Periodontology 2000, Vol.
23, 2000, 142–150
Printed in Denmark ¡ All rights reserved
Mechanisms of risk in
preterm low-birthweight infants
C ATHERINE E . C . S . W ILLIAMS, E LIZ ABETH S . D AVENPORT,
J ONATHAN A . C . S TERNE, V YTHILINGAM S IVAPATHASUNDARAM,
J ANICE M . F EARNE & M ICHAEL A . C URTIS
The picture of the mother giving birth ‘‘early’’ due
to a sudden external stressor is well known by the
layperson. The true causes of this event and how it
progresses are only now becoming more fully under-
stood. The aim of this chapter is to summarize
known risk factors for preterm low birthweight in-
fants together with some putative mechanisms
which may link these risk factors to preterm low
birthweight. The discussion incorporates the defi-
nitions involved with preterm low birthweight, some
brief aspects of the concept of risk, and focuses on
the upsurge of interest in maternal infection, includ-
ing maternal periodontal infection.
The problem of low birthweight
(including preterm birth)
Worldwide, in all population groups, birth weight is
the most important determinant of the chances of a
newborn infant to survive, grow and develop health-
ily (Fig. 1). In this context, birth weight has long been
a subject of epidemiological investigations and a tar-
get for public health interventions (24, 38, 39). Birth
weight is the single outcome of a complex multifac-
torial system and is chosen in many studies as a key
indicator of the underlying health of the population
under investigation. It is important to state that
birthweight is an unrefined measure of fetal growth;
babies may have the same weight but differ in length
and proportion of fat. Over the past 25 years there
have been significant advances in perinatal medi-
cine and in understanding of reproductive physi-
ology. However, despite these advances the preva-
lence of preterm low-birthweight infants has not
changed, and in some population groups it has in
fact increased (29, 31). Considerable attention is
142
Copyright C Munksgaard 2000
PERIODONTOLOGY 2000
ISSN 0906-6713
being focused on the causal determinants of low
birth weight. This is due to the universal impact of
the high public health costs, in both the industrial-
ized and developing worlds, associated with preterm
low birthweight in the short term, through intensive
neonatal care and in the longer term through the
associated increased risks of adult conditions such
as cardiovascular disease, diabetes and obstructive
lung disease (4, 25). It is not clear how low birth
weight is associated with events in later life, al-
though it has been hypothesised that causal pro-
cesses for the development of cardiovascular dis-
ease, obstructive lung disease and diabetes are be-
gun in early life, affecting an individual’s risk
predisposition.
What is preterm low birthweight?
The international definition of low birth weight
adopted by the Twenty-ninth World Health Assembly
in 1976 is a birthweight of ‘‘less than 2500 g’’ (up to
and including 2499 g) (39). Below this value, birth-
weight-specific infant mortality begins to rise rapid-
ly. Low birth weight can be as a result of both a short
gestational period and retarded intrauterine growth.
The normal gestation for humans, full term is 40
weeks. Preterm or premature birth is usually defined
as a gestational age of less than 37 weeks (40). It is
generally true to say that the majority of preterm
births are also low birth weight. Mechanistically, it is
important to distinguish between preterm low birth-
weight and intrauterine growth retardation. A gener-
ally accepted standard definition for intrauterine
growth retardation, also known as ‘‘small for ges-
tational age’’ and ‘‘small for dates’’ infants, is difficult
to find. The following definition is commonly used:
birth weight less than 2500 g with gestational age

Fig. 1. Low birth weight (LBW) and mean birth weight (MBW) worldwide
greater or equal to 37 weeks: that is, these infants are
not preterm. This review will concentrate on the risk
factors for and mechanisms of preterm low birth
weight.
Preterm delivery is usually the outcome of one of
four broad areas of obstetric diagnosis (24): prema-
ture labor, preterm rupture of the membranes, mat-
ernal complications and fetal complications (Fig. 2).
How common are
low-birth-weight births?
In the United Kingdom, 6% of births were low birth
weight in 1992 (29). For North America the average
is around 7%, but the trend is rising (31). There are
marked racial differences. For example, in the United
States in 1989, some 18% of black births were low
birth weight. Global incidence figures for low birth
weight and mean birth weight are given in Fig. 1.
Worldwide the costs of treating this problem are
enormous and a clearer understanding of the predis-
posing factors and causes of preterm low birth
weight are a major health care target.
Mechanisms of risk in preterm low-birth-weight infants
Risk
Risk is a term commonly used, yet rarely defined.
Risk is almost invariably discussed in the context of
negative outcomes, or harm, rarely is it applied in
the sense of beneficial outcome. The concept of risk
carries with it three key factors: the fear of harm,
the gravity of the perceived harm, and the perceived
probability of harm (1, 35). Science addresses risk by
searching for metrics or descriptions of the causes
of an outcome, and in reducing uncertainty by
evaluating the probabilities of an event. What
science cannot solve is how a risk is perceived be-
cause this is embedded in the cultural norms of a
society. The gravity of increased infant mortality and
the fear associated with it are not necessarily con-
stant across all societies. However, the implied costs
to all societies of pre-term low birthweight infants
is omnipresent, as in general these infants demand
greater resources throughout their development (4,
25). By definition preterm low-birth-weight infants
result from a shortened gestational period, and
therefore understanding the biological processes
that lead to the normal initiation of labor at term is
143
Williams et al.
Fig. 2. The multifactorial nature of risk factors for preterm
rupture of the membranes and premature labor
critical to the determination of how preterm labor
may be initiated. However, the initiation of labor in
humans is not fully understood. The instant at which
labor begins is not constant across all pregnancies
and arises due to a sudden change or instability (ho-
meostatic discontinuity) in the maternal system. The
initiation of labor is representative of the unstable
structures described by the non-linear mathematics
of catastrophe theory (41), and the use of these new
concepts may help derive more rigorous models of
this event in the future. Gestation is terminated by
the initiation of labor. Up to this point, fetal growth
is subject to factors that affect the general progress
of a pregnancy. Therefore, preterm low birth weight
is the outcome of changes in a continuous and
stable system, followed by the early onset of a sud-
den, or catastrophic change. Attempts to determine
the factors involved in preterm low birth weight are
complicated by the dichotomy of the systemic na-
ture of fetal development, and the suddenness in the
initiation of labor.
Any description of the factors that lead to preterm
low birth weight is complex and has so far defied
attempts to produce a scoring system that predicts
144
the outcome of a given pregnancy (9, 12). Fetal
fibronectin in the upper vagina may prove to be a
reliable predictor of preterm birth (14). However, the
factors described in the following section are gener-
ally thought to be related to an increased likelihood
of preterm and low-birth-weight events (20). Many
of the factors are co-variables and/or confounders
for each other, and the relative importance of factors
varies between the populations of developing and
industrialized countries.
Genetic risk
The true effect of genetic factors is often difficult to
evaluate because of the influence of environmental
factors. A meta-analysis of family studies (20) con-
cludes that there is a probable genetic effect for
intrauterine growth and a possible effect for ges-
tational duration. Further work is needed to assess
the magnitude of these effects. Maternal body size,
which has a genetic component, has been suggested
as one of the most important determinants of the
size of her baby. This in turn is related to nutrition,
as chronic undernutrition can affect maternal stat-
ure (4).
Demographic and psychosocial risk
Very young maternal age (younger than 18 years)
and older maternal age (older than 36 years) are
thought to affect intrauterine growth and gestational
duration. However, a younger mother may have had
less exposure to other environmental risk factors,
such as smoking, than an older mother. For very
young mothers the effect may be mediated by in-
direct effects on maternal height (20).
Poor socioeconomic conditions, stress and
anxiety, high maternal physical workload and mat-
ernal education have been shown to be related to
increased rates of preterm birth (13, 20, 21). Poten-
tially the most easily modifiable of the above factors
is maternal education.
Obstetric risk
A previous history of: preterm birth, spontaneous
abortion, stillbirth, cervical incompetence, extremely
high parity and multiparity (20) are risk factors for
preterm delivery. The tendency of some women to
repetitive preterm births, spontaneous abortion,
stillbirth and cervical incompetence may have a gen-
etic component. It is generally believed that preg-
nancy outcome is more favorable for multiparae
 Mechanisms of risk in preterm low-birth-weight infants

than for primiparae. However, the trend of primi-

parae being younger than multiparae may confound
the association, as may socioeconomic factors. Fetal
distress, however caused, and maternal compli-
cations such as pre-eclampsia also result in a pre-
term birth.

Nutritional risk

Fetal nutrition and maternal nutrition are not the

same entity. The growth of the fetus is affected by
the nutrients and oxygen it receives from the mother.
A mother’s body weight is one of the important de-
terminants of her ability to nourish her baby. This is
established during her own fetal life and by her past
nutrition in childhood and adolescence, which de-
termine her body weight. Maternal diet in pregnancy
has little effect on birth weight but may program the
infant. A fetus may adapt to undernutrition by modi-
fying metabolism, this may take the form of chang-
ing rates of hormone production, slowing the growth
rate (4).

Fig. 3. Mechanisms of parturition at term

Maternal morbidity as risk

No conclusive evidence is available on the effects of

serious maternal illness, excluding infections, on
preterm low birth weight. Morbidity is again inter-
related to many other factors – genetic, socioecon-
omic, the metabolic cost of the condition and the term low birth weight (20). Other forms of tobacco
effects of treatments used (20). use and recreational substance abuse are also im-
portant, but further information on their effects is
needed.
Infection

Both generalized infections, including episodic ill-

ness such as viral respiratory infections, diarrhea
and malaria (6), and more localized infections of the
genital and urinary systems (2, 15–17, 28) can affect
the gestational period. These infections are more
likely to occur in mothers in poor socioeconomic
conditions. Associations between chorioamnionitis,
where sources of infection gain access to the
extraplacental fetal membranes, and infection of the
amniotic fluid and preterm low birth weight are now
established (34). More specific examples of infection
and preterm low birth weight are presented in a
further section.
Toxic exposure
Cigarette smoking – more than 10 cigarettes per day
(32) and alcohol use – drinking more than 10 units
of alcohol per day are important risk factors for pre-
Antenatal care
It is very difficult to make any conclusions about the
effect of antenatal care. It has been shown that ante-
natal care can positively affect the birth outcome for
high-risk pregnancies. An important aspect is health
education: for example, attempts to modifiy behav-
iour with respect to known risk factors such as smok-
ing. Further work is required to determine the opti-
mal forms of antenatal care (20).
It is clear that the causes of preterm low birth
weight are complex and multifactorial, but there
may be common pathways in the mechanisms in-
volved. Infection is an important risk factor, and the
process of understanding how infections including
the periodontal diseases could be involved may be
facilitated by the examination of the putative mech-
anisms linking known risk factors to preterm low
birth weight.

145
Williams et al.
Mechanisms
Physiology of labor at term
Labor is characterized by coordinated uterine con-
tractions leading to cervical dilatation, and finally
expulsion of the fetus. Some mechanisms of partur-
ition at term are summarized in Fig. 3. In term (‘‘nor-
mal’’) labor, rupture of the membranes occurs after
initiation of contractions. The mechanisms involved
in the initiation of labor in women are not fully
understood (37), although prostaglandins appear to
play a crucial role, and prostaglandin E2 can be used
to induce human labor.
The earliest identified events in labor are increases
in the bioavailability of prostaglandin F2a, and in the
concentration of receptors for the hormone oxytocin
(10). The latter may be stimulated by increases in
prostanoid levels, possibly prostaglandin E2. The
obligatory precursor for prostanoid synthesis is free
arachidonic acid (37). The concentration of this fatty
acid increases in the amniotic fluid during spon-
Fig. 4. Simplified scheme of some of the putative mechanisms involved in preterm labor and premature rupture of the
membranes
146
taneous labor. It also induces abortion or labor when
injected into the amniotic fluid. Fetal membranes
contain phospholipid and a significant amount of
arachidonic is esterified on these phospholipids.
These membranes also contain phospholipase A2,
which can split arachidonic acid from the phospho-
lipids. It has been suggested that bacterial sources of
phospholipase A2 may be significant in the intiation
of premature labor (5).
Oxytocin is one of the most potent agents that
stimulates uterine contractions. As well as the in-
crease in oxytocin receptors during labor, the
stretching of the cervix and myometrium is thought
to initiate a neurogenic reflex to the neurohypoph-
esis of the pituitary gland, which acts as positive
feedback for oxytocin production (10). There is also
evidence for intrauterine oxytocin of decidual origin
(27).
It has been postulated that the estrogen:progester-
one ratio, which increases towards the end of preg-
nancy, results in the myometrium showing greater
contractility, for progesterone inhibits uterine con-

tractility during the course of pregnancy (34). Re-
laxin is a hormone known to be produced by the
ovaries. It is thought to be necessary for cervical
softening, which involves slow connective tissue re-
modeling. Its other action is the speedy inhibition of
myometrial activity (8).
Putative mechanisms involved in preterm labor
To aid the discussion of the possible mechanisms in-
volved with preterm labor, the five common clinical
findings associated with preterm labor have been
used as a starting-point for descriptions (22). These
are: The normal physiological processes happening
‘‘early’’; infection; inflammation; hemorrhage; pla-
cental ischemia and stress. The latter four are used
to illustrate the growing body of evidence (34) that
there are alternative methods of activating the
mechanisms that lead to the common pathways of
initiation of labor (Fig. 4). A very tentative attempt
to link clinical findings in preterm birth (22) and as-
sociated mechanisms with risk factor groups is
shown in Table 1.
Physiological birth occurring early
Multiple pregnancies are at an increased risk for
premature labor. One of the possible mechanisms
that may account for this is the increased stretching
of the myometrium and cervix, causing the ‘‘early’’
initiation of the normal physiological processes (Fig.
3).
Hemorrhage
Decidual hemorrhage can lead to fetal hypoxia,
which can lead to increased corticotropin-releasing
hormone, causing macrophage recruitment with In-
terleukin-8 and tumor necrosis factor-a release. Al-
ternatively, prostanoid production can be directly
stimulated via thrombin generation (22) (Fig. 4).
Table 1. Putative mechanisms in preterm birth and possible associations with risk factor groups
Genetic Demographic Obstetric Nutrition
Physiological ¿ ¿ ¿ ¿
Inflammation ¿ ¿
Hemorrhage ¿ ¿
Placental ischemia ¿ ¿
Stress ¿ ¿
Mechanisms of risk in preterm low-birth-weight infants
Placental ischemia
Local tissue damage can be caused by free radicals
and lipid peroxides. This promotes prostanoid pro-
duction (Fig. 4). Fetal stress can lead to cortico-
trophin-releasing hormone production (22).
Stress
The origin of stress can be maternal or fetal and can
result in the release of adrenal and hypothalamic
stress hormones. These are thought to promote the
release of corticotrophin-releasing factor, which can
increase prostanoid production (22).
Infection and inflammation
There is now evidence linking maternal infection
with preterm delivery (34). Vaginal colonization with
Bacteroides has been linked with a 60% increase in
the risk of preterm delivery (28). Genitourinary tract
infections have been associated with pregnancy
complications for many years. Interestingly, genito-
urinary tract infections have been shown to be as-
sociated with inflammation of the chorioamnion
without evidence of direct infection (18). Subclinical
infection has also been shown to be linked to pre-
term birth (15). The use of metronidazole and ery-
thromycin to treat women with bacterial vaginosis,
who were thought to have an increased risk for pre-
term delivery, has been shown to reduce the rates
of premature delivery (16). However, other work has
shown no reduction in preterm birth rate following
antibiotic usage, except in women with a history of
previous preterm birth (26). These conflicting data
have not been resolved, and a large randomized con-
trolled trial is being carried out to determine
whether antibiotics can improve neonatal outcome
in women presenting with preterm labor or preterm
premature rupture of the membranes. This trial is
ORACLE, the Medical Research Council Preterm
Maternal Antenatal
morbidity Infection Toxic care
¿ ¿ ¿
¿ ¿ ¿
¿ ¿
¿
¿ ¿ ¿ ¿ ¿
147
Williams et al.
Antibiotic Uncertainty Study, which is designed to
test the hypothesis that co-amoxyclav, erythromycin,
both or neither reduces death, chronic lung disease
or major cerebral abnormality before hospital dis-
charge and long-term disabilities in children of
women with definite or suspected spontaneous pre-
term labor or preterm premature rupture of the
membranes (7). Research into a pregnancy specific
disorder, pre-eclampsia, has shown that normal
pregnancy itself is associated with inflammatory
changes very similar to those found in sepsis: name-
ly increased tumor necrosis factor a and interleukin-
6 (36).
From the preceding sections, current understand-
ing of the biological events surrounding normal lab-
or and the putative mechanisms that link known risk
factors for preterm low birth weight to preterm labor
strongly suggest that prostaglandins and proin-
flammatory cytokines play a pivotal role in the initia-
tion process. Given the close relationship between
inflammation and infection it seems likely that alter-
ations to the levels of these inflammatory mediators
resulting from the normal host response to an infec-
tious agent may represent the key mechanism
through which infection is linked to preterm low
Fig. 5. Interactions between risk factors and low birthweight
148
birth weight. Thus increasing levels of maternally or
fetally derived cytokines such as tumor necrosis fac-
tor a may enhance amniochorionic and decidual in-
terleukin-6 expression (3), resulting in prostanoid
production. Alternatively, both polymorphonuclear
leukocytes and many gram-negative organisms pro-
duce the enzyme phospholipase A2, which hydro-
lyzes esterified arachidonic acid (5), the rate limiting
step in the synthesis of prostanoids. In either case, a
key issue which is unresolved but is highly pertinent
to the potential role of periodontal infection and
preterm low birth weight involves the site of action
of the infectious challenge and resulting inflamma-
tory response. Tumor necrosis factor a and interleu-
kin-6 have been shown to cross human fetal mem-
branes in an in vitro culture study (19). Although it
is difficult to extrapolate these results to the in vivo
situation, it is plausible that infections remote from
the genitourinary tract such as in periodontal dis-
ease could influence the fetal-placental unit. How-
ever an alternative mechanism could involve a more
direct challenge by periodontal bacteria and/or their
products. Spread to the amnion could be either
hematogenous via transient bacteremia or the bac-
teria could be introduced into the vagina by orogeni-

tal sexual practice, and then enter the amniotic fluid
via an ascending route. Some evidence for this more
direct mechanism comes from a recent study in
which bacteria were cultured from the amniotic fluid
of women with intact membranes. A high proportion
of fluids were positive for Fusobacterium nucleatum,
an oral gram-negative anaerobe frequently present
in periodontal infections but not normally prevalent
in the vaginal microflora (17).
The possibility that periodontal gram-negative in-
fections may be important with respect to preterm
birth has come from a study in which periodontal
disease was shown to be a significant risk for pre-
term birth (33). The condition of increased gingival
inflammation during pregnancy has been known for
many years. In fact, there have been suggestions that
it may be related to immunosuppression in the sec-
ond trimester (23). The infected periodontium can
also be regarded as a reservoir for both microbial
products and inflammatory mediators. Local prosta-
glandin E2 and both local and systemic tumor ne-
crosis factor a levels have been shown to be in-
creased in periodontitis (30). Furthermore, animal
experiments in which pregnant hamsters were chal-
lenged with Porphyromonas gingivalis, a gram-nega-
tive bacterium frequently associated with peri-
odontitis, have shown significant association be-
tween increasing levels of both prostaglandin E2 and
tumor necrosis factor a and fetal growth retardation.
Such findings could suggest that infection with P.
gingivalis may affect human pregnancy outcome
(11).
Summary
The periodontal diseases share many common risk
factors with preterm low birth weight. Examples are,
age, socioeconomic status and smoking (Fig. 5).
Studies to date have only shown an association be-
tween the two conditions, and this does not indicate
a causal relationship. However, since the inflamma-
tory mediators that occur in the periodontal dis-
eases, also play an important part in the initiation of
labor, there are plausible biological mechanisms that
could link the two conditions. The challenge for the
future is to characterize the nature of the factors that
predispose a mother to give birth prematurely to in-
fants less than 2500 g and to assign relative probabil-
ities to each. Studies are taking place in many parts
of the world to determine the probability of a pre-
term low-birth-weight outcome, the interdepen-
dence of the factors that contribute to a birth event
Mechanisms of risk in preterm low-birth-weight infants
and possible casual relationships between these fac-
tors. Further information about the details of the ef-
fects of maternal infection will come from inter-
vention studies, animal studies and more detailed
examination of the mechanisms.
Acknowledgment
We acknowledge the assistance given by Professor T.
Chard.
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