Effect of Folic Acid Supplementation in Pregnant Women Having Thalassaemia Trait

Folic acid supplementation has been recommended for prevention of neural tube defects in pregnancy when taken periconceptionally up to 12 weeks of gestation. A daily dose of 0.4mg has been endorsed by World Health Organisation to achieve a Red blood cell (RBC) folate level of 906nmol/L (400ng/mL) for reduction of neural tube defect. Hong Kong has no policy on food fortification. Research data conducted in countries with food fortification may not be applicable. It is therefore essential to study the baseline folate status in pregnant women locally.

For pregnant women with thalassaemia, they are believed to have a higher risk of folate deficiency because of an increased rate of erythropoiesis and chronic haemolysis. However, information on folate level of thalassaemia trait in pregnancy is scanty. Unmetabolized folic acid has been detected in maternal and fetal blood when daily dosage greater than 0.8-1mg was taken. In term of the dosage and duration of folic acid supplementation after 12 weeks of gestation, the practice varies widely among public hospitals and Maternity \& Child Health Care centres. It is therefore essential to study the optimal dosage of folic acid supplementation in women with thalassaemia.

Folic acid supplementation is well established for its role in prevention of neural tube defects (NTD) when taken periconceptionally up to 12 weeks of gestation. The naturally occurring form, folate, is a water soluble B vitamin (B9) that is mostly present in dark green leafy vegetables and legumes. However, it is only 50% bioavailable. Folic acid, on the contrary, as a synthetic form of folate is almost completely bioavailable especially when administered in an empty stomach. It has been endorsed by World Health Organisation that RBC folate cutoff of 906 nmol/L (400ng/mL) is required for reduction of NTD. This level is only achievable by taking Folic acid supplementation of 0.4mg/day. Women at higher risk of having recurrent NTD is recommended to take higher dose at 4mg/day.

Patients with thalassaemia have an increased rate of erythropoiesis and chronic haemolysis. They are believed to have a higher rate of folate turnover and consequentially higher risk of folate deficiency. Guideline from Royal College of Obstetricians and Gynaecologists recommends daily intake of 5mg folic acid preconceptionally to prevent NTD. But, it does not specify whether this dosage is applicable to all types and degrees of thalassaemias and research data on the optimal dosage is lacking.

In addition to prevention of NTD, the supplementation of folic acid is also recommended for pregnant thalassaemia women for prevention of antenatal anaemia. In a retrospective study of Chinese population reported in 1989, women with beta-thalassaemia minor taking additional 5mg folic acid had higher pre-delivery haemoglobin concentration of 10.1 g/dL compared to haemoglobin level of 9.7 g/dL in the group taking Obimin (a pregnancy supplement containing 0.25mg folic acid and 90 mg ferrous fumarate). However, there was no further randomised controlled trial to validate this observation. Though a higher folic acid supplementation was believed to be beneficial in prevention of antenatal anaemia, unmetabolized folic acid were detected in maternal and fetal blood when daily dosage greater than 0.8-1mg was taken. Moreover, a higher rate of urinary excretion of folic acid was also observed in pregnant women receiving higher dosage of folic acid supplementation.

In non-pregnant beta thalassaemia major patients, folic acid supplementation at 1 mg daily was advised as cessation of which could lead to a significant reduction in serum folate. This has been counter-proposed by the observation of normal to high serum folate levels in transfusion dependent thalassaemia receiving optimal transfusion. Indeed, folic acid supplementation should be considered for non-transfusion dependent thalassaemia as excessive erythropoiesis is required to maintain satisfactory haemoglobin.

Folate level drops during pregnancy to puerperal period. Information on folate level of thalassaemia trait in pregnancy is scanty. In a paper published in 1985, no difference in serum folate was found between normal women and women with thalassaemia trait, and hence usual supplementation was suggested.

Hong Kong has no policy on food fortification. Research data conducted in countries with food fortification may not be applicable. The folate status may have been changed in last few decades because of better general nutritional status and public knowledge of preconception folic acid supplementation. The preparation of 5mg folic acid is available in all public hospitals and preparation of 0.5mg folic acid is recently introduced. As such, the 5mg folic acid prescription is traditionally adopted and this can be a result of its availability. However, the practice varies widely among public hospitals and Maternity \& Child Health Care centres. There is no standardised guideline on the dosage and indications of folic acid supplementation for pregnant thalassaemic women. More importantly, no recent data on the baseline folate status in pregnant women with thalassaemia is available locally.

Patient blood management in Obstetrics has been advocated with an aim to minimize blood loss by maintaining haemoglobin levels, reduce blood transfusion and optimize patient outcome. Identification and treatment of maternal anaemia is one of the three main pillars to achieve it. Even though thalassaemia can be considered as a risk factor for NTD, it remains controversial as to how much folic acid supplementation is adequate for pregnant women with thalassaemia trait in prevention of maternal anaemia which is a key element in maternity care.

Eligibility Criteria:
Inclusion Criteria:

* Singleton pregnancy
* Alpha thalassaemia trait
* Beta thalassaemia trait

Exclusion Criteria:

* Women taking over 0.6mg folic acid daily for 3 months or more prior to and during pregnancy
* Gestational age \> 16 weeks at first antenatal visit
* Women age =\< 18 years old
* Booking BMI =\< 18 or \>= 35
* Serum ferritin level \< 30ug/L or 68 pmol/L
* Concomitant alpha and beta thalassaemia
* Hb H disease
* Beta thalassaemia major
* Beta thalassaemia intermediate
* Thalassaemia other than alpha or beta type
* Women on long term medications
* Women with risk factors for NTD
* Women with known epilepsy
* Women with bariatric surgery or malabsorption diseases
* Women with known MTHFR polymorphism
* Vegetarian