Chapter 3
Foeto-neonate development: a life course
perspective
3.1 Introduction
The previous chapter, Chapter 2, indicated a trend from exogenous infant mortality to
endogenous infant mortality during the epidemiologic transition. This implies that ‘intrinsic’
factors such as genetic make-up and the circumstances during prenatal life and birth gain a
greater importance as causes of death. Moreover, recent studies suggest that adult disease in
later life may have foetal origins. For instance, growth retardation in utero and low weight at
birth have been associated with increased risks of hypertension, coronary heart disease, and
non-insulin-dependent diabetes later in life (Barker 1994; Godfrey and Barker 2000).
Circumstances, risk factors, and processes during prenatal life, birth, and the neonatal period
are thus becoming increasingly important predictors of morbidity and mortality patterns in
populations. Despite this, within demography and population forecasting, the period before
birth is usually ignored. The present study adopts a foeto-infant approach, or rather foetoneonate approach, that integrates the foetal period and the neonatal period. In this, the
neonatal period is considered to be part of the same, continuing developmental process as
gestation. Such a perspective is also advanced in the new paradigm in the social and
behavioural sciences: the life course perspective.
The life course perspective is briefly discussed in Section 3.2 and provides the
theoretical background for the study. One of the elements in this perspective is a shift of focus
from statistical associations between variables to underlying causal processes and
mechanisms. Knowledge about these processes is fundamental if one wants to understand and
predict events, and if one wants to intervene and change outcomes. However, traditionally,
demographers have focused on statistical associations and on ‘explanations’ based on
demographic and socioeconomic variables. For example, the demographers Carlson, Hoem,
and Rychtarikova (1999) in their study on the risks and patterns of foetal loss analysed
differences between social categories defined by maternal age, parity, marital status,
educational level, and labour force attachment. However, these variables fail to explain foetal
loss. In addition, the precise nature of the relationship between a variable and the outcome
remains unclear. The recent paradigm shift in demography to the life course perspective is
changing this traditional perspective.
In epidemiology, the life course approach to health relates health outcomes not only to
experiences during earlier stages of life, but also to experiences of previous generations. In
line with this idea of intergenerational transmission of health, Section 3.2 also describes a
model that integrates a child’s survival career with the reproductive health career of its
EARLY LIFE CHANGES
mother. Subsequently, the section discusses conceptual issues related to the developmental
processes during prenatal life, birth, and the neonatal period; and is concluded with a brief
discussion of conceptual models of pregnancy and gestation that represent human
development.
The chapter continues in Section 3.3 with the construction of a conceptual model that
helps to answer the research questions posed in Chapter 1. This model integrates various ideas
and elements from the theoretical background in Section 3.2 and introduces order and
sequence into the list of causal factors. The life periods of interest here are gestation, birth,
and the neonatal period. In the model, adverse pregnancy and birth outcomes are regarded
both as intermediate outcomes that summarise the preceding processes of gestation/pregnancy
and birth, and also as risk or causal factors of foetal loss and neonatal death. Being part of the
causal chain, the intermediate outcomes themselves are also affected by risk factors. In
Section 3.3, the following adverse pregnancy and birth outcomes are selected for the study:
congenital anomalies, low birth weight, preterm birth, intrauterine growth retardation, and
birth asphyxia. Finally, Section 3.4 provides a detailed description of these variables.
Additional risk factors are included only later in the study (see Chapter 9).
3.2 Theoretical background
This section provides the theoretical background for the study. In turn, it discusses the life
course perspective, an integrated model of a child’s survival career and its mother’s
reproductive health career, conceptual issues of foetal and neonatal development, and models
of pregnancy and gestation.
3.2.1 LIFE COURSE PERSPECTIVE
In recent years, paradigm shifts have occurred in most of the behavioural and social sciences,
including demography. One important development is the emergence of the life course
paradigm (Giele and Elder 1998; Dykstra and Van Wissen 1999; Willekens 1999, 2001; BenShlomo and Kuh 2002). The life course perspective examines the ordering, sequencing, and
timing of events and transitions in the life course and considers how the individual life course
is embedded in the social, cultural, biological, and historical context. According to Willekens
(1999, 2001), the emergence of the life course paradigm signals four broad changes in
thinking: from structure to process, from macro to micro, from analysis to synthesis, and from
certainty to uncertainty (i.e. from a deterministic to a probabilistic approach). Some of the
newly evolving perspectives that are thought to be relevant for the present study are briefly
discussed below.
Probabilistic events as outcomes of processes
Life events are the outcomes of processes, or event processes (Willekens 1999, 2001).
Similarly, structure may be regarded as the outcome of interacting processes. Over the years,
the focus of attention has shifted from structures to processes. However, most available
information is on structure and events, while underlying processes are generally difficult to
observe. Empirical observations may be viewed as manifestations of underlying processes,
42
CHAPTER 3: FOETO-NEONATE DEVELOPMENT
but a clear distinction needs to be made between the underlying processes and the
observations as manifestations of these underlying processes. To interpret and understand
events, the underlying causal processes must be uncovered (Willekens 2001, p.195).
However, the outcomes of event processes (i.e. occurrences and timing of life events) cannot
be predicted with certainty. Consequently, events are probabilistic and the processes are
random in nature (Willekens 1999, 2001). In the present study, the processes of interest are
those that lead to ‘natural’ loss and death during gestation, birth, or the neonatal period.
A micro-approach to uncovering underlying causal processes
Traditionally, the emphasis in demography is on macro-level description and statistics
(Dykstra and Van Wissen 1999). The dominant method of explanation is statistical
association and differences in individual behaviour are ‘explained’ by differences in certain
characteristics, mainly socioeconomic variables (Coleman 1990; Willekens 1992). How these
factors exactly affect behaviour, i.e. the causal mechanisms or processes underlying the
observed statistical associations and relationships between variables, remains largely
unknown. Yet, to be able to make any valid population forecast for the future, some
understanding of the causal processes is necessary. Willekens (1992) writes: “the ultimate
goal of forecasting-oriented demographic research should be a demographic forecasting
rooted in an understanding of the causal processes at work” (p.258). Knowledge about these
processes is fundamental if one wants to understand and predict events (also at the population
level) and if one wants to intervene and change the outcomes. As a result, a shift from macroresearch to micro approaches is thought to be essential (Willekens 1990, 1992, 1999, 2001).
Micro-approaches focus on lower-level building blocks than macro-level research. The
shift from the macro-level to the micro-level is essentially a shift from the population level to
the individual level. Phenomena at the systems level are believed to emerge from actions and
changes at the lower, individual level (Coleman 1990; Willekens 1999, 2001). This mode of
explanation is known as methodological individualism. For demography and population
studies, this perspective sees that populations change because people change and that
population dynamics should be viewed as the composite effect of individual life courses. The
trend from macro to micro is not only observed in demography, but also in other scientific
disciplines.
Process-context approach
The theoretical approach adopted by the Population Research Centre (PRC) of the University
of Groningen falls within the life course perspective. The approach is a process-context
approach and has been expounded in detail by Willekens (1990, 1992) and De Bruijn (1992,
1993, 1999). The framework relates to earlier and more recent studies in various disciplines
by researchers including McNicoll (1985, 1989, 1994), Greenhalgh (1989, 1994, 1995),
Denzau and North (1994), and D’Andrade and Strauss (1992). The process-context approach
lies at the heart of the HERA research programme. As a result, it has been the foundation of
several research projects including ones on contraceptive and abortion behaviour in Chile
(Den Draak 1998), reproductive health and child spacing behaviour in rural South India
(Hutter 1998a; Rajeswari and Hutter 1999; Hutter et al. 1999), and child survival and
43
EARLY LIFE CHANGES
reproductive health of mother in Kerala (Padmadas 2000). The description of the processcontext approach in the present subsection is based on Hutter (1998a, 1998b) and Hutter and
Willekens (1998).
The process-context approach is a micro-approach that views behaviour and status at a
given moment as the outcome of a set of interdependent processes that involve a series of
events, situations, experiences, decisions, and actions taking place within a context. This
context covers a social, economic, cultural, legal, political, ecological, and technological
context while three types of processes are distinguished: biological, behavioural, and
sociocultural. Moreover, present behaviour and status are not only determined by
contemporary factors but also by conditions, events, and behaviour in the past. All processes
and outcomes are viewed from a dynamic perspective: in a life course perspective, across an
individual’s life course as part of a particular career, and also in a historical context (time),
across generations.
In earlier research projects that were based on the process-context approach, the focus
was mainly on behaviour as the outcome of a behavioural process. However, in the present
study, the focus is on health and survival, while the process of interest is primarily biological
in nature.
Life course approach to health and epidemiology
The life course perspective has not only been adopted in demography, but the paradigm shift
has also occurred in other disciplines, such as sociology (Elder 1999), psychology (Elder and
Kirkpatrick Johnson 2000), and epidemiology and public health (Barker 1994; Kuh and BenShlomo 1997; WHO 2000; Ben-Shlomo and Kuh 2002; Kuh and Hardy 2002). Similarly, in
epidemiology, conventional models focused on statistical associations with little or no
attention to the underlying biological mechanisms or the wider social context. The
development of a life course approach to health is related to discontent with conventional risk
factor epidemiology, also called the black box paradigm (see Susser and Susser 1996). The
life course approach to health “emphasises a temporal and social perspective, looking back
across an individual’s or a cohort’s life experiences or across generations for clues to current
patterns of health and disease, whilst recognising that both past and present experiences are
shaped by the wider social, economic and cultural context” (WHO 2000, p.4). Thus, though
the nature of the processes may be different, there is a clear link with the process-context
approach in demography.
Life course epidemiology studies the long-term effects of physical and social
exposures during different stages of life (e.g. gestation, childhood, adolescence, young
adulthood, and later adult life) on chronic disease risk and health outcomes in later life (WHO
2000; Ben-Shlomo and Kuh 2002). So far, life course epidemiology has mainly focused on
disease in adult life (Hall et al. 2002). The range of early life factors associated with disease in
later adult life is diverse and includes characteristics of the family of origin (e.g. family size,
social class), maternal characteristics before and during pregnancy (e.g. height, weight, blood
pressure, anaemia), and foetal and infant body size (e.g. low birth weight relative to placental
size, small size at birth with failure of infant growth) (Kuh and Ben-Shlomo 1997). Life
course epidemiology takes into account “the temporal ordering of exposure variables and their
44
CHAPTER 3: FOETO-NEONATE DEVELOPMENT
inter-relationships, both directly or through intermediary variables, with the outcome
measure” (Ben-Shlomo and Kuh 2002, p.285).
Ben-Shlomo and Kuh (2002; WHO 2000) have provided an overview of conceptual
life course models that do not preclude each other. Basically, two types of mechanisms are
recognised: firstly, accumulation of risk and, secondly, biological programming or the critical
period model. According to the critical period model, exposure during certain critical periods
in life results in lasting effects on body structure and development, and subsequent disease
outcome. This notion of biological programming is the basis of the ‘foetal origins of adult
disease’ hypothesis that was proposed by Barker (1994). The proposition is that inadequate
nutrition in utero (before birth) and during infancy, and infections during early childhood
increase the risk of hypertension, cardiovascular disease, diabetes, and respiratory disease in
later life. In other words, experiences during the foetal and perinatal period are of major
importance as a formative stage. However, factors that increase or protect against disease risk
may also accumulate gradually over the life course. These factors could be independent and
uncorrelated, but they might also cluster together in socially patterned ways or form chains of
risk. The links between the factors are probabilistic rather than deterministic.
3.2.2 INTEGRATED
MODEL OF A MOTHER’S REPRODUCTIVE AND A CHILD’S
SURVIVAL CAREER
As part of the process-context approach, Hutter (1998a, 1998b) and Padmadas (2000)
developed a model of reproductive health that incorporates the child’s survival career next to
the mother’s reproductive career and her health career. A central element in this model is the
link between health and survival of the child and the reproductive health of the mother. As in
the life course approach to health (see Section 3.2.1), this model thus looks back across
generations and considers the intergenerational transmission of health.
The model is based on two well-known models used by demographers: the fertility
model of Bongaarts and Potter (1983) and the model on child survival by Mosley and Chen
(1984), which has been elaborated by Van Norren and Van Vianen (1986). An important
notion in the fertility model is the idea of proximate determinants that have a direct effect on
the outcome of interest. Bongaarts and Potter (1983) distinguish between variables that affect
fertility directly (the proximate determinants) and factors that affect fertility indirectly. The
proximate determinants of fertility, or intermediate fertility variables, are “the biological and
behavioural factors through which social, economic, and environmental variables affect
fertility” (1983, p.1), or:
Social, economic,
environmental
factors
Î
Proximate
determinants
Î
Fertility
Similarly, Mosley and Chen (1984) identify proximate determinants or intermediate variables
that directly affect child survival. All social and economic factors operate through these
determinants.
45
EARLY LIFE CHANGES
The integrated model of the mother’s reproductive career and the child’s survival
career combines these models. Moreover, it introduces some additional components and
factors, including supplementary maternal factors (e.g. prepregnant nutritional status and
morbidity during pregnancy) and a time component. The reproductive career of the mother is
subdivided into three different time periods: pre-pregnancy, pregnancy, and post-pregnancy.
In addition, various stages are discerned in the survival career of the child, including the
perinatal period, the neonatal period, infancy, and childhood. The model provides a
framework “to study the underlying processes associated with various events, states and
stages at different points of time in the life course (reproductive career) of women and their
influence on the survival career of children” (Padmadas 2000, p.55). It identifies a set of
intermediate variables or proximate determinants that directly influence the survival chances
of children at the various stages of early life. The contextual variables (e.g. socioeconomic,
cultural, and environmental factors) operate through these proximate determinants and affect
child survival indirectly. Figure 3.1 summarises the model.
3.2.3 FOETAL AND NEONATAL DEVELOPMENT
The integrated model of the child’s survival career clearly indicates that the processes of
human development and survival already begin before birth. Prenatal, natal, and postnatal
development, survival, and health are to be considered as part of the same underlying process,
i.e. the foeto-infant approach. This idea or approach is further strengthened by developments
observed during the epidemiologic transition. The epidemiologic transition involves a shift
from exogenous infant mortality to endogenous infant mortality. In other words, the causes of
infant death that gain prominence during the transition are those causes that are the result of
genetic make-up and/or of the circumstances during prenatal life and birth.
The following subsections very briefly discuss the underlying processes of human
development and the conceptual issues related to them. The information is largely derived
from Cunningham et al. (1993) and Van der Veen (2001). Other major sources that were
consulted are Hook and Porter (1980), Kline et al. (1989), Kliegman (1990), WHO (1993),
and Kliegman (1996).
The process of prenatal development and its dating
Obstetricians, other clinicians, and epidemiologists usually express the duration of pregnancy
or gestation as gestational age. Gestational age is measured from the first day of the last
menstrual period (LMP) which occurs about two full weeks before ovulation and fertilisation.
The age is expressed in completed days or completed weeks and to avoid confusion, it should
be noted that the first day is day zero and not day one. As a result, days 0-6 correspond to
completed week zero while the 40th week of gestation is synonymous with completed week 39
(WHO 1993). The ‘normal’ gestational period is on average 280 days, or 40 weeks, from
LMP to the birth of the child. Embryologists and other reproductive biologists, however, base
their expression of age on the time of ovulation (ovulatory/ovulation age) or conception
(postconception or fertilisation age), but these are nearly identical. Conception is about two
weeks later than LMP and in these terms the normal gestation period lasts 267 days.
46
Source: Hutter 1998a
Figure 3.1: Integrated model of mother’s reproductive career and child’s survival career
EARLY LIFE CHANGES
Throughout this book antenatal age is expressed as gestational age based on LMP unless
indicated otherwise.
It is customary to divide gestation or pregnancy into three periods each of three
calendar periods, i.e. three trimesters. The accepted duration of the trimesters is obtained by
dividing 42 weeks into three periods of 14 weeks each. The first trimester is through to the
completion of 14 weeks, the second through to 28 weeks, and the third trimester includes the
29th through to the 42nd week of pregnancy. Each of these trimesters may cluster its own
specific type of complications though the division in trimesters is somewhat crude.
It is worth noting that the time periods and the indications of age above refer to
chronological time and chronological age. A developmental process may also be described on
the basis of developmental periods and developmental age. Developmental age reflects an
observed stage of development, whether somatic, neurologic, physiologic, or behavioural
(Kline et al. 1989, p.187). Some subdivisions of prenatal life are based on developmental
stages, such as the Carnegie embryonic staging system that distinguishes 23 stages of
embryonic development.
In teratology, the study of abnormal development and congenital anomalies, gestation
is divided into three stages or periods: (1) the ovum, from fertilisation through implantation,
(2) the embryonic period, and (3) the foetal period (Cunningham et al. 1993). In the first two
weeks following ovulation, the successive phases of development are fertilisation, cell
division and formation of what is called the blastocyst, and implantation. During fertilisation,
a sperm cell and ovum (oocyte or ‘egg’) are fused into a fertilised ovum or zygote. In itself,
the formation of the zygote can be regarded as the outcome of a process or chain of events,
which includes gametogenesis (i.e. the formation of sperm cells and oocytes), ovulation,
timed sexual intercourse, and fertilisation. Fertilisation is followed by cleavage or cell
division while the zygote moves down the fallopian tube towards the uterine cavity. Within 6
to 9 days of fertilisation, the blastocyst attaches to the uterine wall and implants itself.
Occasionally, the blastocyst implants outside the uterus – usually in the fallopian tubes –
resulting in an ectopic or extrauterine pregnancy (Wilcox 1991). Ectopic pregnancy is
incompatible with prolonged foetal survival and is a relatively important cause of maternal
mortality (Cunningham et al. 1993; Van der Veen 2001).
The embryonic period starts at the beginning of the third week after fertilisation and
lasts through to the end of the eighth week. The term embryo refers to the developing human
form during the early stages of gestation following implantation and the formation of the
amniotic cavity. The term conceptus is used to refer to all tissue products of conception or
fertilisation, including the embryo (foetus), foetal membranes, and the placenta. The
embryonic period is characterised by organogenesis, or the formation of organs, and is the
most critical period regarding the development of malformations. Organ systems such as the
heart, the circulatory system, the nervous system, the bronchial tubes, and the gastrointestinal
tract are formed and/or an important foundation is laid for them (Moore 1986).
Finally, the foetal period commences 8 completed weeks after fertilisation, or 10
weeks after the onset of the last menstrual period, and lasts until term. In this period, the
beginnings of all essential structures are present. The foetal period is characterised by further
growth, development, and maturation. For reasons of convenience, the book will refer to the
48
CHAPTER 3: FOETO-NEONATE DEVELOPMENT
prenatal child as a foetus, irrespective of its gestational stage (ovum, embryonic, foetal) it is
in. In addition, the term ‘conceptus’ will be used more generally to refer to all products of
conception.
Birth, the newborn, and the neonatal period
The mechanism(s) that initiates spontaneous human parturition and consequently results in
the delivery of the foetus, either at term or preterm, is not known. The term parturition
encompasses all physiological processes involved in birthing and includes the processes of
expulsion of the foetus and placenta from the mother’s reproductive tract. Labour, on the
other hand, refers specifically to the sequence of uterine contractions that cause dilatation of
the cervix, expulsion or delivery of the foetus, and finally, expulsion of the placenta and foetal
membranes. Both parturition and labour are divided into several phases, but it is beyond the
scope of this book to discuss these stages. For more information, please refer to one of the
numerous reference books on obstetrics, such as Williams Obstetrics by Cunningham et al.
(1993).
The World Health Organization defines live birth as “the complete expulsion or
extraction from its mother of a product of conception, irrespective of the duration of the
pregnancy, which, after such separation, breathes or shows any other evidence of life (…)
whether or not the umbilical cord has been cut or the placenta is attached” (WHO 1993,
p.129). The product of such a birth is considered liveborn. However, it should be noted that
the term ‘live birth’ involves no implications about the health status of the newborn. The
infant may be in perfect health but may also be in a very poor state and subsequently decease
within a couple of minutes of birth. A relatively rapid and simple examination to assess the
condition of a newborn is provided by the Apgar score (Apgar 1953; Apgar et al. 1958). The
Apgar score is a tool used to identify infants that require resuscitation after birth. The scoring
system is based on physiologic responses to the birth process and comprises five components:
heart rate, respiratory effort, muscle tone, reflex irritability, and colour of body (see Table
3.1). For each of these components, the child is awarded a score of 0, 1, or 2 and these scores
are subsequently summed. The higher the score, up to the maximum of 10, the better the
condition of the newborn. The Apgar score is ordinarily assessed at one minute and five
minutes after birth, though sometimes score may also be considered at 10, 15, and 20 minutes.
Table 3.1: Apgar scoring system
Score
Sign
0
1
2
Heart rate
Respiratory effort
Muscle tone
Reflex irritability
Colour
Absent
Absent
Flaccid
No response
Blue, pale
< 100/min.
Slow, irregular
Some flexion of extremities
Grimace
Body pink, extremities blue
> 100/min.
Good, crying
Active motion
Vigorous cry
Completely pink
Source: Cunningham et al. 1993
49
EARLY LIFE CHANGES
Immediately after birth, the neonatal period commences and the foetus is labelled a
neonate. The neonatal period is an extremely vulnerable stage for the infant as the transition
from intrauterine to extrauterine requires many physiological and biochemical changes. The
body functions of the child are no longer supported by its mother and the placenta, and the
infant needs to make the shift to self-sufficient functioning, including air breathing. Many
specific problems of the newborn are related to poor adaptation due to asphyxia, preterm
birth, congenital anomalies, or adverse effects of delivery (Kliegman 1996, p.433).
Lethal outcomes: loss and death
The continuous developmental process from conception or fertilisation through the neonatal
period may result in a lethal outcome, either before, during or after birth. Various terms have
been applied to denote prenatal lethal outcome, including reproductive loss, pregnancy loss,
intracorporeal death, and miscarriage.
Spontaneous loss of pregnancy may occur at any time after fertilisation. The term
‘spontaneous’ suggests that there also exists non-natural, artificial, or induced losses. While
spontaneous loss can be considered a part of the universal biological processes, induced
abortion involves behavioural and decision processes with social, cultural, and economic
dimensions. Frequency and timing of induced abortion are strongly affected by factors such as
sexual behaviour, contraceptive use, and legislation (Van der Veen 2001). The use of selective
abortion, however, is also based on foreknowledge about certain attributes of the foetus/child.
These attributes are biological and may include sex, chromosomal constitution, and presence
of anomalies. Techniques of prenatal diagnosis include chorionic villus sampling,
amniocentesis, and comprehensive ultrasonography. The tests may diagnose chromosomal
aberrations, neural tube defects, heart and other anomalies, although each diagnostic test has
its own limitations (Cunningham et al. 1993; brochure by Groningen University Hospital
2001). These techniques cannot be performed until the end of the first trimester or the
beginning of the second trimester and therefore, selective abortion is unlikely to take place
very early in pregnancy. Only recently have new first-trimester screening techniques become
available.
The term intrauterine death has been said to be somewhat inadequate since, strictly
speaking, it excludes loss occurring before implantation as well as loss due to ectopic
pregnancy. The WHO promotes the use of the term foetal death to refer to “death prior to the
complete expulsion or extraction from its mother of a product of conception, irrespective of
the duration of the pregnancy; the death is indicated by the fact that after such separation the
foetus does not breathe or show any other evidence of life” (1993, p.129). Nevertheless, some
authors prefer to make a distinction between foetal death and embryonic death/loss. For
convenience, and following the WHO guidelines, this book will use the terms ‘foetal death’
and ‘foetal loss’ to include embryonic loss/death.
Foetal death (including embryonic loss) is subdivided on the basis of gestational age
into spontaneous abortion and late foetal death or stillbirth. However, the defining gestational
age is arbitrary and the limits that are applied show considerable variation. Moreover,
definitions have varied over time as viability was reached at younger gestational ages.
According to WHO criteria, national statistics on late foetal and perinatal deaths should
50
CHAPTER 3: FOETO-NEONATE DEVELOPMENT
include all foetuses weighing at least 500 grams at birth. When data on birth weight is not
available, the corresponding criteria are a gestational age of 22 completed weeks or a crownheel length of 25 centimetres. However, statistics for international comparison should be
restricted to those weighing at least 1,000 grams or, when information on birth weight is
unavailable, to the corresponding gestational age of 28 completed weeks or crown-heel length
of 35 centimetres (WHO 1993). In practice, the criteria that are applied vary from country to
country and sometimes even within countries. In 1996, gestational age limits for the
registration of late foetal deaths or stillbirths varied in Europe from 16 weeks in Norway, 22
weeks in Finland, 24 weeks in the UK and the Netherlands, 180 days in Spain, to 28 weeks in
several other countries including Sweden (Richardus et al. 1998). Clearly, this poses serious
complications in trying to make international comparisons of statistics.
As can be seen from the above, stillbirth does not necessarily take place during the
birth process. In fact, the term stillbirth can refer to late foetal death that occurs before the
initiation of labour. However, the timing of death in relation to labour – i.e. prior to or during
labour – may be an important indicator of the causes and risk factors that contributed to the
loss. Therefore, a distinction is frequently made between antepartum and intrapartum
stillbirths. Deadborn foetuses classified as antepartum stillbirths may have been retained in
utero for quite a considerable time after death before the actual expulsion or birth. This
phenomenon is not only observed among stillbirths but, more generally, among all types of
foetal loss/death, including abortion. In these missed abortions, the dead foetus is retained in
utero and the gestational age at actual loss or death may be very different from the gestational
age at expulsion. For example, foetuses aborting at 10-12 weeks have usually died weeks
earlier (Simpson and Carson 1993). In a study by Boué and Boué (1974 cited by Van der
Veen 2001), the period of intrauterine retention of abortuses amounted to more than 6 weeks.
Some authors, therefore, prefer to developmental age rather than gestational age. The process
of disintegration of a dead foetus retained in utero is called maceration.
The death of a newborn child during the neonatal period is called a neonatal death.
The neonatal period begins at birth and ends 28 completed days after birth, i.e. at the end of
day 27. If the neonatal death occurs within the first seven days of life, i.e. the early neonatal
period (days 0-6), it is referred to as an early neonatal death. The term perinatal mortality
denotes all late foetal deaths (stillbirths) plus early neonatal deaths. Depending on the
gestational age limit applied, the perinatal period commences at 22-28 completed weeks of
gestation. This variation in definitions makes it difficult to compare international figures on
perinatal mortality. Richardus et al. (1998) found that perinatal mortality rate can vary by as
much as 50% depending on its definition. The present study does not analyse perinatal
mortality but, instead, looks at its components (stillbirth and early neonatal death) as well as
foetal loss, neonatal death, and live birth. Reporting all perinatal deaths together is believed to
conceal important distinctions between the components (Kalter 1991). For a brief discussion
of the causes and risk factors for foetal loss (including stillbirth) and neonatal death, please
refer to Section 3.3.3.
51
EARLY LIFE CHANGES
3.2.4 MODELS OF PREGNANCY AND GESTATION
The complicated processes involved in human development and survival may be represented
in a simplified manner by abstractions. In his book on the small epidemiologic transition, Van
der Veen (2001) presented models, or ‘space-time constructs’, that represent various aspects
or dimensions of the process from conception to birth. The representations are a model of
pregnancy (which emphasises and characterises the interactions between the foetus and the
mother), a model of gestation (which emphasises and characterises the developmental process
evolving within the foetus), and an integration of the two models.
Van der Veen (2001) uses the term pregnancy for “a state of being, characterised by
the mother carrying a foetus” (p.51). Pregnancy is represented by a systems model which
describes a stable structure that is based on several elements or entities, and the relationships
or interaction between these entities. The model identifies three basic entities: the mother, the
foetus, and the placenta. The placenta is the organ that is responsible for the transfer of
oxygen and nutrients from mother to foetus and, conversely, the transfer of carbon dioxide
and other metabolic wastes from foetus to mother. The placenta is a foeto-maternal organ
since it is produced by both the foetus and the mother. The foetus is attached to the placenta
by the umbilical cord and surrounded by amniotic fluid within the amniotic sac (Van der Veen
2001). Interaction between the mother and the foetus is largely accomplished through the
placenta, although some foetal-maternal communication is established by more direct cell-tocell contact and biomolecular transfer between the foetal membranes and the maternal,
mucosal lining of the uterine wall (Cunningham et al. 1993). Figure 3.2 depicts the various
entities and interactions within the ‘system of pregnancy’. Entities outside the system, i.e.
outside the maternal body, are referred to as the environment. Interaction between the
environment and the foetus is mostly indirect.
Figure 3.2 A systems model of pregnancy
Source: Van der Veen 2001, adapted from Dancis and Schneider 1986
52
CHAPTER 3: FOETO-NEONATE DEVELOPMENT
Table 3.2: A process model of gestation
Stage
Days from
ovulation
Days from
LMP
Characteristic
Zygote
Morula
Blastocyst
Implantation
Embryo
Foetus
Viable infant
Term and newborn infant
0
1-2
3-6
6-7
7-48
49-181
154+
245+
14
15-16
17-20
20-21
21-62
63-195
168+
259+
Celldivision
Differentiation
Differentiation
Interaction
Organogenesis
Growth and maturation
Growth and maturation
Adaptation
Source: Van der Veen (2001) who adapted it from Kline et al. (1989) and Moore and
Persaud (1998)
The term gestation is used to denote “the developmental process evolving within the
embryo and foetus” (Van der Veen 2001, p.52). A model of gestation thus represents the
schedule of foetal development including the processes of organogenesis and physical growth.
The developmental process from zygote to full-term foetus may be divided into stages of
variable length, as shown in Table 3.2. These stages were also discussed in Section 3.2.3.
Figure 3.3: Gestation as a process of interaction
Source: Van der Veen 2001, adapted from Perry 1997
53
EARLY LIFE CHANGES
The systems model (of pregnancy) and the process model (of gestation) are
complementary. An integration of the two models would involve the components or entities
from the first model plus the process dimension from the latter. Figure 3.3, which Van der
Veen (2001) adapted from Perry (1997), provides such an integrated model. The figure
depicts gestation as a process of interaction. The integrated model represents the foetus and its
environment, the interaction between the foetus and its environment, the positioning of the
various entities and interaction in process time, and the outcomes that arise from this causal
complex. The model highlights the importance of considering interaction and change as two
largely inseparable dimensions of the same process.
3.3 Conceptual model
The general aim of the present study is to gain insights into the demographic consequences of
causal factors and mechanisms that predict and lead to ‘natural’ loss and death during
gestation, birth, and the neonatal period (see Chapter 1). The outcome of interest is thus the
survival status (survival vs. loss/death) of the foetus and neonate between conception and the
end of the neonatal period. As a first step, it is necessary to construct a conceptual model that
identifies the various processes and factors involved, and the relationships and interactions
between them. The model will be based on theoretical assumptions and empirical
observations discussed in the existing literature. Subsequently, the conceptual model will
serve as an important tool, or guideline, in the selection of variables to be included in the
study (see Srinivasan 1988). Following the objectives of the present study given in Chapter 1,
and the framework or perspective outlined in Section 3.2, the desired conceptual model for
the study of foetal loss and neonatal death should:
• focus on causal mechanisms rather than statistical associations,
• make a distinction between processes and outcomes,
• place the subject of interest, the processes, and the outcomes in a context, and
• include the temporal ordering of factors, processes, and outcomes.
The sections below set out the structure of the conceptual model, specify the factors in the
model, and select the variables that will be included in the study. First, however, Section 3.3.1
discusses some relevant concepts of causation.
3.3.1 CONCEPTS OF CAUSATION
Webster’s Ninth New Collegiate Dictionary (1985) defines a cause as “something that brings
about an effect or a result”. However, in most situations it is inappropriate to speak about the
cause of an event (Wulff et al. 1990): there is always a variety of factors that act together.
Moreover, choices made in selecting a certain factor (or factors) as the cause reflect the
interests of the person who made the choice. In addition, Wulff et al. (1990) note that usually
only the causes of undesirable events are discussed, e.g. the cause of death rather than of
survival.
To portray the complexity of causal processes, epidemiologists use the so-called web
of causation (Rockett 1994; Fletcher et al. 1996), which is basically a multifactorial model of
disease causation. The causal complex indicates various pathways that may lead to the
54
CHAPTER 3: FOETO-NEONATE DEVELOPMENT
outcome under study. Other terms that have been applied in this respect, and that refer to
processes, include causal sequence, causal mechanism, and causal chain. In the case of
neonatal morbidity, such a causal sequence “may commence with a prenatal factor (infection)
and involve a perinatal consequence (preterm birth) that results in a final postnatal insult
(neonatal intraventricular haemorrhage)” (Stanley 1997, p.98). The factors in the causal
complex may be non-redundant (i.e. indispensable) or redundant (Wulff et al. 1990). They
may also be proximate or remote to the outcome (Fletcher et al. 1996; Young 1998).
Biomedical scientists usually search for the underlying pathogenic mechanism or the final
common pathway of disease. However, the occurrence of disease is also determined by more
remote causes or risk factors, such as behaviour and characteristics of the environment.
Fletcher et al. (1996) observe that these remote factors may be even more important causes of
disease than pathogenic pathways. The authors offer the spread of HIV/AIDS due to sexual
behaviours and drug use as an example.
Research in public health and epidemiology frequently focuses on what are called the
risk factors for disease or adverse health status. However, the term has various, sometimes
conflicting, definitions. There appears to be a divergence between Anglo-Saxon and Dutch
literature regarding the causal status of risk factors. In the Anglo-Saxon literature, a risk factor
is statistically associated with an increased risk of disease although not necessarily causally
related to the outcome (see Hogue et al. 1991; Rockett 1994; Stedman’s Medical Dictionary
1995; Fletcher et al. 1996). Fletcher et al. (1996) take the relationship between maternal
education and low birth weight as an example of a non-causal, confounded relationship
between a risk factor and an outcome. Although a lack of maternal education is associated
with low birth weight, other factors related to education such as poor nutrition, limited
prenatal care, and cigarette smoking are more directly the causes of reduced weight at birth.
The educational level is a confounding factor. In Dutch literature, a risk factor is stated to
have a causal relationship with the disease or health outcome (see Gunning-Schepers 1995;
Hofman et al. 1996). Determinants of disease that have no causal relationship with the
outcome are labelled risk indicators by these Dutch authors. Perhaps Kleinbaum et al. (1982)
resolved the matter satisfactorily by claiming that “a risk factor is any variable that the
investigator determines to be ‘causally related’ (though not necessarily a ‘direct’ cause) and
antecedent to illness outcome status (i.e. to the disease) on the basis of substantive knowledge
or theory and/or on previous research findings” (p.255).
3.3.2 STRUCTURING THE MODEL
The conceptual model makes reference to the three basic elements: process, outcome, and
context (cf. the life course perspective and the process-context approach in Section 3.2.1).
Processes result in outcomes while both process and outcome are set in and interact with a
context. In the present study, the process of interest (health and survival) is primarily
biological in nature. The process may be divided into three subprocesses:
gestation/pregnancy, birth, and neonatal development. Each of these processes refers to the
development, growth, maturation, and health of the child as well as to its physical adaptation
55
EARLY LIFE CHANGES
to the environment (context). They are part of the continuing, underlying process of health
and survival.
Outcomes in the conceptual model may be regarded as a summary of the subprocesses
that precede it. In addition, each outcome functions as an ‘input’ for the subsequent process.
However, in those instances where death is the outcome, this could be considered as the final
or end outcome. On the other hand, the health status at live birth represents an intermediate
outcome. An intermediate outcome is an outcome of a process that continues afterwards while
a final outcome denotes the end of the underlying process(es) of interest. In terms of the
processes of interest in the present study, intermediate outcomes other than status at birth –
e.g. status immediately after implantation, status at the end of the first trimester, status just
prior to birth and labour – as well as the underlying processes themselves are difficult to
observe since pregnancy functions as a sort of ‘black box’. The outcomes of
gestation/pregnancy are generally not visible or observable until after birth or termination of
the pregnancy.
It is presumed here that birth outcome or status of the child immediately after birth
represents both the gestation/pregnancy outcome and the birth outcome. The
gestation/pregnancy process and the birth process are closely linked, and the mechanisms that
trigger preterm birth or other complications at birth may also have been responsible for
adverse developments during gestation/pregnancy. Throughout the book, the combined
outcome will be referred to as pregnancy and birth outcome. However, it should be noted that
it is impossible to reach an exhaustive and complete assessment of health status immediately
after birth. Indeed, certain already present health problems and symptoms may not show or be
detected until months or even years after birth.
The processes and outcomes are affected by risk factors and other risk determinants.
The risk factors may be characteristics of the foetus/neonate, but may also pertain to elements
in the context and to interactions between the child and the context. During pregnancy, the
child is able to establish direct interaction with its mother through specialised organs such as
the umbilical cord, the placenta and foetal membranes. Interaction with other elements in the
context is mostly indirect (see Section 3.2.4). During birth and the neonatal period, the direct
context of the child expands.
The intermediate outcomes act both as outcomes and as risk factors. An adverse
pregnancy and birth outcome at live birth summarises the preceding processes of
gestation/pregnancy and birth but it is also a risk or causal factor of neonatal death. Being part
of a causal chain, the intermediate outcomes themselves are affected by more remote risk
factors.
Figure 3.4 presents the conceptual model composed on the basis of the reflections
above.
3.3.3 SPECIFYING THE MODEL AND SELECTING THE VARIABLES
The next step is to further specify the factors in the model of Figure 3.4 and to select the
variables that should be included in the study. Nowadays, the probabilities of (early) neonatal
survival and even infant survival are most strongly affected by health status of the newborn at
56
Risk factors
(VI)
(V)
Neonatal process
(I)
Final outcome
(IV)
Foetal survival status
Intermediate outcome
(III)
Gestation/pregnancy
and birth outcome
Risk factors
Birth process
(II)
Gestation/pregnancy
process
Figure 3.4: Processes leading to foetal and neonatal survival status
Final outcome
(VIII)
Neonatal survival
status
Intermediate outcome
(VII)
Neonatal outcome
Context
EARLY LIFE CHANGES
birth. Chapter 2 illustrated how the so-called endogenous causes of infant death, such as
perinatal conditions (including hypoxia and birth asphyxia) and congenital anomalies, gain
importance during the epidemiologic transition. Thus, adverse pregnancy and birth outcome
or adverse health status at birth (adverse intermediate outcome) is an important risk factor for
neonatal death.
The study will initially be limited to the boxes representing ‘neonatal survival status’
(VIII), ‘foetal survival status’ (IV) and ‘pregnancy and birth outcome’ (III) in Figure 3.4. The
focus is thus on adverse outcome and loss/death. At a later stage, in Chapter 9, some
important risk factors that are more remote in the causal chain, and that affect foetal loss and
adverse pregnancy/birth outcome, are selected, described, and analysed (see box I, ‘risk
factors’). For the present study, the conceptual model will thus be contracted to that shown in
Figure 3.5, in which adverse pregnancy and birth outcomes are considered as risk factors for
neonatal death.
The contents of boxes IV and VIII in Figure 3.5, adverse survival status (loss/death),
have already been discussed in Section 3.2.3. Foetal loss/death includes spontaneous abortion,
antepartum stillbirth, and intrapartum stillbirth. Neonatal death covers both early neonatal
death and neonatal death. Adverse pregnancy and birth outcome, the contents of box III, is
specified in the subsection below. The most important risk factors in box I are assumed to be
maternal factors, complications of placenta, cord, and membranes, and birth complications
(see Chapter 9).
Adverse pregnancy and birth outcomes
The adverse pregnancy and birth outcomes in box III summarise the preceding processes of
gestation/pregnancy and birth, describe the health status of the foetus and newborn, and are
the risk or causal factors of foetal loss and neonatal death.
Figure 3.5: Conceptual model for the study of foetal loss and neonatal mortality
Risk
factors
(I)
Adverse
pregnancy and
birth outcome
(III)
Foetal loss /
death (IV)
58
Neonatal
death
(VIII)
CHAPTER 3: FOETO-NEONATE DEVELOPMENT
Van der Veen (2001) applies the term ‘birth outcome’ “to capture the condition of the
newborn with observable characteristics, including the weight of the infant and the presence
of congenital anomalies” (p.63). Bonsel and Van der Maas (1994) describe the health status of
the newborn on the basis of the Apgar score, the presence/absence of congenital anomalies,
birth weight, and pregnancy duration. According to Kliegman (1996), many of a newborn’s
special health problems are related to asphyxia, preterm birth, congenital anomalies, and the
adverse effects of delivery. Moreover, in Chapter 2, the main causes of neonatal mortality
were seen to be perinatal conditions (which include slow foetal growth, disorders related to
short gestation and low unspecified birth weight, and intrauterine hypoxia and birth asphyxia)
and congenital anomalies (see Table 2.6a). Cunningham et al. (1993, p.6) give low birth
weight, usually as a consequence of preterm delivery, and congenital anomalies as the most
common causes of neonatal mortality. Likewise, Shibuya and Murray (1998c) state that in
developed countries congenital malformations, birth asphyxia, and very low birth weight
(< 1,500 g) account for the majority of perinatal deaths. Congenital anomalies (chromosomal
aberrations) are also widely acknowledged to play an important role in spontaneous abortion
(Kline et al. 1989; Van der Veen 2001).
It thus seems logical to select the following adverse pregnancy and birth outcomes, or
intermediate outcomes: congenital anomalies, low birth weight, preterm birth, intrauterine
growth retardation, and birth asphyxia. They are all process outcomes. Congenital anomalies,
low birth weight, and retarded foetal growth may be regarded as outcomes and indicators of
the gestation/pregnancy process while birth asphyxia is an outcome and indicator of the birth
process. Preterm birth as an outcome is probably related to both processes.
Conceptual model for the study
Figure 3.6 presents the operationalisation of the conceptual model for the study. The outcome
after the termination of pregnancy is assessed on the basis of the presence or absence of
anomalies, weight and size, gestational age, and occurrence of birth asphyxia. The adverse
intermediate outcomes (congenital anomalies, low birth weight, preterm birth, foetal growth
retardation/small-for-gestational-age, birth asphyxia) and adverse survival status at
termination of pregnancy (spontaneous abortion, stillbirth) are assumed to summarise the
preceding processes of gestation/pregnancy and birth. In addition, the intermediate outcomes
are risk factors for foetal loss and neonatal death. The prevalence and incidence of factors and
outcomes in the model, as well as the strength of their relationships may be modified by
preventive measures, health care, and iatrogenic1 factors. The link in Figure 3.6 from foetal
loss to adverse intermediate outcome may seem redundant at first sight, but preterm
intrauterine death is likely to bring about preterm expulsion or birth.
The following section, Section 3.4, defines, describes, and discusses the intermediate
outcomes that were selected for the study. After a discussion of data and methods in Chapter
4, Chapter 5 analyses foetal loss and neonatal mortality in the EME region. Subsequently, the
1
Iatrogenic: caused by medical intervention.
59
including:
- maternal factors
- complications of
placenta, cord, and
membranes
- birth complications
Chapter 9
Risk factors
RISK FACTORS
-
-
-
congenital anomalies
low birth weight
preterm birth / low gestational
age
intrauterine growth retardation
/ small-for-gestational-age
birth asphyxia
Chapters 6, 7, and 8
Adverse pregnancy and/or birth
outcome
INTERMEDIATE OUTCOMES /
RISK FACTORS
-
-
spontaneous
abortion
stillbirth
Chapters 5 and 8
Foetal loss
-
-
early neonatal
death
neonatal death
Chapters 5 and 8
Neonatal death
FINAL OUTCOME
(survival status)
Figure 3.6: Operationalisation of the conceptual model
CHAPTER 3: FOETO-NEONATE DEVELOPMENT
relative importance of adverse pregnancy and birth outcome in the region is assessed in
Chapter 6 (congenital anomalies) and in Chapter 7 (low birth weight, preterm birth,
intrauterine growth retardation, birth asphyxia). Chapter 8 deals with the results in terms of
foetal loss, neonatal mortality, and adverse pregnancy and birth outcome in South India.
Finally, Chapter 9 turns attention to the more remote risk factors shown to the left in Figure
3.6.
3.4 Variables: the intermediate outcomes
In the previous section, the following intermediate outcomes were selected for the study:
congenital anomalies, low birth weight, preterm birth, intrauterine growth retardation, and
birth asphyxia. The present section discusses these adverse pregnancy and birth outcomes. It
deals with the terminology and definitions as well as with the aetiology and risk factors for
the outcomes. In conclusion, Section 3.4.4 briefly considers the interrelationships between the
selected outcomes.
3.4.1 CONGENITAL ANOMALIES
A large part of the information below is derived from Kline et al. (1989), Bonsel and Van der
Maas (1994), Shibuya and Murray (1998c), and Van der Veen (2001). Additional sources
include ICBDMS (1991), Cornel (1993), Cunningham et al. (1993), and Hoffman (1995a).
Terminology and definitions
The term congenital anomaly is generally used to cover the large range of human
abnormalities that are of prenatal origin. Congenital anomalies may be defined as “structural
or irreversible functional anomalies of prenatal origin that are present at birth, and may be
diagnosed during pregnancy, at birth, during life or at post mortem” (Cornel 1993, p.1). They
include morphologic abnormalities, monogenic and chromosomal disorders as well as
functional problems. Monogenic disorders or single-gene defects are caused by errors in the
gene structure, while chromosomal disorders occur because of deviations in the number or
structure of one or more chromosomes (Kline et al. 1989; Drugan et al. 1992a; Van der Veen
2001). In general, all monogenic and chromosomal disorders are considered congenital
anomalies even though clinical symptoms may not appear until later in life. Multifactorial
disorders are considered to be the result of interaction between genetic predisposition and
environmental factors (Cunningham et al. 1993; Keeling and Boyd 1993). When their clinical
manifestation appears later in life, they are generally not regarded as congenital anomalies.
Even though the genetic predisposition is present at birth, the environmental component may
not have been acquired until postnatally.
In the International Classification of Diseases (ICD), congenital anomalies are
classified primarily on the basis of anatomical site rather than aetiology or pathogenesis.
Moreover, some congenital diseases, such as congenital infections and some congenital
endocrine and metabolic disorders, are not incorporated in the category ‘congenital
anomalies’ but are instead included in other ICD categories. The exact number of distinct
61
EARLY LIFE CHANGES
congenital anomalies is difficult to estimate but is believed to be over 5,000. Severity of the
impairment, degree of lethality, and survival pattern vary by type of anomaly.
Besides the term ‘congenital anomaly’, other names have been used to denote
abnormalities, or subsets of abnormalities, that are of prenatal origin. Birth defect is an older
term used for congenital anomalies that are present in newborn infants. More specific terms
are malformation, which generally refers to abnormal morphology, and aberration which is
applied to cover all departures from normality in the chromosomal constitution (i.e.
karyotype) of a cell. Conversely, the terms anomaly and disorder are used to cover any kind
of abnormality. Many authors classify anomalies as either major or minor according to their
impact on mortality and morbidity. ‘Major’ anomalies are believed to seriously interfere with
viability or physical wellbeing (Kalter and Warkany 1983). However, the exact distinction
between what is regarded as severe and ‘major’, and what is regarded as ‘minor’ often
remains unclear. Here, I will mostly use the term ‘anomaly’, but also ‘aberration’ (in relation
to chromosomal disorders) and ‘defect’ (in relation to neural tube defects and, sometimes, to
congenital heart anomalies). However, in references to other literature, I have adopted the
term applied by the author(s) since definitions are often lacking.
Aetiology and risk factors
Though all congenital anomalies are prenatal in origin, they arise in different ways. Kalter and
Warkany (1983) have divided congenital anomalies into five cause categories: monogenic
disorders, chromosomal disorders, disorders due to environmental causes, multifactorial
disorders, and disorders with unknown causes. In addition, they estimated the relative
contribution of each cause group to the total number of cases of major congenital anomalies.
Table 3.3 shows that, despite research efforts, the majority of major congenital anomalies still
belong to the unknown cause category. Combined with the figures for multifactorial
disorders, this results in about 80% of cases in which the aetiologic process is not clearly
understood.
Table 3.3: Estimated contribution of cause
categories to major congenital anomalies
Cause
Monogenic causes
Chromosomal causes
Environmental causes
maternal infections
maternal diabetes
all maternal illness
anticonvulsant drugs
Multifactorial causes
Unknown / no identified cause
Source: Kalter and Warkany 1983
62
%
7.5
6
5
2
1.4
3.5
1.3
20
60
CHAPTER 3: FOETO-NEONATE DEVELOPMENT
Table 3.4: Environmental teratogens strongly suspected or proven to cause
congenital anomalies
Maternal infections
Cytomegalovirus
Herpes
Rubella
Syphilis
Toxoplasmosis
Varicella
Venezuelan equine encephalitis
Other maternal disorders
Diabetes mellitus
Hyperthermia
Iodine deficiency
Phenylketonuria
Starvation
Social drugs
Alcohol
Medication
Androgenic hormones (androgens
and certain progestins)
Anticonvulsant drugs
Coumarin
Diethylstilbestrol (DES)
Folic acid antagonists
(e.g. aminopterin)
Isotretinoin
Lithium
Retinol (vitamin A)
Tetracycline
Thalidomide
Other environmental agents
Ionizing irradiation
Methylmercury
Polychlorinated biphenyls
Sources: Kalter and Warkany 1983; Moore 1986; Beckman and Brent 1987; Kline et al. 1989;
Cunningham et al. 1993; Keeling and Boyd 1993; Leck 1994 cited by Shibuya and Murray 1998c
Environmental or exogenous factors and agents that damage the unborn child or cause
abnormal development are labelled teratogens. Kline et al. (1989) define a teratogen as “a
factor extrinsic to the developing organism that acts in the interval between conception and
birth to injure the progeny or provoke abnormal development” (p.3). Teratogens include
micro-organisms, medication and other drugs, chemical substances, and radiation (see Table
3.4). In addition, Beckman and Brent (1987) note mechanical problems (e.g.
oligohydramnios2, uterine malformations, extrinsic pressure, and uterine contractions) as
causes of malformations. Furthermore, advanced maternal age and family history are wellknown and important risk factors for chromosomal aberrations.
Further refinement: three important types of anomalies
The large range of congenital anomalies makes it difficult, and sometimes even irrelevant, to
study all types of anomalies. Indeed, many studies and articles focus on only one specific type
of anomaly. The most frequent congenital anomalies among newborns in the Netherlands are
neural tube defects plus heart defects, skeletal defects, and mental retardation (Bonsel and
Van der Maas 1994). These are also important causes of death. In developed countries, the
major causes of death in the neonatal period and in infancy among all congenital anomalies
are those of the cardiovascular system and those of the central nervous system, or more
specifically congenital heart disease and neural tube defects. Moreover, anomalies of the
2
Oligohydramnios: a volume of amniotic fluid below the normal limits (Cunningham et al. 1993).
63
EARLY LIFE CHANGES
central nervous system (in particular failure of neural tube closure) also appears to be an
important cause of stillbirth (Kalter 1991). Chromosomal anomalies are widely acknowledged
as an important, demonstrable cause of spontaneous loss earlier in pregnancy. Therefore, it
seems to make sense to concentrate in the discussion and analysis of the importance of
congenital anomalies, in Chapter 6, on the following categories of anomalies: chromosomal
aberrations, neural tube defects, and congenital heart disease.
Chromosomal aberrations are due to an abnormality in the chromosomal constitution
or karyotype of the cell. They arise from a deviation in number and/or structure in the
chromosomes. Chromosomes are made up of genes that for their part consist of DNA
(deoxyribonucleic acid). Each human body cell, other than the sperm or egg cell, contains 23
pairs of different chromosomes, thus resulting in a total of 46 chromosomes. One of the pairs
consists of the sex chromosomes, i.e. X and Y. Abnormalities may occur not only in the
structure but also in the number of chromosomes. Deviations in the number include
monosomy (one copy of a chromosome instead of two), trisomy (three copies of a
chromosome instead of two), and triploidy (23*3 chromosomes). Examples of chromosomal
disorders include Down’s syndrome or trisomy 21, Edwards’ syndrome or trisomy 18,
Turner’s syndrome (45,X or a missing sex chromosome), and Klinefelter’s syndrome
(47,XXY or an extra sex chromosome). Chromosomal aberrations are not necessarily
hereditary and they can be observed under the microscope, as opposed to monogenic
abnormalities which cannot. Many studies on spontaneous loss have examined the
embryo/foetus for abnormalities by karyotyping the contents of its cells.
Neural tube defects (NTDs) have multifactorial causes and are included in the category
of anomalies of the central nervous system. Examples of NTDs include: anencephaly, spina
bifida, encephalocele, and hydrocephalus. NTDs can cause severe health problems, such as
symptoms of paralysis, and some may even be incompatible with life. At birth, the most
common types of NTDs are anencephaly and spina bifida (Cunningham et al. 1993; Velie and
Shaw 1996). Anencephaly is characterised by the partial or complete absence of the brain.
Anencephalic infants are usually stillborn or expire soon after birth (Main and Mennuti 1986;
ICBDMS 1991). Spina bifida arises from incomplete closure of the neural tube. In the case of
spina bifida aperta or open spina bifida, the opening is covered by a thin membrane. With
spina bifida occulta or closed spina bifida the opening is covered by a thick membrane or
skin. Besides anencephaly and spina bifida, other frequently discussed NTDs include
encephalocele and hydrocephalus. Encephalocele is a hernia of the brain in which skincovered cerebral membranes and sometimes brain tissue emerge through a defect in the skull.
Hydrocephalus (hydrocephaly) is characterised by an abnormal accumulation of cerebrospinal
fluid within the brain ventricles or between the brain and the skull.
Congenital heart disease (CHD) refers to “structural or functional heart disease present
at birth, even if first discovered much later” (Hoffman 1995b, p.155). Congenital heart defects
are generally considered to be multifactorial in origin, although 6 to 10% directly result from
a chromosomal aberration and a further 5 to 10% can be attributed to monogenic or singlegene disorders (Buskens 1994). The critical period during which congenital heart anomalies
can arise is between 14 and 60 days gestational age (Nora and Hart-Nora 1984 cited by Van
der Veen 2001). Examples of CHD include: ventricular septal defects, anomalies of the heart
64
CHAPTER 3: FOETO-NEONATE DEVELOPMENT
valves, transposition of the arteries, coarctation of the aorta, tetralogy of Fallot, and
hypoplastic left heart. It is suggested that patent ductus arteriosus (PDA) or open ductus
Botalli is only included when pathological, i.e. in children born at term or near-term. CHD is
often not detected until later in life. Only 33 to 60% of CHD cases are diagnosed within the
first month of life. Nevertheless, CHD is frequently associated with other congenital
anomalies. About 25% of children with a cardiovascular anomaly are affected by at least one
other major birth defect.
3.4.2 LOW
BIRTH WEIGHT, PRETERM BIRTH, AND INTRAUTERINE GROWTH
RETARDATION
A large part of the information below is derived from Kramer (1987a), Kline et al. (1989), and
Pittard (1993). Additional sources include Batcup (1993), Cunningham et al. (1993), Keeling
(1993), Ott (1995), Bakketeig (1998), Shibuya and Murray (1998a), Van der Veen (2001).
Low birth weight
The WHO (1993) describes birth weight as the first weight of the foetus or newborn obtained
after birth. For live births, birth weight is preferably measured within the first hour of life
before significant postnatal weight loss. Low birth weight (LBW) is defined as a birth weight
of less than 2,500 grams. Furthermore, very low birth weight (VLBW) is less than 1,500
grams and extremely low birth weight (ELBW) below 1,000 grams (WHO 1993). However, it
is worth noting that these absolute cut-off points are somewhat arbitrary. In developing
countries average birth weight is often lower than the weights observed in developed regions,
yet birth weight-specific neonatal mortality rates may be lower. Some authors propose
adjusting the defining limit of LBW for newborns in developing regions to a more pragmatic
weight threshold such as 2,000 grams.
It is generally recognised that birth-weight distributions are essentially normal
(Gaussian) but slightly negatively skewed with additional births in the lower or left tail, i.e. an
excess of newborns with low birth weights (Wilcox and Russell 1983a; Wilcox and Russell
1986; Chen et al. 1991). It is assumed that the birth weight distribution in any population is a
mixture of two distributions: a predominant distribution that is Gaussian and a residual
distribution with a smaller mean. The predominant distribution is regarded as the distribution
of the normal population while the residual component “may imply less organised, perhaps
pathological, influences” (Wilcox and Russell 1983a, p.318). Breaking down the distribution
into these two components has been used in the analysis of mortality in relation to birth
weight (Wilcox and Russell 1986) and for the calculation of population-specific low birth
weight thresholds (Chen et al. 1991).
The cause of low birth weight is multifactorial. Numerous factors have been associated
with LBW or are thought to affect birth weight, among them genetic and constitutional factors
such as sex of the foetus/infant, maternal height and weight, race, and birth order or parity
(Kramer 1987a, 1987b; Källén 1988; Cunningham et al. 1993). However, there are two
pathological mechanisms or processes that may directly lead to low weight at birth: (1) short
duration of gestation and (2) retarded foetal growth. In other words, a pathological low birth
weight may be the result of preterm birth, intrauterine growth retardation (IUGR), or a
65
EARLY LIFE CHANGES
combination of both. It is generally believed that preterm birth is the predominant cause of
LBW in developed countries whereas the majority of LBW cases in developing countries are
the result of growth retardation. For example, in the United States only about 30% of LBW
babies are believed to have suffered from IUGR (Kliegman 1996), whereas the percentage in
India is thought to be as high as 75 to 80% (UNICEF 1991). In general, it is believed that in
developing countries and countries where LBW is present in more than 10% of births, about
two-thirds of cases are the result of IUGR (Tibrewala et al. 1980; Kliegman 1996). However,
it should be noted that it is difficult to measure duration of gestation accurately and that valid
assessment of gestational age is often lacking in developing countries (WHO 1991; De Onis
et al. 1998). Many studies therefore have focused on LBW as if it were a single pathological
entity. Yet, preterm birth and IUGR differ in their aetiology, causal mechanisms, prognosis,
and outcomes.
Preterm birth
The WHO (1993) defines preterm birth as a birth at less than 37 completed weeks (less than
259 days) of gestation. As with low birth weight, the cut-off point for gestational age has been
chosen arbitrarily. The category ‘preterm birth’ includes many ‘normal’ infants who are
merely in the lower tail of a normal distribution (Bryce 1991). Sometimes, an additional
subcategory of extremely preterm is used to denote infants born at less than 28 completed
weeks of gestation. In the present study, very preterm will refer to births at less than 32
completed weeks of gestation. Apart from ‘preterm’, cut-off points have also been set to
define ‘term’ and ‘postterm’. A term birth is a birth that occurs in the period from 37
completed weeks to less than 42 completed weeks (259 days to 293 days) of gestation.
Postterm refers to a gestation of 42 completed weeks or more (294 days or more) (WHO
1993).
The term ‘preterm birth’ is often used interchangeably with prematurity and
immaturity. However, babies of the same gestational age may differ in their level of
maturation (Paneth 1995). Therefore, it seems appropriate to make a distinction between the
concepts. Whereas preterm birth reflects the gestational age at the time of birth, prematurity
and immaturity describe development rather than chronological age. Therefore, some authors
distinguish gestational age (or chronological age) from developmental age which refers to “an
observed state of development, whether somatic, neurologic, physiologic or behavioural”
(Kline et al. 1989, p.187) (also see Section 3.2.3).
The exact day of conception or fertilisation is usually not known, except in cases such
as artificial insemination, in-vitro fertilisation (IVF), and exposure to insemination on no
more than one dated occasion. In all other cases, methods and indicators need to be applied to
estimate the duration of gestation. The most simple and commonly used method is counting
from the first day of the last menstrual period (LMP) (see Section 3.2.3). Although this is
often one of the most accurate indicators available, for some women (such as those with
irregular menstrual cycles or amenorrhoea) dating LMP is imprecise or simply not possible.
Moreover, not every woman can remember her menstrual dates. Other indicators that are used
to estimate gestational age include clinical measures such as audibility of the foetal heart and
the mother’s sensation of quickening. Furthermore, several methods are based on foetal size.
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CHAPTER 3: FOETO-NEONATE DEVELOPMENT
Fundal height measurement, that is measurement of the height of the uterine fundus above the
symphysis pubis, is regarded as inaccurate in the case of multiple gestation or foetal growth
retardation. Ultrasonographic measurements of size include gestational sac size, crown-rump
length (CRL), biparietal diameter of the head (BPD), head circumference, femur length, and
abdominal circumference (Kline et al. 1989; Newton 1989; Pittard 1993). However, it should
be noted that these methods measure size rather than foetal age (Hall 1990 cited by Shibuya
and Murray 1998a) and that variations in growth rate may therefore affect the gestational age
estimates.
Following delivery, the gestational age of the newborn may be assessed by
examination of several neurodevelopmental and external physical characteristics of the baby.
The most well-known methods are the Dubowitz scoring system, described by Dubowitz et al.
(1970), and the modifications to this scoring system by Ballard and colleagues (1979, 1991).
The external physical characteristics on which the Dubowitz score is based include colour of
the skin, opacity of the skin, sole creases of the foot, and form of the ear. The neurological
signs involve, among other things, posture, flexion of the wrist and ankle, and arm and leg
recoil (Moore 1986; Pittard 1993). The Dubowitz scoring system was modified twice by
Ballard and colleagues (1979, 1991): first, to make it more reliable during the first hours of
life and, later, to include extremely low birth weight babies (Cloherty and Stark 1998).
Preterm birth is an event of largely unknown aetiology. As with LBW, its causes are
multifactorial and the list of associated factors is long. The search for the causes of preterm
birth has been complicated by confounding factors and by the broad definition of ‘preterm’
which encompasses the whole range from extremely to moderate preterm birth (Bryce 1991).
In the majority of preterm deliveries, the cause or causes remain unknown. On the basis of a
meta-analysis of 895 publications, published between 1970 and 1984, Kramer (1987a, 1987b)
identified the factors that have well-established causal effects on gestational duration and
intrauterine growth. Factors with a low prevalence and medical complications of pregnancy
were excluded from the analysis. The only well established direct determinants of gestational
duration turned out to be: low pre-pregnancy weight, cigarette smoking, in-utero exposure of
the mother to diethylstilbestrol (DES), and prior history of prematurity or spontaneous
abortion.
A valuable distinction is between spontaneous preterm delivery and induced or elective
preterm delivery. In cases where the continuation of the pregnancy would seriously jeopardise
the health of the mother and/or the foetus, preterm delivery may become an obstetric necessity
(Batcup 1993). Nevertheless, it is important to know the exact gestational age of the foetus so
that the risks of preterm birth and of pregnancy continuation can be weighed against each
other and the potential health complications anticipated. Reasons for elective preterm labour
induction include severe maternal hypertensive disorders (e.g. pre-eclampsia, eclampsia),
maternal diabetes, placental problems (e.g. placenta praevia), rhesus disease, and intrauterine
growth retardation (Batcup 1993).
Spontaneous preterm birth has also been associated with various factors. Risk factors
include infections (e.g. maternal infections, urinary tract infections, amniotic fluid infections),
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EARLY LIFE CHANGES
uterine abnormalities, multiple gestation, hydramnios3, cervix incompetence, and premature
rupture of membranes (Kline et al. 1989; Gjerdingen 1992; Batcup 1993; Cunningham et al.
1993). More generally, preterm birth is associated with “medical conditions in which there is
inability of the uterus to retain the fetus, interference with the course of pregnancy, premature
separation of the placenta, or an undetermined stimulus to effective uterine contractions prior
to term” (Kliegman 1996, p.455). Moreover, it has been suggested that preterm birth is a
mechanism to remove high-risk cases from the foetal population before they die in utero
(Carlson et al. 1999).
Intrauterine growth retardation and small-for-gestational-age
Intrauterine growth retardation (IUGR) has no generally accepted standard definition. It refers
to embryonic and foetal growth that falls behind the level of ‘normal’ growth rate. But what is
‘normal’ growth rate? And how can a growth-retarded or growth-restricted foetus be
distinguished from a normally grown or growing foetus? Ideally, the growth pattern of an
individual foetus should be compared to its own expected growth pattern in order to assess
whether growth rate is ‘normal’ or ‘abnormal’ (Kurniawan 1997). However, antepartum
information on individual growth potentials is not readily available. Therefore, growth curves
based on reference populations have commonly been used as a standard for comparison.
The growth curves relate size to gestational age. Size is often operationalised as
weight, but may also be expressed as head circumference or body length. A newborn whose
birth weight falls below a specific cut-off point within the reference weight-for-gestationalage distribution, i.e. below the growth curve that is accepted as ‘normal’, is considered to be
small-for-gestational-age or SGA. Sometimes, such an infant is also referred to as small-fordate or light-for-date. Similarly, the distributions and curves also indicate which newborns
may be considered to be appropriate-for-gestational-age (AGA) or large-for-gestational-age
(LGA).
Commonly applied cut-off points used to define SGA are the 3rd, 5th, and 10th
percentiles, and two standard deviations below the mean. However, their accuracy in
distinguishing compromised newborns from normal, healthy ones has been questioned.
McIntire et al. (1999) studied a sample of singleton live births in a hospital in Dallas (USA) in
1988-1996 to determine the threshold at which morbidity and mortality increase significantly.
Both neonatal morbidity and mortality turned out to be higher among term infants whose birth
weight was at, or below, the 3rd percentile. This suggests that the 5th and 10th percentiles
include a large group of normal, healthy infants. Another method used to set the threshold
values and to define SGA is the foetal growth ratio (FGR). FGR is the observed birth weight
divided by the mean birth weight for gestational age of a foetal growth distribution (Kramer et
al. 1990; Frisbie et al. 1996). The cut-off point is usually set at 0.85 with FGR below 0.85
indicating growth retardation. Besides the choice of a cut-off point or threshold value, the
formulation of a foetal growth standard introduces the complex issue of selecting an
appropriate reference population. Birth weight appears to depend on race, sex, and parity, and
it may therefore be advisable to construct and apply race-, sex- and parity-specific standards
3
Hydramnios: a large excess of amniotic fluid (Cunningham et al. 1993, p.185).
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CHAPTER 3: FOETO-NEONATE DEVELOPMENT
(Goldenberg et al. 1989). Some authors also decide to exclude multiple births, infants with
congenital anomalies, and infants with known risk factors from the reference population.
However, if the standard curve is applied to mixed populations, for example to racially mixed
populations, specified standards may not be appropriate. While it may be obvious that there is
not one right or correct standard, in order to improve comparability between studies, the use
of a consistent method is important (Goldenberg et al. 1989). According to Kline et al. (1989),
a separate statistical growth norm for a subgroup should only be applied when the distribution
of birth weight for gestational age differs immutably from the comparison population. In other
words, the factors involved have to be intrinsic or otherwise unalterable. The authors advise
using specific curves for each sex, multiple births, and altitude, possibly by race and ethnicity
but not by parity.
SGA is generally used as a proxy for IUGR although IUGR and SGA are not truly
synonymous since state (i.e. small-for-gestational-age) measured at one point in time is
assumed to imply a rate of growth (Kline et al. 1989, p.208). Some SGA infants may simply
represent the lower tail of the ‘normal’ foetal growth distribution and may not be growth
retarded in terms of their own individual growth pattern. When weight is not the basis of the
diagnosis, growth-retarded infants are found in almost every weight category, although
perhaps more frequently in low birth weight categories (Kurniawan 1997). Modern
technology, such as ultrasonography, has made it possible to monitor individual intrauterine
growth. The field of biometry searches for models to predict size and to individualise growth
curves. Examples include the Rossavik growth model (Rossavik and Deter 1984 cited by
Kurniawan 1997), the use of growth potential realisation indices to construct neonatal growth
assessment scores (Deter et al. 1990), and individualised birth weight ratio (Sanderson et al.
1994). Moreover, Bates et al. (1996) defined IUGR retrospectively on the basis of postnatal
catch-up growth. Deter et al. (1995) found that only 40% of IUGR neonates were SGA and, in
a study by Simon et al. (1994), only 67% of SGA infants were found to be IUGR (both cited
by Kurniawan 1997). However, such definitions have yet to be agreed on and the methods
require detailed data that is not easily obtainable.
IUGR is frequently divided into two subtypes: symmetric and asymmetric IUGR.
Symmetric, proportional, or stunted growth-retarded neonates have proportional reductions in
weight, length, and head circumference. Conversely, asymmetric, disproportional, or wasted
IUGR is characterised by a relative sparing of the most vital parts of the body (most notably
the brain). The type of growth retardation is believed to be related to underlying causes, the
timing of the onset, and its prognosis. However, so far no evidence has been found to support
the hypothesis of two distinct subtypes with variations in brain sparing and timing of onset
(Kramer et al. 1989; Vik et al. 1997). The main factor influencing degree of disproportionality
in IUGR cases seems to be the severity of the growth retardation. Therefore, Kramer et al.
(1989) suggest that proportionality among intrauterine growth-retarded infants should be
considered as a continuum rather than reflecting two distinct subtypes.
The various issues described above, i.e. problems related to definition and diagnosis,
have complicated the search for the causes of and risk factors for IUGR/SGA. The group of
infants who are labelled as SGA is very heterogeneous. Indeed, the clear identification of risk
factors is obscured by the difficulty in distinguishing between ‘normal’ variation in size and
69
EARLY LIFE CHANGES
‘abnormal’ or pathological smallness. On the basis of a meta-analysis, Kramer (1987a, 1987b)
identified factors that have causal effects on intrauterine growth. The well-established direct
determinants of intrauterine growth were: infant sex, racial/ethnic origin, maternal birth
weight, parity, prior LBW history, maternal morbidity and malaria, maternal height and prepregnancy weight, gestational weight gain and caloric intake, paternal height and weight,
cigarette smoking, and alcohol consumption. Small size may be the natural result of genetic
make-up, sex, race, and small parental size. Nevertheless, improvements such as better
nutrition and health during childhood that lead to taller and heavier mothers and fathers, are
likely to have cumulative effects over following generations (Thomson 1983). Lin and
Santolaya-Forgas (1998) estimate that up to 70% of SGA infants are small simply because of
constitutional factors determined by maternal ethnicity, parity, weight, or height.
In general, IUGR is associated with “medical conditions that interfere with the
circulation and efficiency of the placenta, with the development or growth of the foetus, or
with the general health and nutrition of the mother” (Kliegman 1996, p.455). The basic
concept of foetal growth restriction in the literature has been one of inadequate maternalfoetal supply of oxygen and nutrients which initiates foetal adaptation measures (Lin and
Santolaya-Forgas 1998, p.1052). Clinical situations that usually involve reduced placental
blood flow include: multiple gestation, substance abuse, vascular disease, renal disease,
infectious disease, abnormal cord insertion, and vascular tumours. The full list of (suspected)
risk factors for IUGR/SGA is long but includes: maternal infections (e.g. rubella,
cytomegalovirus), hypertensive disorders (e.g. hypertension, pre-eclampsia), anaemia,
malnutrition and inadequate energy and protein intake, drug and alcohol abuse, cigarette
smoking, placental abnormalities and infarcts, chromosomal and other congenital anomalies
in the foetus, and high altitude (Thomson 1983; Kline et al. 1989; Cunningham et al. 1993;
Keeling 1993; Pittard 1993; Prada and Tsang 1998; Lin and Santolaya-Forgas 1998).
Maternal diabetes mellitus and gestational diabetes are commonly acknowledged as cause of
excessive growth or macrosomia. However, Kliegman (1996) states that while mild diabetes
mellitus may lead to macrosomia, severe diabetes mellitus may lead to growth retardation
through the mechanisms of vascular disease and placental insufficiency.
3.4.3 BIRTH ASPHYXIA
A large element of the information below is derived from Shibuya and Murray (1998b).
Additional sources include Kliegman (1990), Cunningham et al. (1993), and Kollée (1995).
Terminology and definitions
Birth asphyxia (BA) is difficult to define and diagnose. Over the years, it has been defined in
a variety of ways and some argue that the term is imprecise and should not be used. Indeed,
there is no gold standard on how to diagnose asphyxia in utero or at birth. Diagnostic criteria
for asphyxia that are applied in developed countries include: late deceleration (foetal heart
rate), moderate/severe meconium4, an Apgar score of 0-3 at one minute, an Apgar score of 04
Meconium: the first faeces of the newborn. In the situation of foetal distress and suffocation, it is
sometimes excreted before birth, into the amniotic fluid.
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3 at five minutes, neonatal encephalopathy5 (seizures and recurrent apnoea6), and umbilical
blood with a pH level of less than 7.20 (i.e. metabolic acidosis). However, the predictive
value of most of these markers for mortality and morbidity is limited. A low Apgar score, for
instance should not be misused as evidence of asphyxia or future neurologic damage. Low
Apgar scores may also be explained by other perinatal factors such as immaturity or preterm
birth, congenital anomalies, maternal sedation and anaesthesia, infection, and trauma (Paneth
and Kiely 1984 cited by Shibuya and Murray 1998b; ACOG 1986 cited by Cunningham et al.
1993). Metabolic acidosis, on the other hand, is believed to be an important criterion in the
definition of asphyxia as it seems unlikely that there is any significant intrapartum asphyxia in
its absence. It has even been stated that birth asphyxia is perhaps best defined as hypoxia of
sufficient severity and duration to produce metabolic acidosis. The most reliable indicator of
neurological abnormality among the various indicators of birth asphyxia is seen as hypoxicischaemic encephalopathy (HIE). HIE is a condition that indicates that the infant has suffered
sufficient asphyxia to cause brain injury and is, as such, a relatively reliable indicator of
adverse outcome.
Asphyxia signifies suffocation and is closely related to conditions such as hypoxaemia,
hypoxia, anoxia, and ischaemia. Hypoxaemia denotes a subnormal level of oxygen in arterial
blood. Hypoxia refers to a reduced oxygen supply to tissue, which may lead to damage to
organs, while anoxia refers to a complete lack of oxygen. Ischaemia indicates blood flow to
cells or organs that is insufficient to maintain their normal function (Aarnoudse et al. 1995;
Stedman’s Medical Dictionary 1995; Kliegman 1996).
In the ICD, birth asphyxia is included among the ‘conditions originating in the
perinatal period’. However, its detailed classification within this major category has changed
in the most recent revisions. The eighth revision of the ICD classifies birth asphyxia within
the broader category of ‘anoxic and hypoxic conditions not elsewhere classified (776)’ which
includes hyaline membrane disease, respiratory distress syndrome, foetal distress, intrauterine anoxia, and unspecified asphyxia of newborn. In ICD-9, birth asphyxia is defined
more clearly on the basis of clinical signs (such as foetal heart rate, acidosis, and neurologic
involvement) and is classified in the category of ‘intrauterine hypoxia and birth asphyxia
(768)’. In the 10th revision, intrauterine and birth asphyxia are split into ‘intrauterine hypoxia
(P20)’ and ‘birth asphyxia (P21)’. The latter category further distinguishes between severe,
mild and moderate, and unspecified asphyxia. This distinction is primarily based on
traditional clinical signs such as heart rate, respiration, skin colour, muscle tone, and Apgar
score at one minute (Shibuya and Murray 1998b; WHO 1992). ICD-10 thus makes a clear
distinction between asphyxia in utero and asphyxia at birth. However, asphyxia at birth is
often a continuation of the process of intrapartum asphyxia. Moreover, asphyxia in the
newborn may be the result of intrapartum and postpartum factors as well as intrauterine
factors. Further, the strict distinction between asphyxia in utero and asphyxia at birth is not
always clear in the literature.
5
6
Encephalopathy: any disorder of the brain (Stedman’s Medical Dictionary 1995).
Apnoea: absence of breathing (Stedman’s Medical Dictionary 1995).
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EARLY LIFE CHANGES
Table 3.5: Frequently mentioned risk factors for birth and perinatal asphyxia
Intrauterine and intrapartum
Maternal
Analgesics and anesthetics
Diabetes
Hypertension, pre-eclampsia
Hypotension
Placental and umbilical
Placental insufficiency
Placental infarcts
Abruptio placentae
Placenta praevia
Cord prolapse
Cord compression
Intrauterine and intrapartum
Foetal
Arrhythmia
Infection
Multiple pregnancy
Abnormal presentation
Cephalopelvic disproportion
Shoulder dystocia
Postpartum
Neonatal
Meconium or amniotic fluid aspiration
Immaturity
Pulmonary and airway disorders
Congenital disorders
CNS injury
Notes: CNS - central nervous system
Sources: Erkkola et al. 1984; Donn and Nagile 1986 cited by Shibuya and Murray 1998b; Kliegman 1990; Kollée 1995
Aetiology and risk factors
Kollée (1995) estimated that about half of the cases of asphyxia in the newborn are caused by
intrauterine factors. Another 40% are believed to develop during delivery whereas only 10%
occur immediately after birth. The time of occurrence and the duration are important since
these affect the prognosis. Intrapartum or postpartum asphyxia that lasts for only a short time
has a more favourable prognosis than asphyxia that has persisted for considerable time in
utero.
Table 3.5 lists several frequently noted risk factors and conditions that are associated
with asphyxia during the perinatal period. As can be seen, many of the conditions that
contribute to foetal or neonatal asphyxia are the same medical or obstetric problems that are
associated with high-risk pregnancy in general. Diabetes, chronic hypertension, preeclampsia7, and hypotension are all maternal disorders that affect utero-placental perfusion.
Cephalopelvic disproportion (CPD) is categorised as ‘foetal’ in the table, although it should
be noted that it could be foetal or maternal in origin, or a combination of both. In developing
countries, the perinatal risk factors that are potentially preventable, i.e. by monitoring,
diagnosis, and management, still predominate (Donn and Nagile 1986 cited by Shibuya and
Murray 1998b).
7
Pre-eclampsia: hypertension in pregnancy accompanied by protein in the urine and/or oedema (see
Section 9.2.1).
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CHAPTER 3: FOETO-NEONATE DEVELOPMENT
3.4.4 INTERRELATIONSHIPS
The selected adverse intermediate outcomes (congenital anomalies, LBW, preterm birth,
IUGR/SGA, and BA) are interrelated. This seems logical since they are all outcomes of the
same, underlying process(es).
Congenital anomalies have been related to reduced birth weight, preterm birth, and
intrauterine growth retardation (Ott 1993; Bonsel and Van der Maas 1994; Bennebroek
Gravenhorst et al. 1995). The presence of a congenital anomaly may cause growth retardation
and preterm birth, but the adverse outcomes may also be the result of a shared underlying
mechanism (Källén 1988; Milli et al. 1991 cited by Van der Veen 2001). Moreover, early
growth retardation may play a contributory role in the genesis of certain malformations.
There is also evidence that IUGR is more common in preterm than in term infants, and
that foetuses born preterm weigh less than their undelivered peers (Ott 1993). One of the
possible explanations is that a poorly functioning placenta may cause both IUGR and preterm
birth (Källén 1988). It is worth noting that this relationship also affects standard growth
curves constructed on the basis of birth weight.
Finally, birth asphyxia has been associated with low birth weight, preterm as well as
postterm birth, and IUGR as well as macrosomia (Mir et al. 1989). In addition, congenital
anomalies may increase the risk of complications at birth (Cunningham et al. 1993) and thus
of birth asphyxia.
3.5 Summary and conclusions
In recent years, a paradigm shift has occurred in most behavioural and social disciplines,
including demography, and the health sciences. The new life course perspective examines the
ordering, sequencing, and timing of events and transitions in the life course and considers it
in relation to the wider context. A clear distinction is made between processes and outcomes.
Life events are regarded as the outcomes of underlying processes. Conventional modes of
explanation have been sought from statistical association between variables. The new
paradigm attempts to uncover the underlying causal mechanisms and processes. Knowledge
about these processes is essential if one wants to understand and predict events and if one
wants to intervene and change the outcomes.
The present study also builds on the life course paradigm. A life course approach to
health looks back across an individual’s life experiences or even across generations to explain
current patterns in health and disease. Barker (1994), for example, pointed out that adult
disease in later life may have foetal origins. The present study takes on a foeto-infant
approach, or rather foeto-neonate approach, that integrates the foetal period with the neonatal
period. In this, the neonatal period is considered to be part of the same continuing
developmental process as gestation. This approach is supported by developments observed
during the epidemiologic transition. Chapter 2 indicated a shift from exogenous infant
mortality to endogenous infant mortality during the epidemiologic transition. Thus, the causes
of infant death that gain relative importance during the transition are those causes that are the
result of genetic make-up and/or of the circumstances during prenatal life and birth. The
prenatal period demonstrates a strong link between a child’s survival career and the
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EARLY LIFE CHANGES
reproductive health career of its mother (the previous generation). During gestation, mother
and foetus interact while additional relationships between the foetus and its context (or
environment) occur only indirectly, through the mother.
After outlining the theoretical background, the chapter continued to the construction of
a conceptual model. The aim of the study is to gain insights into the causal factors and
mechanisms that predict and lead to loss and death during gestation, birth, or the neonatal
period. The model identifies various processes and factors involved, and the relationships and
interactions between them. It introduces order and sequence to the list of causal factors. The
continuing, underlying process of health and survival was divided into three subprocesses:
gestation/pregnancy, birth, and neonatal development. In addition, the model makes a
distinction between intermediate outcomes and final outcomes. An intermediate outcome was
defined as one in a process that continues while a final outcome denotes the end of the
underlying process of interest. Intermediate outcomes are both outcomes and risk factors. An
adverse pregnancy/birth outcome summarises the preceding processes of gestation/pregnancy
and birth, but is also a risk or causal factor for neonatal death. Being part of a causal chain,
the intermediate outcomes themselves are affected by more remote risk factors.
Subsequently, the factors in the model were further specified and variables were
selected for the study. Initially, the study will be limited to adverse pregnancy and birth
outcome (an intermediate outcome) and foetal loss and neonatal mortality (final outcomes).
At a later stage, Chapter 9 will turn attention to some important risk factors that are more
remote in the causal chain. For the present, the following adverse pregnancy and birth
outcomes were selected for the study: congenital anomalies, low birth weight, preterm birth,
intrauterine growth retardation/small-for-gestational-age (IUGR/SGA), and birth asphyxia.
These are assumed to summarise the preceding processes of gestation/pregnancy and birth, to
describe the health status of the foetus and the newborn, and to be the main risk or causal
factors of neonatal death, stillbirth, and spontaneous abortion in developed regions.
The selected intermediate outcomes were defined, described, and discussed in the final
section of this chapter. Their definition and operationalisation was found not to be entirely
unambiguous or uncomplicated. Criteria for low birth weight, preterm birth, and IUGR/SGA
are based on various conventions about what is to be regarded as ‘normal’ and what not. Their
ability to distinguish the healthy from the sick, high-risk neonate is questionable, at least in
some situations. The definition and operationalisation of birth asphyxia is even less
straightforward. Various criteria have been applied but there appears to be no general
agreement on how to diagnose birth asphyxia. Finally, the large variety of congenital
anomalies makes it difficult, and sometimes even irrelevant, to study all types of anomalies.
Therefore, it makes sense to concentrate further analysis on three types of anomalies that are
important causes of spontaneous abortion, stillbirth, and neonatal mortality: chromosomal
aberrations, neural tube defects, and congenital heart disease.
74