Prenatal Vitamins Therapeutic Class Review (TCR) February 10, 2020 No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, digital scanning, or via any information storage or retrieval system without the express written consent of Magellan Rx Management. All requests for permission should be mailed to: Magellan Rx Management Attention: Legal Department 6950 Columbia Gateway Drive Columbia, Maryland 21046 The materials contained herein represent the opinions of the collective authors and editors and should not be construed to be the official representation of any professional organization or group, any state Pharmacy and Therapeutics committee, any state Medicaid Agency, or any other clinical committee. 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FDA-APPROVED INDICATIONS Prenatal vitamins are approved for nutritional supplementation of females of childbearing potential during pre-conception, pregnancy, or lactation.1 Current products are listed in Appendix A. OVERVIEW Prenatal vitamins provide supplementation for both the mother and fetus. While prenatal supplements contain numerous vitamins and minerals, the folic acid, iron, and calcium content are particularly important.2 When folic acid stores are replenished before pregnancy, a 50% reduction in neural tube defects has been observed.3 The 2017 American College of Obstetricians and Gynecologists (ACOG) Neural Tube Defect Practice Bulletin recommends periconceptional folic acid supplementation as it has shown to reduce the occurrence and recurrence of neural tube defects.4 All women of child-bearing potential should take folic acid supplementation daily. For women at low-risk of neural tube defect, folic acid supplementation of 400 mcg per day is recommended. Supplementation should be initiated at least 1 month prior to pregnancy and continued through the first 12 weeks of pregnancy. For females at high- risk, defined as those who have had a prior neural tube defect pregnancy, who have a neural tube defect themselves, or who have a partner who has a neural tube defect or a child with a neural tube defect, folic acid supplementation of 4 mg/day is recommended. Supplementation in high-risk patients should be initiated ≥ 3 months prior to pregnancy and continued until 12 weeks of gestational age. Higher levels of folic acid supplementation (> 400 mcg/day) should be achieved by taking an additional folic acid supplement and not by taking excess multivitamins, since they may contain vitamin A, which is potentially teratogenic at high doses. In 2017, the U.S. Preventive Services Task Force (USPSTF) reaffirmed its 2009 statement on folic acid for neural tube defect prevention.5 The USPSTF recommends that all women planning or capable of pregnancy take a daily supplement 400 mcg to 800 mcg of folic acid (Grade A recommendation). This recommendation does not apply to women who have had a prior pregnancy affected by neural tube defects or women taking certain anti-epileptic medicines. Most organizations recommend that these women take higher doses of folic acid.6 The task force found that most women in the U.S. are not ingesting fortified foods at a level thought to provide optimal benefit. In a setting in which food is fortified with folic acid, the effective amount of additional folic acid supplementation is unclear. The Centers for Disease Control (CDC) and March of Dimes actively recommend folic acid as one of the nutrients needed in prenatal vitamins.7,8 Iron is recommended to prevent maternal anemia, preterm labor, low birth weight, and aid in maternal/fetal muscle development. Calcium, along with vitamin D, is important for skeletal development, as well as preventing future maternal osteoporosis.9 For pregnant and lactating women ages 14 to 18 years old, the Institute of Medicine (IOM) recommended daily allowance (RDA) is 1,300 mg/day and 600 IU/day of calcium and vitamin D, respectively.10 For pregnant and lactating women ages 19 to 50 years old, the RDA is 1,000 mg and 600 IU daily calcium and vitamin D supplementation, respectively. Some vitamins contain omega-3 fatty acids, such as docosahexaenoic acid (DHA), in their products to support neural and ophthalmic development. The March of Dimes actively recommends at least 200 mg of DHA/day for women.11 Prenatal Vitamins Review – February 2020 Page 2 | Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2004-2020 Magellan Rx Management. All Rights Reserved. According to the Academy of Nutrition and Dietetics (formerly the American Dietetic Association), daily vitamin supplementation is not a substitute for a healthy diet.12 Prenatal vitamins should be used along with balanced meals to ensure adequate levels of vitamins and minerals and ensure a healthy pregnancy outcome. PHARMACOLOGY13 Calcium is used to maintain calcium balance. Adult pregnant and lactating females require 1,000 mg elemental calcium per day. Calcium supplementation decreases the risk of preeclampsia and hypertensive disease in pregnancy. Folic acid is necessary for formation of a number of coenzymes in many metabolic systems, especially for purine and pyrimidine synthesis. Folic acid is essential for neural tube development occurring within 28 days of conception. Iron replaces iron found in hemoglobin, myoglobin, and enzymes. Iron allows for the transportation of oxygen via hemoglobin. Iron stores are vital for maternal safety. Maternal iron stores at conception are a strong indicator of maternal iron status and risk of iron deficiency and anemia in later pregnancy. The recommendation for pregnant females within the first trimester is 15 mg of elemental iron per day; and 27 mg of elemental iron per day during the second and third trimesters. Lactating females require 9 mg to 10 mg of elemental iron per day. PHARMACOKINETICS14 Prenatal supplements are available as over-the-counter (OTC) and prescription. They differ in their consistency, quality level, and relative bioavailability for fat-soluble and water-soluble vitamins and important minerals. Most OTC supplements now contain higher levels of folic acid. CONTRAINDICATIONS/WARNINGS15 Hypersensitivity to any component of the formulation and pre-existing hypervitaminosis are considered contraindications. Iron toxicity is a boxed warning. Severe iron toxicity may occur in overdose, particularly if ingested by children. It should be stored out of reach of children and in child resistant bottles. Iron supplementation should be avoided in patients with hemochromatosis and hemosiderosis. Prenatal vitamin formulations containing omega-3 fatty acids, such as ALA (alpha-linolenic acid, EPA (eicosapentaenoic acid), and DHA (docosahexaenoic acid), from fish oils may potentially have antithrombotic activities; thereby, increased bleeding times may be noticed. The administration of DHA should be avoided in patients with inherited or acquired bleeding diatheses, including patients taking anticoagulants. Prenatal vitamins should be used with caution in patients with severe hepatic and renal impairment. Use caution in patients with kidney stones due to the calcium content. DRUG INTERACTIONS16 The absorption of iron can be inhibited by eggs and milk. Some products may contain phenylalanine. Pyridoxine supplements should not be taken with levodopa alone. The actions of levodopa may be antagonized with concomitant use. Prenatal Vitamins Review – February 2020 Page 3 | Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2004-2020 Magellan Rx Management. All Rights Reserved. ADVERSE EFFECTS17 Common reactions to prenatal supplements are gastrointestinal including abdominal pain, constipation, dark stools, diarrhea, nausea, and vomiting. Allergic reactions can occur. SPECIAL POPULATIONS18 Pediatrics Prenatal vitamins are approved in adolescents and adult females. Pregnancy All products are generally recognized as safe (Pregnancy Category A). Hepatic Impairment Prenatal vitamins should be used in caution in patients with severe hepatic impairment. Renal Impairment Prenatal vitamins should be used with caution in patients with severe renal impairment. Use caution in patients with kidney stones due to the calcium content. DOSAGES19 Prenatal vitamins are available as oral dosage forms, including tablet, caplets, capsules, softgel capsules, chewable tablets, liquid, powder, and bars. They should be taken once daily with food, unless otherwise specified. If patients cannot tolerate prenatal vitamins, time of dosing can be changed; taking the vitamin prior to sleep or changing the dosage form may help. CLINICAL