May 22, 2021
**Carnitine – A Conditionally Essential Nutrient in Preconception, Pregnancy and Postpartum**
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Carnitine – A Conditionally Essential Nutrient in Preconception, Pregnancy and Postpartum

Emily Rydbom, CN, BCHN, CNP & Michael Stone, MD, MS, IFMCP

The body produces L-carnitine from the essential amino acid lysine. Healthy individuals, including strict vegetarians, can generally synthesize enough L-carnitine to prevent deficiency, but there are certain conditions like pregnancy that increase l-carnitine excretion and change an individual’s need (1).

Common nutrient co-factors found in the diet help to synthesize carnitine, include the essential amino acid Lysine-lysine promotes calcium uptake, is essential for carnitine production and collagen formation (found in red meat, fish and poultry), another essential amino acid Methionine-methionine protects cells from pollutants, slows cell aging, and is essential for absorption and bioavailability of selenium and zinc (found in egg whites, wild game, chicken, turkey and wild-caught fish), as well as Iron (Fe2+), Vitamin B3 (NAD), Vitamin B6 (P5P), and Vitamin C.

These same nutrient co-factors are in high demand during pregnancy. Using Bruce Ame’s Triage Theory (10) as an example, the body will preferentially prioritize when and how co-factors are used based on the its’ greatest physiological need (often at the expense of other “less” important pathways). In the case of carnitine synthesis, the kidneys efficiently conserve carnitine to maintain stable blood concentrations.

Yet, it is not uncommon for most women in pregnancy to have an increased need. We address this via focused dietary carnitine emphasis and supplementation.

Omnivores and Vegetarians

We now know that Carni, Carnus, Carn, Carne means meat/flesh. So, is this a ‘must-eat-meat’ conversation? No. Referring to the triage theory is elucidating when discussing the bioavailability of L-carnitine from food. In individuals adapted to low-carnitine diets (i.e., vegetarians) the bioavailability of L-carnitine was higher (66%-86%) than in those adapted to high-carnitine diets (i.e., regular red meat eaters; 54%-72%) (1). Most dietary carnitine is absorbed in the small intestine. And L-carnitine is the form found in food.

Since we lead with food first, it is important to note that carnitine rich foods are primarily found in animal flesh-based proteins (beef and chicken) and fish (cod). In lower levels, carnitine is found in whole fat milk, whole wheat, avocado, cheese and asparagus.

Supplemental Bioavailability

Is a supplement better than food? In a non-pregnant state, we can safely say the answer is more than likely no (especially since deficiency is not common), but we find that women often feel better with key timing and focused supplementation in pregnancy. Supplemental L-carnitine (doses, 0.6-7.0 g) is less efficiently absorbed compared to smaller amounts in food. Between 54% and 86% of L-carnitine from food is absorbed, compared to 5%-25% from oral supplements (1). We use a food first, supplement second approach.

Carnitine Across the Preconception, Pregnancy and Postpartum Timeline

Male Fertility

L-Carnitine is concentrated in the epididymis, where sperm mature and acquire their motility. In a cross-sectional study of fertile and infertile men it was found that L-carnitine concentrations in semen were positively correlated with the number of sperm, the percentage of motile sperm, and the percentage of normal appearing sperm (1,6). Acetyl-l-carnitine, l-carnitine fumarate and alpha-lipoic acid has been shown to improve oxidative markers in sperm. Oxidative stress infertility is increasing in incidence and is now estimated to impact 30-80% of infertile men (7).

Female Fertility

L-carnitine (LC) has been known to reduce reactive oxygen species and enhance adenosine triphosphate production (ATP-cellular energy) – part of what contributes to a high-quality embryo. In human studies with females undergoing IVF, higher numbers of good-quality embryos on days 2, 3 and 5 were found in culture media when supplemented with L-carnitine compared to controls (9). Researchers are now considering its implementation as a treatment for female infertility (8).

Pregnancy – Energy

Low carnitine is generally due to impaired mitochondrial energy metabolism or to carnitine not being efficiently reabsorbed by the kidneys. One of the earliest symptoms of vitamin C deficiency is fatigue, thought to be related to decreased synthesis of L-carnitine (1). Clinically, we see significant improvement in fatigue with dietary carnitine emphasis, co-factor considerations, microbiome support, and in many cases carnitine supplementation (particularly in the 3rd trimester) in pregnant women experiencing fatigue independent of pregnancy-induced anemia.

A word about fatigue and hypothyrdoid

Thyroid hormone stimulates carnitine-dependent fatty acid import and oxidition and increases carnitine bioavailability. If a thyroid is "sluggish" then L-carnitine supplementation may be useful in alleviating fatigue symptoms in hypothyroid patients (21). Hypothyroid diagnoses in preconception and pregnancy often require different clinical interventions. According to the American Thyroid Association, levothyroxine requirements frequently increase during pregnancy, usually by 25-50%.

Gestational Diabetes Mellitus (GDM) > Macrosomia

GDM rates are increasing worldwide and are now estimated to impact 10-15% of pregnancies, with the prevalence of GDM increasing from 5% to 14% in the US (11,13). Long-term associations of GDM in pregnancy include increased occurrence of hypertension and metabolic syndrome for the mother (12). It is also associated with a common birth phenotype (outcome), macrosomia or large for gestational age, yet macrosomia can also occur independently of GDM (4). Babies born to mothers with GDM are also prone to obesity, and type 2 diabetes mellitus (T2DM) as adults (4). Free carnitine deficiency is significantly related to GDM and carnitine is a protective factor for macrosomia (LGA). Deficiency of free carnitine may elevate lipid levels impacting/mediating the pathogenesis of GDM (4).

It appears that free carnitine levels are influenced by age (>35 years old), weight (elevated pre-pregnancy BMI), and weight gain (gestational weight gain in pregnancy) (4). Yet, for all women plasma l-carnitine concentrations markedly decline during pregnancy (2). In our own peer-reviewed study (5), we showed free carnitine deficiency in 97% of our 50% Medicaid study population. Pregnancy is commonly understood to be as an insulin resistant state. Carnitine supplementation may be effective in normalizing insulin sensitivity of GDM, which is why we emphasized replacement via diet and supplementation throughout pregnancy (along with a Low GI, ME diet emphasis). After tracking biomarkers (free, total and acyl carnitines) both in the 1st and 3rd trimesters, addressing deficiencies and insufficiencies, we showed total rates of GDM at <1% (N=110) (5).

In a recent meta-analysis of randomized controlled trials it was shown that l-carnitine supplementation might have a positive effect in achieving an improved body weight and BMI especially in overweight and obese subjects (19).

Depression

Prenatal and postpartum depression is increasing and common; in the postpartum time period it is now estimated that 1 in 8 mothers and 1 in 10 fathers (yes-men, too) experience postpartum depression. Dietary carnitine emphasis and carnitine supplementation may prove to be a clinical tool in mediating mental wellness. Three trials that compared acetyl-l-carnitine (ALCAR) treatment (1-3 g/day for 7-12 weeks) and antidepressant medications found ALCAR was as effective as antidepressants in treating depressive symptoms (1,20).

Clinical Considerations

What about TMAO?

It has been shown that the increase of plasma concentration of TMAO, as a result of TMA production via dietary supplements of choline and carnitine or TMAO production by gut bacteria increases the risk of cardiovascular disease, chronic kidney disease and colorectal cancer. Yet lower plasma concentrations of TMAO has been associated with digestive disorders such as inflammatory bowel disease and ulcerative colitis (14). So, what does that mean in the setting of carnitine in pregnancy? Normal dietary intake of carnitine or moderate supplementation are unlikely to produce TMAO at levels associated with adverse outcome (14). Let’s dive a little deeper here…

Trimethylamine N-oxide (TMAO) is a small, colorless amine oxide formed from trimethylamine (TMA), which is generated by the metabolism of gut microbiota from dietary precursors (choline, betaine, and l-carnitine) (4). Low TMAO and its metabolites in early pregnancy, including betaine, l-carnitine, and choline, have threshold effects, meaning too little OR too much is associated with worse outcomes (4). GDM risk sharply increases with decreasing concentrations of these metabolites below certain thresholds. Decreasing concentrations of betaine at ≤200 nmol/mL and l-carnitine at ≤112 nmol/mL were associated with a marked increase in the risk of GDM, independently of TMA and TMAO. The conversion from betaine, choline, and l-carnitine to TMA depends on gut microbiota*, and the conversion from TMA to TMAO depends on activity of FMOs (Flavin-containing monooxygenases- which catalyze NADPH-dependent oxidative metabolism of a wide array of foreign chemicals, including drugs, dietary-derived compounds, and environmental pollutants), especially FMO3 in the liver (14). Humans possess five functional FMO genes: FMO1, 2, 3, 4, and 5 and FMO3 plays a crucial role in the conversion of TMA>TMAO in the liver for excretion through urine and participates in host-gut microbiome metabolic interactions14. And it appears that TMA, rather than TMAO, is more likely to play a role in the etiology of GDM (4).

What to Assess

To address carnitine antecedents (genetics), triggers (diagnosis/condition) and mediators (nutrition, nutrients, lifestyle, age, weight), we consider the following:

  1. Genetics – if available (consider FMO3 polymorphic variants)
  2. Dietary preferences
  3. Nutrient Co-factor availability
  4. Lab Markers
  5. Microbiome support (prebiotics/probiotics/phytonutrients/herbs/spices-particularly when discussing TMAO above) - An imbalance of pro-TMA bacteria (firmicutes) to bacteroides (a bacteria that does not contribute to TMA production) can be an effect of a high-fat diet (18). In this case, it may be important to consider that elevated TMAO may indeed by a “response or causative” factor of an imbalanced microbiome (17,18).
    *Due to differences in intestinal bacteria composition, omnivores tend to produce more TMAO than vegans or vegetarians following consumption of L-carnitine16.
  6. Age
  7. Diagnoses – preconception (infertility), hypothyroid-related fatigue, fatigue, and mood challenges
  8. Pregnancy Status
  9. Gestational Age
  10. Pre-Pregnancy BMI
  11. Gestational Weight Gain
  12. Birth Status-Preterm (babies born preterm can often cannot synthesize adequate carnitine and supplementation/fortification may be necessary)

Labs We Check in Pregnancy

Free, Total and Acyl Carnitines in the 1st and 3rd trimester. These are often covered under Global OB coverage.

Nutrition Approach in Pregnancy

Low GI, Mediterranean Diet, omnivore with emphasis on phytonutrient intake and quality/frequency of red meat intake and vegetarian with adequate protein intake. In the case of a vegan diet, supplementation of carnitine is often required. Interestingly, dietary components such as indoles, found in the cruciferous family can inhibit activity of FMO3 and decrease the amount of TMAO produced as a percentage of total TMA excreted (14).

Nutrients We Use

GrowBaby PreGenesis Prenatal Pack-used in preconception and pregnancy-postpartum and breastfeeding (contains 500 mg L-carnitine) - check them out

GrowBaby Male PreGents Preconception Pack (contains 500 mg, L-carnitine) - check them out

Sources

1: Linus Pauling Institute, L-Carnitine: https://lpi.oregonstate.edu/mic/dietary-factors/L-carnitine

2: Bai M, Zeng Q, Chen Y, Chen M, Li P, Ma Z, Sun D, Zhou H, Zheng C, Zeng S, Jiang H. Maternal Plasma l-Carnitine Reduction During Pregnancy Is Mainly Attributed to OCTN2-Mediated Placental Uptake and Does Not Result in Maternal Hepatic Fatty Acid β-Oxidation Decline. Drug Metab Dispos. 2019 Jun;47(6):582-591. doi: 10.1124/dmd.119.086439. Epub 2019 Mar 27. PMID: 30918014.

3: Kim MK, Park JK, Paek SK, Kim JW, Kwak IP, Lee HJ, Lyu SW, Lee WS. Effects and pregnancy outcomes of L-carnitine supplementation in culture media for human embryo development from in vitro fertilization. J Obstet Gynaecol Res. 2018 Nov;44(11):2059-2066. doi: 10.1111/jog.13763. Epub 2018 Aug 1. PMID: 30066982.

4: Sun M, Zhao B, He S, et al. The Alteration of Carnitine Metabolism in Second Trimester in GDM and a Nomogram for Predicting Macrosomia. J Diabetes Res. 2020;2020:4085757. Published 2020 Aug 11. doi:10.1155/2020/4085757

5: Stone LP, Stone PM, Rydbom EA, et al. Customized nutritional enhancement for pregnant women appears to lower incidence of certain common maternal and neonatal complications: an observational study. Glob Adv Health Med. 2014;3(6):50-55. doi:10.7453/gahmj.2014.053

6: Matalliotakis I, Koumantaki Y, Evageliou A, Matalliotakis G, Goumenou A, Koumantakis E. L-carnitine levels in the seminal plasma of fertile and infertile men: correlation with sperm quality. Int J Fertil Womens Med. 2000;45(3):236-240.

7: Gamidov SI, Ovchinnikov RI, Popova AY. [Double-blind, randomized placebo-controlled study of efficiency and safety of complex acetyl-L-carnitine, L-carnitine fumarate and alpha-lipoic acid (Spermactin Forte) for treatment of male infertility]. Urologiia. 2019 Sep;(4):62-68. Russian. PMID: 31535807.

8: Agarwal A, Sengupta P, Durairajanayagam D. Role of L-carnitine in female infertility. Reprod Biol Endocrinol. 2018;16(1):5. Published 2018 Jan 26. doi:10.1186/s12958-018-0323-4

9: Kim MK, Park JK, Paek SK, Kim JW, Kwak IP, Lee HJ, Lyu SW, Lee WS. Effects and pregnancy outcomes of L-carnitine supplementation in culture media for human embryo development from in vitro fertilization. J Obstet Gynaecol Res. 2018 Nov;44(11):2059-2066. doi: 10.1111/jog.13763. Epub 2018 Aug 1. PMID: 30066982.

10: Ames BN: Low micronutrient intake may accelerate the degenerative diseases of aging through allocation of scarce micronutrients by triage. PNAS 103(47)17589-17594, 2006.

11: Chamberlain J. J., Doyle-Delgado K., Peterson L., Skolnik N. Diabetes technology: review of the 2019 American Diabetes Association standards of medical care in diabetes. Annals of Internal Medicine. 2019;171(6):415–420. doi: 10.7326/M19-1638

12: Geach T. A metabolomic signature to predict the transition from GDM to T2DM. Nature Reviews Endocrinology. 2016;12(9):p. 498. doi: 10.1038/nrendo.2016.115.

13: Lowe W. L., Scholtens D. M., Kuang A., et al. Hyperglycemia and adverse pregnancy outcome follow-up study (HAPO FUS): maternal gestational diabetes mellitus and childhood glucose metabolism. Diabetes Care. 2019;42(3):372–380. doi: 10.2337/dc18-1646.

14: Fennema D, Phillips IR, Shephard EA. Trimethylamine and Trimethylamine N-Oxide, a Flavin-Containing Monooxygenase 3 (FMO3)-Mediated Host-Microbiome Metabolic Axis Implicated in Health and Disease. Drug Metab Dispos. 2016 Nov;44(11):1839-1850. doi: 10.1124/dmd.116.070615. Epub 2016 May 17. Erratum in: Drug Metab Dispos. 2016 Dec;44(12 ):1949. PMID: 27190056; PMCID: PMC5074467.

15: https://ods.od.nih.gov/factsheets/Carnitine-HealthProfessional/

16: Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, Britt EB, Fu X, Wu Y, Li L, Smith JD, Didonato JA, Chen J, Li H, Wu GD, Lewis JD, Warrier M, Brown JM, Krauss RM, Tang WH, Bushman FD, Lusis AJ, Hazen SL. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 2013;19:576-85.

17: Ley, R., Turnbaugh, P., Klein, S. et al. Human gut microbes associated with obesity. Nature 444, 1022–1023 (2006). https://doi.org/10.1038/4441022a

18: Yang Y, Liu Y, Zheng L, Wu T, Li J, Zhang Q, Li X, Yuan F, Wang L, Guo J. Serum metabonomic analysis of apoE(-/-) mice reveals progression axes for atherosclerosis based on NMR spectroscopy. Mol Biosyst. 2014 Dec;10(12):3170-8. doi: 10.1039/c4mb00334a. Epub 2014 Sep 22. PMID: 25241798.

19: Askarpour M, Hadi A, Miraghajani M, Symonds ME, Sheikhi A, Ghaedi E. Beneficial effects of l-carnitine supplementation for weight management in overweight and obese adults: An updated systematic review and dose-response meta-analysis of randomized controlled trials. Pharmacol Res. 2020 Jan;151:104554. doi: 10.1016/j.phrs.2019.104554. Epub 2019 Nov 17. PMID: 31743774.

20: Veronese N, Stubbs B, Solmi M, Ajnakina O, Carvalho AF, Maggi S. Acetyl-L-Carnitine Supplementation and the Treatment of Depressive Symptoms: A Systematic Review and Meta-Analysis. Psychosom Med. 2018 Feb/Mar;80(2):154-159. doi: 10.1097/PSY.0000000000000537. PMID: 29076953.

21: An JH, Kim YJ, Kim KJ, Kim SH, Kim NH, Kim HY, Kim NH, Choi KM, Baik SH, Choi DS, Kim SG. L-carnitine supplementation for the management of fatigue in patients with hypothyroidism on levothyroxine treatment: a randomized, double-blind, placebo-controlled trial. Endocr J. 2016 Oct 29;63(10):885-895. doi: 10.1507/endocrj.EJ16-0109. Epub 2016 Jul 16. PMID: 27432821.

Posted on May 22, 2021