Minimal Transfer of Atorvastatin and Its Metabolites in Human Milk: A Case Series

Abstract

Background:

Statins are historically contraindicated during breastfeeding due to theoretical concerns of disruptions in infant development from drug exposure and nutritional changes in milk. Breastfeeding mothers requiring statins often discontinue statins or postpone treatment until breastfeeding cessation, contributing to delays in treatment up to 14 years. This study aims to determine the transfer of atorvastatin and its active metabolites into human milk and evaluate the infant’s risk of drug exposure.

Materials and Methods:

Milk samples and health information were released from the InfantRisk Human Milk Biorepository for three women taking 20 mg, 40 mg, and 80 mg of atorvastatin daily at steady state conditions. The concentration of atorvastatin (AT) and its active metabolites, ortho-hydroxy AT (2OH AT) and para-hydroxy AT (4OH AT), was quantified in timed milk samples using liquid chromatography–mass spectrometry.

Results:

The highest absolute infant dose of AT was 0.00027 mg/kg/day, and the highest weight-adjusted relative infant dose of the combined analytes was 0.09%, far below established thresholds for infant safety. Milk cholesterol levels were within previously established norms in the range of 10 mg/dL. The mothers reported no adverse outcomes in the two exposed infants.

Conclusions:

The transfer of atorvastatin and its metabolites was exceedingly low. While the impact on milk composition in states of hyperlipidemia (whether treated or untreated) is not well understood, it is unlikely that the drug in the milk would be present in clinically significant levels to adversely affect a breastfed infant.

Introduction

Heart disease is the leading cause of death in women in the United States, and women also have greater cardiovascular mortality than men.¹ Women of reproductive age have considerably lower cardiovascular risk. However, many factors increase the risk of cardiovascular disease in women, including polycystic ovarian syndrome, hypertensive disorders of pregnancy, gestational diabetes, preterm delivery, low infant birth weight/growth restriction, premature menopause <40 years old, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, and breast cancer.^2,3 Though these factors increase the risk of cardiovascular disease, hypercholesterolemia represents the highest population-adjusted cardiovascular risk factor in women.⁴

For the general population with hypercholesterolemia, the most common interventions are diet and lifestyle modifications as well as medications such as atorvastatin (AT). AT, commonly referred to as a statin, inhibits 3-methylglutaryl coenzyme A reductase (HMG CoA reductase). This inhibition increases low-density lipoprotein (LDL) receptors on hepatocytes and promotes LDL catabolism. Statin treatment in large analyses has found that for every 39 mg/dL reduction in LDL, major adverse cardiovascular events are reduced by 20–25%.⁵

It is well documented that LDL cholesterol and triglyceride concentrations rise progressively during pregnancy. The risk of cardiovascular complications due to these elevations is uncertain at this time.⁶ Information on cholesterol and triglyceride variations in pregnant patients with familial hypercholesterolemia is limited, but a study in 22 pregnant patients with familial hypercholesterolemia identified that LDL cholesterol levels and triglycerides increased significantly from baseline to gestational week 36 in these patients compared with the reference group.⁷ Lactation plays an important role in helping women return to baseline lipid levels. Elevated triglycerides may resolve three times faster when breastfeeding, underscoring the benefits of breastfeeding in normalizing lipid evels.⁸

Maternal hypercholesterolemia may result in nutritional changes in milk, though cholesterol in human milk has not been well-studied. A study in healthy Chinese populations without hypercholesterolemia concluded that cholesterol levels are highest in colostrum, decrease in transitional milk, and are lowest in mature milk. Cholesterol levels in milk also varied based on the study’s differing ethnicities.⁹ A case report of a breastfeeding woman with familial homozygous hypercholesterolemia 7 weeks postpartum found milk cholesterol concentrations three times higher than the control (6.5 mg/g versus 2.4 mg/g total milk fat).¹⁰ The mother’s plasma LDL was 544 mg/dL at the same time. Evidence regarding maternal dietary modifications and changes in cholesterol and phospholipid concentrations is limited. Milk cholesterol concentrations are 9–15 mg/dL compared with 0–0.4 mg/dL in infant formulas.¹¹ The Fate of Early Lesions in Children study found an increased risk of atherosclerosis in a child if exposed to hypercholesterolemia during pregnancy.¹²

Women considering pregnancy or already pregnant were not adequately studied or included in the 2018 guidelines on managing blood cholesterol from the American College of Cardiology and the American Heart Association. This body of experts does not support the use of statins during pregnancy and advocates for interruptions in statin therapy when planning a pregnancy or using contraception to prevent pregnancy. A subsequent publication regarding the role of nonstatin therapies published by the American College of Cardiology also recommends statin therapy be discontinued during conception, pregnancy, and lactation.¹³

Statins are also not currently recommended in lactation or pregnancy due to concerns about changes in cholesterol concentrations in human milk and the unknown consequences of altering lipid metabolism on neurodevelopment in infants. It has been theorized that inhibition of cholesterol synthesis could disrupt the development of the brain and nervous system in developing infants.¹⁴ There are also concerns regarding untreated hypercholesterolemia and statin interruptions around pregnancy and breastfeeding. A group of researchers examined statin treatment delays in women with familial hypercholesterolemia and found up to a 14-year statin treatment delay due to preconception, pregnancy, and breastfeeding.¹⁵ Information suggests that breastfeeding for at least 6 months is associated with reduced maternal cardiovascular risk through reductions in blood pressure and body mass index, and in select subgroups, it was identified that patients had lower triglycerides and higher high-density lipoprotein cholesterol.¹⁶ Another analysis found that women who optimally breastfeed can prevent infant gastrointestinal infections, acute otitis media, and hospitalizations for lower respiratory tract infections as well as maternal hypertension, diabetes, and myocardial infarctions. The most astounding finding is that for every 597 women optimally breastfeeding, 1 maternal or infant death is prevented.¹⁷ These findings are reassuring but still beg the question of whether to stop breastfeeding in favor of initiating medications.¹⁸ Still, given the statin treatment delays, there may be a higher risk of cardiovascular events in women with familial hypercholesterolemia during the childbearing period or as a cumulative effect later in life. There are no data evaluating maternal AT use and excretion into human milk. This study aimed to assess the transfer of AT into human milk and evaluate the infant’s risk of drug exposure.

Materials and Methods

The InfantRisk Human Milk Biorepository (HMB), Texas Tech University Health Sciences Center Amarillo IRB # A21-4214, provided the deidentified materials for this investigation. Electronic consent was obtained from the HMB participants. The HMB observationally collects milk samples with various exposures of interest from lactating volunteers. The samples are accompanied by questionnaires with self-reported histories for the breastfeeding dyad. For this study, milk samples were requested from the participants under steady-state conditions at 0, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose. Mothers were advised to empty both breasts, gently mix the milk, and then aliquot 1–2 ounces into a provided collection tube. The collected samples were frozen and shipped overnight to our facility, where they are stored at −80° C until the analysis. The HMB was queried for milk donors taking AT, resulting in three deidentified volunteers with corresponding milk samples and health questionnaires pertaining to the maternal–infant dyads. Compliance with ethical standards and approval by the relevant institutional review board (IRB # A21-4214) ensure the protection of participant privacy and welfare throughout the HMB. HMB participant deidentification maintains these protections throughout this study.

An LC-MS/MS method was developed and validated for the simultaneous estimation of AT and its active metabolites in human milk. We used an Agilent 1260 infinity liquid chromatograph–mass spectrometer and Agilent (Ultivo Triple Quadrupole) Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) system. Separation was conducted on a C18 column (50 mm × 2.1 mm, 1.8 µm)—Zorbax SB. Chromatographic elution was performed with a mobile phase consisting of 0.1% formic acid in water–acetonitrile using gradient elution pumped through the column at a flow rate of 0.4 mL/min. The injection volume was 10 µL, and the LC-MS/MS system was operated in the positive ion mode for the detection of AT and its metabolites along internal standard (IS). Multiple reaction monitoring transitions measured at positive mode at m/z 559.0 → 440.0 for AT, m/z 575.0–440.2 for both ortho and para hydroxy AT, and m/z 564.2 → 445.2 for IS. Quantitation of all analytes in human milk was conducted using a peak area ratio of analytes to IS, with a detection limit of 0.078 ng/mL and a quantification limit of 0.156 ng/mL.

Milk samples and related health information were released from the InfantRisk HMB for participants taking AT. The concentration of AT and its active metabolites, ortho-hydroxy AT (2OH AT) and para-hydroxy AT (4OH AT), was quantified in timed milk samples using highly specific and sensitive liquid chromatography–mass spectrometry. The relative infant dose was calculated using the formula: relative infant dose (%) = estimated daily infant dose via breast milk (mg/kg/day) using average drug concentrations/maternal dose (mg/kg/day) × 100. Average infant milk intake was assumed to be 150 mL/kg/day.

Cholesterol assay

A simple fluorometric method for determination of total cholesterol in collected human milk samples is described, using reagents purchased from Cayman Chemicals. This assay is based on an enzyme coupled reaction that would free cholesterol from esters and then convert into ketone by oxidation in turn release H₂O₂. This reacts with substrate and gives fluorescence. This kit is designed for human plasma and serum. However, it was imperative to validate that the milk sample does not interfere with the assay. This was achieved by conducting tests with multiple dilutions of the milk samples to confirm that the measured cholesterol concentration decreases proportionally with increasing dilution factor. Additionally, testing a sample spiked with a known amount of cholesterol using the standard to ensure that the expected level of cholesterol is detected was also determined.

Results

Three breastfeeding women taking AT had consented to HMB and provided all requested milk samples. Table 1 presents an overview of the demographic characteristics of the participants and their infants as well as the relevant pharmacokinetic data. AT was administered once daily at 20 mg, 40 mg, and 80 mg, respectively. Understanding the drug concentration–time profile in milk samples helps assess the potential risk of infant exposure and the extent of AT transfer. AT and its equipotent active metabolites 2OH AT and 4OH AT and cholesterol levels were quantitated in all milk samples (Fig. 1). The kinetics are not linear, so values cannot be proportionally adjusted to follow the same concentration curve based on concentration profile of AT and its metabolites found in Figure 1. The cholesterol assay revealed that woman taking 80 mg had higher milk cholesterol concentrations compared with those detected in milk from women taking the 20 mg and 40 mg doses.

FIG. 1.

Concentration profile of atorvastatin (AT) and active metabolites (2OH AT and 4OH AT) and their corresponding cholesterol levels in human milk of two women at (1A) and (1B) 20 mg, (2A) and (2B) 40 mg, and (3A) and (3B) 80 mg dosages.

Table 1.

Patient Demographics and Pharmacokinetic Data

Parameter	Patient 1: 20 mg atorvastatin per day			Patient 2: 40 mg atorvastatin per day			Patient 3: 80 mg atorvastatin per day
Maternal history
Maternal age (years)	32			32			31
Pertinent current medical conditions	High cholesterol, minimal change disease			High cholesterol, anxiety			Asthma, blood clotting disorder, PCOS, GERD, heart disease
Pertinent past medical conditions	Anxiety, depression, gestational diabetes, high blood pressure, mastitis, PCOS			N/A			Anxiety
Gestational age at delivery (weeks)	40.14			32			39
Birth weight (grams)	2,920			1,276			3,844
Concomitant maternal medications	Prednisone, 40 mg 1× daily			Escitalopram, magnesium supplement			Amlodipine, apixaban, colchicine, budesonide inhaler, cetirizine, docusate
Maternal atorvastatin dose (mg/kg/day)	0.35			0.62			1.26
Milk total free cholesterol (mg/dL)	5.96			7.24			17.39
Patient pharmacokinetic data
Analyte	AT	2OH	4OH	AT	2OH	4OH	AT	2OH	4OH
AUC (ng.hr/mL)	10.6	11.7	6.6	31.48	35.25	10.2	44.29	49.82	25.17
C_avg (ng/mL)	0.441	0.488	0.275	1.31	1.46	0.425	1.84	2.07	1.05
C_max (ng/mL)	0.703	0.383	0.772	3.78	2.62	0.6	5.11	8.2	3.9
T_max (hour)	10	4	12	2	4	4	2	4	4
Infant Dose (mg/kg/day)	0.000066	0.000072	0.00004	0.00019	0.00022	0.00022	0.00027	0.00031	0.00015
Relative Infant Dose (%)	0.019	0.02	0.011	0.03	0.03	0.03	0.02	0.02	0.012
Infant data
Diet	55% breast milk, 45% formula			Breast milk, breast milk fortified with human milk fortifier, solids			Formula, solids, rice cereal, water
Age at time of sampling	4–6 months			7–11 months			7–11 months
Adverse events suspected via atorvastatin exposure	None (presumed 4–6 months of exposure)			None (5 months of exposure)			Mom stopped breastfeeding after atorvastatin was initiated
Infant development	Right on track with developmental milestones			Developing a bit slower than is typical, but without concern			Right on track with developmental milestones

PCOS, polycystic ovarian syndrome; GERD, gastroesophageal reflux disease; AUC, area under the curve.

The absolute infant dose of AT was calculated at 0.000066, 0.00019, and 0.00027 mg/kg/day for AT 20 mg, 40 mg, and 80 mg, respectively. The weight-adjusted relative infant dose (RID) of the combined analytes was 0.05%, 0.09%, and 0.052% for AT 20 mg, 40 mg, and 80 mg, respectively. These RIDs are far below the standard 10% clinical threshold for infant safety. The mothers reported no short-term or immediate adverse effects in the two exposed infants.

Discussion and Conclusion

This study demonstrated an exceedingly low transfer of AT and its equipotent active metabolites, 2OH AT and 4OH AT, at all doses of AT. The RID, a weight-adjusted measure of infant exposure, was <0.1% including all analytes in all participants. It is commonly accepted that a drug with a RID <10% is likely to be an acceptable safe degree of exposure for a breastfed infant. While the impact on milk composition in states of hyperlipidemia (whether treated or untreated) is not well understood, it is unlikely that the drug would be present in milk at clinically significant levels to adversely affect a breastfed infant. Human milk cholesterol concentrations have been recorded around 9–15 mg/dL compared with around 0–0.4 mg/dL in infant formulas.¹¹ Although we employed a different method, our observations of milk cholesterol levels, averaging around 10 mg/dL in mothers undergoing AT treatment, align with previously established norms. However, further investigation into milk and blood cholesterol levels in both treated and untreated hyperlipidemic patients would be valuable and interesting.

Several available HMG CoA reductase inhibitors have limited evidence regarding transfer into breast milk. Rosuvastatin was evaluated in a study with a woman taking 40 mg for hypercholesterolemia, and the RID was calculated to be <1%.¹⁹ Another study found that a woman taking 20 mg of rosuvastatin estimated the RID to be 1.5%.²⁰ Information on pravastatin was presented at the 1988 annual American College of Clinical Pharmacology meeting regarding pravastatin 20 mg twice daily for five doses in 11 women, and the RID was calculated at 0.2%.²¹ There are currently no published data on simvastatin, lovastatin, fluvastatin, or pitavastatin transfer into human milk. Though statins are not routinely recommended in the peripartum period, a systematic review and meta-analysis found that pravastatin started between 12 and 20 weeks of pregnancy may reduce risk of preeclampsia and risk of intrauterine growth restriction, preterm birth, and neonatal intensive care unit admissions in neonates.²² A cohort study of over 1 million pregnancies with 469 women dispensed statins before conception and continuous use of statins after pregnancy did not identify increased risk of congenital abnormalities, but there was an association with low birth weight and preterm birth.²³ To date, several observational studies have not identified increased risks of birth defects or miscarriage with statin use during pregnancy. The U.S. Food and Drug Administration requested removal of the contraindication with statin use in pregnancy but still advises that statins should be stopped in most pregnant patients and avoided when breastfeeding.²⁴

The understanding of hypercholesterolemia and management with statin medications during the peripartum period is currently lacking. This knowledge gap poses challenges for healthcare providers in offering optimal care for women with hypercholesterolemia during this critical time. It has been established that statins reduce the risk of cardiovascular outcomes in patients with hypercholesterolemia. Though there is an association between LDL reductions and cardiovascular event rates decreasing, statins also have pleiotropic effects which may be beneficial in the peripartum period, such as pravastatin’s potential role in reducing preeclampsia risk. Breastfeeding has been found to lower maternal cardiovascular risk through reductions in blood pressure and body mass index. Despite existing recommendations advising against the use of statin medications in the peripartum period, information suggests that breastfeeding confers significant health benefits for the mother. Women who breastfed for at least 6 months are at decreased risk of hypertension, diabetes, hyperlipidemia, and elevated body mass index. The current paradox lies in the maternal cessation of breastfeeding while on statins due to a theoretical risk of infant harm while foregoing the concrete maternal and infant benefits of breastfeeding. This study demonstrates that the actual risk to the infant is likely smaller than previously perceived. The amount of AT and its metabolites in milk was negligible (<10 parts per billion in all participants), and the milk cholesterol was similar to levels observed in healthy women.

There are several limitations in this study. While the three women in this report attempt to fill a gap in knowledge, it is a small sample with milk-only analysis. Complementary maternal and infant blood analysis would have made our analysis more robust. We used a new method to quantify cholesterol in milk for which there is no current comparison. This study did not include the predrug milk cholesterol levels from the moms, which would have provided a useful comparison. There is a need for more information to determine the real risk of statin exposure versus the perceived risks in the long term. The American College of Obstetricians and Gynecologists, the American Academy of Pediatrics, and the World Health Organization recently expanded their recommendation that the optimal duration women should breastfeed is 2 years. This expansion is for maternal benefits rather than infant benefits.²⁵ For mothers who are at increased cardiovascular risk, ideally, the combination of continuing medications, such as AT, as well as breastfeeding for as long as able, might provide further benefit to the mother. However, given the current cases and uncertainties regarding the changes to milk cholesterol concentrations in mothers with or without familial hypercholesterolemia, caution is recommended until more data are available with providers evaluating each patient on a case-by-case basis before prescribing statins.

Footnotes

Acknowledgments

The authors extend their heartfelt thanks to Dr. Thomas Hale, founder of the InfantRisk Center of Excellence, for his invaluable guidance in our research on lactation pharmacology. Their deepest gratitude also goes to the many mothers who generously donated their time and milk, making this study possible.

Authors’ Contributions

Conceptualization: K.K.; Data curation: P.D. and K.K.; Formal analysis: P.D. and K.K.; Investigation: P.D. and K.K.; Methodology: P.D. and K.K.; Project administration: K.K. and L.C.; Resources: K.K.; Software: P.D.; Supervision: K.K. and L.C.; Validation: P.D.; Visualization: P.D.; Writing—original draft: L.C., K.H., P.D., and K.K.; Writing—reviewing and editing: L.C., K.H., P.D., and K.K.

Disclosure Statement

K.K. has consulted for Adnovate Clinical Development Strategies Ltd. and Reunion Pharmaceutical and co-authors Hale’s Medications and Mothers’ Milk. All other authors have no relevant financial or nonfinancial interests to disclose. They certify that they have no affiliations with or involvement in any organization or entity with any financial or nonfinancial interest in the subject matter or materials discussed in this article.

Funding Information

No funding was received for this article.

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