Developmental Readiness of
Normal Full Term Infants to
Progress from Exclusive
Breastfeeding to the Introduction
of Complementary Foods
Reviews of the Relevant Literature Concerning
Infant Immunologic, Gastrointestinal, Oral Motor
and Maternal Reproductive and Lactational
Audrey J. Naylor, MD, DrPH, Editor
Ardythe L. Morrow, PhD, Co-Editor
This publication was made possible through support provided by G/PHN/HN, U.S. Agency for International Development, under the terms of
Cooperative Agreement No. HRN-A-00-97-00007-00. The opinions expressed herein are those of the author(s) and do not necessarily reflect
the views of the U.S. Agency for International Development.
Developmental Readiness of
Normal Full Term Infants to
Progress from Exclusive
Breastfeeding to the Introduction
of Complementary Foods
Reviews of the Relevant Literature Concerning
Infant Immunologic, Gastrointestinal, Oral Motor
and Maternal Reproductive and Lactational
Audrey J. Naylor, MD, DrPH, Editor
Ardythe L. Morrow, PhD, Co-Editor
Reviews Prepared by:
June 20, 2001
Armond S. Goldman, MD
Division of Immunology, Allergy
Department of Pediatrics
The University of Texas Medical
Galveston, Texas, USA
Alan S. McNeilly, PhD
MRC Human Reproductive
University of Edinburgh
Center for Reproductive Biology
Edinburgh, Scotland, UK
Audrey J. Naylor, MD, DrPH
San Diego, California, USA
W. Allan Walker, MD
Pediatric Gastroenterology and
Department of Pediatrics
Harvard Medical School
Boston, Massachusetts, USA
With Assistance from:
Sarah Danner, MSN
Rapid City, South Dakota, USA
Sandra Lang, Mphil, RM, Dip Ed
Preston, Lancashire, UK
Ardythe Morrow, DrPH
The LINKAGES Project, Academy for
Washington, DC, USA
Technical coordination of this review was provided by Wellstart International in
collaboration with LINKAGES: Breastfeeding, LAM and Related
Complementary Feeding and Maternal Nutrition Program. LINKAGES is
supported by G/PHN/HN, U.S. Agency for International Development, under
Cooperative Agreement No. HRN-A-00-97-00007-00 and managed by the
Academy for Educational Development. The opinions expressed herein are
those of the author(s) and do not necessarily reflect the views of USAID.
This document may be reproduced as is and in its entirety, without permission, as long the
document gives full credit to its authors, Wellstart International, the LINKAGES Project and
Recommended citation: Naylor AJ, ed. and Morrow A, co-ed. 2001. Developmental Readiness of
Normal Full Term Infants to Progress from Exclusive Breastfeeding to the Introduction of
Complementary Foods: Reviews of the Relevant Literature Concerning Infant Immunologic,
Gastrointestinal, Oral Motor and Maternal Reproductive and Lactational Development.
Wellstart International and the LINKAGES Project/Academy for Educational Development,
The LINKAGES Project
Academy for Educational Development
1825 Connecticut Avenue, NW
Washington, DC 20009
4062 First Avenue
San Diego, CA 92103-2045
Developmental Readiness of Normal Full Term Infants
to Progress from Exclusive Breastfeeding to the
Introduction of Complementary Foods
Reviews of the Relevant Literature Concerning Infant
Immunologic, Gastrointestinal, Oral Motor and Maternal
Reproductive and Lactational Development
Table of Contents
Introduction and Background .....................................................................................................1
Specific Purpose of these Reviews .............................................................................................. 2
Process Utilized for these Reviews .............................................................................................. 2
Definitions ..................................................................................................................................... 2
Immune System Development in Relation to the Duration of
Exclusive Breastfeeding ...................................................................................................... 3
Armond S. Goldman, MD
Gastrointestinal Development in Relation to the Duration of
Exclusive Breastfeeding .................................................................................................... 13
W. Allan Walker, MD
Infant Oral Motor Development in Relation to the Duration of
Exclusive Breastfeeding .................................................................................................... 21
Audrey J. Naylor, MD, DrPH with assistance of Sarah Danner and Sandra Lang
Maternal Reproductive and Lactational Physiology in Relation to the Duration of
Exclusive Breastfeeding .................................................................................................... 27
Alan S. McNeilly, PhD
Summary and Conclusions ........................................................................................................ 35
Introduction and Background
This review of the developmental readiness of normal full term infants to progress from
exclusive breastfeeding to the introduction of complementary foods has been undertaken as a
result of the international debate regarding the best age to introduce complementary (semi-solid
and solid) foods into the diet of the breastfed human infant. Since 1979 the World Health
Organization has recommended that normal full term infants should be exclusively breastfed for
“four to six months.” Over the two decades since this recommendation was established further
evidence regarding the benefits of breastmilk and breastfeeding has accumulated. In addition,
there have been increasing reports suggesting an association between discontinuing exclusive
breastfeeding prior to six months of age and an increase in infant morbidity and mortality.
Throughout the world many professionals as well as a number of governments have concluded
that there is sufficient evidence to recommend continuing exclusive breastfeeding for “about six
months.” Even within WHO, UNICEF and other international agencies, some documents
continue to recommend exclusive breastfeeding for “four to six months” while others now use
“about six months.” There is an urgent need to review this matter and determine whether or not
there is sufficient scientific evidence to change the global recommendation. WHO responded to
this need and arranged for a review of the recent studies that relate duration of exclusive
breastfeeding (“four to six months versus six months”) to infant morbidity and mortality as well
as growth and maternal health.
Another relevant aspect of this global concern needing further attention relates to the infant’s
internal biologic processes that are proceeding along largely genetically predetermined
developmental pathways. These begin at the moment of conception and continue throughout life.
A number of these developmental processes are important to infant feeding. The human neonate
is delivered from a protected intrauterine environment–sterile, warm, and protective–following
nine months of development during which the nutritional, immunologic and endocrine needs
were provided for by maternal systems. The newly born infant can no longer obtain fluids,
nutrients, and immune protection through the umbilical cord. The ambient temperature is no
longer held at maternal body temperature and the environment is no longer sterile. Though this
transition is filled with life threatening hazards, there are many biologically active protective
systems in place to increase the likelihood of infant survival, some within the infant and some
provided by the mother. Obvious and increasingly well understood is the ability of the normal
mother-infant dyad to continue the flow of nutrients, fluids, immune substances and other
biologically essential and active substances through frequent breastfeeding beginning very
shortly after birth. This mother-baby interdependency works remarkably well for a number of
months while the infant proceeds with its internally driven biological processes of growth and
development. While some of these processes are very visible (physical growth, neuromotor
development) others of equal importance are progressing without clear signs. Renal, hepatic,
neurologic systems are gradually maturing. The infants own gastrointestinal tract and immune
system are becoming more prepared to become independent of maternal resources. Oral motor
abilities are also steadily progressing in preparation for the time when breastmilk alone will no
longer be able to fulfill all infant nutritional and fluid needs. New oral motor functions will be
called into action to assure successful continuation of the intake of foods and fluids.
Specific Purpose of these Reviews
It is with such biologically driven infant developmental processes in mind that the current
reviews have been undertaken. The rationale for these reviews is that each process undergoing
development during the first year of a human infant’s life will reach a stage where the infant is
biologically and developmentally most ready for the introduction of foods other than
breastmilk. In addition it seems reasonable that the age of this readiness for both diet and
behavioral changes is similar for each of the developmental processes. In other words, it is likely
that there is a convergence of the developmental maturation of these processes such that all
systems are “ready” at the same time.
The reviews do not focus on health outcomes associated with discontinuing exclusive
breastfeeding at a particular age but rather on the biologic/developmental readiness for this
complex experience. Four processes or functions were selected for inclusion: gastrointestinal,
immunologic, oral motor and the maternal reproductive processes that relate to the continuation
of lactation and the provision of breastmilk.
Process Utilized for these Reviews
Contributors invited to participate as reviewers and authors are well-known experts in their
particular area of expertise. After individual papers were drafted, each reviewer had an
opportunity to read all papers. A meeting (via teleconference) was then arranged to discuss the
findings and consider the following:
• Do the reviews provide evidence regarding the age at which the normal full term infant is
developmentally ready to discontinue exclusive breastfeeding and begin receiving
• Is there evidence of the convergence of the age of readiness of the several developmental
To allow readers to draw their own conclusions concerning these questions, each of the four
reviews that follow is presented as an independent contribution. The reader may turn to the
summary and conclusion section, pages 35-36, for the results of the teleconference.
Certain terms used throughout this review are defined here to ensure clarity for the reader:
• Exclusive breastfeeding is the provision of breastmilk only, with no other liquids or foods
• Full breastfeeding is defined as the provision of breastmilk, with only water, tea or juice
given in addition to breastmilk.
• Complementary feeding is defined as giving solid or semi-solid foods in addition to
Immune System Development in Relation to the
Duration of Exclusive Breastfeeding
Armond S. Goldman, MD
The optimal length of exclusive breastfeeding by full-term infants has been estimated from
clinical outcomes such as growth, development, and susceptibility to infectious diseases. Indeed,
there is evidence from epidemiological investigation that exclusive breastfeeding for about 6
months affords greater health benefits than exclusive breastfeeding for a shorter duration.
However, few investigations have been designed to ascertain the optimal duration of exclusive
breastfeeding, whether from an epidemiologic or basic science perspective.
One approach to the question would be to ascertain when the human immune system becomes
fully mature. To explore that approach, three interrelated questions were posed in this review, as
1. When does the immune system of a well, term infant no longer require the effects of
exclusive breastfeeding for its complete development?
2. Are there upper and lower limits of the age of immunological readiness that are
dependent or independent of breastfeeding?
3. Does the age of readiness of the immune system converge with the age of readiness of
other major organ-systems such as the gastrointestinal tract?
To examine these questions, it is helpful to first consider the organization and complexities of
host defenses, general concepts of developmental immunology, the known developmental delays
in the immune system, and the agents in human milk that seem to compensate for those
The Immune System
The external environment is first encountered by the skin, the respiratory tract, and the
alimentary tract. Each of these vital systems is exposed to environmental pathogens. Innate and
specific adaptive defenses have evolved to protect those vital structures as well as systemic sites
that may become invaded if first lines of defense at the skin or mucosa fail.
Innate defenses are produced in the absence of antigenic exposures, and their protective effects
are not necessarily specific just for the encountered foreign agent. These defenses are particularly
important during first contact with a microbial pathogen. Innate defenses include structural
barriers (skin and its secretions; the epithelium of the gastrointestinal and respiratory tracts),
myeloid cells, and soluble agents including gastric HCl, mucin, lactoferrin, and lysozyme in
external secretions and complement components in the systemic circulation.
In addition, certain defense agents produced at low levels by unstimulated leukocytes are greatly
enhanced in their production once the cells are activated. Some examples include the production
of interferons by virus-infected cells, the synthesis of proinflammatory cytokines by monocytes
stimulated by bacterial lipopolysaccharides, the generation of toxic oxygen radicals by
neutrophils during phagocytosis, and the liberation of active fragments of complement
components after activation of the classic or alternative pathways of the complement system.
Specific Adaptive Immunity.
Specific adaptive defense involves protective agents that react specifically with antigens; these
protective agents increase after the host is exposed to the antigens. These protective agents are
members of a superfamily of protein molecules that are typified by antibodies, which are
designated as immunoglobulins (Ig). Other members of the immunoglobulin superfamily include
major histocompatibility (MHC) molecules that bind small peptides or antigen fragments that are
presented to antigen receptors on T cells in the context of MHC molecules.
Even though specific adaptive immunity and innate immunity are often presented as separate
processes, they are closely related in that specific immunity may lead to an augmentation of
innate defenses and conversely some types of innate immunity influence the function of cells that
produce antigen recognition molecules. The origins, main physical features, and function of
antigen recognition molecules are as follows.
B Cells and the Generation of Antibody Diversity.
A repertoire of genes is responsible for the enormous diversity of antibody molecules and hence
for their recognition of a wide spectrum of antigenic determinants. There are genes for joining
(J), diversity (D), variable (V) and constant (C) regions of immunoglobulin molecules. The
complete immunoglobulin gene and antibody diversity are created when one member of each of
these categories of genes is selected and spliced together. Complete IgM molecules are produced
by B cells found in blood. The resultant IgM antibodies are not glycosylated and therefore not
secreted. Instead, they remain on the surface of B cells where they act as antibody receptors for
antigens. Antigen binding specificity is found in all antibodies on the surface of each B cell.
Further antibody diversity is created by somatic mutations of B cells in germinal centers. B cells
that produce higher affinity antibodies are selected for survival.
When surface immunoglobulin molecules on B cells are cross-linked by antigens, the cells
proliferate and are transformed into plasma cells that secrete antibodies with the same antigen-
binding specificities as the cell surface antibodies. If the host is repeatedly immunized, the class
or isotype of the immunoglobulin switches from IgM to IgG, IgA, or IgE depending upon the
types of modulating agents that influence the selection of C-region genes of B cells.
Immunoglobulins are four-chain, globular glycoproteins produced by the B-cell lineage.
Immunoglobulin monomers are composed of an identical pair of light (L) chains and an identical
pair of heavy (H) chains. Each L and H chain is in turn comprised of C and V regions. V region
domains bind antigenic determinants, whereas C region domains are responsible for other
properties of each chain.
There are five classes, or isotypes, of immunoglobulins. Each of these classes have special
biological functions: IgA, IgG, IgM, IgD, and IgE. For example, a type of polymeric IgA called
secretory IgA is the predominant immunoglobulin in human milk and other external secretions
such as saliva. Secretory IgA is assembled from dimers or trimers of IgA produced by plasma
cells at mucosal sites and part of polyimmunoglobulin receptors on the basolateral membranes of
epithelial cells. The IgA molecules (usually dimers) complexed with their receptors are
transported across the epithelial cells. The intracellular part of original receptor is digested. The
rest of the receptor remains complexed with the H chains of IgA. Secretory IgA antibodies are
especially directed against microbial antigens encountered at mucosal sites. Furthermore,
secretory IgA is adapted to persist and function at mucosal sites because of its innate resistance to
intestinal and pancreatic proteolytic enzymes. At mucosal sites, the antibodies neutralize
bacterial toxins or interfere with the attachment of bacterial pathogens or their toxins to epithelial
T Cells and Cellular Immunity.
T cell differentiation. Undifferentiated lymphocytes enter the cortex of the thymus where they
proliferate and express CD3, TcR, CD4, and CD8 transmembrane molecules. Most of them die
in the thymus, while a smaller number lose either CD8 or CD4. CD4-CD8+ cells or CD4+ CD8-
cells are selected respectively by an interaction with thymic stromal MHC class I (with CD4-
CD8+ cells) or class II molecules (with CD4+CD8- cells) to leave the thymus and enter the
TcR Structure. The TcR structure is similar to an immunoglobulin, but the structure is limited to
two different peptide chains. In the vast majority of TcR, there is one α-chain and one β-chain.
Each chain also has a V and a C region. The antigen-binding diversity of TcRs is created by a
mechanism that is similar to that found in B cells. Consequently, TcRs as well as antibodies have
an enormous antigen-binding repertoire, although the TcR repertoire is limited to peptide
T Cell Populations. Mature T-cells that are CD4+ are helper cells, whereas those that are CD8+
are cytotoxic/suppressor cells. T helper cells are further divided into two subsets according to the
cytokines they produce. T helper cells that produce cytokines that lead to cellular immunity by
enhancing cytotoxic T-cells and recruiting and activating macrophages are termed Th1 cells. The
resultant protection is called cellular immunity. This part of the immune system is particularly
important in protection against intracellular infecting agents such as viruses, mycobacteria, and
fungi. Those that produce cytokines that enhance antibody formation by the B-cell lineage are
termed Th2 cells. Th1 cytokines include IL-1 and interferon-γ, whereas Th2 cytokines include IL-
4, IL-6, and IL-10.
Mature T-cells are long-lived and recirculate in the blood, lymphatics, and peripheral lymphoid
organs including lymph nodes, spleen, and mucosal sites. Resting T-cells produce only low levels
of cytokines, but after they are engaged by antigen producing/presenting cells and stimulated by
certain cytokines, they become activated and produce cytokines that orchestrate many aspects of
the immune system.
General Concepts of Developmental Immunology
There are five general concepts of developmental immunology that are useful in considering the
questions posed in this review. They are as follows:
1. Some developmental delays in the immune system are rectified relatively soon after birth,
whereas others develop much more slowly.
2. Regardless of the rate of development, immunological components of human milk often
compensate for or directly influence the rate of development of those parts of the immune
system. The development of the immune system therefore cannot be understood unless it
is considered in the context of breastfeeding.
3. Certain immunological components of human milk may set in motion a train of
developmental events that persist long after breastfeeding ceases. Because the proximity
of cause and effect relation is missing, this may lead to uncertainty regarding the optimal
duration of exclusive breastfeeding.
4. Even if the development of parts of the immune system are complete, the infant may
nevertheless benefit from immunological components in human milk. Secretory IgA
antibodies in human milk are such an example. In that case the mother develops specific
secretory antibodies in her milk that are directed against the microbial pathogens found in
her gastrointestinal and respiratory tracts. These maternally generated specificities
augment the child’s defenses since those same antigen-binding specificities at the
mucosal sites of the infant may not appear in time to ward off an infection. This
immunological head start from the mother may therefore be highly advantageous.
5. It is likely that the central question, “When does the immune system of the well term
infant no longer require the effects of exclusive breastfeeding for its complete
development?,” will also have to be considered in respect to the external environment of
the infant. The reason is that some environmental agents also affect the rate of
immunological development. For example, the production of memory T cells depends
upon antigen stimulation as well as certain immunostimulatory cytokines that are released
as infecting agents interact with the immune system. It also should be recognized that the
environmental load of microbial pathogens may exceed the capacity of the infant’s
mucosal immune system, whereas the combined protection afforded by the infant’s
immune responses and the immune factors provided by human milk may suffice.
Developmental Delays in the Human Immune System
The development of the immune system during intrauterine and postnatal life is complex and
tightly controlled. In addition and germane to the questions raised in this review, the
development of many parts of the immune system is delayed and those delays appear to be
compensated for or modulated by maternal factors transmitted via the placenta or the mammary
gland. Developmental delays at birth include immunoglobulin isotype switching, the production
of IgG antibodies to polysaccharide (T-independent) antigens, the elaboration of lysozyme by
epithelial cells, generation of memory T-cells, generation of certain complement components
(C3, C4, C8, and C9), the production of PAF-acetylhydrolase, and synthesis of many cytokines
including IL-1, IL-3, IL-6, IL-8, IL-10, TNF-α, interferon-γ, interferon-β, G-CSF, GM-CSF, and
M-CSF. In addition, there are developmental delays in certain neutrophil functions and
deployment in response to bacterial infections, in the ability of blood monocytes or aveolar
macrophages to produce cytokines that aid in the stimulation of T cells, and the capacity of
primitive human haemopoietic cells to respond to Flt-3 ligand, Steel factor and IL-3. Moreover,
there is considerable variation in the rate of development of different agents. For instance, IgG
antibodies to thymic-dependent antigens begin to be produced shortly after birth whereas IgG
antibodies to thymic-independent antigens are not made until two years of age.
One word of caution should also be included concerning the interpretation of some of the studies
of developmental delays in the immune system. Although decreases in functions may be found in
newborn cells, the decrease may be incident to the soluble agents in the plasma that inhibit those
functions. For example, the synthesis of interferon alpha by umbilical cord blood monocytes is
inhibited by increased cortisol levels in those specimens.
Agents in Human Milk That Compensate for Those Developmental Delays
A host of investigations performed over the past 40 years indicate that the protection afforded by
breastfeeding is mainly due to defense agents in human milk, many of which are developmentally
delayed in the infant. Other agents in human milk do not directly compensate for developmental
delays in the production of those same agents, but nevertheless protect the recipient. For example
some enhance functions that are poorly expressed in the recipient, change the physiological state
of the intestines from one adapted to intrauterine life to one suited to extrauterine life, or prevent
inflammation in the recipient’s gastrointestinal tract.
Antiinflammatory, and immunomodulating agents that are adapted to mucosal sites, are often
multifunctional, and are not well represented in other milks used in human infant feeding. The
antimicrobial factors include secretory IgA, and lactoferrin. The defense system in human milk is
comprised of antimicrobial, lysozyme, mucin, glycoconjugates, oligosaccharides, and antiviral
lipids generated by partial digestion of milk fat. The antiinflammatory agents involve some of the
antimicrobial factors, enzymes that degrade inflammatory mediators, cellular protective agents,
epithelial growth factors, and antioxidants. The immunomodulators include nucleotides,
cytokines, and antiidiotypic antibodies.
In addition to the soluble and compartmentalized immune agents, human milk, particularly early
in lactation, contains many leukocytes (~1-3 x 106/mL). About 80% of those cells are
neutrophils, 15% are macrophages, and 5-10% are lymphocytes. The vast majority of the
lymphocytes are T cells. Furthermore, virtually all leukocytes in human milk are activated. In that
respect, the neutrophils and macrophages have an increased expression of CD11b/CD18 and a
decreased expression of L-selectin, the macrophages are more motile than blood monocytes, and
the T cells display the memory phenotype, CD45RO, and other phenotypic markers of activation.
The fate of these cells in the recipient is uncertain, but there is evidence from experimental
animal models that milk T cells enter tissues of the neonatal animal. Furthermore, some
observations suggest that cellular immunity to tuberculosis or to schistosomal antigens may be
transferred to the infant by breastfeeding. Thus, it is possible that some of these maternal cells
function in the recipient infant to compensate for certain developmental delays in the T cell
Although the agents in human milk that cause immunomodulation in vivo are not known,
immunomodulatory effects of breastfeeding have been demonstrated. For example in a recent
study, 14 days after the live MMR vaccination, only breastfed children had increased production
of interferon-gamma and increased percentages of CD56+ and CD8+ T cells. These findings are
consistent with a Th1 type response by breastfed children, not evident in formula-fed children.
Are Experimental Animal Models Helpful?
Can we extrapolate from experimental animal models to the human species and thus find
answers to the questions posed in this review? Curiously enough, the dearth of information found
in the research literature regarding the development of the human immune system also pertains to
many other mammalian species. In most species comparatively little is known about the changes
in the daily production of many immune factors by the mammary gland as lactation proceeds.
Furthermore there are too many differences between non-human mammals and humans except
for our most closely related evolutionary relatives, Pan troglodytes and Pan paniscus
(chimpanzees), to apply information from other mammalian species to humans.
The Rates of Development of the Immune System in Exclusively Breastfed Infants
There is very little information in the published scientific literature that tracks the development
of immune components of the immune system. Usually the status of newborn infants is compared
to much older children or adults and not to older infants or toddlers. Furthermore, no longitudinal
investigations have been published. Moreover, the effect of exclusive, partial or no breastfeeding
has been difficult to discern from the reports in the literature. In most of the publications the type
of infant feeding is not stipulated. In others, the completeness or duration of breastfeeding is not
Although the duration of certain developmental delays is known, it is unclear when optimal
levels for other agents are reached. In particular, little is known concerning the developmental
patterns of the production of cytokines by not only cells of the hemopoietic lineage such as T
cells, B cells, NK cells, monocytes, macrophages, and dendritic cells, but also epithelial cells that
line the gastrointestinal and respiratory tracts.
The problem is further compounded by two other large gaps in our knowledge. In most reports
concerning the longitudinal patterns of postnatal development of the immune system, the effects
of the type of infant nutrition, breastfeeding or non-breastfeeding, are unknown. Furthermore,
there is little information concerning the longitudinal patterns of production of many immune
factors other than major antimicrobial ones in the human mammary gland. Thus, the relationships
between the rates of development of components of the immune system and the capacity of the
mammary gland to produce agents that compensate for or influence the developmental delays in
the immune system, are not precisely established.
Conclusions and Future Research
At the present time, there is little if any information that provides answers to the questions raised
in this review. The subset of issues that should be addressed is as follows.
1. Although a great deal is known, the complete extent of, and controls over, the immune
system are yet to be defined.
2. The ontogeny of most of the components of the human immune system has not been
3. The patterns of developmental delays in the immune system vary according to the
component, but the extent of the variability is unknown.
4. The time for the optimal development of each immune factor that is developmentally
delayed has not been determined.
5. It is uncertain whether a developmental delay in one factor influences the development of
others in the immune system.
6. Certain immunological components of human milk may set in motion a train of
developmental events that persist long after breastfeeding ceases. This may cause some
uncertainty regarding the optimal duration of exclusive breastfeeding.
7. Even if the development of parts of the immune system are complete, the infant may
nevertheless benefit from immunological components in human milk. Therefore, clinical
outcome studies would be required to determine the optimal duration of exclusive (or
8. Environmental agents may also affect the rate of immunological development. Thus the
studies would also have to control for those confounding variables.
9. Moreover, the nutritional state of the child (poverty or excess) may be inappropriate for
the post-breastfeeding development of the immune system.
It is evident that these types of investigations, though of interest, will be impractical to conduct
because of their complexities and expense and ethical issues that preclude invasive procedures in
infants and children who are or are not breastfeeding. A compromise would be to investigate a
few components of the immune system that are developmentally delayed and that are well
represented in human milk. Those investigations would require a great deal of planning and
human, laboratory and fiscal resources and they would not definitely answer the question. They
would, however, be a logical start.
Adderson EE, Johnston JM, Shackerford PG, Carroll WL. Development of the human antibody
repertoire. Pediatr Res 1992; 32: 257-263.
Boat TF, Kleinerman JI, Fanaroff AA. Human tracheobronchial secretions: Development of
mucous glycoprotein and lysozyme-secreting systems. Pediatr Res 1977; 11: 977-980.
Cairo MS, Suen Y, Knoppel E, Dana R, Park L, Clark S, van de Ven C, Sender L. Decreased G-
CSF and IL-3 production and gene expression from mononuclear cells of newborn infants.
Pediatr Res 1992; 31: 574-578.
Caplan MS, Hsueh W, Kelly A, Donovan M. Serum PAF-acetylhydrolase increases during
neonatal maturation. Prostaglandins 1990; 39: 705-714.
Chheda S, Palkowetz KH, Rassin DK, Goldman AS. Deficient quantitative expression of CD45
isoforms on CD4+ and CD8+ T-cell subpopulations and subsets of CD45RAlowCD45ROlow T
cells in newborn blood. Biol Neonate 1996; 69: 128-132.
Chheda S, Palkowetz KH, Garofalo R, Rassin DK, Goldman AS. Decreased interleukin-10
production by neonatal monocytes and T cells: Relationship to decreased production and
expression of tumour necrosis factor-α and its receptors. Pediatr Res 1996; 40: 475-483.
Cohen SB, Dominiguez E, Lowdell M, Madrigal JA. The immunological properties of cord
blood: overview of current research presented at the 2nd EUROCORD workshop. Bone
Marrow Transplant 1998; 22(Suppl 1): S22-25.
English BK, Hammond WP, Lewis DB, Brown CB, Wilson CB. Decreased granulocyte-
macrophage colony-stimulating factor production by human neonatal blood mononuclear
cells and T cells. Pediatr Res 1992; 31: 11-216.
Garofalo RP, Goldman AS. Cytokines, chemokines, and colony-stimulating factors in human
milk: The 1997 update. Biol Neonate. 1998; 74: 134-142.
Goldman AS. Host Responses to Infection. Pediatr Rev 2000; 21: 342-349.
Goldman AS. Modulation of the gastrointestinal tract of infants by human milk. Interfaces and
interactions. An evolutionary perspective. J Nutr 2000; 130(2S Suppl): 426S-431S.
Goldman AS, Chheda S, Garofalo R. Evolution of immunological functions of the mammary
gland and the postnatal development of immunity. Pediatr Res 1998; 43: 155-162.
Goldman AS, Chheda S, Palkowetz KH, Rudloff HE, Garofalo R, Schmalstieg FC. Cytokines in
human milk: Their properties and potential effects upon the mammary gland and the recipient
infant. In: Neville MC and Medina D (eds.) Journal of Mammary Gland Biology and
Neoplasia, Third Edition. New York: Plenum Publishing Corporation. 1996; 1: 251-258.
Goldman AS, Goldblum RM. Transfer of maternal leukocytes to the infant by human milk. In:
Olding L (ed) Reproductive Immunology/Current Topics in Microbiology and Immunology.
Springers Verlag EMBH and Co. KG, Heidelberg; 1997: 205-213.
Goldman AS, Ogra PL. Anti-infectious and infectious agents in human milk. In: Ogra PL,
Mestecky J, Lamm ME, Strober W, Bienenstock J, McGhee JR (eds.) Mucosal Immunology,
Second Edition. San Diego, CA: Academic Press. 1999; 96: 1511-1522.
Goldman AS, Prabhakar BS. Immunology. In: Baron SB (ed) Medical Microbiology, 4th Edition.
Galveston, TX: The University of Texas Medical Branch Press. 1996: 1-34.
Goldman AS, Thorpe LW, Goldblum RM, Hanson LA. Antiinflammatory properties of human
milk. Acta Paediatr Scand 1986; 75: 689-695.
Grigg J, Riedler J, Robertson CF, Boyle W, Uren S. Alveolar macrophage immaturity in infants
and young children. Eur Respir J 1999: 1198-1205.
Hanson LA, Padyukov L, Strandvik B, Wramner L. The immune system of the hunter-gatherer
meets poverty and excess. Lakartidningen. 2000; 97: 1823-1826.
Koldovsky O, Goldman AS. Growth factors and cytokines in milk. In: Ogra PL, Mestecky J,
Lamm ME, Strober W, Bienenstock J, McGhee JR, (eds.) Mucosal Immunology, Second
Edition. San Diego, CA: Academic Press. 1999; 97:1523-1530.
Lee SM, Knoppel E, van de Ven C, Cairo MS. Transcriptional rates of granulocyte-macrophage
colony-stimulating factor, granulocyte colony-stimulating factor, interleukin-3, and
macrophage colony-stimulating factor genes in activated cord versus adult mononuclear cells:
alteration in cytokine expression may be secondary to posttranscriptional instability. Pediatr
Res 1993; 34: 560-564.
May JT. Antimicrobial factors and microbial contaminants in human milk: recent studies. J
Paediatrics Child Health 1994; 30: 470-475.
Nanthakumar NN, Fusunyan RD, Sanderson I, Walker WA. Inflammation in the developing
human intestine: A possible pathophysiologic contribution to necrotizing enterocolitis. Proc
Natl Acad Sci U S A. 2000; 97: 6043-6048.
Newburg D. Oligosaccharides and glycoconjugates in human milk. J Mammary Gland Biol
Neopl 1996; 1: 271-283.
Pabst HF, Spady DW, Pilarski LM, Carson MM, Beeler JA, Krezolek MP. Differential
modulation of the immune response by breast- or formula-feeding of infants. Acta Paediatr
1997; 86: 1291-1297.
Reissland P, Wandinger KP Increased cortisol levels in human umbilical cord blood inhibit
interferon alpha production of neonates. Immunobiology 1999; 2000: 227-233.
Rowen JL, Smith CW, Edwards MS. Group B streptococci elicit leukotriene B4 and interleukin-8
from monocytes: neonates exhibit a diminished response. J Infect Dis 1995; 172: 420-426.
Suen Y, Lee SM, Qian J, van de Ven C, Cairo MS Dysregulation of lymphokine production in
the neonate and its impact on neonatal cell mediated immunity. Vaccine 1998; 16: 1369-
Telemo E, Hanson LÅ. Antibodies in milk. J Mammary Gland Biol Neopl 1996; 3: 243-249.
Toivanen P, Rossi T, Hirvonen T Immunoglobulins in human fetal sera at different stages of
gestation. Experientia 1969; 25: 527-528.
Vigano A, Esposito S, Arienti D, Zagliani A, Massironi E, Principi N, Clerici M Differential
development of type 1 and type 2 cytokines and beta-chemokines in the ontogeny of healthy
newborns. Biol Neonate 1999; 75: 1-8.
Wilson CB, Westfall J, Johson L, Lewis DB, Dower SK, Alpert AR 1986 Decreased production
of interferon-gamma by human neonatal cells. Intrinsic and regulatory deficiencies. J Clin
Invest 77: 860-867.
Yolken RH, Peterson JA, Vonderfecht SL, Fouts ET, Midthun K, Newburg DS 1992 Human
milk mucin inhibits rotavirus replication and prevents experimental gastroenteritis. J Clin
Invest 90: 1984-1991.
Zandstra PW, Conneally E, Piret JM, Eaves CJ. Ontogeny-associated changes in the cytokine
responses of primitive human haemopoietic cells. Br J Haematol 1998; 101: 770-778.
Gastrointestinal Development in Relation to the
Duration of Exclusive Breastfeeding
W. Allan Walker, MD
This manuscript reviews the development of digestive, absorptive, and protective functions of the
human gastrointestinal tract during the first six months of life. Development will initially be
considered during intrauterine existence and then during the postpartum period. Emphasis will be
placed on those gut functions that remain immature after birth. Evidence will be considered that
supports the role of breastfeeding and other extra-uterine, environmental factors that influence
the maturation of gut functions. The review will underscore the possible consequences of
persistent immaturities of gut function with regard to infant health and susceptibility to disease.
Finally, the potential importance of exclusive breastfeeding for the first six months of life will be
considered with regard to providing passive factors that may facilitate the efficient function of
the immature gut, as well as bioactive factors (hormones, growth factors, cytokines, etc.) that
may accelerate the development of the infant’s own gut function.
Development of morphologic function of the human gastrointestinal tract progresses rapidly
during the first trimester. By eleven weeks postpartum, the multi-layered endothelium has
matured into a single layer of polarized enterocytes, and developmental modifications have
begun to increase the surface area of the small intestine. During the second trimester, epithelial
cells differentiate into specific cell lineages. By the beginning of the third trimester, morphologic
development of the gut is virtually complete. Thus, the newborn full-term infant at birth appears
to have a fully anatomically developed gastrointestinal tract. Functional development of the
human gut however, progresses at a different pace in utero. Intra-luminal digestive enzymes
develop slowly; the capacity to digest proteins, lipids, and complex carbohydrates is incomplete
at birth and remains so for much of the first year of life. Microvillus enzymes for end stages of
digestive function, e.g., sucrase-isomaltase, lactase, and trehalase, slowly develop during the
second and third trimester. Because of a paucity of human tissues for study during the third
trimester, the development of mucosal nutrient carriers for amino acids, fatty acids, and
monosaccharides are not completely understood, however, it is postulated that by birth the small
intestine has about 75% of its fully developed capacity to transport these nutrients across the
In order for “succus entericus” to be digested and absorbed, it must be mixed with intestinal
secretions and moved sequentially along the small and large intestine for maximal absorption
before final elimination by defecation. This process requires a coordinated peristaltic movement,
i.e., rhythmic contractions of smooth muscle in a cephalad to caudal direction. In general, the
enteric nervous system and intestinal smooth muscle are developed in utero and are functional at
term. However, the subtle activity of sphincter and peristaltic contractions is not completely
developed at birth because of the delayed appearance of neurotransmitter receptors and other
mediated trophic factors released by proteins, lipids and carbohydrates in the enteric contents.
Another important capacity of gut function is the host defense system that protects the enormous
epithelial surface area against the uptake of pathologic microorganisms and foreign antigens. At
full-term, the gut epithelium and lymphoid compartments are almost completely developed,
including the lymphoid aggregates in Peyer’s patches and the microfold cells (M-cells) overlying
these patches to sample luminal antigens, T cells and microphage in the lamina propria and intra-
epithelial lymphocytes between enterocytes. However, for an appropriate efferent response of
these mucosal immune components, the gut must leave the sterile intrauterine environment and
enter the extra-uterine environment containing microorganisms and foreign antigens. In the
maturation of mucosal immunity the crucial first step is initial bacterial colonization. The nature
of this colonization is an important determinant of the infant’s ability to prevent inappropriate
immune responses to stimulation, e.g., inflammatory and allergic reactions.
At birth, the newborn enters the extra-uterine environment where the gastrointestinal tract must
function independently from the maternal capacity to provide nutrient and immune protection in
utero. As previously stated, at term, the human newborn’s gastrointestinal tract is anatomically
mature and has the capacity to assume most of the digestive, absorptive, and protective functions.
However, several subtle immaturities of these functions require the ongoing dependence on
maternal help via the ingestion of colostrum and then mature breast milk, because luminal
enzymes provided by release of pancreatic secretions is not yet coordinated. The digestion of
proteins, lipids and complex carbohydrates is immature. Efficient breakdown of lipids to fatty
acids for absorption is impaired by a decreased lipase activity. In like manner, the breakdown of
protein to amino acids and the breakdown of complex carbohydrates to monosaccharides are
altered by low levels of proteases and amylase, respectively. Although some suggest that the
mucosal surface active transport of fatty acids, amino acids and monosaccharides are sufficiently
developed to provide adequate transport across the gut and into the newborn circulation, the
process has not been studied in detail. In addition, other luminal mucosal immaturities may affect
efficient utilization of enteric nutrients, including the uptake of iron (Fe++) and zinc (Zn++). At
birth the capacity of the newborn to produce acid for secretion into the stomach is hampered by
an immature receptor response to enteric hormones such as pentagastrin. This immaturity, along
with the lack of coordinated peristalsis in the small intestine, allows for excessive colonization of
the small intestine with ingested bacteria. Increased levels of bacteria in the small intestine can
cause a diversion of nutrients to bacteria and thereby provide less for digestion and absorption
across the infant’s intestine. Furthermore, breakdown products of bacterial metabolism include
production of short chain fatty acids such as butyrate which can have serious effects on mucosal
inflammatory responses. Other dysmotilities in newborn gut function can hamper efficient
digestion and absorption. For example, all newborns have a physiologic regurgitation of ingested
food because of the immaturity of the lower esophageal sphincter, due to a poor response to
hormonal stimulation. In addition, the newborn infant’s stomach does not release its content via
the pyloric sphincter in a coordinated fashion. This combination of immature motility responses
can lead to regurgitation, inefficient small intestinal digestion and absorption, and aspiration
Intestinal defenses, particularly the mucosal immune system, are, for the most part, intact and
capable of response to luminal stimuli at birth. However several aspects of the mucosal immune
response remain immature, making the infant susceptible to specific gastrointestinal and systemic
diseases. In order for the newborn’s mucosal immune system to function properly, it must have
the appropriate environmental luminal stimuli. This means that the newborn gut must establish
via initial colonization a stable intestinal flora which is the primary stimulus for an efficient
immune response. The nature of colonizing bacteria can determine whether the gut immune
system results in bacterial infection and inflammation or an intact mucosal defense which prevent
these disease processes. At birth, the capacity of plasma cells in the lamina propria to release
polymeric IgA (pIgA), the principal protective immunoglobulin in secretions, in response to
luminal stimuli is immature; it takes several months to a year for protective levels of pIgA to
appear in intestinal secretions. In essence, the newborn infant is pIgA deficient and therefore
susceptible to the same diseases as genetically pIgA deficient individuals, e.g., intestinal
infections and systemic allergy.
In addition, the intrauterine environment favors a T helper cell response in newborns that is Th2
predominant. Th2 helper cells produce a cytokine response (IL4, IL5, etc.) that favors humoral
immunity and antibody responses, including IgE. While this imbalance in Th subclasses may
favor the protection from rejection of the fetus in utero, it creates problems in the extra-uterine
environment. In the absence of a balance in the Th responses between Th1, Th2, and Th3, cells
can, in allergy-prone infants, lead to atopic food allergy. A proper balance in Th subclasses is
achieved by appropriate colonization of the infant’s gut, as found to occur with exclusive
breastfeeding. In addition, the immature intestinal epithelium allows the absorption of intact
proteins and peptides that can contribute to inappropriate systemic immunologic responses,
further contributing to the development of intestinal food allergy in young infants.
As part of the fetal/newborn immune response both in utero and in the extra-uterine environment,
the immature gut reacts to luminal stimuli by over-responding with sustained inflammation. This
increased propensity to inflammation may be an important defense for the premature neonate and
infant against adverse effects of microbial penetration, but it also has its drawbacks. For example,
the immature inflammatory response to microbial stimuli is considered an important risk factor
to the development of necrotizing enterocolitis in the premature infant and specific infectious
gastroenteritis in the older infant.
An important component of the neonatal mucosal response is systemic non-responsiveness to the
ingestion of foreign antigens such as cow’s milk protein. This response is termed oral tolerance.
The young infant lacks the capacity to produce oral tolerance. If this immaturity exists beyond
the newborn period, infants can develop diseases such as allergy and autoimmunity. Oral
tolerance is not completely understood at present but is hypothesized to be due to the
development of appropriate antigen presentation by antigen presenting cells to T helper cells in
such a way that cytokines can down regulate systemic humoral and cellular responsiveness to that
antigen. Maturation of the infant’s gut to develop oral tolerance requires an appropriate bacterial
colonization and a balance of T helper cells (Th1 vs. Th2 vs. Th3). A failure to provide proper
extra-uterine luminal environmental stimuli may delay maturation of the infant’s intestinal
defenses and could predispose the infant to age-related diseases in infancy and later childhood.
Role of Human Milk in Gut Function
Since the development of gastrointestinal digestive, absorptive, and protective function with the
birth of the full-term infant is almost complete, obvious reasons to promote exclusive
breastfeeding for the first six months of life are not apparent. That is, infants not breast-fed or
partially breast-fed for that period do not necessarily develop life-threatening diseases nor do
they become obviously severely malnourished. However, as we understand the subtle
immaturities in the human infant’s gut function after birth and the factors in human milk that
facilitate gut function and stimulate a rapid development of mature infantile gut function, a
strong argument for exclusive breastfeeding can be made.
As stated previously, the ingestion of mother’s colostrum and mature milk can be considered an
extended maternal influence over the infant into the extra-uterine environment. We know from
several reviews that the composition of maternal milk differs from mothers delivering
prematurely, in colostrum, and in mature milk. For example, the composition of colostrums and
mature milk from mothers delivering prematurely favors factors more appropriate for the
premature and newborn infant, e.g., higher concentrations of pIgA, cytokines and growth factors.
In addition, there is evidence that human milk ingestion passively and actively facilitates
appropriate function of the infant’s gastrointestinal tract.
Intraluminal digestion of lipids, protein, and complexe carbohydrates is incomplete at birth and
during infancy. Human milk contains enzymes, such a lipase, that facilitates efficient digestion of
these foods. In addition, the lipid, protein, and carbohydrate composition of human milk is
appropriate for the combined digestive capacity of human milk itself in the infant’s luminal
enzymes, thereby more effectively dealing with immature luminal digestion. The surface of the
small intestine epithelium and its transporters of end stage digestive products, e.g., fatty acids,
amino acids and monosaccharides, appears to be appropriate for neonatal absorption of nutrients.
However, efficient transport of trace metals essential to normal metabolic function of the
newborn may be incomplete. There is evidence to suggest that human milk contains soluble
transporters for iron (Fe++) and zinc (Zn++) that can more efficiently facilitate the absorption of
these ions, which milk may account for the normal levels of these trace elements in the
circulation of breast-fed infants, even though human milk itself contains low levels of these trace
Although not completely studied, there is evidence that breast-fed infants appear to have a more
coordinated motility of their gastrointestinal tract and less difficulty with esophageal
regurgitation, gastric emptying, or elimination of waste. The basis for this observation is at this
point speculative but may be explained by the composition of human milk nutrients, e.g., non-
digestible oligosaccharides whose breakdown products can stimulate gut motility.
In this review, a strong emphasis has been placed on the initial colonization of the gut as an
important environmental, luminal factor to the appropriate development of mucosal defenses,
particularly mucosal immune responsiveness. Human milk ingestion facilitates the colonization
of the gut with bacterial flora that activate the mucosal immune response to luminal antigens.
The presence of “bifidous factor” and non-digestible oligosaccharides in human milk facilitates a
bacterial flora rich in lactobacilli and bifido bacteria organisms. These factors facilitate the
production of lactic acid which results in an acid milieu in the gut (pH=5) favoring the
proliferation of lactobacilli. Non-digestible human milk oligosaccharides are metabolized by
small intestinal bacteria to produce short-chain fatty acids which maintain this same milieu.
Oligosaccharides also can inhibit the attachment of pathogens to glyconjugates on the intestinal
surface as a first step in invasion. These human milk factors are currently under investigation as
“prebiotics,” i.e., nutrients that facilitate the production of “good bacteria” or probiotics. By
facilitating the growth of health-promoting intestinal bacteria, the gut also develops a balance
between T helper cells. A clinical study in Finland has shown the beneficial effect of lactobacilli
given to infants with allergic dermatitis to food allergens in reducing IgE mediated response.
As noted above, the immature fetal and newborn gut over-responds to luminal stimuli by an
excessive sustained inflammatory response, which can predispose infants to gastrointestinal
disease. Human milk contains multiple anti-inflammatory molecules (TGFβ IL-10, PAF
acetylhydrolase) that down regulate excessive inflammatory responses in the immature intestine
until the infant’s own intestinal host defenses develop. The anti-inflammatory protection of the
infant’s gut may be very important in the prevention of symptomatic infection and inflammatory
diseases during infancy. The most obvious example of human milk providing both passive and
active protection to the infant’s gut involves pIgA. While the full-term infant is relatively pIgA
deficient for the first months of life, the pIgA in human milk is directed against the infant’s
intestinal antigens. Colostrum contains high concentrations of pIgA which decrease in mature
milk. Human milk also contains growth factors and cytokines that facilitate the maturation of
IgA-producing plasma cells in the infant lamina propria.
Furthermore, several studies have suggested that specific nutrients abundant in human milk may
be effective as protective nutrients important in the maturation of the infant’s intestinal defenses.
For example, human milk contains large quantities of nucleotides. Under conditions of stress,
e.g., entering the extra-uterine environment, exogenous nucleotides may become conditionally
essential nutrients. Exogenous nucleotides may facilitate enterocyte proliferation and
differentiation, enhancing mucosal and systemic immune and cellular responsiveness. Omega-3
fatty acids exist in human milk and may exert anti-inflammatory effects with a decreased
production of prostaglandins and inflammatory cytokines by their incorporation into the cellular
lipid membrane of lymphocytes and enterocytes. Lactoferrin in human milk has antibacterial
effects (competing for iron with luminal bacteria) and anti-inflammatory effects directly
interfering with the transcription of TNFα, mRNA, etc., in the nucleus of enterocytes and
lymphocytes. These examples of protective nutrients illustrate the importance of further defining
the function of human milk nutrients during the first six months of life.
Summary and Conclusions
In this review of gut development, the maturation of gastrointestinal digestive, absorptive, and
protective function has been examined during gestation. In general, the human gut is
anatomically and functionally mature at birth in the full-term infant. However, subtle
immaturities in luminal digestion, mucosal absorption and protective function exists at birth that
may predispose the infant during the first six months of life to age-related gastrointestinal and
systemic diseases. Since access to gastrointestinal tissue during the third trimester and during
infancy is problematic, a complete understanding of immaturities is lacking. However, it is
suggested that exclusive breastfeeding provides both passive and active support of the infant’s
gut function during the first six months of life as an extra-uterine extension of maternal influence
over the fetus in the intrauterine environment. Several examples are provided of the benefit of
human milk ingestion facilitating the immature infant gut function in a more efficient fashion.
This review provides objective evidence supporting the recommendation that infants should be
exclusively breast-fed up to the sixth month of life.
Baily D, Turnbull G, Bartsch R., et al. Comparative analysis of adult and fetal human small
intestinal microvilli. Digestion 1997; 58(2): 155-60.
Berin MC, McKay DM, Perdue MH. Immune-epithelial interactions in host defense. Am J Trop
Med Hyg 1999; 60(4): 16-25.
Carver J. Dietary; nucleotides: effects on the immune and gastrointestinal systems. Acta
Paediatrica 1999; 88: 83-8.
Carver JD, Walker WA. The role of nucleotidase in human nutrition. Nutritional Biochemistry
1995; 6: 58-72.
Chailler P, Menard D. Ontogeny of EGF Receptors in the human gut. Frontiers in Bioscience
Chailler P, Basque JR, Corriveau L., et al. Functional characterization of the keratinocyte growth
factor system in human fetal gastrointestinal tract. Pediatr Res 2000; 48(4): 504-10.
Chu SW, Walker WA. Bacterial toxin interaction with the developing intestine: A possible
explanation for toxigenic diarrhea of infancy. Gastroenterology 1993; 104: 916-25.
Dai D, Walker WA. Role of bacterial colonization in neonatal necrotizing enterocolitis and its
prevention. Acta Paed Sinc 1998; 39: 357-365.
Dai D, Walker WA. Protective nutrients and bacterial colonization in the immature human gut.
Adv Pediatr 1999; 6: 353-382.
Nanthakumar N, Fusunyan RD, Sanderson IR, Walker WA. Inflammation in the developing
human intestine: A possible pathophysiologic basis for necrotizing enterocolitis PNAS 2000;
Freund JN, Domon-Dell C, Kedinger M., et al. The Xcx-1 and Cdx-2 homeobox genes in the
intestine. Biochem Cell Biol 1998; 76(6): 957-69.
Fusunyan R, Baldeon M, Nanthakumar N, et al. Intestinal epithelial cells express toll like
receptor 2,4 constitutively and in response to inflammatory mediators. Pediatr Res 2001; 49:
Groer M, Walker WA. What is the role of a pre-term breast milk supplement in the host defenses
of the pre-term infant? Science vs. Fiction. Adv Pediatr. 1996; 43: 335-58.
Hamosh M, Hamosh P. Development of digestive enzyme secretion. In: Sanderson IR, Walker
WA (eds), Development of the Gastrointestinal Tract. B.C. Decker, Ontario, Canada, 1999:
Insoft RM, Sanderson IS, Walker WA. The development of immune function within the human
intestine and its role in neonatal diseases. Pediatr Clin N A 1996; 43(2): 551-71.
Israel E, Schiffrin EJ, Carter EA, et al. Prevention of necrotizing enterocolitis: use of prenatal
cortisone to modify the immature intestinal mucosal barrier in the rat. Gastroenterology
Levy E, Menard D. Developmental aspects of lipid and lipoprotein synthesis and secretion in
human gut. Micro Res Techn 2000; 49(4): 363-373.
LozniewskiA, Muhale F, Hatier R., et al. Human embryonic gastric xenografts in nude mice: a
new model of Helicobacter pylori infection. Infect Immun 1999; 67(4): 1798-1805
Manson WG, Coward WA, Harding M., et al. Development of fat digestion in infancy. Arch Dis
Child Fetal Neo 1999; 80(3): F183-7.
Menard D, Corriveau L, Beaulieu JF. Insulin modulates cellular proliferation in developing
human jejunum and colon. Biol Neo 1999; 75(3): 143-51.
Montgomery RK, Mulberg AE, Grand RJ. Development of the human Gastrointestinal tract:
twenty-five years of progress. Gastroenterology 1999; 116: 702-31.
Muhale F, Norali A, Duprez A., et al. Acid secretion and response to pentagastrin or omeprazole
in human fetal stomach xenografts. JPJN 2000; 30(3): 246-52.
Okamura M, Kurauchi O, Itakura A., et al. Hepatocyte growth factor in human amniotic fluid
promotes the migration of fetal small intestinal epithelial cells. Am J Ob Gyn 1998; 178: 175-
Ouellette AJ. Paneth cells and innate immunity in the crypt microenvironment. Gastroenterology
1997; 113(5): 1779-84.
Perin NM, Thomson AB. Ontogeny of the small intestine. Arquivos de Gastroenterologia 1998;
Premji SS. Ontogeny of the gastrointestinal system and its impact on feeding the preterm infant.
Neo Network 1998; 17(2): 17-24.
Reid CJ, Harris A. Developmental expression of mucin genes in the human gastrointestinal
system. Gut 1998; 42(2): 220-226.
Salzman NH, Polin RA, Harris MC, et al. Enteric defensin expression in necrotizing
enterocolitis. Pediatr Res 1998; 44(1): 20-26.
Sanderson IR & Walker WA (eds.) Development of the Intestinal Tract. B.C. Decker, Ontario,
Speikermann G, Walker WA. Oral tolerance and its role in clinical disease. JPGN 2001 (in
Strober W. Interactions between epithelial cells and immune cells in the intestine. Ann N.Y. Acad
Sci 1998; 859: 37-45.
Tanaka M, Lee K, Martinez-Augustin O, He Y, Sanderson IR, Walker WA. Exogenous
nucleotides alter the proliferation, differentiation and apoptosis of human small intestinal
epithelium. J Nutr 1996; 126: 424-33.
Teitelbaum JE, Walker WA. The role of omega-3 fatty acids in intestinal inflammation. J Nutr
Biochemistry 2001; 12: 21-32.
Walker WA, Duffy L. Diet and bacterial colonization: Role of probiotics and prebiotics. J Nutr
Biochem 1997; 9: 668-675.
Xanthou M, Bines J, Walker WA. Human milk and intestinal host defense in newborns. An
update. Adv Pediatr 1995; 42: 171-208.
Yoshikai Y. The interaction of intestinal epithelial cells and intraepithelial lymphocytes in host
defense. Immunol Res 1999; 20(3): 219-35.
Infant Oral Motor Development in Relation to the
Duration of Exclusive Breastfeeding
Audrey J. Naylor, MD, DrPH
with the assistance of
Sarah Danner, MSN and Sandra Lang, Mphil, RM, Dip Ed
Effective oral motor function is fundamental to a newborn human infant’s successful transition
from intra to extra-uterine phases of life. The development of this function begins prenatally. By
the completion of gestation the fullterm newborn infant is prepared to successfully transfer
colostrum and soon thereafter maternal milk with its more “mature” nutritional and
immunological profile from its mother’s breasts through its oral cavity to the intestinal tract. As
the newborn grows older there is a need to progress from the liquid intake of neonates and young
infants to the increasingly solid diet of the older infant and young child using hands, spoons or
other devices. Throughout the first 12 months after birth oral motor function progressively
develops to match other biologically driven developmental processes. The following discussion
reviews the current understanding of the development of oral motor function. Of particular
interest will be to consider at what postnatal age the normal term infant is developmentally ready
to discontinue exclusive breastfeeding and begin the intake of semi solid and solid
Oral Anatomy and Function
Anatomical structures of importance to oral motor function include the oral cavity, the lips, the
upper and lower jaw, the tongue, cheeks, the hard and soft palate, the hyoid bone and thyroid
cartilage, the epiglottis, the constrictor muscles of the pharynx and more than 40 other muscles as
well as six cranial nerves (I, V, VII, IX, X, and XII). These structures participate in a complex
process of transporting both food and air through the oral cavity. Sucking, chewing and tongue
activity prepare food for swallowing. Within the pharnyx both liquid and solid foods are
swallowed and guided into the esophagus while air moves toward the larnyx and trachea. This
process requires a sequence of well-coordinated neuromuscular actions. Additionally adjustments
are occurring as the infant grows, develops and matures both anatomically and neurologically.
A number of important differences exist between the anatomy of the newborn and that of the
older child and adult including:
• the oral cavity and lower jaw (mandible) is smaller than in the older infant and adult
• the lower jaw is slightly retracted
• sucking pads, (fatty tissue deposits within the cheek muscles), contribute to limited space
and provide a degree of important stability for early sucking efforts
• oral space restrictions result in the tongue filling the space and in restricting its movement
• airway protection is more anatomically assured due to higher position of the larynx and
the close approximation of the epiglottis and soft palate.
Newborn and Young Infant Feeding Reflexes
In addition to the anatomical differences described in the previous section, full term infants begin
their extra-uterine life with five important prenatally developed reflexes well in place, including
swallowing, sucking, gag, phasic bite and rooting. These reflexes, which fade or disappear
altogether during the first year, are the basis for the development of successful lifelong oral
motor function. Each will be briefly described.
Swallowing is present in the fetus by the end of the first trimester, considerably earlier than
sucking. The fetus is reported to have much experience with this important oral motor function,
having swallowed significant amounts of amniotic fluid prior to delivery. While reflexive
sucking fades over the first few months after delivery, swallowing, triggered by liquids or solids
in the oropharnyx, remains present throughout life.
Sucking becomes evident in the fetus by the middle of the second intrauterine trimester. It can be
elicited in the newborn by touching the lips, cheeks, and inside of the mouth including the
tongue, gums, hard palate and mucous membranes. When stimulation is initiated by an object in
the infant’s mouth (e.g., finger, mother’s nipple) the infant extends the tongue over the lower
gum, raises the lower jaw and initiates the sucking sequence. By about three months sucking
becomes decreasingly automatic and more voluntary.
The gag reflex is present early in the third trimester and is stimulated when the posterior two
thirds of the tongue or the pharyngeal wall is touched. The reflex is less intense after about six
months of age but does not disappear. The area of stimulation, however, gradually decreases to
about a quarter of the posterior tongue.
The phasic bite reflex, also present early in the last trimester, results in the rhythmical opening
and closing of the jaw when the gums are stimulated.
Rooting, the last reflex to appear prenatally, is a side-to-side head turning and the wide opening
of the mouth. This response occurs when the skin surrounding the mouth is stroked. It assists the
infant in locating the breast and nipple and preparing to attach. It is usually most notable when an
infant is hungry. In the normal infant this reflex is no longer present after about 3 months of age.
Development of Oral Motor Function
The described anatomical structures and reflexes of the newborn infant contribute to assuring
successful initiation of oral feeding essential for neonatal survival. Early studies using
cineradiography and more recent (and safer) real-time ultrasound techniques, provide images of
the anatomy and reflexive events occurring within the oral cavity of the neonate during the intake
and transporting of food and air. These studies demonstrate that normal full term newborn infants
apply the dorsum of their tongue to the mother’s nipple and surrounding areola. Then, almost
simultaneously, an anterior-posterior peristaltic wave-like contraction of the tongue and
depression and vertical grooving of the posterior portion of the tongue occur, as well as
contraction of the lower jaw (mandible), drawing the nipple and areolar tissue into the mouth to
the junction between the hard and soft palate. The mandible (and thus the gums) holds the nipple
in place and compresses the lactiferous sinuses. This combination of tongue and jaw action
expresses milk from the nipple into the mouth. The negative intra-oral pressure and space
resulting from the depression and grooving of the posterior tongue and subsequent relaxing of the
mandible, causes the milk to move toward the posterior oral cavity and briefly collect in the
groove formed near the back of the tongue. The lower jaw then relaxes and lowers. This further
increases the negative intra oral pressure. The peristaltic wave of the tongue moves away from
the nipple, presses against the soft palate and seals the milk within the oropharnyx and stimulates
swallowing. During swallowing the muscles of the palate and oro- and hypo- pharyngeal regions
close the nasal cavity. The laryngohyoid complex, arytenoids and backward movement of the
epiglottis close the airway. Breathing is briefly interrupted as the milk passes into the upper
esophagus stimulating peristaltic contractions and moving the milk into the stomach. Breathing is
then resumed and the sequence of suck-swallow-breathe begins again. This suck-swallow-
breathe sequence is considered to be well developed by about 37 weeks of gestation and prepares
the term infant to begin breastfeeding immediately after birth.
The rapidity of the sequence varies with the intensity of hunger as well as the stage of the
particular feed. Early in a breastfeeding episode, sucking is more rapid. As the maternal milk
ejection reflex begins to activate and milk flow occurs, sucking slows down. The amount of milk
flowing influences the strength and bursts of sucking and pausing.
As the first year of life progresses, the biologically driven oral motor development of the infant
assures successful transition from the liquid intake of neonates to the solid foods needed by the
older infant, child and adult. The disappearance of rooting and sucking reflexes along with
significant changes in anatomy occur in preparation for this transition. Many oral motor
specialists consider sucking as the oral stage of swallow and the intake stage of eating liquids and
semisolid foods. Two phases of sucking development are evident as the infant progresses,
suckling and sucking. The major distinction between these phases relates to the movement and
configuration of the tongue.
During suckling the tongue musculature moves in a backward-forward peristaltic wave and
stripping action which helps to draw out liquid from mother’s breast into the infant’s mouth.
(The cine and ultrasound studies noted previously described suckling.) Sucking is a more mature
behavior and emerges gradually between six and nine months as the anterior tongue motion shifts
from the backward - forward movement to an increasingly voluntary and refined up and down
motion. A new type of swallow also appears which can be initiated without a preceding suckle to
move the tongue in a backward direction.
The change in tongue movement to an up-down motion is accompanied by anatomical alterations
leading to an increase in the vertical space in the oral cavity. This increase in space results from
growth of the infant’s head, increasingly downward movement of the lower jaw, and the
absorption of the fat pads of the cheeks. Increase in space also allows for greater lateral tongue
movement. As the up-down and lateral movement gradually replace backward-forward tongue
action, the deep grooving of the posterior tongue, previously needed to channel a liquid bolus,
also diminishes allowing for additional lateral tongue movement. Thus between six and nine
months it becomes possible for infants to receive semisolid foods without reflexively pushing
these foods out and to effectively collect a bolus of food, move it about in their mouths, and
direct it to the posterior portion of the tongue. There swallowing is triggered and the bolus is then
transferred to the esophagus and finally into the stomach.
In addition to the anatomical growth and changes in reflexive responses which contribute to an
infant’s oral motor ability to successfully transition from liquids to semi-solid and solid foods,
there are important changes in proximal (central) musculature resulting in greater strength and
stability of trunk, shoulder and neck muscles. These relate to the development of the ability to
independently control the head and to sit up. In addition, they contribute to the development of
fine motor coordination of more distal muscles including the tongue and lips and their function in
bringing in and manipulating more solid food in preparation for swallowing. This development
of proximal musculature occurs at or after six months.
Summary and Conclusion
This review of the development of infant oral motor function was undertaken to understand the
processes taking place during gestation and over the first six to nine months after birth which
assure effective oral intake throughout this phase of life. It was also of interest to determine when
the oral motor function of normal human infants was developmentally ready to transition from an
entirely liquid intake to the inclusion of semi-solid or solid foods. Four aspects of oral motor
development were included in the review:
• A description of oral anatomy and recognized differences between that of the neonate and
of older infants, children and adults.
• A description of the oral reflexes of the newborn and young infant and important changes
occurring during the first six to nine months which facilitate successful transition from an
exclusive liquid oral intake to semi-solid and solid foods.
• A description of the development of oral motor function in terms of the interplay between
the biologically driven changes in oral anatomy and neonatal reflexes related to initially
transferring liquids from the oral cavity to the esophagus and later to transferring solid
• A brief commentary regarding the importance of the development of increased strength of
proximal musculature (trunk, shoulder and neck) as it relates to head control and
coordination of tongue and lip function essential to effectively bring semi-solid and solid
foods into the intra-oral cavity, move them about and prepare them for swallowing.
Though formal case control studies concentrating on the longitudinal development of oral motor
function are limited, considerable work has been done regarding overall infant neurologic
development. These reports combined with extensively reported clinical experience from
specialists in infant oral motor development and therapy provide strong indication that under
normal circumstances, oral motor function is developmentally ready for the introduction of semi-
solid and solid foods and thereby the discontinuation of exclusive breastfeeding between six and
nine months of age. While infants can be offered such foods at an earlier age, their oral anatomy,
reflexive responses and resulting oral motor function indicate that this is developmentally
premature and may increase the risk of aspiration.
Alexander, R, Boehme, R, Cupps, B (1993). Normal Development of Functional Motor Skills:
The First Year of Life. San Antonio, Texas: Therapy Skill Builders.
American Academy of Pediatrics: Committee on Nutrition (1980). On feeding of supplemental
foods to infants. Pediatrics, 65(6): 1178-1181.
Ardran, GM, Kemp,FH, Lind, J (1958). A cineradiographic study of bottle feeding. British
Journal of Radiology, 31: 11-22
Bosma, JF (1963). Maturation of the function of the oral and pharyngeal region. Amer Jour
Orthodontics, 49(2): 94-104.
Bosma, JF (1963a). Oral and pharyngeal development and function. Jour Dent Res, 42(1): 375-
Bu’Lock, F, Woolridge, MW, Baum, JD (1990). Development of co-ordination of sucking,
swallowing and breathing: ultrasound study of term and preterm infants. Dev Med Child
Neurol, 32: 669-76.
Byard, RW, Gallard,V, Johnson, A,Barbour, J, Bonython-Wright, B, Bonython-Wright, D
(1996). Safe feeding practices for infants and young children. Jour Paed Child Health, 32(4):
Danner, SC (2001) Normal sequence of oral motor development and feeding milestones.
Hammer, LD (1992). The development of eating behavior in children. Pediatric Clinics of North
America, 39(3): 379-394.
Medoff-Cooper, B, Ray, W (1995). Neonatal sucking behaviors. Image: Jour Nursing Scholar
ship, 27 (3): 195-200.
Morris, SE, Klein, MD(2000). Pre-feeding Skills: A Comprehensive Resource for Mealtime
Development. Second Edition. San Antonio, Texas. Therapy Skill Builders.
Radtka, S (1977). Feeding reflexes and neutral control. In Wilson, JM (ed) Oral-Motor Function
and Disfunction in Children. Chapel Hill, North Carolina: 96 - 105.
Woolridge, MW (1986) The “anatomy” of infant sucking. Midwifery, 2, 164-171.
Maternal Reproductive and Lactational Physiology in Relation to the
Duration of Exclusive Breastfeeding
Alan S. McNeilly, PhD
The concept that there might be a right time, in terms of the reproductive physiology of either the
mother or the baby, for the mother-baby unit to cease exclusive breastfeeding is extremely
difficult to determine. Clearly, if the mother decides not to breastfeed at all then the mother
totally controls the destiny of the baby. Conception in the absence of contraceptive cover can
occur within six weeks postpartum, with an inter-birth interval of less than 12 months. This may
have a disastrous effect on the baby depending on family circumstances, with infant morbidity
and mortality being directly related to short inter-birth intervals. However, the scope of this paper
is the consequence of breastfeeding on fertility and so I will not address the non-breastfeeding
situation further. There is no dispute that exclusive breastfeeding can maintain infertility in the
mother for prolonged periods. In the absence of natural or artificial contraceptives inter-birth
intervals of four years or more have been recorded. While this may be the extreme, it illustrates
that the continued suckling of the baby is more than capable of sustaining an effective block to
resumption of fertility in the mother. This gives the obvious advantage to the growing infant in
that there is no direct competition with another sibling for the attentions of the family in the
upbringing of the baby.
On the other hand it is also clear that the biological effect of breastfeeding on suppressing
fertility is a very rapidly removed suppressor. Once the reproductive system of the mother has
returned to normal, then any abrupt decline in suckling will result in a rapid return of ovulatory
cycles and pregnancies may occur without any intervening menstrual period. It would be
presumed in this case that it is the biologic will of the mother to replace any infant no longer
capable of suckling–through for example major illness or death–with a new sibling, and so
passing on her/their genes.
If this is the case then it is the baby who is controlling when fertility resumes in the mother, and
the mothers reproductive system is being controlled entirely by the suckling of the baby. The
point at which the suckling stimulus declines to a level at which fertility returns in the mother is
quite variable amongst women. It is clear now from the major studies on the use of lactational
amenorrhea method (LAM) that exclusive breastfeeding prevents almost all pregnancies for at
least six months, and is certainly very effective up to nine months. Of course the decision as to
when suckling patterns change to such an extent that the suckling stimulus declines below the
level capable of suppressing fertility is not directly controlled by the infant.
It appears from limited studies that the amount or strength of suckling undertaken by the baby
relates to several factors which may or may not be correlated:
• the ease of milk let-down
• the amount of milk available
• the amount of nutrition other than breast milk that the baby receives, although this
obviously is not an issue when there is exclusive breastfeeding.
It is perhaps time to review the mechanisms whereby sucking does switch off or modulate the
reproductive axis in women since there may be better clues as to whether there really is a right
reproductive time for full breastfeeding to no longer be required.
The Endocrinology of the Normal Menstrual Cycle
The normal menstrual cycle is controlled by GnRH (Gonadotropin Releasing Hormone), the
hypothalamic hormone that controls the production of the pituitary gonadotrophins, Follicle
Stimulating Hormone (FSH) and Luteinizing Hormone (LH). GnRH is released as pulses
approximately every hour, except at mid cycle where release is continuous to facilitate the
preovulatory LH surge. FSH stimulates ovarian follicle growth while LH stimulates steroid
production by the follicle, and subsequently by the corpus luteum formed from the follicle after
ovulation. Ovulation of the preovulatory follicle is induced by a massive release of LH from the
pituitary, the preovulatory LH surge, triggered in turn by a sustained large release of GnRH from
the hypothalamus induced by the rising levels of estradiol secreted by the dominant preovulatory
follicle. Before the preovulatory LH surge, estradiol, secreted by the follicle, is generated by a
continuous release of LH pulses released at approximately hourly intervals. Blockade of this
pulsatile secretion is known to stop ovarian steroid production and cause infertility. Furthermore,
the release of FSH is regulated by the negative feedback effects of estradiol and inhibin secreted
by the developing and dominant follicles, which leads to a suppression of FSH secretion. Thus in
the normal cycle, FSH secretion is suppressed during the luteal phase of the cycle due to the
steroid and inhibin feedback from the corpus luteum of the cycle. Around menses, when the
corpus luteum fails and levels of steroids and inhibin decline, this triggers a release of FSH
which stimulates follicle growth in the next cycle. A number of follicles start to grow, and
around day five of the menstrual cycle a number of antral follicles up to 10 mm may be present.
These follicles, together with a lead follicle, produce increasing amounts of estradiol and inhibin
which suppresses FSH secretion. This decline in FSH starves all but the single dominant follicle
of FSH and all other follicles then die, leaving a single dominant follicle to go on to ovulate. This
is a tightly regulated system to avoid high numbers of eggs being ovulated at any one time. A key
issue is the regular pulsatile secretion of GnRH/LH which is an absolute requirement for normal
follicle growth. We have estimated that the total amount of LH released during the day due to
pulsatile secretion of LH releases about 5% of the total LH stored in the pituitary. Equally
important is the amount of LH required to generate the preovulatory LH surge, which, in those
species in which it has been measured, constitutes 60 to 80% of the total amount of LH present in
the pituitary. The co-ordination of the patterns of secretion of LH and FSH is crucial for normal
reproductive function during the menstrual cycle. Inadequate FSH will lead to inadequate
induction or maintenance of follicle growth; inadequate pulsatile LH will lead to an absence of
sufficient estradiol secretion to generate a preovulatory GnRH/LH surge, thus blocking ovulation.
In addition, inadequate LH released either during the preovulatory LH surge or in the luteal phase
may lead to inadequate corpus luteum function and a failure to maintain a pregnancy. All these
possibilities occur during the suppression and subsequent return of fertility in breastfeeding
women and the timing of these events is directly related to the suckling stimulus.
Earliest Time to Resumption of Fertility
During pregnancy the high level of placental steroids feedback on the hypothalamo-pituitary axis
and lead to an almost complete shutdown of the synthesis and release of GnRH, which in turn
leads to a suppression of the synthesis and release of LH and FSH in the immediate postpartum
period. The maximum rate of recovery from this suppression due to pregnancy, which will allow
the resumption of fertile menstrual cycles, can be assessed by monitoring the changes which
occur if a mother chooses not to breastfeed. Within two weeks of birth, there is a resumption of a
limited pulsatile LH secretion and a return to near normal levels of FSH. As a consequence, there
is a small increase in the secretion of estradiol indicating limited ovarian follicle growth. Normal
pulsatile secretion of LH can resume by four weeks, with a first menses within five to seven
weeks. However, in the majority of cases, this first period of bleeding is preceded by an absence
of ovulation, or the formation of an inadequate corpus luteum secreting small amounts of
progesterone. This pattern of steroid and ovarian activity is associated with the release of a
reduced amount of LH during the preovulatory LH surge. This may be a consequence of an
inadequate amount of LH in the pituitary, due to the delay in synthesis of adequate amounts of
LH, an insufficient amount of estradiol released by the follicle, or an inadequate release of GnRH
during the preovulatory surge. It is not clear which factors are key, but the principal message is
that within six to eight weeks postpartum, the key elements of the fertile normal menstrual cycle
have been re-established in the absence of suckling. Indeed inter-birth intervals as short as ten
months have been recorded. Suckling clearly delays this rate of return of fertility.
The Suckling-induced Suppression of Fertility
It is now clear that it is the suckling stimulus of the baby that is the key factor which suppresses
fertility during breastfeeding. We also have a reasonable concept of how this suppression occurs
at different levels of the reproductive axis. During exclusive breastfeeding the suckling stimulus
disrupts the frequency of pulsatile secretion of GnRH from the maternal hypothalamus. As a
consequence, the pattern of pulses of LH required to induce normal secretion of estradiol from
the developing follicle is not sustained. Furthermore, the GnRH pulsatile release mechanism –
pulse generator – is highly sensitive to estradiol, and low levels of estradiol that in the normal
menstrual cycle have little effect on pulsatile GnRH release, can dramatically suppress pulsatile
GnRH and hence LH secretion. During this time the pituitary remains sensitive to GnRH, and the
ovaries remain responsive to gonadotrophin stimulation, indicating that the suppression of
fertility does not involve effects at either the pituitary or ovary. Replacement of a pulsatile
pattern of GnRH in women with lactational amenorrheoa who are exclusively breastfeeding
results in a return of normal ovulatory menstrual cycles, confirming our concept that the principal
effect of suckling is to disrupt the normal pattern of GnRH secretion. The mechanisms in the
hypothalamus whereby the suckling stimulus suppresses the GnRH pulse generator are unknown,
but in women do not appear to involve opioids or dopamine. Thus variations in the suckling
pattern will have a dramatic effect on the rate of return of reproductive activity in the mother.
However, the crucial issue is what or who precipitates this change in suckling activity.
Milk Production, the Suckling Stimulus and Resumption of Fertility
A major problem with giving guidance as to the amount of suckling that is required to maintain
the suppression of fertility is the immense variation in the suckling stimulus itself, and the pattern
of suckling adopted by each mother infant pairing during exclusive breastfeeding. There appear
to be no clear patterns emerging from monitoring infant feeding patterns, in relation to the return
of fertility, which vary considerably in different societies. In studies in Scotland, Sweden and the
USA, it appears that a minimum frequency of suckling can be defined which will sustain
infertility in the mother, but these norms are not a universal standard. Indeed, we all know that
frequencies of feeding vary dramatically amongst individual mother baby pairs during exclusive
breastfeeding, and all will suppress fertility equally effectively. Certainly studies in animals have
shown that increasing the suckling stimulus, e.g., in rats, by replacement of older litters with
newborn litters, prolonged the duration of infertility in the mothers. However, despite several
valiant efforts, there is no good simple measure of suckling strength of the baby, and particularly
not that required for suppression of fertility. Nevertheless, even in the absence of any good
evidence for the strength of the suckling stimulus required to maintain suppression of fertility,
frequencies less than five times per day appear to allow the resumption of fertility. However,
since a frequency this low is unlikely to occur during exclusive breastfeeding, this may not be an
issue. Certainly there are individual reports of higher frequencies of suckling being associated
with an earlier return of fertility, but it appears in this situation that the duration of each suckling
episode is short, due to an extremely efficient milk-ejection system established within the
This then poses the major question of who determines the frequency of suckling, the baby or
mother? Studies in red deer have shown that the frequency of suckling initiated by the offspring
increases if milk production is low. In this case the calves were increasing the frequency to gain
sufficient nutrition for survival. In well-nourished deer with copious milk supply calves suckled
much less frequently, resulting in an earlier onset of reproductive activity. There have been no
directly comparable studies in women, but it is quite possible that the apparent small effects of
poor nutrition in delaying the resumption of fertility may be related to a subtle change in suckling
patterns. If low milk production indicates a poor nutritional state of the mother, then it could be
an indirect advantage to the mother to continue breastfeeding to maintain infertility. This would
then prevent the undernourished mother having to maintain one sibling while being pregnant
with another, hence increasing the nutritional load on the mother. Indeed it is clear that
undernourished mothers regain lost body weight after breastfeeding provided that the inter-birth
interval is sufficiently long for her to replace her reserves. This may relate to the observation that
mothers may reduce their metabolic rate during lactation thus requiring less energy to make milk
and sustain a normal healthy body. Certainly the baby is unlikely to reduce the suckling input in
the face of poor nutrients since this would have a detrimental effect on the health of itself.
The overall conclusion would seem to be that the baby adjusts its suckling frequency and pattern
of suckling to ensure sufficient nutrient intake. Whether this is done with any regard to the
suppression of fertility is totally unclear. Certainly in our experience, whenever supplements are
introduced, the effects on fertility in the mother is dependent on the impact the supplements have
on the pattern of suckling. In most cases there is no change in the frequency of suckling, but a
reduction in the duration of each feed, unless of course, the supplements were introduced as part
of a weaning strategy. If the duration declined rapidly, then even with the maintenance of
frequency, fertility resumed in the mother. The impact of supplements has been a matter of
debate and the effects seem to depend on the nutritional value of the supplement provided, and
obviously, on the frequency with which they are given, but principally on the effect on suckling
behavior of the baby. Thus any assessment of the risk of supplements affecting fertility must be
taken at a local level.
What these observations do appear to indicate is that:
• the mother does not directly regulate her reproductive status to suit her baby, but responds
to the suckling influence of the baby;
• a wide variation in the pattern of suckling during exclusive breastfeeding will result in a
maintenance of infertility in the mother; and
• the timing of resumption of fertility is not within the control of the mother if the baby
continues to suckle.
Thus, it appears that the baby is the crucial controller of the continued period of infertility in the
mother. If the mother weans the baby abruptly, or the baby dies, then the reproductive axis of the
mother is ready for immediate resumption, and pregnancies can occur very soon after weaning.
Of course if the baby is weaned then it still has around nine more months of maternal care before
there is any rivalry from a new younger sibling, and this extra time may prove very important to
the well being of the baby.
Is There a Reproductive Time for the Cessation of Full Breastfeeding?
It appears that the maternal reproductive axis responds passively to the suckling infant, and there
is no clear active suppression induced from the maternal side, even in the case of poor maternal
nutrition. Thus an absolute duration of infertility associated with breastfeeding that provides
reproductive benefit to the mother is not evident. However, it would clearly be of benefit to the
mother not to be pregnant and exclusively breastfeeding at the same time both from the effects on
the mother’s and the baby’s well-being. Since exclusive breastfeeding is usually associated with
a complete absence of fertility, and this can be maintained for at least six months, the indirect
benefit of the suppression of fertility is to give at least an 18 month inter-birth interval. However,
since the maternal reproductive axis can be switched on within seven days of weaning, it is clear
that there is a reproductive drive to reproduce that is held in check by the suckling baby, and it is
biologically important to maintain this at a high state of readiness for conception. The ability of
the reduced suckling stimulus to induce periods of inadequate luteal function which would be
unable to sustain a pregnancy further emphasizes that the maternal axis is not in control of the
duration of infertility during breastfeeding.
From a reproductive angle there are no major milestones in the neonatal period that appear to
require maternal suppression of fertility. When babies are bottle fed there is no evidence of any
consequences in terms of their reproductive capacity in adult life, although this has not been
studied extensively. Certainly for the good health of the growing baby it is important to maintain
a single contact between the baby and its mother during the early years. By suckling the baby
certainly is in control of the suppression of fertility of the mother. Thus the baby is also
principally in control of the duration of the period of infertility. In terms of any relation between
the reproductive axis in the baby and the duration of breastfeeding there seems to be no
interactions of note since the reproductive axis of the female neonate is almost quiescent. In male
infants it now appears that there is a continued low level activity of development in the testes
which could possibly be compromised if inappropriate supplements were given as well as or
instead of breast milk. This will require considerably more research before the true level of risk,
if any, is identified for infant boys.
Exclusive breastfeeding in most societies is associated with a complete suppression of fertility in
the mother. This suppression arises almost entirely from the suckling stimulus, with little direct
maternal influence. Certain factors which influence maternal milk supply may indirectly
influence suckling behavior, for instance low milk supply leading to increased suckling stimulus
and further suppression of fertility, but in the main, the maternal reproductive axis responds in a
passive manner to the suckling stimulus.
Indirectly there may be issues related to any supplements that may be given if exclusive
breastfeeding is not maintained. There is evidence in some species that factors given in neonatal
life may influence reproductive health in adults. At present there is no evidence for any major
effects in humans, but studies in other primates suggest that exposure to low doses of some
factors such as estrogenic compounds may affect the development of the male reproductive tract.
These studies will require considerable further work before there is hard evidence one way or the
other regarding the influences in humans.
From a reproductive aspect in both the mother and baby, there appears to be no specific influence
of exclusive breastfeeding that can be related to a recommended absolute duration of
breastfeeding. The maternal reproductive axis is programmed to return to normal rapidly when
the suckling stimulus declines, and for the baby, the principal need to suppress fertility is to delay
the arrival of a rival sibling. However, these are consequences which are unrelated to the
reproductive axis in the baby.
Glasier A, McNeilly AS, Baird DT. Induction of ovarian activity by pulsatile infusion of LHRH
in women with lactational amenorrhoea. Clin Endocrinol 1986; 24: 243-252.
Gray RH, Campbell OM, Zacur HA, Labbok MH, MacRae SL. Postpartum return of ovarian
activity in nonbreastfeeding women monitored by urinary assays. J Clin Endocrinol Metab
1987; 64: 645-650.
Howie PW, McNeilly AS. Effect of breast-feeding patterns on human birth intervals. J Reprod
Fertil 1982; 65: 545-557.
Illingworth PJ, Jung RT. Diminution of energy expenditure during lactation. BMJ 1986; 292:
Illingworth PJ, McNeilly AS. Estrogens and progestogens in the postpartum period. In: I.S.
Fraser, R.P.S. Jansen, R. Lobo and M. Whitehead, M. (eds.). Guidelines to Estrogens and
Progestogens in Clinical Practice, 1997 Churchill-Livingstone, London: 255-264.
Kennedy KI, Labbok MH, Van Look PFA. Consensus statement: lactational amenorrhoea
method for family planning. Int J Gynaecol 1996; 54: 55-57.
Kennedy KI, Rivero R McNeilly AS. Consensus statement on the use of breastfeeding as a
family planning method. Contraception 1989; 39: 477-496.
Lewis P, Brown J, Renfree M. The resumption of ovulation and menstruation in a well-nourished
population of women breastfeeding for an extended period of time. Fertil Steril 1985; 55:
Loudon ASI, McNeilly AS, Milne JA. Nutrition and lactational control of fertility in red deer.
Nature 1983; 302: 145-147.
McNeilly AS. Suckling and the control of gonadotropin secretion. In: Knobil E. and Neill J.
(Eds) The Physiology of Reproduction, New York: Raven Press, 1994; 1179-1212.
McNeilly AS. Lactation and fertility. J Mamm Gland Biol Neoplasia 1997; 2: 291-298.
McNeilly AS, Forsyth IA, McNeilly JR. Regulation of postpartum fertility in lactating mammals.
In: Lamming G.E. (Ed.) Marshall’s Physiology of Reproduction, 4th Edition. 1993. London:
Chapman & Hall; 1037-1101.
McNeilly AS, Glasier AF, Howie PW, Houston MJ, Cook A, Boyle H. Fertility after childbirth:
pregnancy associated with breast feeding. Clin Endocrinol 1983; 18: 167-173.
McNeilly AS, CCKTay, Glasier A. Physiological mechanisms underlying lactational
amenorrhoea. In: Campbell K.L. and Wood J.W. (eds.), Human Reproductive Ecology:
Interactions of Environment, Fertility and Behaviour. Ann New York Acad Sci 1994; 709:
Poindexter AN, Ritter MB, Besch PK. The recovery of normal plasma progesterone levels in the
postpartum female. Fertil Steril 1983; 39: 494-498.
Prieto CR, Cardenas H, Salvatierra AM, Boza C, Montes CG, Croxatto HB. Sucking pressure
and its relationship to milk transfer during breastfeeding in humans. J Reprod Fertil 1996;
Rasmussen & McGuire. Effects of breastfeeding on maternal health and well-being. Food Nutr
Bull 1996; 17: 364-369.
Stallings JF, Worthman CM, Panterbrick C, Coates RJ. Prolactin response to suckling and
maintenance of postpartum amenohrrea among intensively breastfeeding Nepali women.
Endocr Res 1996; 22: 1-28.
Thapa S, Short RV, Potts M. Breast feeding, birth spacing and their effects on child survival.
Nature 1988; 335: 679-682.
WHO: The World Health Organization multinational study of breastfeeding and lactational
amenorrhoea. I. Description of infant feeding patterns and of the return of menses. Fertil
Steril 1998; 70: 448-460.
WHO: The World Health Organization multinational study of breastfeeding and lactational
amenorrhoea. II. Factors associated with the length of amenorrhoea. Fertil Steril 1998; 70:
Zinaman, MJ, Cartledge T, Tomai T, Tippett P, Merriam GR. Pulsatile GnRH stimulates normal
cycle ovarian function in amenorrhoeic lactating postpartum women. J Clin Endocrinol
Metab 1995; 80: 2088-2093.
Summary and Conclusion
In the course of these reviews contributors selected articles of their own choosing. A total of 125
articles were examined, 34 regarding immunologic development, 36 regarding gastrointestinal
development, 33 regarding maternal reproductive physiology and lactation, and 13 related to oral
motor function. As noted, reviewers were each asked to draw independent conclusions
concerning the age of developmental readiness in their particular area of expertise. They then
read the papers of all other authors. The teleconference provided an opportunity for joint
discussion of all four papers and consideration of the original questions.
The expert reviewers noted the lack of longitudinal studies that could be used to respond to the
questions posed by these reviews, especially with regard to immunologic and gastrointestinal
development. In spite of this deficiency however, the group noted certain well-evidenced points
pertinent to the optimal duration of exclusive breastfeeding. Exposure of the infant to pathogens
that commonly accompany food frequently results in symptomatic infection. Illness reduces the
ability of the infant to suckle effectively, thus reducing the amount of milk consumed and the
transfer of immune substances from mother to infant. Reduced demand from ill infants results in
reduced lactation and may increase maternal risk for return of fertility. Thus, exclusive
breastfeeding to about six months allows the infant greater immunologic protection and limits
exposure to pathogens at a vulnerable age. This in turn permits the energy and nutrients that
might otherwise be diverted to provide for immunologic responses to be available and utilized
for other growth and developmental processes.
Though reports of results of formally designed longitudinal studies of oral motor function are
also limited, the development of this function has been observed and described for many years by
specialists in oral motor function and malfunction as well as pediatric neurologists. These clinical
reports indicate that the majority of normal full term infants are not developmentally ready for
the transition from suckling to sucking or for managing semi-solids and solid foods in addition to
liquids until between six and eight months of age.
Considerable work has been carried out concerning the relationship of lactation to maternal
reproductive physiology and the return of maternal fertility. (Lactational amenorrhea is now
understood as an effective modern family planning method to be considered as an option for the
first six months post-postpartum, if the guidelines are understood and followed). It is clear that
milk production is largely an infant driven physiology. Under most circumstances, during the
period of exclusive breastfeeding, mothers will provide what the infant requires, assuming that
the infant is allowed to nurse as needed. Exclusive breastfeeding with a frequent nursing pattern
is very likely to maintain infertility, lengthening the time between pregnancies and allowing a
mother to give her full biologic, cognitive and emotional attention to the particular infant.
Using the available information on the development of infant’s immunologic, gastrointestinal
and oral motor function, as well as maternal reproductive physiology, the expert review team
concluded that the probable age of readiness for most full term infants to discontinue exclusive
breastfeeding and begin complementary foods appears to be near six months or perhaps a little
beyond. They also felt that there is probable convergence of such readiness across the several
relevant developmental processes.
The consensus opinion of the expert review group was that given the available information and
the lack of evidence of significant harm to either normal mothers or normal infants, there is no
reason to conclude that exclusive breastfeeding should not continue to six months.
The expert reviewers noted the need for longitudinal studies to allow for a more careful
examination of the very questions posed by this effort, particularly with regard to immunologic
and gastroenterologic processes. Given the global implications for maternal and infant health,
gaps in scientific knowledge identified in these reviews should be considered as priority topic
areas for future research funding.