Pre- and postnatal development

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CHAPTER 14 Pre- and postnatal development

PRENATAL STAGES

The absolute size of an embryo or fetus does not afford a reliable indication of either its chronological age or the stage of structural organization, even though graphs based on large numbers of observations have been constructed to provide averages. All such data suffer from the difficulty of timing the moment of conception in humans. It has long been customary to compute the age, whether in a normal birth or an abortion, from the first day of the last menstrual period of the mother but, as ovulation usually occurs near the 14th day of a menstrual cycle, this ‘menstrual age’ is an overestimate of about 2 weeks. Where a single coitus can be held to be responsible for conception, a ‘coital age’ can be established and the ‘fertilization age’ cannot be much less than this, because of the limited viability of both gametes. It is usually held that the difference may be several days, which is a highly significant interval in the earlier stages of embryonic development. Even if the time of ovulation and coitus were known in instances of spontaneous abortion, not only would some uncertainty still persist with regard to the time of fertilization, but there would also remain an indefinable period between the cessation of development and the actual recovery of the conceptus.

To overcome these difficulties, early embryos have been graded or classified into developmental stages or ‘horizons’, on the basis of both internal and external features. The study of the Carnegie collection of embryos by Streeter (1942, 1945, 1948), and the continuation of this work by O’Rahilly & Müller (1987), provided, and continues to provide, a sound foundation for embryonic study and a means of comparing stages of human development with those of the animals routinely used for experimental study, namely the chick, mouse and rat. Recent use of ultrasound for the examination of human embryos and fetuses in utero has confirmed much of the staging data.

The development of a human from fertilization to birth is divided into two periods, embryonic and fetal. The embryonic period has been defined by Streeter as 8 weeks postfertilization, or 56 days. This timescale is divided into 23 Carnegie stages, a term introduced by O’Rahilly & Müller (1987) to replace developmental ‘horizons’. The designation of stage is based on external and internal morphological criteria and not on length or age.

Embryonic stages

Embryonic stages 1–10 are shown in detail in Fig. 8.1. It should be noted that estimations of embryonic length may be 1–5 mm less than equivalent in vivo estimates, reflecting the shrinkage caused by the fixation procedures that are inevitably used in embryological studies. O’Rahilly & Müller (2000) have revised some of the ages that were previously assigned to early embryonic stages, pointing out that inter-embryonic variation may be greater than had been thought and that consequently some ages may have been underestimated. They note that as a guide, the age of an embryo can reasonably be estimated from the embryonic length within the range 3–30 mm, by adding 27 to the length. Correlating the age of any stage of development to an approximate day may be unreliable, and a generalization using the number of weeks of development might be now more appropriate.

The stages of development encompass all aspects of internal and external morphogenetic change that occur within the embryo within the duration of the stage. They are used to convey a snapshot of the status of the development of all body systems within a particular timeframe. Figure 14.1 shows the external appearance of embryos from stage 6 to stage 23, with details of their size and age in days. The correlation of external appearance of the embryo with internal development is shown in Fig. 14.2.

Fig. 14.1 The external appearance and size of embryos between stages 6 and 23. Early in development, external features are used to describe the stage, e.g. somites, pharyngeal arches or limb buds.

(Adapted by permission from Rodeck CH, Whittle MJ 1999 Fetal Medicine. London: Churchill Livingstone.)

Fig. 14.2 Timetable of development of the body systems. The development of individual systems can be seen progressing from left to right. Embryonic stages, weeks of development and embryo length are shown. Embryonic stages are associated with external and internal morphological features rather than embryonic length. To identify the systems and organs at risk at any time of development, follow a vertical progression from top to bottom.

Obvious external features provide some guidance to the changes occurring within embryos during successive stages. Somite number is related to early embryonic stages and once the number of somites is too great to count with accuracy, the degree of development of the pharyngeal arches is often used. External staging becomes more obvious when the limb buds appear. The upper limb bud is clearly visible at stage 13, and by stage 16 the acquisition of a distal paddle on the upper limb bud is characteristic. At stage 18 the lower limb bud now has a distal paddle, whereas the upper limb bud has digit rays that are beginning to separate. By stage 23, the embryo has a head that is almost erect and rounded, and eyelids are beginning to form. The limbs look far more in proportion and fingers and toes are separate. At this stage the external genitalia are well developed, although they may not be sufficiently developed for the accurate determination of the sex.

Historically, the onset of bone marrow formation in the humerus was used by Streeter to indicate the end of the embryonic and the beginning of the fetal period of prenatal life. The fetal period occupies the remainder of intrauterine life: growth is accentuated, although differentiative processes continue up to and beyond birth. Overall, the fetus increases in length from 30 mm to 500 mm, and increases in weight from 2–3 g to more than 3000 g.

Fetal staging

Currently there is no satisfactory system of morphological staging of the fetal period of development, and the terminology used to describe this time period reflects this confusion. The terms ‘gestation’, ‘gestational age’ and ‘gestational weeks’ are considered ambiguous by O’Rahilly & Müller (2000) who recommend that they should be avoided. However, they are widely used colloquially within obstetric practice. Staging of fetal development and growth is based on an estimate of the duration of a pregnancy. Whereas development of a human from fertilization to full term averages 266 days, or 9.5 lunar months (28 day units), the start of pregnancy is traditionally determined clinically by counting days from the last menstrual period; estimated in this manner, pregnancy averages 280 days, or 10 lunar months (40 weeks). Figure 14.3 shows the embryonic timescale used in all descriptions of embryonic development and the obstetric timescale used to gauge the stage of pregnancy. Studies that discuss fetal development and the gestational age of neonates, particularly those born before 40 weeks’ gestation, use the clinically estimated stages and age unless they specifically correct for this. If a fetal ageing system is used, it must be remembered that the age of the fetus may be 2 weeks more than a comparable fetus that has been aged from postovulatory days.

Fig. 14.3 The two timescales used to depict human development. Embryonic development, in the upper scale, is counted from fertilization (or from ovulation, i.e. in postovulatory days; see O’Rahilly & Müller 1987). Throughout this book, times given for development are based on this scale. The clinical estimation of pregnancy is counted from the last menstrual period and is shown on the lower scale; throughout this book, fetal ages relating to neonatal anatomy and growth will have been derived from the lower scale. Note that there is a 2-week discrepancy between these scales. The perinatal period is very long, because it includes all preterm deliveries.

The predicted date of full term and delivery is revised after routine ultrasound examination of the fetus. Early ultrasound estimation of gestation increases the rate of reported preterm delivery (delivery at <37 weeks) compared with estimation based on the date of the last menstrual period (Yang et al 2002), possibly because delayed ovulation is more frequent than early ovulation: the predicted age of a fetus estimated from the date of the last menstrual period may differ by more than 2 weeks from estimates of postfertilization days.

A number of biometric indices used to determine fetal growth in utero have been evaluated ultrasonographically; the consensus appears to be that some revision of fetal gestational age may be required when using charts based on fetal biometry, and that using fewer biometric variables for the estimation produces a larger standard error. First-trimester growth charts based on biparietal diameter, head circumference and abdominal circumference of normal singleton fetuses correlated against crown–rump length (from 45 to 84 mm) are said to be more accurate than gestational age (Salomon et al 2003). O’Rahilly & Müller (2000) recommend that the term ‘crown–rump length’ should be replaced by greatest length, exclusive of lower limbs in ultrasound examination. Femur length/head circumference ratio may be a more robust ratio to characterize fetal proportions than femur length/biparietal diameter (Johnsen et al 2005), and combining kidney length, biparietal diameter, head circumference and femur length also increases the precision of dating (Konje et al 2002). Johnsen et al (2004) reported that analysis of measurements of biparietal diameter and head circumference at 10–24 weeks gestation gave a gestational age assessment of 3–8 days greater than charts in present use.

Constructions of ultrasound biometry charts for fetal aging now take into account the ethnic population under consideration and it is recommended that locally developed charts specific to the population should be used. The use of these charts means that factors that may influence fetal biometry, including maternal age and nutritional status, can be identified, facilitating accurate prediction of small-for-date and growth-retarded fetuses.

Although accurate morphological stages are not available for the fetal period, the developmental progression is broadly clear. During the fourth and fifth months, the fetus has a head and upper limbs that are still disproportionately large. Although the rates of growth of the trunk and lower limbs increase during the remainder of intra-uterine life, the disproportion is present after birth and, to a diminishing degree, is retained throughout childhood and on into the years of puberty. A covering of primary hair, lanugo, appears. Towards the end of this period, sebaceous glands become active; the sebum that is secreted blends with desquamated epidermal cells to form a cheesy covering over the skin, the vernix caseosa, that is usually considered to protect the skin from maceration by the amniotic fluid. About this time the mother, becomes conscious of fetal movement, formerly termed ‘quickening’.

In the sixth month, the lanugo darkens, the vernix caseosa is more abundant and the skin becomes markedly wrinkled. The eyelids and eyebrows are now well developed. During the seventh month, the hair of the scalp is lengthening and the eyebrow hairs and the eyelashes are well developed. The eyelids themselves separate and the pupillary membrane disappears. The body becomes more plump and rounded in contour and the skin loses its wrinkled appearance as a result of the increased deposition of subcutaneous fat. Fetal length has increased to approximately 350 mm and weight to about 1.5 kg. Towards the end of this month the fetus is viable: if born prematurely it is able to survive without the technological assistance found in Neonatal Intensive Care Units and its postnatal development can proceed normally.

Throughout the remaining lunar months of normal gestation, the covering of vernix caseosa is prominent. There is a progressive loss of lanugo, except for the hairs on the eyelids, eyebrows and scalp. The bodily shape is becoming more infantile but, despite some acceleration in its growth, the leg has not quite equalled the arm in length proportionately, even at the time of birth. The thorax broadens relative to the head, and the infra-umbilical abdominal wall shows a relative increase in area, so that the umbilicus gradually becomes more centrally situated. Average lengths and weights for the eighth, ninth and tenth months are 40, 45 and 50 cm and 2, 2.5 and 3–3.5 kg, respectively. The rate of fetal growth slows from 36 to 40 weeks in response to the physical limitation imposed by the maternal uterus. Birth weight thus reflects the maternal environment more than the genotype of the child. This slowing of the growth rate enables a genetically larger child developing within a small mother to be delivered successfully. After birth, the growth rate of the neonate increases and the rate of weight gain, reaches a peak some 2 months postnatally.

Just before birth, the lanugo almost disappears, the umbilicus is central. The testes, which begin to descend with the processus vaginalis of peritoneum during the seventh month and are approaching the scrotum in the ninth month, are usually scrotal in position. The ovaries are not yet in their final position at birth; although they have attained their final relationship to the uterine folds, they are still above the level of the pelvic brim.

Obstetric stages

In obstetric practice the duration of the period of gestation is regarded as nine calendar months, which is approximately 270 days. The period of pregnancy is divided into thirds, termed trimesters. The first and second trimesters each cover a period of 12 weeks, and the third trimester covers the period from 24 weeks to delivery. Although the expected date of delivery is computed at 40 weeks of pregnancy, the term of the pregnancy, i.e. its completion resulting in delivery, is considered normal between 37 and 42 weeks. Neonates delivered before 37 weeks are called preterm (or premature); those delivered after 42 weeks are post-term. The period from the end of week 24 and up to 7 days after birth, is termed the perinatal period. Fetuses that are delivered and die before 24 weeks are considered to be miscarriages of pregnancy, although technological advances in neonatal care can now assist the delivery and support of infants younger than 24 weeks. Infants born after 24 weeks of pregnancy which subsequently die are classed as stillborn and contribute to the statistics of perinatal mortality.

THE NEONATE

The neonatal period extends from birth to 28 days postnatally, and is divided into an early neonatal period from birth to 7 days, and a late neonatal period from 7 to 28 days.

In Western societies, technological advances have enabled successful management of preterm infants, many at ages that were considered non-viable a decade or two previously. Maturational processes involving local interactions and pattern formation still drive development at local and body-system levels in preterm infants. The sudden release of such fetuses into a gaseous environment, of variable temperature, with full gravity and a range of microorganisms, promotes the rapid maturation of some systems and the compensatory growth (in terms of responses to the effect of gravity or enteral feeding or exposure to microorganisms), of others. To understand the multitude of mechanisms that operate within a newly delivered fetus, as much information as possible concerning normal embryological and fetal development is required.

Details of the relative positions of the viscera and the skeleton in a full term neonate are shown in Figs 14.4–14.6. The newborn infant is not a miniature adult, and extremely preterm infants are not the same as full-term infants. There are immense differences in the relations of some structures between the full-term neonate, child and adult, and there are also major differences between the 20-week gestation fetus and the 40-week fetus, just before birth. The study of fetal anatomy at 20, 25, 30 and 35 weeks is vital for the investigative and life-saving procedures carried out on preterm infants today.

Fig. 14.4 A–C, Topographical representation of the anatomy of a full-term neonate. The surface markings of all organs are shown, with some coloured and others only in outline. The female genital tract is shown on the right of the body, with the male tract on the left.

Fig. 14.5 Topographical representation of the anatomy of a full-term female neonate. The cut surfaces of the organs are the same colours as in Fig. 14.4.

Fig. 14.6 The extent of the ossified skeleton in the full term neonate. Note the derivation of the parts of the skeleton: the skull is derived from paraxial mesenchyme and neural crest mesenchyme; the axial skeleton, vertebrae and ribs are derived from paraxial mesenchyme; the skeletal elements in the limbs are derived from the somatopleuric mesenchyme, which forms the limb buds.

Neonatal measurements and period of time in utero

The 10th to 90th centile ranges for length of full-term neonates are 48–53 cm (Fig. 14.7A). Length of the newborn is measured from crown to heel. In utero, length has been estimated either from crown–rump length, i.e. the greatest distance between the vertex of the skull and the ischial tuberosities, with the fetus in the natural curved position, or from the greatest length exclusive of the lower limbs. Greatest length is independent of fixed points and thus much simpler to measure. It is generally taken to be the sitting height in postnatal life, and is the measurement recommended by O’Rahilly & Müller (2000) as the standard in ultrasound examination. The 10th to 90th centile ranges for weight of the full-term infant at parturition ranges are 2700–3800 g (Fig. 14.7B), the average being 3400 g; 75–80% of this weight is body water and a further 15–28% is composed of adipose tissue. After birth, there is a general decrease in the total body water, but a relative increase in intracellular fluid. Normally, the newborn loses about 10% of its birth weight by 3–4 days postnatally, because of loss of excess extra-cellular fluid and meconium. By 1 year, total body water makes up 60% of the body weight.

Fig. 14.7 Standardized graphs of (A) fetal length and (B) weight from 24 weeks of pregnancy, showing the 10th, 50th and 90th centiles.

Low birth weight has been defined as less than 2500 g, very low birth weight as less than 1500 g, and extremely low birth weight as less than 1000 g. Infants may weigh less than 2500 g but not be premature by gestational age. Measurement of the range of weights that fetuses may attain before birth has led to the production of weight charts, which allow babies to be described according to how appropriate their birth weight is for their gestational age, e.g. small for gestational age, appropriate for gestational age or large for gestational age (Fig. 14.8). Small for gestational age infants, also termed ‘small-for-dates’, are often the outcome of intrauterine growth retardation. The causes of growth restriction are many and various and beyond the scope of this text.

Fig. 14.8 Intrauterine growth status and its appropriateness for gestational age. Gestational age is more closely related to maturity than birth weight. The mortality for the weight ranges is indicated.

For both premature and growth-retarded infants, an assessment of gestational age, which correlates closely with the stage of maturity, is desirable. Gestational age at birth is predicted by its proximity to the estimated date of delivery and the results of ultrasonographic examinations during pregnancy. It is currently assessed in the neonate by evaluation of a number of external physical and neuromuscular signs. Scoring of these signs results in a cumulative score of maturity that is usually within ±2 weeks of the true age of the infant. The scoring scheme has been devised and improved over many years. For an account of methods of assessing gestational age in neonates, consult Gandy (1992).

INTEGRATION OF TYPES OF GROWTH DURING DEVELOPMENT

In the later prenatal months and in the postnatal period, the various types of growth occur in differing patterns. The extent of tissue growth in organs depends on the specific duration of multiplicative growth for the cell types (Fig. 14.9). Different cell populations complete their initial developmental proliferation and become differentiated at different times, the final stage of differentiation usually being cessation of cell division.

Fig. 14.9 The duration of multiplicative growth for various human tissues.

Growth of a body can be described in two ways, isometric and allometric. Isometric growth implies a progressive proportional increase in all organs and systems with time: it does not occur in the developing embryo, which displays differential rates of growth. Allometric growth describes the differences in the relative rates of growth between one part of the body and another, and is most clearly seen in the changes in body proportion between fetuses, neonates, children and adults. Between 6 and 7 weeks after fertilization, the head is nearly one-half of the total embryonic length. It subsequently grows proportionally more slowly, and at birth it is one-quarter of the entire length. During childhood, this pattern of growth continues with lengthening of the torso and limbs until, in adults, the head is one-eighth the length (Fig. 14.10).

Fig. 14.10 Allometric growth in humans. The head is very large in proportion to the rest of the body during the embryonic period. After this time the head grows more slowly than the torso and limbs and by adulthood the head is only one-eighth of the body length.

Growth of the liver, spleen and kidneys, and skeletal and muscular tissues generally follow pre- and postnatal growth curves given for the entire body. Other tissues have very different growth rates; the brain, skull, lymphoid tissues and reproductive organs all show differing growth rates during childhood and adolescence (Fig. 14.11).

Fig. 14.11 Growth curves of different tissues, regions of the body and systems. Note that the growth of lymphoid tissue, thymus, lymph nodes and intestinal lymph masses decreases after puberty.

(Adapted with permission from Tanner JM 1962 Growth at Adolescence, 2nd edn. Oxford: Blackwell Publishing.)

The amount and distribution of adipose tissue within the body change with age and hormonal status. Subcutaneous fat deposits are estimated by measurements taken by calipers applied to a fold of fat pinched up from the underlying muscles, usually over triceps and beneath the angle of the scapula. Fat is laid down in the fetus from about 34 weeks, and the amount increases to the 9th postnatal month. After this time subcutaneous fat decreases (i.e. it has a negative growth velocity), until 6–8 years, when it begins to increase again. This early decrease in fat is less marked in girls than in boys so that, after 1 year, girls have more fat than boys. From 7 years the increase in fat occurs in both sexes. At adolescence, the limb fat in boys (triceps measurement) decreases, and is not regained until the late 20s, whereas girls show a slight slowing of the increase in limb fat, but no loss. At this time the trunk fat (subscapular measurement) stops increasing in boys, but shows a steady increase in girls. Postpubertal girls, but not boys, show fat deposits in a secondary sexual distribution, i.e. in the breasts, over the upper arms, lower abdomen and thighs. Adult men are more likely to deposit fat around the anterior abdominal wall.

GROWTH IN UTERO

Alterations in the availability of nutrients to the fetus at particular stages of pregnancy elicit adaptive responses by the fetus that ensure fetal coping, but which may result in pathology in adult life: the nutritional status of pregnant women is therefore of fundamental importance for the health of the next generation. For example, poor nutrition at critical stages of fetal life may permanently alter the normal developmental pattern of a range of organs and tissues, e.g. the endocrine pancreas, liver and blood vessels, resulting in their pathological responses to certain conditions in later adult life (Barker et al 1993). An increase in placental size occurs in pregnancy as an adaptive response to both high altitude and mild undernutrition, particularly during mid-pregnancy. However, although a larger placenta may be better able to deliver the full nutritional requirements of the fetus, the perfusion of a larger placenta is not without problems. It may produce changes in fetal blood flow and placental enzymes, and in the normal structure of the fetal vessel wall or of its responses to circulating trophins, e.g. catecholamines or angiotensin II, which will continue into adult life. Undernutrition in later pregnancy does not produce the same sequelae and placental enlargement does not occur. However, fetal growth slows and fetal wasting may occur as oxygen, glucose and amino-acids are redistributed to the placenta to maintain its function.

Maternal starvation during pregnancy decreases fetal IGF-I concentrations, and this may, along with a general hypoglycaemia, impair the development of the fetal β cells of the pancreas. Moreover, fetal undernutrition may induce insulin resistance in the tissues. The coexistence of insulin resistance and impaired β-cell development in the fetus appears to be important in the pathogenesis of non-insulin-dependent diabetes. The risk of developing this ‘type 2’ diabetes is greatest in those individuals with low weight at birth and at 1 year, and who become obese as adults, thus challenging an already impaired glucose–insulin metabolism. Fetal IGF-I concentrations are also lower in infants who are short at birth as a result of a long period of maternal undernutrition: these individuals have an exaggerated responses to growth hormone-releasing factor, which, together with low IGF-I concentrations, suggests a degree of growth hormone resistance.

It is now thought that the balance of hormonal environment in intrauterine and early postnatal life is necessary for future adult health. The presence of altered concentrations of hormones during critical periods of development may act as endogenous functional teratogens (Plagemann 2004).

Different birth phenotypes have been correlated with different pathological sequelae. Infants who are thin at birth, with a low ponderal index (weight/length³), tend to develop a combination of insulin resistance, hypertension, non-insulin-dependent diabetes and lipid dis-orders, whereas those who are short in relation to head size tend to develop hypertension and high plasma fibrinogen concentrations. These associations have been reported in babies born small for dates, rather than in those born prematurely. Some babies of average weight also develop cardiovascular pathology: they were either small at birth in relation to the size of their placenta, and thin at birth or, although of average weight, were short in relation to head size and had below average weight gain during the first year (Barker et al 1993). For more recent views on this concept the reader is directed to consult Godfrey & Barker (2000) and Gluckman et al (2005).

GROWTH IN CHILDHOOD

The rates of prenatal and postnatal growth can be indicated by increments in body length or weight which, when plotted, form a growth curve (see Fig. 14.7). Growth curves can be plotted for individuals if accurate measurements are taken, preferably by the same person, for the entire period of growth, i.e. a longitudinal study. An alternative method is to collect a series of averages for each year of age obtained from different individuals, i.e. a cross-sectional study. Cross-sectional studies are valuable for the construction of standards for height and weight attained by healthy children at specific ages, and can establish percentile limits of normal growth, but they cannot reveal individual differences in either the rate of growth or the timing of particular phases of growth.

The data from longitudinal and cross-sectional studies can also be used to plot the increments in height or weight from one age to the next. This produces a velocity curve, which reflects a child’s state at any particular time much better than the growth curve, in which each point is dependent on the preceding one. The oldest published longitudinal study, still of great value today, was made by Count Philibert de Montbeillard on his son (Fig. 14.12). It shows that the velocity of growth in height decreases from birth onwards, and that a marked acceleration of growth, the adolescent growth spurt, occurs from 13 to 15 years (see below; Fig 14.13).

Fig. 14.12 A longitudinal study of growth. A, The height of de Montbeillard’s son (1759–1777) from birth to 18 years. B, A growth velocity curve, plotting increments in height from year to year.

(After D’Arcy Thompson, On Growth and Form, 1942, Cambridge University Press.)

Fig. 14.13 Typical individual velocity curves for height: English boys and girls.

(After Tanner JM, Whitehouse RH, Takaishi IM 1966 Standards from birth to maturity for height, weight, height velocity and weight velocity. Arch Dis Child 41: 454–71, with permission from BMJ Publishing.)

Cross-sectional data permit comparison of prenatal and postnatal growth. Childhood growth charts are used to predict normal childhood development. The velocity curve for the prenatal and postnatal period (Fig. 14.14) shows that the peak velocity for length is reached at about 4 months (note that these prenatal charts use the obstetric measurements of gestational time, in which fetal age is estimated from the last menstrual period, 2 weeks before fertilization). Growth in weight usually reaches its peak velocity after birth.

Fig. 14.14 Cross-sectional data showing growth in length in the prenatal and early postnatal period (A) and the corresponding velocity curve for this period (B).

(After D’Arcy Thompson, On Growth and Form, 1942, Cambridge University Press.)

Growth has always been regarded as a regular process. Tanner (in Harrison et al 1964) noted that the more carefully measurements are taken, the more regular is the succession of points on a growth curve. However, a longitudinal study of growth measured weekly, semi-weekly and daily, recorded that growth in length and head circumference occurred by saltatory increments, with a mean amplitude of 1.01 cm for length (Lampl 2002); growth stasis, steep changes in growth and incremental growth have all been recorded in infancy, childhood and adolescence (Caino et al 2006).

Charts of height and weight correlated to age are compiled from extensive cross-sectional growth studies. Such charts show the mean height or weight attained at each age, termed the 50th centile, and also the centile lines for the 75th, 90th and 97th centiles, in addition to the 25th, 9th and 2nd centiles. The data shown in Fig. 14.15 are derived from United Kingdom cross-sectional references. Any comparison of an individual growth curve with these data must also take into account ethnicity and the nutritional and family history of that individual.