As a new parent, you’re committed to finding the best available baby formula for your infant. That’s no small task, considering the wide range of brands and products on the market. In this article, we bring clarity on what to look for — and what to avoid — in the formula you choose for your baby, as well as making our own recommendations about the very best products. 

As a bonus, we’ll also explain the differences between baby formula regulations in the U.S. and in Europe, and why going with a top-quality European formula may make a big difference for your baby.

Understanding formula

What Is Baby Formula?

Quite simply, baby formula — also known as infant formula or, simply, formula — is a supplement or substitute for breast milk. Babies can be fed exclusively with formula or in combination with breastfeeding. Formula can be purchased as a powder or as a concentrated liquid, both of which must be mixed with water, or as a pre-mixed, ready-to-use liquid.

The best infant formulas resemble breast milk as much as possible, in terms of the proportion and types of nutrients they contain. A high-quality infant formula will have lactose (the main carb found in breast milk) as its carbohydrate base, typically through organic non-fat cow’s milk, and will include supplemental whey powder as a protein source and a blend of vegetable oils as sources of fat.

Unfortunately, as will be discussed in further detail below, many of the leading brands of infant formula instead rely on sugar or inexpensive, processed sweeteners such as corn syrup solids for most, if not all, of their carbohydrate content, contain toxic ingredients that may disrupt a baby’s hormone system, and more.¹

What Are the Ingredients in Baby Formula?

As baby formula is designed to approximate the nutritional content of breast milk, its primary components are relatively straightforward. All formulas contain a blend of carbohydrates, proteins, fats, vitamins, and minerals. Many formulas include other ingredients such as nucleotides, enzymes, amino acids, prebiotics, probiotics, and long-chain polyunsaturated fatty acids (omega-3 and omega-6).² However, even with the same basic framework, formula recipes can differ significantly, most notably in terms of the types of proteins, carbohydrates, and fats that they contain.

Carbohydrate Source – Lactose Is Best

Along with protein and fat, carbohydrates are one of the key components of baby formula. Using the best carbohydrate source is vital in ensuring that baby formula is as nutritious and beneficial to infant development as possible. Because their immature digestive systems cannot break down complex carbohydrates, babies need simple sugars in their diet. 

Lactose, which is composed of one glucose and one galactose molecule, is certainly the ideal carbohydrate source for baby formula, for the simple reason that lactose is the main carbohydrate source found in breast milk.³ Thus, even newborns have the ability to digest lactose. 

Lactose intolerance is very uncommon in infants, and parents sometimes misinterpret symptoms such as stomach upset and skin rash as signs of lactose intolerance when they actually indicate that a baby is struggling to break down milk proteins.⁴ As lactose is the carbohydrate source in breast milk, babies are born with lactase enzymes to help break down lactose molecules. Lactose is also helpful for calcium absorption and for maintaining the population of “good” gut bacteria.

Lactose intolerance is very uncommon in infants, and parents sometimes misinterpret symptoms such as stomach upset and skin rash as signs of lactose intolerance when they actually indicate that a baby is struggling to break down milk proteins.⁴ As lactose is the carbohydrate source in breast milk, babies are born with lactase enzymes to help break down lactose molecules. Lactose is also helpful for calcium absorption and for maintaining the population of “good” gut bacteria.

On the other hand, some baby formulas are made with sucrose (table sugar, composed of glucose and fructose), corn syrup (composed only of glucose), or maltodextrin (a less-sweet corn sugar with longer glucose chains). All of these carbohydrate sources (especially sucrose) are sweeter than lactose and have a higher glycemic index, which means that although a baby may enjoy their taste, the pancreas must work harder to regulate blood sugar levels.³ 

Many of the leading U.S. baby formulas are made with corn sugars because they are an inexpensive ingredient. The wording on formula labels sometimes creates further confusion by listing ingredients such as corn syrup solids or glucose syrup, which amount to essentially the same thing. It is also worth noting that much of the corn in the United States has undergone some form of genetic modification, which may be a concern for some parents. So although the FDA has deemed baby formulas made with corn syrup and/or sucrose to be “safe” for infants, they are certainly not the healthiest or most natural sources of carbohydrates.

Researchers are still investigating the long-term health effects of consuming so much sucrose or corn syrup from infancy, but studies suggest that steadily ingesting corn syrup from a young age can lead to childhood obesity and health problems such as type 2 diabetes, liver damage, and cardiovascular disease. At the very least, corn syrup and sucrose-based formulas are sweeter than both breast milk and lactose-based formulas, leading infants to develop a taste for sugary foods that can persist throughout their lives.^{1 5}

Protein Source – Whey, Whey, Whey Better

Although breast milk and cow’s milk contain a variety of different individual proteins, these proteins are all classified as either whey or casein proteins. However, the ratio of these proteins in cow’s milk is very different than their ratio in breast milk. Cow’s milk contains 80 percent casein proteins and 20 percent whey proteins, whereas breast milk contains 40 percent casein and 60 percent whey. 

Casein proteins are more difficult than whey proteins for infants to digest, and are also more likely to cause an allergic response. It is important to choose a baby formula that specifically lists whey as an ingredient, as it means that the whey to casein ratio has been altered to more closely resemble breast milk. Furthermore, some baby formulas contain 100% whey proteins, and these products can be helpful for infants who are prone to acid-reflux or those with a family history of milk allergies.⁶

For some babies, it is beneficial to have additional help with breaking down milk proteins, which is the function of a protein hydrolysate formula, in which the proteins are already partially or fully hydrolyzed (broken down). Protein hydrolysate formulas are also less likely to cause allergic responses.⁷ 

For babies who are allergic to the proteins in cow’s milk even after being extensively hydrolyzed, there are specialized formulas in which the proteins are broken down into their smallest components — amino acids. It’s worth keeping in mind that while these formulas are less likely to cause allergic responses, they are much more highly processed, and are not organic.

Baby formulas made from soy do not contain whey or casein and are an option for babies with milk protein allergies.

Baby formulas made from soy do not contain whey or casein and are an option for babies with milk protein allergies. However, they are not typically recommended as a first choice because they need to be heavily processed and supplemented with additional amino acids in order to provide adequate protein content.⁸ 

In addition, soy formulas do not contain lactose, which is the optimal carbohydrate source for growing infants. There are also concerns about soy-based formulas due to their phytoestrogen content, as phytoestrogen can act like the hormone estrogen in the human body. It is also important to note that some babies with a milk allergy may also have a soy allergy.⁹

Fat Source – A Vegetable Oil Blend

Approximately half of the calories in breast milk come from fat, and this is the ratio that infant formulas try to approximate, as fat is essential for normal infant weight gain and overall growth.¹⁰ Interestingly, unlike protein and carbohydrate content, the blend of fats in breast milk changes to correspond with the mother’s diet, which means that infants are capable of digesting a variety of different fatty acids. 

Fats are also much less likely to cause an allergic response than proteins or carbohydrates. And, indeed, the fatty acids in baby formula are usually a blend of different vegetable oils, such as palm, coconut, soy, safflower, and sunflower.¹¹ Many baby formulas contain palm (olein) oil as the primary fat source because it is a source of palmitic acid, a fatty acid found in breast milk. Although palm olein oil is not harmful, it is not an ideal primary fat source for infants — especially babies who were born early — as it can inhibit calcium absorption and is not the most easily-absorbable source of fatty acids. 

Fats are also much less likely to cause an allergic response than proteins or carbohydrates. And, indeed, the fatty acids in baby formula are usually a blend of different vegetable oils, such as palm, coconut, soy, safflower, and sunflower.¹¹ Many baby formulas contain palm (olein) oil as the primary fat source because it is a source of palmitic acid, a fatty acid found in breast milk. Although palm olein oil is not harmful, it is not an ideal primary fat source for infants — especially babies who were born early — as it can inhibit calcium absorption and is not the most easily-absorbable source of fatty acids. 

Coconut oil is a better choice as the primary fat source in baby formula (ie. higher up on the list of ingredients) as it is unlikely to cause indigestion and contains medium-chain triglycerides that are very easily absorbed.¹²   

Other Key Ingredients: Prebiotics, Probiotics, Long-Chain  Polyunsaturated Fatty Acids

Some baby formulas contain prebiotics and, less frequently, probiotics, which are intended to promote the presence of “good bacteria” in an infant’s digestive tract and attempt to replicate the immunity-boosting properties of breast milk. Probiotics are strains of helpful microorganisms such as Bifidobacterium and Lactobacillus that colonize the gut, whereas prebiotics like galactooligosaccharides and fructooligosaccharides are compounds that help those microorganisms grow and thrive in the intestines.¹³ Many benefits of probiotics have been proposed, ranging from preventing childhood eczema, infant colic, urinary tract infections and infectious diarrhea, to lowering the risk of asthma and food allergies.¹⁴

In both the United States and Europe, it is also increasingly common to find formulas that are supplemented with long-chain polyunsaturated fatty acids such as docosahexaenoic acid (DHA) and arachidonic acid (ARA), which are found in breast milk and are thought to positively contribute to brain and eyesight development.¹⁵  

FDA vs. European Commission Regulations

The U.S. Food and Drug Administration (FDA) sets out guidelines for the minimum amount of 29 specific nutrients that must be included in infant formula, as well as the maximum limit for nine of those nutrients.¹⁶ FDA guidelines also require that formula should facilitate normal infant growth and that all of the ingredients must be demonstrated to be “safe” and free from contamination. 

The key area that the FDA does not regulate is the specifics of which carbohydrate, protein, and fat sources may be used.

However, the key area that the FDA does not regulate is the specifics of which carbohydrate, protein, and fat sources may be used. This means, for example, that many formulas rely on inexpensive and ubiquitous corn syrup and sucrose as their primary carbohydrate sources. As a result, even though the ingredients in various U.S. formulas may be very different, the Nutrition Facts labels tend to be quite similar.¹⁷

The European Commission, which regulates baby formulas in the European Union, has more stringent regulations, in addition to also setting out basic guidelines for nutrient content. For example, all European baby formulas must be free from “detectable levels of pesticide residue.”¹⁸ In fact, some European cow’s milk formulas come from grass-fed cows raised on biodynamic Demeter or Bioland farms — which means that the farms are not only organic, but also sustainable and completely free from genetically modified organisms (GMOs).¹⁹ 

The European Commission, which regulates baby formulas in the European Union, has more stringent regulations, in addition to also setting out basic guidelines for nutrient content. For example, all European baby formulas must be free from “detectable levels of pesticide residue.”¹⁸ In fact, some European cow’s milk formulas come from grass-fed cows raised on biodynamic Demeter or Bioland farms — which means that the farms are not only organic, but also sustainable and completely free from genetically modified organisms (GMOs).¹⁹ 

Many U.S. baby formulas are also advertised as being “non-GMO,” but there is currently no accepted definition of what exactly constitutes genetic modification, leading to inconsistent and sometimes misleading information. And although the FDA regulates the food safety of genetically-modified plants just as they do for any other plant, manufacturers are not required to specifically identify GMO ingredients on food labels.²⁰

Many U.S. baby formulas are also advertised as being “non-GMO,” but there is currently no accepted definition of what exactly constitutes genetic modification, leading to inconsistent and sometimes misleading information.

Another difference between European and American regulations is that the FDA’s range for iron content in baby formula is much broader than the range set out by the European Commission. Nevertheless, all European formulas still meet the minimum FDA requirements, whereas most American formulas have iron contents that are close to the top end of the FDA requirements, and exceed the top end of the European Commission range.^{19 21} 

More significantly, the European Commission requires that at least 30% of the carbohydrates in baby formula must come from lactose. Furthermore, European baby formula made with intact cow’s milk proteins cannot contain any sucrose, and protein hydrolysate formulas cannot contain more than 30% sucrose as a carbohydrate source.²² There are other differences between American and European formulas, such as a new EU regulation that will require all European baby formulas to contain a certain proportion of the omega-3 fatty acid DHA by 2020. There are also ingredients that are specifically prohibited from European baby formulas, such as guar gum, locust gum, pectins, fructans, and carrageenan.¹⁹

Formula Stages, Whole Milk, and Solid Foods

When considering which formula to purchase, it is important to note that European baby formulas are sold according to stages. Stage 1 formulas are typically advertised for babies from birth to six months, while Stage 2 formulas are designed for babies aged six to 12 months. However, babies older than six months can happily continue on Stage 1, particularly if they are also eating iron-rich solid foods. On the other hand, babies younger than six months should not be fed Stage 2 formula, as it contains higher levels of certain minerals, such as calcium and iron, in quantities that are not recommended for young infants. Stage 1 formula is sometimes referred to as “first milk” and Stage 2 formula is also known as “follow-on milk.”^23 24

The American Academy of Pediatrics does not recommend feeding whole cow’s milk or goat’s milk to babies under 12 months, largely because of its high protein and mineral content. However, babies can begin supplementing their intake of breast milk and/or infant formula with solid food around the age of six months.²⁵

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Our Top Baby Formula Recommendations:

The fat in HiPP Organic formulas comes from a blend of organic palm, rapeseed, and sunflower oils. This formula is free from gluten, soy, maltodextrin, and starch. It also contains vital prebiotics (galacto-oligosaccharides derived from lactose) and probiotics (lactic acid cultures), as well as omega-3 and omega-6 fatty acids. (Please note, the Stage 1 version of this product contains DHA, while the Stage 2 version does not.)

We recommend purchasing this product through Huggable.com (here’s their HiPP Dutch 1 and HiPP Dutch 2). Their main differentiator is that if the first formula you try isn’t right, they’ll send you a week’s worth of an alternative for free. You can also find HiPP Dutch at others retailers such as OrganicStart. Stay tuned for our in-depth analysis comparing the best sites to buy European formula online, coming soon.

Holle infant formula contains nothing artificial and has very few additional ingredients; it is worth noting that Holle formulas do not contain prebiotics, probiotics, or any long-chain polyunsaturated fatty acids. While this has downsides, fewer ingredients means a higher likelihood your baby will tolerate it well. In addition to being certified organic, Holle infant formulas are especially notable because they have also earned Demeter certification for adhering to the strictest standards for holistic, sustainable, and biodynamic agriculture — this means no GM technology, chemical or synthetic pesticides or fertilizer, and a commitment to ecosystem preservation and the most natural farming and processing methods. Holle also manufactures comparable goat’s milk formulas for infants who do not tolerate cow’s milk.

Like Holle, Lebenswert Bio formulas have a relatively short list of ingredients, and a major focus on natural, sustainable farming methods. These formulas have earned Germany’s esteemed Bioland certification, which has far higher standards than the EU’s minimum requirements for organic food products. The Lebenswert Bio Stage 1 formula does not contain prebiotics, probiotics, or long-chain polyunsaturated fatty acids such as DHA. The primary carbohydrate is lactose. We particularly recommend Lebenswert Bio as great formula to use as a supplement to breastfeeding.

We recommend purchasing this product through Huggable.com (here’s their Holle Bio 1 and Lebenswert Bio 1). Their main differentiator is that if the first formula you try isn’t right, they’ll send you a week’s worth of an alternative for free. You can also find Holle and Lebenswert Bio formulas at other retailers such as OrganicStart (Holle Bio 1 and Lebenswert Bio 1) and TastyGanics (Holle Bio 1 and Lebenswert Bio 1). Stay tuned for our in-depth analysis comparing the best sites to buy European formula online, coming soon.

This is an organic product with added whey, lactose as the carbohydrate source, and a mixture of organic palm, rapeseed, and sunflower oils. It contains galacto-oligosaccharides as a prebiotic and omega-3 and omega-6 fatty acids, including DHA. The most substantial difference between the British and Dutch versions of this product is that the British version does not contain probiotics (ie. Lactobacillus).

We recommend purchasing this product through Huggable.com (HiPP UK 1). Their main differentiator is that if the first formula you try isn’t right, they’ll send you a week’s worth of an alternative for free. You can also find HiPP UK at other retailers such as OrganicStart and TastyGanics. Stay tuned for our in-depth analysis comparing the best sites to buy European formula online, coming soon.

Happy Baby products are entirely organic and are advertised as “non-GMO.” However, the emphasis of organic European baby formulas on having the fewest and most natural ingredients — and the added quality assurance that comes from Demeter and Bioland certifications — sets them apart from their American counterparts. Some babies may be sensitive to the large amount of prebiotics contained in the Happy Baby Stage 1 formula, as it includes two types of prebiotics, and in a higher quantity than most other infant formulas.

Since it’s made in the US, Happy Baby Organic Stage 1 formula is easy to find online. You can buy it from the Happy Family Organics website or from other retailers such as Amazon.

Formula Comparison Chart

What Ingredients Are in Other American Baby Formulas?

Although we are not endorsing these products, it is useful to know what kinds of ingredients are in other baby formulas.

Similac Pro-Advance

• Main protein sources are nonfat milk and whey protein concentrate
• Uses lactose as the primary carbohydrate source
• Does not include palm oil, which could mean better calcium absorption, and uses high oleic safflower, soy, and coconut for vegetable oil blend
• Contains DHA and two types of prebiotics: 2′-Fucosyllactose and fructo-oligosaccharides
• Advertised as “non-GMO”
• Not organic

Enfamil Gentlease

• First ingredient on the list is corn syrup solids
• Designed to be easy to digest, with partially hydrolyzed nonfat milk and whey protein concentrate solids
• Palm olein, soy, coconut, and high oleic sunflower oils
• Contains DHA; does not contain prebiotics or probiotics
• Contains taurine and l-carnitine
• Not organic; only the more expensive Enfamil Premium Gentlease is “non-GMO”

Enfamil NeuroPro

• Main protein sources are nonfat milk and whey protein concentrate
• Main carbohydrate is lactose
• Contains a blend of palm olein, coconut, soy, and high oleic sunflower oils
• Focus is on “brain-building” and helping babies reach developmental milestones
• Contains a blend of DHA, ARA, and MFGM (“milk fat globule membrane”), a component of breast milk thought to help cognitive development
• Contains two prebiotics: galacto-oligosaccharides and polydextrose
• Contains nucleotides
• Contains taurine and l-carnitine
• Not organic
• Advertised as “non-GMO”

Similac Alimentum

• Designed to be easy to digest, for babies with colic and allergies due to cow’s milk protein sensitivity.
• The main protein is casein hydrolysate (from cow’s milk)
• Does not contain lactose — main carbohydrates are corn maltodextrin and sugar
• Contains DHA and ARA
• Blend of high oleic safflower, soy oil, and medium-chain triglycerides
• Contains taurine and l-carnitine
• Not organic
• Advertised as containing no artificial growth hormones

Plum Organics (“Premium” and “Gentle”)

• Range of formulas includes “Premium” and “Gentle” (which has partially hydrolyzed proteins)
• No added corn syrup solids, glucose syrup solids, or maltodextrin
• Organic lactose is the carbohydrate source
• Organic nonfat milk and organic whey protein concentrate are protein sources
• Blend of organic palm, soy, coconut, and high oleic safflower or sunflower oil
• USDA Certified Organic; advertised as “non-GMO”
• Contains DHA and ARA
• Contains taurine

The Honest Company (“Premium” and “Sensitive”)

• Range of formulas include “Premium” and “Sensitive”
• For “Premium” formula, organic lactose is carbohydrates source
• “Sensitive” formula uses very little lactose, with organic glucose syrup syrup solids and organic maltodextrin as carbohydrates
• Organic nonfat milk and organic whey protein concentrate are protein sources
• Blend of organic palm, soy, coconut,, and high oleic safflower or sunflower oil
• Contains DHA and ARA
• USDA Certified Organic; advertised as “non-GMO”
• Contains fructo-oligosaccharides as a prebiotic

Earth’s Best Organic Dairy

• Organic nonfat milk and organic whey protein concentrate are protein sources
• Organic lactose is the main carbohydrate source
• Blend of organic palm, soy, coconut, high oleic safflower or sunflower oils
• Contains fructo-oligosaccharides as a prebiotic
• Contains DHA and ARA
• USDA Certified Organic; advertised as “non-GMO”
• Contains nucleotides
• Contains taurine

References:

1. Sears, William. “Corn Syrup in Formula.” Parenting, www.parenting.com/article/corn-syrup-in-formula.

2. “Infant Formula: Your Questions Answered.” Mayo Clinic, Mayo Foundation for Medical Education and Research, 2018, www.mayoclinic.org/healthy-lifestyle/infant-and-toddler-health/in-depth/infant-formula/art-20045782.

3. Young, Bridget. “Why Is There Sugar In Baby Formula? Everything You Need To Know.” Baby Formula Expert, 2016, www.babyformulaexpert.com/sugar-in-baby-formula.

4. “What Should I Do If I Think My Baby Is Allergic Or Intolerant To Cows’ Milk?” NHS, 2016, www.nhs.uk/common-health-questions/childrens-health/what-should-i-do-if-i-think-my-baby-is-allergic-or-intolerant-to-cows-milk.

5. “Best Baby Formula – Carbs & Sugars – Baby Formula Expert.” Baby Formula Expert, www.babyformulaexpert.com/baby-formula-carbs.

6. Young, Bridget. “Best Baby Formula – Protein Source.” Baby Formula Expert, www.babyformulaexpert.com/baby-formula-protein-source.

7. Young, Bridget. “Baby Formula – Hydrolyzed Protein.” Baby Formula Expert, www.babyformulaexpert.com/baby-formula-protein-type.

8. McDermott, Annette. “Milk Protein Allergy: What Are My Formula Options?” Healthline, 2017, www.healthline.com/health/allergies/milk-protein-allergy-formula-options#1.

9. “Types Of Formula Milk.” NHS: Your Pregnancy and Baby Guide, 2016, www.nhs.uk/conditions/pregnancy-and-baby/types-of-infant-formula/#soya-formula.

10. Murray, Donna. “What Is The Composition Of Breast Milk?” Verywell Family, 2018, www.verywellfamily.com/whats-in-breast-milk-4047820.

11. “Choosing Formula.” Ask Dr. Sears, www.askdrsears.com/topics/feeding-eating/bottle-feeding/choosing-formula.

12. Young, Bridget. “Best Baby Formula — Baby Formula Fat.” Baby Formula Expert, www.babyformulaexpert.com/baby-formula-fat.

13. University of Illinois College of Agricultural, Consumer and Environmental Sciences. “New infant formula ingredients boost babies’ immunity by feeding their gut bacteria.” ScienceDaily, 29 February 2012, www.sciencedaily.com/releases/2012/02/120229155540.htm.

14. O’Dowd, Yvette. “Choosing Baby Formula – 5 Facts To Help You Decide.” BellyBelly, 2015, www.bellybelly.com.au/baby/choosing-baby-formula-5-facts-to-help-decide.

15. Agostoni, Carlo. “Role Of Long-Chain Polyunsaturated Fatty Acids In The First Year Of Life”. Journal Of Pediatric Gastroenterology And Nutrition, vol 47, no. Suppl 2, 2008, pp. S41-S44. doi:10.1097/01.mpg.0000338811.52062.b2.

16. “Questions & Answers For Consumers Concerning Infant Formula.” U.S. Food And Drug Administration, 2018, www.fda.gov/food/foodborneillnesscontaminants/peopleatrisk/ucm108079.htm#1.

17. Young, Bridget. “Best Baby Formula – FDA Regulation & Pediatrician Knowledge.” Baby Formula Expert, www.babyformulaexpert.com/baby-formula-fda-regulation.

18. “Food For Infants And Young Children.” European Commission – Food Safety, www.ec.europa.eu/food/safety/labelling_nutrition/special_groups_food/children_en.

19. Young, Bridget. “Best European Baby Formulas.” Baby Formula Expert, 2017, https://babyformulaexpert.com/european-formula.

20. “Questions & Answers On Food From Genetically Engineered Plants.” U.S. Food And Drug Administration, 2018, www.fda.gov/food/ingredientspackaginglabeling/geplants/ucm346030.htm.

21. Young, Bridget. “Best Baby Formula – The Ultimate Multi-Vitamin.” Baby Formula Expert, babyformulaexpert.com/baby-formula-vitamins-minerals.

22. Rosenbloom, Cara. “Is European Baby Formula Really Better?” Today’s Parent, 2018, www.todaysparent.com/baby/baby-food/is-european-baby-formula-really-better.

23. Watkins, Sasha. “Should I Change Formula Once My Baby Starts Solids?” BabyCentre, 2014, www.babycentre.co.uk/x25010521/should-i-change-formula-once-my-baby-starts-solids.

24. “A guide to infant formula for parents who are bottle feeding: health professionals’ guide.” UNICEF UK, 2014, www.unicef.org.uk/babyfriendly/wp-content/uploads/sites/2/2016/12/Health-professionals-guide-to-infant-formula.pdf.

25.  Institute of Medicine Committee on the Evaluation of the Addition of Ingredients New to Infant Formula. (2004) Infant Formula: Evaluating the Safety of New Ingredients. Washington, DC: National Academies Press; 2004. Ch. 3, “Comparing Infant Formulas with Human Milk.” Retrieved from: www.ncbi.nlm.nih.gov/books/NBK215837.