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Supplementation in pregnancy: Getting the balance right

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Iron deficiency negatively affects foetal development

The risk of preterm birth and low birth weight is increased if the expecting mother has an iron deficiency, which can result in iron deficiency anaemia (IDA) during pregnancy. Iron is important for development of the foetal brain and cognitive abilities of the infant.1,2

The increased burden of oxygen delivery to the foetus, exacerbates IDA and can result in intrauterine growth restriction, reduced iron for the infant and increased maternal and perinatal morbidity and mortality. The World Health Organization (WHO) defines IDA as a haematocrit of <33% and/or a haemoglobin of <11g/dL at any time during pregnancy. Oral iron prophylaxis to pregnant women improves their iron status and prevents the development of IDA. 3,7

The WHO reports that the prevalence of anaemia in women of reproductive age women in sub-Saharan Africa is around 57%. South Africa has the lowest burden (34%) in the region.1,3

According to Dorsamy et al, poor nutrition, chronic infections, lack of access to healthcare facilities and poor compliance with micronutrient supplementation all contribute to maternal anaemia in South Africa.3

The WHO recommends daily oral iron with 30mg to 60mg of elemental iron for pregnant women to prevent maternal anaemia, puerperal sepsis, low birth weight, and preterm birth. The equivalent of 60mg of elemental iron is 300mg ferrous sulphate heptahydrate, 180mg ferrous fumarate or 500mg of ferrous gluconate.4

Calcium supplementation reduces adverse gestational outcomes

Calcium supplementation in pregnancy has the potential to reduce adverse gestational outcomes by decreasing the risk of developing hypertensive disorders during pregnancy. Hypertensive disorders are associated with a significant number of maternal deaths and considerable risk of preterm birth, the leading cause of early neonatal and infant mortality.5

The WHO recommends an intake of 1.5g–2g elemental calcium per day with the total daily dosage divided into three doses (preferably taken at mealtimes) from 20 weeks’ gestation until the end of pregnancy. Target group includes all pregnant women, particularly those at higher risk of gestational hypertension and in areas with low calcium intake.5

Folic acid supplementation prevents more than just neural tube defects

Demands for folate increase during pregnancy because it is required for the foetus’ growth and development. Folate deficiency has been associated with abnormalities in both mothers (eg anaemia, peripheral neuropathy) and foetuses (congenital abnormalities).6

Dietary supplementation with folic acid around the time of conception has long been known to reduce the risk of for example neural tube defects (NTDs) in the foetus.6

Evidence suggests that folate may also play an important role in the timing of labour, reducing the risk of pre-term birth. In observational studies, a shorter duration of pregnancy has been associated with low serum folate levels and with the absence of folic acid supplementation during pregnancy.6

In addition to the prevention of NTD and reducing the risk of pre-term birth, supplementation with folic acid also appears to have other beneficial effects, including the prevention of pre-eclampsia, congenital heart disease and oral clefts.6

Folic acid should be commenced as early as possible (ideally before conception) to prevent NTDs. The WHO recommends folic acid supplementation with 400µg for pregnant women to prevent maternal anaemia, puerperal sepsis, low birth weight and preterm birth.4

How safe are supplements during pregnancy?

Iron

Numerous studies have evaluated the safety of routine iron supplementation during pregnancy. Participants ranged from 45 to 1164 who were treated with an iron supplementation posology of 20mg to 200mg per day. The teams reported mild or moderate and impermanent adverse events (AEs), such as nausea, constipation and diarrhoea.7

No significant difference was observed when comparing iron supplementation and control groups. The rates of nausea ranged from close to 30% to a bit over 60% in both groups, and the vomiting rates were both a little over 10% to 41%.7

Similar results were reported for constipation (defined as three or less evacuations per week). Based on these results, the United States Preventive Services Task Force concluded that there is sufficient evidence that AEs associated with iron supplementation are virtually inexistent (at worse, little).7

Friedrisch and Friedrisch caution that iron supplementation during pregnancy can cause is the development of IOL in iron-replete women and in patients with diseases that lead to iron overload, such as some haemoglobinopathies and hereditary haemochromatosis.

Calcium supplementation

Brown and Wright recommend that all pregnant women should be encouraged to increase their dietary calcium intake. In instances where intake is suboptimal or dairy is excluded from the diet, supplementation should be recommended.1

Several large placebo-controlled trials using supplementation up to 2500mg per day exclusive of dietary intake, have shown no AEs in pregnancy. Increased cardiovascular risk with calcium supplementation is controversial and not well supported, state the authors.1

Most studies examined the risk between 500mg per day and 1g per day of calcium, but no risk is assumed with supplementation in generally healthy adults below the tolerable upper limit of 2500mg per day.1

Folic acid

Supplementation at 40µg is largely considered safe. Evidence for AEs such as cancer, diabetes, thyroid disorders, and allergic disease below the tolerable upper intake level of 1000µg is weak or inconclusive.1

Experimental and observational evidence suggests that there may be risks related to changes in neurodevelopment with folic acid exposure above this level, but further studies are required in relation to dosage and timing.1

Traditionally, doses of 4mg have been used for high-risk patients. However, doses of 400µg-800µg of folic acid lower risk of NTDs, with no further reduction in risk with doses >1000µg.1

The 2020 Standard Treatment Guidelines and Essential Medicines List for South Africa caution that folic acid given to patients with vitamin B12 deficiency can mask vitamin B12 deficiency and lead to neurological damage unless vitamin B12 is also given.8

South African recommendations

The guidelines do recommend supplements before and during pregnancy and lactation, which can help to prevent, or lessen the effect of several conditions or complications associated with pregnancy. Specifically:8

  • Folic acid, given for at least one month before conception and during pregnancy (particularly the first 12 weeks) can help to prevent NTDs
  • Iron can help to prevent anaemia
  • Calcium can help to prevent pre-eclampsia.

General measures

Encourage pregnant women to:

  • Eat a balanced diet to prevent nutritional deficiency
  • Avoid unpasteurised milk, soft cheeses, raw or undercooked meat, poultry, raw eggs, and shellfish
  • Cut down on caffeine
  • Reduce tea intake (tea should not be consumed within two hours of taking iron tablets).

Medical measures

Prevention of NTDs

  • Oral folic acid 5mg daily is recommended for all women intending to become pregnant or pregnant women (first trimester of pregnancy). The guidelines caution that children born to women taking valproic acid (used to treat epilepsy, bipolar disorder and prevent migraine headaches) are at significant risk of birth defects (10%) and persistent developmental disorders (40%). Valproic acid is contra-indicated and should be avoided in pregnancy and women of child-bearing potential.

Prevention of anaemia

  • During pregnancy, after delivery and during lactation: Ferrous sulphate compound BPC (dried), oral, 170mg (± 55mg elemental iron) 12 hourly with meals, or ferrous fumarate, oral, 200mg once daily (±65mg elemental iron). Taking iron tablets with meals decreases iron absorption but improves tolerability. (Note: Do not take iron tablets with milk)
  • If daily iron is poorly tolerated (eg epigastric pain, nausea, vomiting and constipation), intermittent iron supplementation may be administered. The guidelines recommend oral ferrous sulphate compound BPC 340mg per week, (± 110mg elemental iron), with meals
  • From confirmation of pregnancy: Calcium, elemental, oral, 1g daily (given as calcium carbonate) every 12 hours. Although the benefit is greatest in high-risk women, consider using this agent in all pregnant women. Calcium reduces iron absorption from the gastrointestinal tract. Supplements should therefore be taken four hours apart from each other.
REFERENCES:

1. Brown B and Wright C. Safety and efficacy of supplements in pregnancy. Nutrition Reviews, 2020.
2. Milman N. Oral Iron Prophylaxis in Pregnancy: Not Too Little and Not Too Much! J Pregnancy, 2012.
3. Dorsamy V, Bagwandeen C and Moodley J. The prevalence, risk factors and outcomes of anaemia in South African pregnant women: a protocol for a systematic review and meta-analysis. Systematic Reviews, 2020.
4. WHO. Daily iron and folic acid supplementation during pregnancy. https://www.who.int/elena/titles/guidance_summaries/daily_iron_pregnancy/en/
5. Kumar A and Kaur S. Calcium: A Nutrient in Pregnancy. J Obstet Gynaecol India, 2017.
6. Greenberg JA, Bell SJ, Guan Y and Yu Y-H. Folic Acid Supplementation and Pregnancy: More Than Just Neural Tube Defect Prevention. Rev Obstet Gynecol, 2011.
7. Friedrisch JR and Friedrisch BK. Prophylactic Iron Supplementation in Pregnancy: A Controversial Issue. Biochemistry Insights, 2017.
8. South African National Department of Health. Standard Treatment Guidelines and Essential Medicines List for South Africa. http://www.kznhealth.gov.za/pharmacy/PHC-STG-2020.pdf

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