Frequently asked questions

Iron deficiency anaemia (IDA) in pregnancy affects around a third of women and about 20% in the post birth period.

It is associated with pregnancy complications such as, preterm birth, small for gestational age babies, postpartum haemorrhage, depression, stillbirth, and neonatal death.

Women also describe symptoms of malaise, fatigue, poor exercise tolerance and impaired cognition. We do not know whether management of anaemia will reduce these risks.

Currently a diagnosis of anaemia is made when routine bloods are taken at booking and 28 weeks’ gestation or incidentally when women are investigated for a pregnancy related condition. Treatment is therefore reactive, and if successful will increase maternal haemoglobin.

However, a significant proportion of women, 30-60%, fail to produce the required haematological response to iron treatment. The reasons are multi-factorial, including poor adherence, side effects, and impaired absorption from the gut.

In addition, IDA is more likely to be diagnosed in the third trimester, when the demands for iron from the mother, placenta and fetus are at maximum. Therefore, treatment is always playing catch up. Even when successful, there is a residual risk of poor outcomes.

If IDA can be prevented, the demands from the pregnancy, particularly in the third trimester can be more readily met. This trial aims to establish the clinical and cost-effectiveness of universal oral-iron supplements for prevention of anaemia. In addition, we will incorporate a medication adherence intervention and the processes to evaluate the impact of prevention of maternal anaemia on long-term infant neurodevelopment (and maternal outcomes).

Most trials to date have been small and define the increase in haemoglobin as the primary outcome measure. But this does not equate to clinical effectiveness, using clinically significant outcomes measures relevant to pregnant women.

Also, if a trial of prevention is successful in preventing adverse clinical outcomes we need to know that it is safe and cost effective, before generalising to the whole pregnant population. Safety is paramount as there are some reports associating iron treatment with higher rates of infection.

We have therefore powered our study on clinically relevant endpoints for a composite primary outcome of pre-term birth, stillbirth, neonatal death and small for gestational age (SGA).

There is little robust data to support this hypothesis.

A first problem with this assertion is the criterion for diagnosing anaemia during pregnancy. Haemoglobin levels naturally fall in the second and third trimesters because of the dilutional effect. This means that some women with ‘mild anaemia’ may be miss-classified as anaemic when they are merely showing the natural physiological change that occurs.

Women who exhibit the normal physiological adaptations in pregnancy are likely to have an uncomplicated pregnancy, and so their inclusion in cohort studies is likely to confound the results.

True anaemia does not appear to be benign and does not confer any benefit on either the mother or her baby. The epidemiological evidence is clear that as well as the outcomes mentioned above, there are potentially deleterious neurocognitive consequences for the offspring of women with iron deficiency anaemia (IDA)  during pregnancy.

If a trial participant develops anaemia, clinicians should:

• Adhere to guidelines such as those provided by the British Society for Haematology (BSH).
• Refrain from unblinding. Anaemia development is a secondary outcome and maintaining trial fidelity is crucial.
• Stop the trial medications
• Manage anaemia according to local unit guidelines, as if the participant were not in the trial.
• Assure Participants who develop anaemia that they:
  • will not be withdrawn from the PANDA prevention study, unless they specifically request it.
  • will continue to receive standard care as per local guidelines and policies.
  • will still contribute to all primary and secondary outcomes and follow-up, including for their baby.

We have completed preparation work and studies for this definitive trial.

Our patient and public involvement (PPI) work has shown that it is a subject of importance to pregnant women.

During the many focus groups, they related how they found iron deficiency anaemia (IDA) in pregnancy to be significantly debilitating. They also related experiencing haphazard management with differing and conflicting opinions among professionals.

A key objective of our dose finding study was to discover which dosing schedule for oral iron had the highest level of adherence, lowest side effect profile and best maintained the haemoglobin level.

The dose finding study was a randomised trial comparing three regimens of oral iron, a daily dose (200mg ferrous sulphate), alternate day dose and 3 times a week. A low dose schedule of once daily iron was selected to take forward into the main trial.

From the first 2 workstreams an intervention to help women adhere to the medication was developed.

We have updated the section on adverse event reporting in the protocol. Please refer to the most up-to-date version for more details. We hope that it is clear and helpful:

PANDA Protocol (PDF 973KB)

An important observation in the dose-finding trial was that the specific side effect symptoms we studied were not significantly impacted by the dose of iron.

The level of nausea and vomiting diminished or remained stable across pregnancy, whereas heartburn, indigestion and constipation worsened as the uterus became larger.

The patterns of change and severity of symptoms did not differ between the three dosing regimens. This suggests that these symptoms were not significantly influenced by taking iron.

We suggest that women who describe these symptoms are advised that these are more likely to be common features of (normal) pregnancy.

Dose modification should not be considered a first response but rather advise the use of simple remedies for indigestion, heartburn, nausea and constipation.

If dose-modification is discussed, we suggest changing from daily to alternate daily, for a period of 1-2 weeks, then resuming daily tablets.

Some women may report symptoms of nausea, constipation, vomiting, heartburn and indigestion while on iron.

From previous research, we know that these symptoms occur frequently in otherwise normal pregnancies and are not attributable to iron.

If women develop these symptoms and express concern, we advise:

1. Checking that there is no other evidence of an underlying medical condition, e.g. inflammation of the gut. If there are no other clinical indicators of disease:
2. Reassure them that these symptoms are experienced by many normal pregnant women, and advise them to try simple remedies for these symptoms:
   
   Indigestion and Heartburn: Eat smaller, more frequent meals, avoid spicy and fatty foods, and stay upright after eating.
   
   Nausea: Ginger tea, eating crackers, or small, frequent meals can help.
   
   Constipation: Increase fibre intake, drink plenty of water, and stay active.

If their symptoms persist, consider changing from daily to alternate daily iron supplements for 1-2 weeks, then resume daily tablets.

The absorption of iron can be affected by other drugs. For example, antacids, some types of antibiotics and mineral supplements. Similarly, iron itself can affect the absorption of some drugs.

To minimise these affects it is important to advise women on the correct way to take iron, which is on an empty stomach at least 30 minutes before food.

It can be taken with a drink of orange juice but not other drinks such as tea or coffee as they reduce iron absorption.

If other drugs are being taken, then it is advised to leave a 2 hour gap between taking the iron and the other medication.

The answer is yes, women can still take over the counter (OTC) supplements even if they contain iron.

The amounts of iron they contain is small and so will not affect the trial. We do however want to record what OTC supplements women are taking during their pregnancy.

We are advising women who are taking thyroxine to take the medications at different times of the day. If that taken together this could have a negative effect on absorption.

No, it is acceptable for these women to be recruited to the trial.

If you are unsure of whether a condition can be accepted, please contact the study team at PANDA@nhsbt.nhs.uk.

No there is no upper limit. We are using a low dose of iron in the IMP that will only deliver 65mg of elemental iron a day.

Some may be worried about overdosing but the evidence shows that the body regulates the amount of iron very tightly within narrow boundaries. If it is not required, then oral iron is not absorbed from the gut and iron within the body is stabilised in the holding cells such as macrophages and not released into the circulation.

This effect is medicated by a protein called Hepcidin produced in the liver. It is sensitive to the amount of iron in the blood stream and responds very rapidly.

Nevertheless, we do recognise that there have been some suggestions that excess iron may increase the rates of gestational diabetes mellitus (GDM) and pre-eclampsia (PET).

The evidence around this is poor and conflicting. But the safety of iron is paramount and very important to us.

The of monitoring adverse events and outcomes is integral to the trial and will be monitored by the independent data monitoring committee.

Like any other trial should there be concerns, these will be raised by that committee and the trial management group advised on any actions that need to be taken.

No, these women can be included but they need to be advised to take their iron separately from their medication for IBS.

No they are not. Only women with actual disease e.g. thalassaemia major are excluded.

We want to recruit women from all groups in society and so women from ethnic minorities who may carry the gene for sickle cell or thalassaemia can be offered participation in the trial.

If they can take the tablets they are not excluded from participation.

The level at which ferritin becomes abnormal in pregnancy is uncertain and subject to some degree of controversy. Also, from our and others epidemiological work, it is a weak predictor of adverse outcomes when compared to haemoglobin.

Other work has also shown that in women with anaemia the ferritin level can be high as well as low. The evidence available suggests that ferritin levels in pregnancy are not necessarily a true measure of iron deficiency.