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.