as in these families.
  • There is NO safety data about high-dose niacin supplementation

The assumption is that something occurring naturally can’t be bad, BUT the entire HRT fiasco came from initial studies suggesting all women should take oestrogen because it prevents heart disease, and women with early menopause have more heart disease, so extra oestrogen must be good.  But women with extra oestrogen just turned out to have more strokes, more clots (and… MORE heart disease!) – the painful lesson from the HRT trials is that jumping in early, on the first promise of something useful, is not without risk. 

After much pain, a few law suits, and many more trials, we eventually settled on “HRT benefits may outweigh risks, in some women, sometimesmaybe”.

The unfortunate but inevitable consequence of over-enthusiastic journalism that reports gross extrapolations of animal studies is that women are offered premature - and currently unfounded - hope of a treatment that is not only unproven, but also untested.  With headlines like these, the only winners are manufacturers of Vitamin B3 supplements.  

Nevertheless, let's look forward to the follow-up study findings from this Australian team of researchers!

Important information for Medibank Private members

By , 22 August 2015

Medibank Private is taking action to increase shareholder profits by drastically limiting the value of their insurance product for their members.  These measures are touted at improving healthcare outcomes but, in truth, are without any evidence basis and are completely unvalidated.  Despite loyal premium payments, Medibank members are at risk of finding themselves completely without insurance coverage, at no fault of their own, their doctor, or their chosen Private Hospital.  This is the thin end of a tactical wedge being aimed between patients and their healthcare choices;  the endpoint would likely be similar to overseas models of Private Healthcare, where insurers dictate from which doctors and hospitals patients may receive care, as determined by the insurers' commercial interests.

Read what the Australian Private Hospitals Association has to say about the move here.  Remember, all Australians are entitled to switch Health Funds at any time without penalty.

Vote with your feet.


Influenza vaccination in pregnancy - proven efficacy

By , 11 September 2014

Every now and then, a "landmark paper" - a paper of great clinical significance - comes along.  I believe we've seen one this week!

A paper published this week in the New England Journal of Medicine is the first to show, through the power of a randomised control trial (or RCT, the most rigorous way of determining whether a cause-effect relationship exists between a treatment and an outcome), that influenza vaccination during pregnancy protects mothers and babies.

The researchers enrolled over 2300 pregnant women and randomised them to receive the current influenza vaccination or placebo (saline), between 20 and 36 weeks of pregnancy.  From the date of vaccination, women were contacted weekly to detect symptoms of a "flu-like illness" and, if reported, they were tested specifically for influenza through highly-specific PCR testing.  Women were followed up until about 6 months after birth, and their babies were followed up from birth to about 6 months of age.  

As well as showing that both mothers and babies had "boosted" immunity (through testing the levels of protective antibodies in their blood), the researchers found an almost 50% reduction in PCR-proven influenza infection in both mums and babies.

This is of major public health importance for two reasons: firstly, pregnant women are recognised as being the adult group at highest-risk of severe influenza illness during epidemics and pandemics, even in high-income countries like Australia.  Secondly, young infants are particularly susceptible to (and may be severely affected by) influenza illness, and no vaccine is currently licensed to protect this age group.

Influenza vaccination is already recommended (and PBS subsidised) for pregnant women in Australia.  It does not contain live virus, and the composition of the vaccine changes every year, to keep up with the current seasonal influenza virus strains.  This study provides final validation that influenza vaccination in pregnancy is a good idea, and the researchers are to be congratulated.

Now, go and get your vaccination!


Epidurals and postpartum depression

By , 30 July 2014

A recent study has suggested an association between epidural use in labour and a reduced rate of postpartum depression.  Hmmm...seems a little too good to be true...

The research paper, published here in Anesthesia & Analgesia, found that women who used epidural analgesia in labour had a 14% risk of postpartum depression, compared to nearly 35% of women who did not have an epidural.  Sounds great!  While I'm all in favour of women accessing highly effective pain relief in labour, this headline prompted me to read a little deeper...

The study was a prospective observational study, which means that confounding factors (other aspects that may contribute to the study findings) cannot be accounted for entirely (best achieved through a randomised controlled trial).  Ok, not a biggie; but the authors rightfully describe their findings as an association, which doesn't infer a causal link between the exposure (epidurals) and the outcome (postpartum depression).  This is an important limitation of all observational studies, which is generally overlooked in the media.

Additionally, the overall rates of postpartum depression described in the study are alarmingly high - around 25%.  Partly this is because the authors defined postpartum depression according to a score on the Edinburgh Postnatal Depression Scale (EPDS).  While the EPDS is a useful tool, it is a self-reported questionnaire designed to screen women for symptoms of emotional distress during or after pregnancy, and reflects the woman's experience over the preceding seven days.  While it is very helpful in identifying women at risk, it is not equivalent to a diagnosis of clinical depression per se.

Finally, the authors suggest a possible biological link between pain, post-traumatic stress-type symptoms, and postnatal depression, citing previous studies that associate pain and depression.  However, women in this study who chose not to have an epidural, received no other form of pain relief, as "other forms of analgesia are not available at our hospital".  This is unlike any hospital I've ever worked in, and makes no sense; moreover, it limits the external validity, or "generalisability" of the study (medical speak for how well we can expect study findings in a particular population to apply to any other population - i.e. our patients).

So, overall, an interesting study that presents an intriguing association between epidural use and a (thankfully) positive birth outcome.  But these findings must always be interpreted with measured caution and, hopefully, responsible journalism will prevail over attention-grabbing headlines that make sweeping statements that may unduly influence women's birth choices.  


More research to support whooping cough vaccination during pregnancy

By , 19 May 2014

Whooping cough, also called the 100 day cough, is an illness cause by the bacterium Bordetella pertussis.  While often causing an irritating cough in adults, pertussis can be life-threatening in children, especially newborn infants.  In fact, over 90% of deaths from pertussis infection occur in babies under two months of age.  Pertussis vaccination forms part of the Australian Immunisation Schedule, and begins in children at two months of age.  Unfortunately, therefore, children cannot be vaccinated during the highest-risk period of their lives.  Immunisation does not provide lifelong immunity and, until recently, pertussis vaccine boosters were recommended for dads-to-be and new mums, in attempt to reduce the likelihood of their new baby being exposed to parents  with active pertussis infection.

The idea of vaccinating pregnant women has been around for a while, with the rationale that maternal antibodies will pass through the placenta, giving baby "passive immunity" against the infection at birth and in the newborn period.  Additionally, the safety of this vaccine is well-established (it is comprised of proteins only; it is not a "live" vaccine).  However, this concept has not been readily proven, as "protective levels" of antibody in baby's blood have not been accurately set.  Furthermore, there has also been concern that such maternal antibodies may dampen the baby's immune response to their own childhood vaccinations, lessening the protective effect of the vaccine schedule.

A research paper published this month in JAMA has provided further insights into the possible benefits of vaccinating expectant mothers during each pregnancy.  These researchers randomised women to pertussis vaccination during pregnancy, or vaccination after birth.  Most of the mothers vaccinated after birth had received vaccination at some point previously during their lives.  They measured levels of protective antibodies in mothers near delivery, and in children at birth, two months of age, and after completion of their routine childhood pertussis vaccination program.  Reassuringly, they found that vaccination during pregnancy did not dampen the children's response to routine childhood vaccination.  Additionally, they confirmed that levels of protective antibodies were significantly higher (4-5 fold) in children of mothers vaccinated during pregnancy.  Although this study was not powered to prove a reduction in newborn pertussis infection rates (this would need an enormous study), and the protective threshold of antibody levels is not known, this research adds strength to the argument for vaccination of all mothers during each pregnancy, to maximise the levels of protective antibodies present during their babies' most vulnerable time for infection.


Are babies who are "turned" by ECV still more likely to be born by caesarean section?

By , 16 May 2014

...a little, yes.

A new systematic review published ahead of print in Obstetrics & Gynaecology this week has confirmed that the rate of subsequent caesarean section is higher in women who have had a baby successfully turned from a breech to a cephalic presentation by ECV.  In this study, the rate of caesarean section after successful ECV was 21%, which compares to an intrapartum caesarean section rate for women with cephalic-presenting babies of around 12-15%.  Nevertheless, ECV remains a safe, simple, and scientifically valid method for women wishing to avoid caesarean section; the authors found that three women need to undergo an attempted ECV to prevent one caesarean section.  In medicine this is called the "number needed to treat", or NNT.  The lower the NNT, the more efficient the treatment is, and a NNT of three is excellent. 


Does low dose aspirin reduce the risk of miscarriage?

By , 3 April 2014

According to an RCT published in The Lancet this week - maybe...

Low-dose (75-100mg) daily aspirin ("LDA"), commenced before 16 weeks, has been shown in high-powered studies to reduce the risk of some adverse pregnancy outcomes such as pre-eclampsia, fetal growth restriction, and preterm birth.  The effect is strongest in high-risk women (viz. women who have suffered such adverse events in previous pregnancies; see Villa et al, BJOG 2013 and Roberge et al Ultrasound O&G 2013).  As often happens in medicine, "indication creep" means that we become tempted to prescribe these proven therapies for indications in which they are unproven.  Recurrent miscarriage or recurrent pregnancy loss ("RPL", defined as three or more consecutive pregnancies ending in miscarriage before 20 weeks) causes immeasurable anguish to couples, and it is normal to seek out ways of mitigating against future pregnancy loss.  Interestingly, LDA coupled with low dose heparin has been shown to reduce the rate of subsequent miscarriage in women with RPL who also have antiphospholipid syndrome; whereas this recipe has no effect in women with RPL in the absence of antiphospholipid syndrome (Kaandorp et al Cochrane 2009).

The use of LDA in women without RPL (that is, one or two miscarriages only) has found mixed results with small, unpowered studies previously.  The authors of this most recent, large, placebo-controlled RCT (dubbed the "EAGeR study") sought to scrutinise this relationship more clearly.  They studied the effect of commencing such women on LDA before conception, and found no improvement in livebirth or miscarriage rates for women who had "one or two" previous miscarriages, and concluded that routine LDA should not be used in this group.  Interestingly, however, their data did reveal a statistically significant improvement in pregnancy and livebirth rates in a group of women who had one previous miscarriage, before 20 weeks, within the last year.  Hmm... tough to explain the mechanism there, and perhaps it's a statistical anomaly ("Lies, damned lies, and statistics"), but certainly that little chestnut requires more research.  Miscarriage has a very complex group of causes, and there's no biologically plausible way that aspirin would improve many of them (such as chromosomal problems).

So, bottom line, LDA shouldn't be used indiscriminately with the hope of improving livebirth rates - we have good evidence for particular populations of women who benefit, and quality evidence to refute benefit in other populations.  This study adds to this knowledge.  

PS- I often get raised eyebrows when discussing aspirin use in pregnancy ("isn't that harmful?") - there is extensive evidence for the safety of low-dose aspirin when suitably prescribed in pregnancy (James et al O&G Survey 2008).


Excisional procedures for CIN2-3 do not increase the risk of preterm birth.

By , 2 April 2014

Pre-cancerous lesions of the cervix (i.e. CIN2-3), detected by Pap smear screening and confirmed by colposcopy and biopsy, and frequently treated by an excisional procedure such as a LLETZ or LEEP.  In women who have not yet completed their childbearing, these procedures have been thought to increase the risk of preterm birth, and this is factored into decision-making when choosing active treatment (excision) versus a "wait and see" approach (conservative).  Some previous studies have suggested that the changes to cervix's microstructure due to the disease process itself, and not the treatment procedure, may be the real cause of this risk of preterm birth.  This week a large meta-analysis of available evidence has been published in the journal Obstetrics & Gynecology.  Comparing >6'500 women who underwent a LLETZ/LEEP to women who have not, they confirmed this procedure is associated with an increase in the risk of birth before 37 weeks by about 60% (or an absolute risk increase of 3%).  However, when comparing to women who underwent a LLETZ/LEEP to women known to have dysplasia but managed without surgery, there was no difference in the rates of birth before 37 weeks.  This is the strongest evidence to date to suggest that LLETZ procedures may not be an independent risk for preterm birth, and this information will no doubt alter how we counsel women when deciding their treatment options.  

*(Data excluded laser and cone biopsies)

Article available here.


Eating allergenic foods during pregnancy won't cause allergies in children

By , 24 March 2014

Heard the old wives' tale about avoiding "allergy foods" in pregnancy, lest your child develop allergies? 

Well some more evidence to put that to rest: 
A cohort study in press has examined the association between mothers' intakes of common food allergens during pregnancy, with the rates of childhood asthma and allergy.   The researchers found NO evidence that avoiding food allergens results in a reduced risk of childhood allergy; in fact, a modest reduction was found in the odds of childhood asthma/allergies when mothers' diets were high in peanuts, milk, and wheat

So, bottom line, prospective parents do not need to worry about restricting their diets out of fear of causing allergies in their children.  

View abstract here


Paracetamol use in pregnancy linked to ADHD

By , 3 March 2014

Although media outlets like to lead with attention-grabbing headlines, we need to be careful not to jump to conclusions prematurely... 

An interesting article published recently in JAMA Pediatrics which observed an association between paracetamol use in pregnancy and neurodevelopment disorders such as ADHD. 

However, it is important to remember that statistical associations do not prove causation. Although this is a very large, prospective study, it is non-randomised and so not all potential confounders (i.e. things that can influence results other than a true causal relationship between paracetamol and ADHD) cannot be accounted for. The researchers were careful to control their data for things like fevers and infections (as recalled by the women), but can't account for all reasons why women might take paracetamol, and therefore can't account for the potential interactions between these and risk of ADHD; development of ADHD is complex and may involve genetic predisposition, non-inhereited factors and, potentially, environmental exposures. Other conditions that have similarly complex causes, such as predisposition to migraines or pain syndromes (which could not all be accounted for in a study of this design) are also reasons why women may take paracetamol. And so true relationships become a little difficult to prove.

An important lesson in effects of study design was demonstrated by the Womens' Health Initiative HRT trials - while observational data suggested HRT use may protect women from heart disease, follow-up data from randomised trials showed the opposite - HRT increased cardiovascular risk. Additionally, conditions for which paracetamol is used, such as fever, are known to be harmful to developing babies. 

So, while this study has provided some important information, more study will be required, along with subsequent risk-benefit analyses, before we can unequivocally recommend avoiding paracetamol in pregnancy.


Twin Birth Study published!

By , 14 October 2013

Canadian researchers have recently published the findings of a randomised control trial comparing outcomes for mothers and babies of twin pregnancies, comparing planned vaginal birth to planned vaginal delivery.  This study took place over 7 years and across more than 100 countries, and followed the outcomes of more than 2800 women with twins who gave birth between 32 weeks and 38 weeks 6 days of pregnancy.  Their findings were in line with previous large observational studies, which have shown that twins tend to be born earlier and with slightly more complications than their singleton counterparts.  Additionally, they confirmed that the second baby to be born (usually called "twin 2") generally bears more risk than the first twin.  Importantly, however, this large, well-conducted study found no difference in outcomes between those who planned a vaginal birth and those who planned a caesarean section.  This finding gives clinicians and expecting mums valuable information with which to base their choices and plans about childbirth.  The abstract of this landmark clinical trial is available here.


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29 July 2013

Thank you for visiting our website. This site has been created help you find the information about common conditions in obstetrics and gynaecology, and about Dr David Moore's practice.  Please check back regularly as the site is frequently updated.

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