Protocol development in integrative medicine is not typically a simple process. Individuals require individualized care, and what works for one patient may not work for another.

To establish these protocols, we first developed a Rating Scale that could be used to discern the rigor of evidence supporting a specific nutrient’s therapeutic effect.

The following protocols were developed using only A through C-quality evidence.

Class
Qualifying studies
Minimum requirements
A
Systematic review or meta-analysis of human trials
 
B
RDBPC human trials
2+ studies and/or 1 study with 50 + subjects
C
RDBPC human trials
1 study

Pregnancy may be a difficult time for some individuals, with various challenges. From nausea and vomiting to meeting various heightened nutritional requirements, supplemental nutrients can be a very useful tool for expecting mothers. (Khorasani 2020) 

For example, multivitamin and mineral supplements can help mothers to hit these nutritional targets, and thereby reduce the risk of certain birth defects and preterm delivery. (Wolf 2017) Some nutrients may require supplementation beyond a prenatal multivitamin in order to hit therapeutic targets for reducing the risk of pre-eclampsia or hospitalization. (Makrides 2014)(Regitz-Zagrosek 2018) Certain nutrients such as EPA and DHA are even associated with improved measures of infant cognitive development. (Nevins 2021) Finally, certain therapeutics may reduce nausea and vomiting experienced during pregnancy. (Khorasani 2020) 

Based on current research findings, the ingredients in the protocol below have been associated with improved health outcomes in women who are pregnant.

Prenatal Multivitamin

Variable based on ingredient and formulation, for 5-6 weeks within the preconceptional period

      • A 2021 Australian systematic review of guidelines for complementary medicines and therapies found many of the guidelines to be recommending the following common ingredients in prenatal multivitamins: folic acid, vitamin D, iodine, iron, vitamin B6, and vitamin B12. (Ee 2021)
      • A 2017 systematic review (SR) and meta-analysis (MA) of multivitamin supplementation in high-income countries examined 98,926 females in 35 studies, finding reduced relative risk of small gestational age by 23%, neural tube defects by 33%, cardiovascular defects by 17%, urinary tract defects by 40%, and limb deficiencies by 32%. Due to the difficulty of having an ethical placebo group in studies on pregnancy, of the 35 studies, only four were randomized controlled trials. (Wolf 2017)
    • Folic acid
        • A 2021 SR and MA of 39 studies examining folic acid supplementation concluded that folic acid was associated with a positive impact on an offspring’s neurodevelopmental outcomes, including improved intellectual development and reduced risk of autism traits, ADHD, behavioral, and language problems. (Chen 2021)
        • A Cochrane review found risk of neural tube defects was lowered at a dose of > 400 µg per day. (De-Regil 2015)
    • Iodine
        • A Cochrane review found RCTs showing iodine supplementation reduced the risk of postpartum hyperthyroidism by 68%. (Harding 2017)
        • Iodine content in multivitamin products studied was typically found to be sufficient (> 150 μg). (Leung 2009)
    • Iron
        • Many women, even in developed countries, may be at risk of low iron status. A cohort study found that 68-82% of pregnant Australian females were not meeting the recommended daily intake of iron. (Livock 2017).
        • A 2015 Cochrane review found preventative iron supplementation reduced the risk of maternal anemia at term by 70%, iron-deficiency anemia at term by 67%, and iron deficiency at term by 57%. This Cochrane review found moderate-quality evidence of a borderline significant reduction in preterm babies of 7%. (Peña-Rosas 2015)
        • The same Cochrane review found no significant differences in effectiveness or likelihood of side effects for daily vs. weekly dosing of iron. (Peña-Rosas 2015) 
    • Vitamin B12
        • A 2021 SR of complementary medicines and therapies in clinical guidelines in pregnancy found no consistent recommendations for B12, except four organizations recommending routine supplementation for vegetarians and vegans and two recommending the intervention after screening for deficiencies. (Ee 2021)
        • The lowest quartiles in three different Irish cohorts had 2-3x the risk of neural tube defects versus the highest quartiles. To reduce neural tube defects, the authors recommended vitamin B12 levels of at least >221 pmol/L (>300 ng/L) prior to conception. (Molloy 2009)
    • Vitamin B6
        • A 2021 SR of complementary medicines and therapies in clinical guidelines in pregnancy found five guidelines recommended routine supplementation with vitamin B6, for its moderate-quality evidence for nausea and vomiting and safety. (Ee 2021)
        • 20-80 mg of vitamin B6 daily was found to be effective for nausea and vomiting in pregnancy in this 2020 SR. (Khorasani 2020)
    • Vitamin D
      • A 2019 Cochrane review found a reduced relative risk of pre-eclampsia by 52%, gestational diabetes by 49%, low birthweight by 45%, and may reduce risk of severe postpartum hemorrhage by 32%. (Palacios 2019)
      • A 2021 SR of complementary medicines and therapies in clinical guidelines in pregnancy found three regulatory bodies recommending vitamin D at 400 IU to all pregnant women, and four organizations recommended over 1000 IU if a deficiency of less than 50 nmol/L of 25-hydroxyvitamin D was found. (Ee 2021) 
Prenatal Multivitamin in the Fullscript catalog

Omega-3 Fatty Acids

> 1g of combined EPA and DHA per day from early pregnancy (<20 weeks) to 34 weeks (Sun 2020)

  • Omega-3 fatty acids are an ingredient typically not found in a prenatal multivitamin or not in high enough quantity. A 2018 Cochrane meta-analysis (MA) of the addition of omega-3 fatty acids during pregnancy concluded that high-quality evidence showed a risk reduction of 11% for preterm birth (less than 37 weeks), a 42% risk reduction of early preterm birth (less than 34 weeks), and a 10% risk reduction of low birth weight. Studies tended towards favoring higher DHA formulations, though there was no tendency towards higher or lower doses of omega-3s being favorable. (Middleton 2018)
  • Subgroup analysis of a 2020 SR and MA found that prenatal supplementation with ≥ 1g of combined EPA and DHA significantly reduced preterm birth. (Sun 2020)
  • Five of eight RCTs examined in a 2021 SR on omega-3 fatty acid supplementation during pregnancy found significantly improved measures of infant cognitive development by 6-11%. (Nevins 2021)
  • A 2021 SR and MA of 11 RCTs showed no significant effect or adverse effects of omega-3 fatty acids for perinatal depression prevention or treatment across different dosages and ratios of EPA and DHA. (Suradom 2021)

Omega 3’s Ingredient Review

Omega-3 Fatty Acids in the Fullscript catalog

Ginger

35-500mg of ginger daily for 2 months (Khorasani 2020)

  • Ginger is an ingredient typically not found in prenatal multivitamins, though it may be very useful for typical morbidities found in pregnancy. A 2021 SR of complementary medicines and therapies in clinical guidelines in pregnancy found six regulatory bodies recommending ginger for the treatment of nausea and/or vomiting in pregnancy. (Ee 2021) Five of these bodies also recommended the use of vitamin B6 for the same indication.
  • A 2020 SR on alternative medicine treatments for nausea and vomiting in pregnancy found ginger and vitamin B6 to be equally effective for up to 60 days at doses of 35-500 mg for ginger and 20-80 mg for vitamin B6. Beyond 60 days, vitamin B6 was found to be superior to ginger. (Khorasani 2020)

Ginger Ingredient Review

Ginger in the Fullscript catalog

Calcium

1-2g per day, especially if dietary intake less than 600 mg, from 28-32 weeks until delivery (Hofmeyr 2018)(Regitz-Zagrosek 2018)

  • Calcium is an ingredient typically not found in high enough quantities in prenatal multivitamins, though it is commonly recommended; a 2021 SR of complementary medicines and therapies in clinical guidelines in pregnancy found five organizations recommending calcium supplementation for low dietary intake for prevention of pre-eclampsia. For instance, one organization recommended 1.5-2 g per day for dietary intake of less than 600 mg per day. (Regitz-Zagrosek 2018) 
  • The risk of preterm birth was found to be 24% lower in high dose (over one gram) calcium supplementation in a 2018 Cochrane review. Additionally, pre-eclampsia risk was lowered by 55% overall and 64% in women with low calcium diets. Publication bias was noted. Lastly, maternal death and/or serious morbidity were reduced by 20% (Hofmeyr 2018)

Calcium Ingredient Review

Calcium in the Fullscript catalog

Magnesium

365 mg of magnesium citrate or aspartate per day from 13-24 weeks until birth (Makrides 2014)

  • Magnesium is an ingredient typically not found in high enough quantities in prenatal multivitamins, though it may have certain benefits; a 2014 Cochrane SR found magnesium supplementation to be associated with higher Apgar scores in newborns, along with less likelihood of hospitalization by 35%. Null effects were noted on perinatal mortality, low birth weight, or pre-eclampsia. (Makrides 2014)
  • Additionally, a 2021 MA of RCTs found no significant effect of magnesium supplementation in pregnancy on leg cramps. No side effects were noted. (Liu 2021)
  • There was considerable heterogeneity in dosing in magnesium trials. However, more common formulations were magnesium citrate or aspartate, at doses of 365 mg per day. (Makrides 2014)

Magnesium Ingredient Review

Magnesium in the Fullscript catalog

Disclaimer

The Fullscript Medical Advisory Team has developed this protocol to help health care practitioners make decisions when building treatment plans. By adding this protocol to your Fullscript template library, you understand and accept that the recommendations in the protocol are for initial guidance and may not be appropriate for every patient.

View protocol on Fullscript
References
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