Lachie Hayes, Haematologist Said:

There is recent safety data in pregnancy from an RCT of oral iron vs oral iron plus IV iron polymaltose performed by the Launceston group. Infusion related incidents were minimal.

Pregnancy outcome was assessed as a secondary / post-hoc outcome in terms of birth weight etc over 200 women which isn't huge numbers but is a start and may not have been powered to detect a significant difference if number of adverse events small.

Interestingly they targeted mild-moderate anaemia and intervened early at around 26 weeks ie. this was more of a safety study and study on treetment of iron deficiency rather than iron deficiency anaemia. Patients with Hb <85 due to IDA were excluded and treated with IV iron but data on these was not reported - would be interesting to see what the increment was and how quickly this occurred.

It's likely that the effect of IV iron was diluted by the concomitant use of oral iron following the infusion and the early intervention at ~26 weeks which may have allowed for oral iron to exert it's full effect.

I tend to get referred these patients late, with persistent Hb <90 or less after failing oral iron or being intolerant of oral iron. Iron polymaltose appears to be a safe and effective option in this select group.

A prospective randomized, controlled trial of intravenous versus oral iron for moderate iron deficiency anaemia of pregnancy

I can't quite agree with that last sentiment

As there are only a few people around Australia using IV iron polymaltose at high rates, I will seek their views on this question.  In the meantime, let me offer my response.

If the former ADRAC's experience is any guide, most of us won't see many reactions to IV iron polymaltose and so far, they've only been mild.  For skin rashes, oral antihistamine is fine.  For a febrile reaction I use a short course of systemic steroid (prenisolone starting at 25 mg and tapering to nil over 5 days), and it works well.

I'm glad you mentioned 'evidence based'.  Expert Opinion is still considered Evidence, albeit Grade III (US Preventive Services Task Force) or IV (Cochrane).  The method of infusion of iron polymaltose in the TGA-Approved Product Information has no evidence base at all.  It was developed by the manufacturers of iron dextran as a prudent way to administer a product known to cause serious allergic reactions, and copied over to iron polymaltose in ignorance of the fundamental differences between iron dextran and iron dextrin.

This Expert's Opinion, based on 20 years' experience at about 100 infusions per year, is that any amount of iron polymaltose up to 3,000 mg can be safely infused over 60-90 minutes with or without premed.  The iron polymaltose may be mixed in as little as 100 mLs of normal saline for the purpose.

So, until the Monash group at Box Hill publishes something that confirms this  - probably in the next year or so - this is the most definitive word on the subject. 

The paper cited was the basis for removing the pre medication from hospital guidelines as it is evidence based. It seems likely we will continue with no pre med, but is there a concensus  on how best to treat or deal with these early onset reactions so the TDI may continue?

Dr Nicholl is correct in his reference.  The Box Hill gastroenterology group have shown in this small series that there were no immediate, nasty effects from omitting pre-medication with TDI.  The Australian Adverse Drug Reactions Advisory Committee had, however, received a consistent 5-10 reports per year of reactions to parenteral iron, about half of which seem to me to have been true allergy.  All were minor.

Since Prof Gibson's Internal Medicine Journal report, we have also stopped using routine pre-med and have only had one instance of allergic-type rash in about 35 TDI recipients.

So the message should be, I think, that there remains no evidence of severe anaphylaxis with total dose intravenous iron polymaltose, but minor allergic reactions can still occur.  They all respond to oral non-sedating antihistamines.  Routine use of antihistamine pre-med seems to be sending a contradictory signal, but would do no harm if an individual clinician chose to do so.

I don't know if there is consensus on this point but I remember coming across a paper that questioned the value of premedication. In the Internal Medicine Journal (Volume 36, Number 10, October 2006 , pp. 672-674) there is a report of an  audit of the in-hospital safety and tolerability of 401 infusions of iron polymaltose in 386 patients that showed no cases of anaphylaxis or other cardiorespiratory compromise. The infusions were terminated prematurely because of adverse events in six patients (1.6%). No adverse events occurred within the first 150min of the infusions. Premedication (in 24%) was not associated with fewer adverse events. The conclusions were that fear of anaphylaxis should not inhibit the use of total dose iron infusion and the practices of premedication and of medical supervision during the first 150 min of the infusion should be abandoned.

We have been using TDI in our pregnant population to treat iron deficiency anaemia resistant to oral therapy for a number of years without significant problems or adverse reactions. The hospital recently changed the TDI infusion guidelines and removed the use of antihistamine (loratadine) prior to the infusion. A recent spate  of adverse reactions including rash and  welts during the test dose phase of the infusion has us now questioning if the antihistamine was preventing the reactions or if something else is going on. Are there any comments in regard to this population?

I agree with my colleagues about the importance of not losing sight of the development of anaemia in the antenatal period.  I also support the use of IVI if indicated as it certainly appears safe and well tollerated.

A recent challange is that of dealing with placenta percretas the incidence of which does appear to be increasing.  Techniques do exist to circumvent the massive haemorrhages often seen at the time of delivery. 

I agree with James that there is no direct evidence to address this question.

However, there is a plethora of evidence attesting its safety and efficacy [eg Singh, K. Fong, Y. F. Kuperan, P. A comparison between intravenous iron polymaltose complex (Ferrum Hausmann®) and oral ferrous fumarate in the treatment of iron deficiency anaemia in pregnancy. European Journal of Haematology Volume 60(2), February 1998, pp 119-124].  I am seeking further material from a literature review published in 2003, in a European journal not immediately available to me.

Another valuable bit of evidence is that the baby's birth weight is better if iron deficiency is treated or prevented during pregnancy [Rasmussen KM, Stoltzfus RJ: New evidence that iron supplementation during pregnancy improves birth weight: New scientific questions. Am J Clin Nutr 78:673, 2003.]  Although this refers to iron supplementation, presumably oral, it fits with the obvious concept that a healthy mum will produce a healthier baby.

What should not require 'evidence' is the fact that a bone-weary mother with iron-depleted cytochrome oxidase enzymes will not be able to do as good a job in those vital first weeks as would an iron-replete mother.  Tissue iron deficiency, whether accompanied by anaemia or not, takes a significant toll on the physical, intellectual and emotional reserves of the individual.

A reasonable question to which I can only give an opinion based answer, but I will sound out some colleagues. I am not aware of any evidence the IVI is a potential problem for the foetus However, giving iron IVI is not physiological and naturally adverse effects for the mother and the foetus need to be considered.There is some old animal toxically data but I don't think it helps in answering the question.

Dr Isbister, I presume IV iron poses no risk to the baby in utero?

Obviously, the cause of anaemia needs to be identified.  Haemoglobin levels below 105 gm/L should be investigated, in particular to establish iron status. Therapy is determined by the cause, stage of pregnancy and the severity of anaemia. In general, in relationship to iron deficiency/depletion early in pregnancy appropriate oral iron therapy may be adequate, but the response needs to be monitored. In late preganancy response to oral iron may be inadequate, especially if the patient’s Hb “set point” is at the lower range there is minimal stimulus for a rapid response and iron stores take a long time to be repleted. It is this circumstance where IVI therapy is most appropriate. As mentioned previously, when there is a great acceptance and “comfort” with the use of currently available IV iron preparations there will hopefully be wider and earlier use of intravenous iron.

Dr Isbister what is your recommended best practice in relation to management of antenatal anaemia?At what point should we be considering oral and then IV iron therapy. Is there a target Hb we should be working towards so as to reduce the risk of a patient requiring a  blood transfusion postpartum??  

I agree that a complacency has come into the problem of antenatal anaemia. I remember as a medical student in the 1960’s we received several lectures on anaemia in pregnancy and its management. IVI iron was even advocated at that time accepting there was a risk to balance against the benefits and the avoidance of blood transfusion. It seems that in recent years there has been more interest in failure of a pregnant women to develop the increased red cell mass with greater increase in plasma volume leading to haemodilution of pregnancy. Failure of this adaptation  being associated with hypertension and poor placental development and dysmaturity has received more attention.

I agree with most of the previous comments. I would like to make a few points:

1. Obvoiusly acute red cell and other blood product transfusion during major obstetric haemorrhage is not the the issue here - we should advocate for appropriate and timely use of blood products for maternal resuscitation which saves lives. It is important not to confuse messages about elective and emergency use of blood products.

2. For elective post-partum transfusion we should treat the patient - not the numbers. Most women are able to make an informed choice on red cell transfusion depending on their symptoms of anaemia.

3. There is no evidence to support the old axiom of there being no role for one unit - women often feel a whole lot better after one bag.

4. We have become very complacent about antenatal anaemia over the last 10 years - we probably should be more active in supplementing as suggested by other comments.

5. It seems that many of the strategies we use to reduce the likelihood of anaemia and blood loss in women who refuse blood products could be used in the general pregnant population.

As a registered midwife in the UK in the 1980's the general maxim was not to give blood transfusions to young mothers due to the risk/fear of HIV transmission. To that end all women were screened antenatally for anaemia and treated with iron therapy. Women were at times discharged home with Hbs of 6 or less on iron therapy and with home support usually from a relative. It was extremely rare to see a blood transfusion given for post partum anaemia. I can only ever remember a blood transfusion being given for a patient with massive haemorraghe and DIC following a delay in treating a broad ligament haematoma following an instrumental delivery. I think the 'safety' of transmission of infective viral risk has led to some complacency in the clinical management of antenatal detection and treatment of anaemia and the management of post partum anaemia. Lower Hbs should be tolerated blood is not risk free and a young mother who contracts Dengue fever from a red cell transfusion or who has an ABO incompatible transfusion is a very devestating complication if the therapy could have been avoided.  

Many important comments have been made and the importance of iron status cannot be overemphasized. I agree with the comments about IVI iron that concerns about reactions are a hangover from the past. We should also balance the risks of IVI against the well know risk of allogeneic blood transfusion. Dr Lucy Bowyer makes a valid point about postpartum mothers needing adequate aerobic capability when they get home and are breastfeeding. However, allogeneic transfusion should not be the default decision in this context. Several women contracted HIV in this setting in the 1980’s. It is important to emphasize that improving the ultimate outcome from transfusion for the patient in the long-term is more important than short-term gains (surrogate endpoints). In the setting to which Lucy reference transfusion should be the last resort and well understood and consented by the patient. IV iron, close monitoring and additional home support are less risky than an allogeneic blood transfusion.

I agree with the comments on Venofer (our iron-sucrose iv infusion), we use it regularly and it's very well tolerated.  I top up all my women with resistant iron-deficiency anaemia, I realise there is no data on whether or not we reduce our PPH rate, but symptomatically the women all feel better about 3 weeks post infusion.

With regard to post-partum anaemia, please remember the mother needs to be active, breast feed her baby and frequently look after other children, she can't just sit around convalescing (speaks the mother of 3 children).  With an Hb of 60 gm/L in my clinical experience over the last 20 years, most of these women will be breathless, feel weak and have a diminished breast milk supply.  In our hospital they have usually had an Hb of over 105 gm/L prior to delivery and will therefore feel clinically symptomatic and I would consider transfusion.

Dr Marc Miller alluded to a commonly-held concern about anaphylaxis with IV iron treatment.

This dates back to the days of iron dextran (Imferon), which did have a 2% rate of severe anaphylaxis and a 40% rate of late serum sickness.  However Imferon hasn't been available in Australia for nearly 20 years.  Those of us who use IV iron polymaltose (Ferrosig or Ferrum H) find it very safe and effective.  Iron polymaltose has a much lower molecular weight than iron dextran, and this appears to the reason it causes less problems.

The medical literature doesn't provide much help, because only Australia, New Zealand and South Africa call it iron polymaltose.  The US literature refers to the safety of 'low molecular weight dextran' (eg Auerbach M Goodnough LT Picard D and Maniatis A The role of intravenous iron in anemia management and transfusion avoidance. Transfusion2008;48:988-1000.)  In Europe and UK, 'iron dextrin' is considered as safe and effective as iron sucrose, and a paper from South Africa uses the terms iron dextrin and iron polymaltose interchangeabley (van Zyl-Smit R & Halkett JA. Experience with the use of an iron polymaltose (dextrin) complex given by single total dose infusion to stable chronic haemodialysis patients. Nephron. B316-23, 2002 Oct.) 

Australian researchers (eg Prof Peter Gibson, a gastro-enterologist  at Box Hill in Victoria) are using up to 3,000mg as IV infusions over 60-90 minutes. Prof Gibson's group abandoned routine antihistamine/steroid premedication some years ago, without any problems.

I'd encourage obstetricians to consider IV iron polymaltose for patients with iron deficiency anaemia in the last trimester.  Anything else is a case of 'too little, too late'.  Not only does definitive iron replacement fix the anaemia, it replenishes cytochrome oxidases.  Undertreated iron deficiency is probably the reason for the physical, intellectual and emotional fatigue so often seen in 'supermums'.

The issue of the group and save for all caesarean sections is an interesting one. I know there is considerable practice variation across NSW - across public and private sectors and between metro, regional and rural facilities. I agree that a blanket group and save for all caesarean sections is probably unwarranted.

I think that where we take our eye off the ball is in the antenatal diagnosis of anaemia (particularly iron deficiency anaemia). Rather than watch the Hb drift below 10.5 gm/L with iron stores diminishing, we need to be a little more aggressive about getting pregnant women iron replete before delivery (irrespective of mode but more so for caesarean section). I have seen many women who have been hospitalised for long periods during their pregnancy (eg placenta praevias) become iron deficient (?nutritional due to hospital food) when this is the perfect opportunity to keep on top of the situation.

Regarding postpartum transusion I do not routinely transfuse if >60gm/L  if haemodynamically stable unless the woman has significant symptoms of anemia or has a severe underlying medical condition such as coronary artery disease or sickle cell disease (fortunately very uncommon in our pregnant population). I would routinely recommend transfusion below 60 gm/L due to the increasing risk of hyperdynamic cardiac failure.

During pregnancy I do not treat unless the Hb is less than 10.5 gm/L. There is a physiologic dilutional anemia during pregnancy due to increased circulating volume but overall an there is an increase in red cell mass so in pregnancy these lower levels of haemoglobin are well tolerated in the abscence of iron deficiency. I would give ferrous sulphate below 10.5 if other causes of anemia are excluded. I would not transfuse a woman in pregnancy with iron deficiency anemia. Very rarely I have used parenteral iron for a symptomatic women with haemoglobin less than 8 gm/L who cannot tolerate oral iron but in general I try to avoid this due to the small risk of severe anaphylaxis.

I am an obstetrician. We have moved to fewer and fewer "elective" transfusions, lot more use of intravenous iron (?necessary) antenatally. However, we occasiionally face massive haemorrhage wehn obviously blood transfusion and other components is necessary in large amounts.

A more interesting question for us is the group and save for elective Caesarean section. Although I am in Melbourne, I read a recent NSW coronial report that criticized a hospital for not doign g&s (though I think this was for emergency CS), and I think even suggested that deliveries only occur at hospitals with onsite blood bank, whihc is clearly impossible. NICE in UK have recommended against routine G&S for elective CS, and the facts are that for elective CS overall, the tranfusion rate is less (about 1%) than that for planned vaginal delivery. With the elective CS rate now approaching 20%, this would mean 60,000 G&S per annum for only 600 (many probably not necessary) transfusions.

What else where you interested in from obstetric viewpoint?