Clinical trial NCT04310059: Effect of Folic Acid Supplementation in Pregnant Women Having Thalassaemia Trait
Official title: A Randomized Controlled Trial to Study the Effect of Folic Acid Supplementation in Pregnant Women Having Thalassaemia Trait
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: NA
Conditions: Thalassemia
Folic Acid Deficiency Anemia
Lead sponsor: The University of Hong Kong
Sponsor class: OTHER
Collaborators: name: Queen Mary Hospital, Hong Kong
First posted: 2020-03-17
Enrollment: 270
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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.

Detailed description: 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

Primary outcomes:
measure: Haemoglobin level
timeFrame: Change in level throughout the pregnancy, up to 42 weeks
measure: Maternal RBC folate concentration
timeFrame: Change in level throughout the pregnancy, up to 42 weeks
measure: Maternal serum folate concentration
timeFrame: Change in level throughout the pregnancy, up to 42 weeks
measure: Cord blood RBC
timeFrame: Upon birth
measure: Cord blood serum folate concentration
timeFrame: Upon birth
Secondary outcomes:
measure: Ferritin level
timeFrame: Change in level throughout the pregnancy, up to 42 weeks
measure: Maternal Vitamin B12
timeFrame: Maternal Vitamin B12 at first antenatal visit
measure: Cord blood vitamin B12
timeFrame: Cord blood vitamin B12 upon birth
Other outcomes:
Locations:
Study officials:
References:
citation: Daly LE, Kirke PN, Molloy A, Weir DG, Scott JM. Folate levels and neural tube defects. Implications for prevention. JAMA. 1995 Dec 6;274(21):1698-702. doi: 10.1001/jama.1995.03530210052030.
citation: Czeizel AE, Dudas I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med. 1992 Dec 24;327(26):1832-5. doi: 10.1056/NEJM199212243272602.
citation: Crider KS, Devine O, Hao L, Dowling NF, Li S, Molloy AM, Li Z, Zhu J, Berry RJ. Population red blood cell folate concentrations for prevention of neural tube defects: Bayesian model. BMJ. 2014 Jul 29;349:g4554. doi: 10.1136/bmj.g4554.
citation: US Preventive Services Task Force; Bibbins-Domingo K, Grossman DC, Curry SJ, Davidson KW, Epling JW Jr, Garcia FA, Kemper AR, Krist AH, Kurth AE, Landefeld CS, Mangione CM, Phillips WR, Phipps MG, Pignone MP, Silverstein M, Tseng CW. Folic Acid Supplementation for the Prevention of Neural Tube Defects: US Preventive Services Task Force Recommendation Statement. JAMA. 2017 Jan 10;317(2):183-189. doi: 10.1001/jama.2016.19438.
citation: Cordero AM, Crider KS, Rogers LM, Cannon MJ, Berry RJ. Optimal serum and red blood cell folate concentrations in women of reproductive age for prevention of neural tube defects: World Health Organization guidelines. MMWR Morb Mortal Wkly Rep. 2015 Apr 24;64(15):421-3.
citation: Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group. Lancet. 1991 Jul 20;338(8760):131-7.
citation: Management of Beta Thalassaemia in Pregnancy. Green-top Guideline No 66: Royal College of Obstetricians & Gynaecologists; 2014. p. 1-17.
citation: Lao TT. Obstetric care for women with thalassemia. Best Pract Res Clin Obstet Gynaecol. 2017 Feb;39:89-100. doi: 10.1016/j.bpobgyn.2016.09.002. Epub 2016 Sep 23.
citation: Leung CF, Lao TT, Chang AM. Effect of folate supplement on pregnant women with beta-thalassaemia minor. Eur J Obstet Gynecol Reprod Biol. 1989 Dec;33(3):209-13. doi: 10.1016/0028-2243(89)90131-7.
citation: Plumptre L, Masih SP, Ly A, Aufreiter S, Sohn KJ, Croxford R, Lausman AY, Berger H, O'Connor DL, Kim YI. High concentrations of folate and unmetabolized folic acid in a cohort of pregnant Canadian women and umbilical cord blood. Am J Clin Nutr. 2015 Oct;102(4):848-57. doi: 10.3945/ajcn.115.110783. Epub 2015 Aug 12.
citation: Caudill MA, Cruz AC, Gregory JF 3rd, Hutson AD, Bailey LB. Folate status response to controlled folate intake in pregnant women. J Nutr. 1997 Dec;127(12):2363-70. doi: 10.1093/jn/127.12.2363.
citation: Baghersalimi A, Hemmati Kolachahi H, Darbandi B, Kamran Mavardiani Z, Alizadeh Alinodehi M, Dalili S, Hassanzadeh Rad A. Assessment of Serum Folic Acid and Homocysteine in Thalassemia Major Patients Before and After Folic Acid Supplement Cessation. J Pediatr Hematol Oncol. 2018 Oct;40(7):504-507. doi: 10.1097/MPH.0000000000001295.
citation: Tripathi G, Kalra M, Mahajan A. Folate supplementation in transfusion-dependent thalassemia: Do we really need such high doses? Indian J Med Paediatr Oncol. 2016 Oct-Dec;37(4):305. doi: 10.4103/0971-5851.195746. No abstract available.
citation: Tso SC, Wong RL. Folate status in pregnant Chinese women in Hong Kong. Int J Gynaecol Obstet. 1980;18(4):290-4. doi: 10.1002/j.1879-3479.1980.tb00498.x.
citation: White JM, Richards R, Byrne M, Buchanan T, White YS, Jelenski G. Thalassaemia trait and pregnancy. J Clin Pathol. 1985 Jul;38(7):810-7. doi: 10.1136/jcp.38.7.810.
citation: Guideline: Fortification of Rice with Vitamins and Minerals as a Public Health Strategy. Geneva: World Health Organization; 2018. Available from http://www.ncbi.nlm.nih.gov/books/NBK531762/
citation: Atta CA, Fiest KM, Frolkis AD, Jette N, Pringsheim T, St Germaine-Smith C, Rajapakse T, Kaplan GG, Metcalfe A. Global Birth Prevalence of Spina Bifida by Folic Acid Fortification Status: A Systematic Review and Meta-Analysis. Am J Public Health. 2016 Jan;106(1):e24-34. doi: 10.2105/AJPH.2015.302902. Epub 2015 Nov 12.
citation: Joseph CA, Dedman D, Fern K, Chakraverty P, Watson JM. Influenza surveillance in England and Wales: November 1991-June 1992. Commun Dis Rep CDR Rev. 1992 Dec 4;2(13):R149-52. No abstract available.
citation: Gilchrest BA, Rowe JW, Brown RS, Steinman TI, Arndt KA. Relief of uremic pruritus with ultraviolet phototherapy. N Engl J Med. 1977 Jul 21;297(3):136-8. doi: 10.1056/NEJM197707212970304.