Chapter 7. Embryogenesis and fetal development
BS. Nguyễn Hồng Anh
Contemporary obstetrics incorporates physiology an pathophysiology o the etus, an its evelopment an environment.
As a result, the etus is consiere a patient an is given the
same meticulous care provie or the mother. Section 6 is
eicate to the etal patient, however, virtually every aspect o
obstetrics can aect the eveloping etus.
GESTATIONAL AGE
Several terms ene pregnancy uration an thus etal age
(Fig. 7-1). Gestational age or menstrual age is the time elapse
since the rst ay o the last menstrual perio (LMP), a time
that actually precees conception. Tis starting time, which is
usually approximately 2 weeks beore ovulation an ertilization an nearly 3 weeks beore blastocyst implantation, has
traitionally been use. Embryologists escribe embryoetal
evelopment in ovulation age, or the time in ays or weeks
rom ovulation. Another term is postconceptional age, which is
nearly ientical to ovulation age.
Until recently, clinicians customarily calculate menstrual age, an with this, term pregnancy averages 280 ays
or 40 weeks between the rst ay o the LMP an birth.
Tis correspons to 9 an 1/3 calenar months. However,
menstrual cycle length variability among women reners
many o these calculations inaccurate. Tis realization, combine with the requent use o rst-trimester sonography, has
le to more accurate gestational age etermination (Duryea,
2015). Much o this change stems rom the accuracy o early
sonographic measurement. As a result, the American College
o Obstetricians an Gynecologists, the American Institute o
Ultrasoun in Meicine, an the Society or Maternal-Fetal
Meicine (2019) together recommen the ollowing:
1. First-trimester sonography is the most accurate metho to
establish or rearm gestational age.
2. In conceptions achieve with in vitro ertilization (IVF), the
embryo age an egg transer ate are use.
3. I available, the gestational ages calculate rom the LMP
an rom rst-trimester sonography are compare, an the
estimate ate o connement (EDC) is recore an iscusse with the patient.
4. Te best obstetrical estimate o gestational age at elivery is
recore on the birth certicate.
Te embryoetal crown-rump length in the rst trimester
is accurate ± 5 to 7 ays. Tus, i sonographic gestational
age iers by more than 5 ays prior to 9 weeks’ gestation,
or by more than 7 ays later in the rst trimester, the EDC is
change. Tese an iscrepant values in the secon an thir
trimester are iscusse urther in Chapter 14 (p. 248).
■ Naegele Rule
An EDC base on the LMP can be quickly estimate as ollows: a 7 ays to the rst ay o the LMP an subtract
3 months. For example, i the rst ay o the LMP was October 5, the ue ate is 10–05 minus 3 (months) plus 7 (ays)
= 7–12, or July 12 o the ollowing year. Tis calculation has
been terme the Naegele rule. Te perio o gestation can also
be ivie into three units o approximately 14 weeks each.
Tese three trimesters are important obstetrical milestones.
In aition to estimating the EDC with either Naegele rule
or “pregnancy wheels,” calculator tools in the electronic meical recor an smartphone applications can provie a calculate
EDC an gestational age. For example, the American College
o Obstetricians an Gynecologists (2020) has evelope a calculator application that incorporates sonographic criteria an
the LMP or embryo transer ate (Chap. 14, p. 248).
EMBRYONIC DEVELOPMENT
Te complexity o embryoetal evelopment is immense.
Figure 7-2 shows a evelopmental sequence o various organ
systems. New inormation regaring organ evelopment
continues to accrue. For example, imaging techniques help
to unravel the contributions o gene regulation an tissue
interaction to eventual three-imensional organ morphology
(Anerson, 2016). Others have escribe the sequence o gene
activation that unerlies cariac evelopment (p. 126).
■ Zygote and Blastocyst Development
During the rst 2 weeks ater ovulation an then ertilization,
the zygote—or preembryo—progresses to the blastocyst stage.
Te blastocyst implants 6 or 7 ays ollowing ertilization. Te
58-cell blastocyst ierentiates into ve cells—the inner cell
mass, which evelops into the embryo. Te remaining 53 cells
orm placental trophoblast. Details o implantation an early
evelopment o the blastocyst an placenta are escribe in
Chapter 5 (p. 86).
■ Embryonic Period
Te conceptus is terme an embryo at the beginning o the
thir week ater ovulation an ertilization. Primitive chorionic
villi orm, an this coincies with the expecte ay o menses.
Te embryonic perio, uring which time organogenesis takes
place, lasts 6 weeks. It begins the thir week rom the LMP
an continues through the eighth week. Te embryonic isc
is well ene, an most pregnancy tests that measure human
Embryonic Period
(Organogenesis) Fetal Period (Growth)
Crown-rump
length (cm)
Period: Implantation
1 2 3
Weight (g)
Brain
Weeks 4 5 6 7 8 9 12
6-7
Neural tube
12 16 21 25 28 32
110 320 630 1100 1700 2500
16 20 24 28 32 36 38
Hemispheres, cerebellum,
ventricles, choroid plexus Temporal lobe, sulci, gyri, cellular migration, myelinization
Lips, tongue, palate, cavitation, fusion
Canals, cochlea, inner ears, ossicles
Face
Eyes
Ears
Pinnae
Diaphragm
Lungs
Heart
Intestines
Urinary tract
Genitalia
Axial skeleton
Limbs
Skin
Optic cups, lens, optic nerves, eyelids
Pinnae
Transverse septum, diaphragm
Tracheoesophageal septum, bronchi, lobes
Primitive tube, great vessels, valves, chambers
Foregut, liver, pancreas, midgut
Glomeruli
Genital folds, phallus, labioscrotal swelling
Vertebral cartilage, ossification centers
Buds, rays, webs, separate digits
Vernix
Brows
Canaliculi Terminal sacs
Eyes open
Abdominal wall,
gut rotation
Mesonephric duct Metanephric duct collecting sytem
Fingernails
Penis, urethra, scrotum
Clitoris, labia
Lanugo hair
FIGURE 7-2 Embryofetal development according to gestational age determined by the first day of the last menses. Times are approximate.Embryogenesis and Fetal Development 123
CHAPTER 7
chorionic gonaotropin (hCG) become positive by this time.
As shown in Figure 7-3, the boy stalk is now ierentiate.
Tere are villous cores in which angioblastic chorionic meso-
erm can be istinguishe an a true intervillous space that
contains maternal bloo.
During the thir week, etal bloo vessels in the chorionic
villi appear. In the ourth week, a cariovascular system has
orme (Fig. 7-4) (Moore, 2008). Tereby, a true circulation
is establishe both within the embryo an between the embryo
an the chorionic villi. Partitioning o the primitive heart
begins. Also in the ourth week, the neural plate orms, an
it subsequently ols to orm the neural tube. By the en o
the th menstrual week, the chorionic sac measures approximately 1 cm in iameter. Te embryo is 3 mm long an can be
Yolk sac
Embryo
Amnion
Chorion
Body stalk Developing villi
Allantois
A C
Yolk
sac
Allantois
Body stalk Chorion
Amnion
Developing
neural groove
B
FIGURE 7-3 Early human embryos. Ovulation ages: A. 19 days (presomite). B. 21 days (7 somites). C. 22 days (17 somites). (After drawings
and models in the Carnegie Institute.)
Otic pit
Lens placode
Arm bud
Leg bud
E
Third
branchial arch
Hyoid
arch
Otic pit
Arm bud
Leg bud
D
Somites
Mandibular
arch
Heart
prominence
C
Neural fold
Rostral neuropore
Neural tube
Somites
Caudal neuropore
B
Neural fold
Rostral neuropore
Neural groove
Neural tube
Caudal neuropore
Somites
A
Mandibular
arch
FIGURE 7-4 Three- to four-week-old embryos. A, B. Dorsal views of embryos during 22 to 23 days of development showing 8 and 12
somites, respectively. C–E. Lateral views of embryos during 24 to 28 days, showing 16, 27, and 33 somites, respectively.124 Placentation, Embryogenesis, and Fetal Development
Section 3
measure sonographically. Arm an leg bus have evelope,
an the amnion is beginning to ensheathe the boy stalk, which
thereater becomes the umbilical cor. At the en o the sixth
week, the embryo is approximately 9 mm long, an the neural
tube has close (Fig. 7-5). Cariac motion is almost always
iscernable sonographically (Fig. 7-6).
Te cranial en o the neural tube closes by 38 ays rom
the LMP, an the caual en closes by 40 ays. Tus, the
neural tube has close by the en o the sixth week. An by
the en o the eighth week, the crown-rump length approximates 22 mm. Fingers an toes are present, an the arms
ben at the elbows. Te upper lip is complete, an the external ears orm enitive elevations on either sie o the hea.
Tree-imensional images an vieos o human embryos rom
the Multi-Dimensional Human Embryo project can be seen
at: embryo.soa.umich.eu/.
FETAL DEVELOPMENT AND PHYSIOLOGY
■ Fetal Period Epochs
Te transition rom embryonic to etal perios occurs at 7 weeks
ater ertilization, corresponing to 9 weeks ater the LMP. At
this time, the etus approximates 24 mm in length, most organ
systems have evelope, an the etus enters a perio o growth
an maturation. Tese phases are outline in Figure 7-2.
A B C
FIGURE 7-5 Embryo photographs. A. Dorsal view of an embryo at 24 to 26 days and corresponding to Figure 7-4C. B. Lateral view of an
embryo at 28 days and corresponding to Figure 7-4D. C. Lateral view of embryofetus at 56 days, which marks the end of the embryonic
period and the beginning of the fetal period. The liver is within the white, halo circle. (From Werth B, Tsiaras A: From Conception to Birth:
A Life Unfolds. New York, Doubleday, 2002.)
A B
FIGURE 7-6 A. This image of an 8-week, 3-day embryo depicts measurement of the crown-rump length, which is 1.93 cm at this gestational age. B. Despite the early gestational age, M-mode imaging readily demonstrates embryonic cardiac activity. The heart rate in this
image is 161 beats per minute.Embryogenesis and Fetal Development 125
CHAPTER 7
12 Gestational Weeks
Te uterus usually is just palpable above the symphysis pubis.
Fetal growth is rapi, an the etal crown-rump length is 5 to
6 cm (Fig. 7-7). Centers o ossication have appeare in most etal
bones, an the ngers an toes have become ierentiate. Skin
an nails evelop, an scattere ruiments o hair appear. Te
external genitalia are beginning to show enitive signs o male or
emale gener. Te etus begins to make spontaneous movements.
16 Gestational Weeks
Fetal growth slows at this time. Te crown-rump length is 12 cm,
an the etal weight approximates 150 g. Clinically, the sonographic crown-rump length is not measure beyon 13 weeks,
which correspons to approximately 8.4 cm. Instea, biparietal iameter, hea circumerence, abominal circumerence,
an emur length are measure. Fetal weight in the secon an
thir trimesters is estimate rom a combination o these measurements (Chap. 14, p. 248).
Eye movements begin at 16 to 18 weeks, coinciing with
mibrain maturation. By 18 weeks in the emale etus, the
uterus is orme an vaginal canalization begins. By 20 weeks
in the male, testicles start to escen.
20 Gestational Weeks
Tis is the mipoint o pregnancy as estimate rom the LMP.
Te etus now weighs somewhat more than 300 g, an weight
increases substantially in a linear manner. From this point
onwar, the etus moves approximately every minute an is
active 10 to 30 percent o the ay (DiPietro, 2005). Brown
at orms, an the etal skin becomes less transparent. Downy
lanugo covers its entire boy, an some scalp hair can be seen.
Cochlear unction evelops between 22 an 25 weeks, an this
maturation continues or 6 months ater elivery.
24 Gestational Weeks
Te etus now weighs almost 700 g. Te skin is characteristically wrinkle, an at eposition begins. Te hea is still
comparatively large, an eyebrows an eyelashes are usually recognizable. By 24 weeks, the secretory type II pneumocytes have
initiate suractant secretion (Chap. 32, p. 587). Te canalicular perio o lung evelopment, uring which the bronchi an
bronchioles enlarge an alveolar ucts evelop, is nearly complete. Despite this, a etus born at this time will attempt to
breathe, but many will ie because the terminal sacs, require
or gas exchange, have not yet orme. Although epenent
on racial an ethnic actors, an as iscusse in Chapter 45
(p. 785), the overall survival rate at 24 weeks barely excees 50
percent (Janevic, 2018). By 26 weeks, the eyes open. Nociceptors are present over all the boy, an the neural pain system is
evelope (Kaic, 2012). Te etal liver an spleen are important early sites or hemopoiesis (Fanni, 2018).
28 Gestational Weeks
Te crown-rump length approximates 25 cm, an the etus
weighs about 1100 g. Te thin skin is re an covere with vernix caseosa. Te pupillary membrane has just isappeare rom
the eyes. Isolate eye blinking peaks at 28 weeks. Te bone
marrow now becomes the major site o hemopoiesis. Te otherwise normal neonate born at this age has a 90-percent chance
o survival without physical or neurological impairment.
32 and 36 Gestational Weeks
At 32 weeks, the etus has attaine a crown-rump length
approximating 28 cm an a weight o about 1800 g. Te skin
surace is still re an wrinkle. In contrast, by 36 weeks, the
etal crown-rump length averages about 32 cm, an the weight
approximates 2800 g (Duryea, 2014). Because o subcutaneous at eposition, the boy is more rotun, an the previous
wrinkle acies are now uller. Normal etuses have a nearly
100-percent survival rate.
40 Gestational Weeks
Tis is consiere term, an the etus is ully evelope. Te
average crown-rump length measures about 36 cm, an the
average weight approximates 3500 g.
■ Central Nervous System Development
Brain Development
Te cranial en o the neural tube closes by 38 ays rom the last
menstrual perio, an the caual en closes by 40 ays. Hence,
olic aci supplementation to prevent neural-tube eects
must be in place beore this point to be ecacious (Chap. 9,
p. 168). Te walls o the neural tube orm the brain an spinal
cor. Te lumen becomes the ventricular system o the brain
an the central canal o the spinal cor. During the sixth week,
the cranial en o the neural tube orms three primary vesicles. In the seventh week, ve seconary vesicles evelop: the
telencephalon—uture cerebral hemispheres; iencephalon—
thalami; mesencephalon—mibrain; metencephalon—pons
an cerebellum; an myelencephalon—meulla. Tis is, in
part, controlle by Hox genes, an eects result in abnormal
signaling that leas to neuropathic anomalies (Arent, 2018).
Meanwhile, fexures evelop an ol the brain into its typical
FIGURE 7-7 This image of a 12-week, 2-day embryo depicts measurement of the crown-rump length. The fetal profile, cranium, and
a hand and foot also are visible in this image.126 Placentation, Embryogenesis, and Fetal Development
Section 3
conguration. Te en o the embryonic perio signies completion o primary an seconary neutralization.
At 3 to 4 months’ gestation, neuronal proliferation peaks.
As expecte, isorers in this cerebral evelopment phase
proounly worsen unction (Ortega, 2017; Volpe, 2018).
One example is Zika virus inection (Rothan, 2019). Neuronal migration occurs almost simultaneously an peaks at 3 to
5 months. Tis process is characterize by movement o millions o neuronal cells rom their ventricular an subventricular zones to areas o the brain in which they resie or lie
(Fig. 7-8). Upregulation o gene expression or neuronal migration has been escribe (Di Donato, 2017). Noninvasive methos to stuy etal neuroevelopment also have been reporte
(Goetzl, 2016; Wang, 2015).
As gestation progresses, the etal brain appearance steaily
changes. Tus, it is possible to ientiy etal age rom its external appearance (Volpe, 2018). Neuronal prolieration an
migration procee along with gyral growth an maturation (see
Fig. 7-8). Sequential maturation stuies using magnetic resonance (MR) imaging have characterize the eveloping etal
brain (Dubois, 2014; Meng, 2012; Wang, 2015).
Myelination o the ventral roots o the cerebrospinal nerves
an brainstem begins at approximately 6 months, but most
myelination progresses ater birth. Tis lack o myelin an
incomplete skull ossication permit etal brain structure to be
seen sonographically throughout gestation.
Spinal Cord
Whereas the superior two thirs o the neural tube give rise
to the brain, the inerior thir orms the spinal cor. In the
embryo, the spinal cor extens along the entire vertebral
column length, but ater that it lags behin vertebral growth.
Ossication o the entire sacrum is visible sonographically by
approximately 21 weeks (Chap. 15, p. 276). By 24 weeks, the
spinal cor extens to S1, at birth to L3, an in the ault to L1.
A B C
FIGURE 7-8 Neuronal proliferation and migration are complete at
20 to 24 weeks. During the second half of gestation, organizational
events proceed with gyral formation and proliferation, differentiation, and migration of cellular elements. Approximate gestational
ages are shown. A. 20 weeks. B. 35 weeks. C. 40 weeks.
Spinal cor myelination begins at migestation an continues
through the rst year o lie. Synaptic unction is suciently
evelope by the eighth week to emonstrate fexion o the
neck an trunk. During the thir trimester, integration o nervous an muscular unction procees rapily (Molina, 2017).
■ Cardiovascular System
Te embryology o the heart is highly complex. At its earliest
stages o ormation, the etal heart unergoes molecular programming, an more than a hunre genes an molecular actors are integral to its morphogenesis (Kathiriya, 2015; Moore,
2020). Tese molecular actors inclue the hypoxia-inducible
factor—HIF an homeobox (HOX)—amily.
o summarize its embryology, the straight cariac tube is
orme by the 23r ay uring an intricate morphogenetic
sequence, uring which each segment arises at a unique time.
Between 4 an 7 weeks the heart unergoes extensive growth
an morphological moication, leaing to the ormation o a
partially septate our-chambere heart with a set o primitive
valves (Sylva, 2014). Te valves evelop, an the aortic arch
orms by vasculogenesis. Chapter 8 o Hurst’s Te Heart has
a ull escription (orres, 2017). Late in etal lie, coronary
angiogenesis vascularizes the myocarium (Lu, 2021).
Fetal Circulation
Tis unique circulation is substantially ierent rom that o
the ault an unctions until birth, when it changes ramatically. For example, etal bloo is oxygenate by the placenta
an oes not nee to enter the pulmonary vasculature. Tus,
most o the right ventricular output bypasses the lungs. In aition, the etal heart chambers work in parallel, not in series.
Tis eectively supplies the brain an heart, compare with the
rest o the boy, with more highly oxygenate bloo rom the
ominant right ventricle.
Oxygen an nutrient materials require or etal growth
an maturation are elivere rom the placenta by the single
umbilical vein (Fig. 7-9). Te vein then ivies into the uctus
venosus an the portal sinus. Te uctus venosus is the major
branch o the umbilical vein an traverses the liver to enter
the inerior vena cava irectly. Because it oes not supply oxygen to the intervening tissues, it carries well-oxygenate bloo
irectly to the heart. In contrast, the portal sinus carries bloo
to the hepatic veins primarily on the let sie o the liver, an
oxygen is extracte. Te relatively eoxygenate bloo rom the
liver then fows back into the inerior vena cava, which also
receives more eoxygenate bloo returning rom the lower
boy. Bloo fowing to the etal heart rom the inerior vena
cava, thereore, consists o an amixture o arterial-like bloo
that passes irectly through the uctus venosus an less welloxygenate bloo that returns rom most o the veins below the
level o the iaphragm. Te oxygen content o bloo elivere
to the heart rom the inerior vena cava is thus lower than that
leaving the placenta.
Because the ventricles o the etal heart work in parallel, this
allows the right ventricle to account or two thirs o the total
cariac output. Well-oxygenate bloo enters the let ventricle,Embryogenesis and Fetal Development 127
CHAPTER 7
which supplies the heart an brain, an less oxygenate bloo
enters the right ventricle, which supplies the rest o the boy.
Congenital cariac eects may contribute to ysregulate
brain evelopment or placenta ysunction (Fantasia, 2018;
Laurisen, 2017).
Tese two separate circulations are maintaine by rightatrium anatomy, which eectively irects entering bloo to
either the let atrium or the right ventricle, epening on
its oxygen content. Tis separation o bloo accoring to its
oxygen content is aie by the pattern o bloo fow in the
inerior vena cava. Te well-oxygenate bloo tens to course
along the orsomeial aspect o the inerior vena cava an the
less oxygenate bloo fows along the lateral vessel wall. Tis
ais their shunting into opposite sies o the heart. Once this
bloo enters the right atrium, the conguration o the upper
interatrial septum—the crista dividens—preerentially shunts
LV
RV
RA
Ductus
arteriosus
LA
Superior vena cava
Foramen ovale
Inferior vena cava
Ductus
venosus
Portal
sinus
Portal v.
Aorta
Umbilical aa.
Umbilical v.
Hypogastric
aa.
Placenta
Oxygenated
Mixed
Deoxygenated
FIGURE 7-9 The intricate nature of the fetal circulation is evident. The degree of blood oxygenation in various vessels differs appreciably
from that in the postnatal state. aa = arteries; LA = left atrium; LV = left ventricle; RA = right atrium; RV = right ventricle; v = vein.128 Placentation, Embryogenesis, and Fetal Development
Section 3
the well-oxygenate bloo rom the meial sie o the inerior
vena cava through the oramen ovale into the let heart. Here,
it is irecte to the heart an brain (Dawes, 1962). Ater these
tissues extract neee oxygen, the resulting less oxygenate
bloo returns to the right atrium through the superior vena
cava. Bloo fow velocity in the superior vena cava rises rom
20 weeks until term (Steopoulou, 2021).
Te less oxygenate bloo coursing along the lateral wall o
the inerior vena cava enters the right atrium an is efecte
through the tricuspi valve to the right ventricle. Te superior
vena cava courses ineriorly an anteriorly as it enters the right
atrium, ensuring that less well-oxygenate bloo returning rom
the brain an upper boy also will be shunte irectly to the
right ventricle. Similarly, the ostium o the coronary sinus lies
just superior to the tricuspi valve so that less oxygenate bloo
rom the heart also returns to the right ventricle. As a result o
this bloo fow pattern, bloo in the right ventricle is 15 to 20
percent less saturate with oxygen than bloo in the let ventricle.
Almost 90 percent o bloo exiting the right ventricle
is shunte through the uctus arteriosus to the escening
aorta. High pulmonary vascular resistance an comparatively
lower resistance in the uctus arteriosus an the umbilical–
placental vasculature ensure that only about 8 percent o right
ventricular output goes to the lungs (Fineman, 2014). Tus,
one thir o the bloo passing through the uctus arteriosus is
elivere to the boy. Te remaining right ventricular output
returns to the placenta through the two hypogastric arteries.
Tese two arteries course rom the level o the blaer along
the abominal wall to the umbilical ring an into the cor
as the umbilical arteries. In the placenta, this bloo picks up
oxygen an other nutrients an is recirculate to the umbilical vein.
Circulatory Changes at Birth
Ater birth, the umbilical vessels, uctus arteriosus, oramen
ovale, an uctus venosus normally constrict or collapse. With
the unctional closure o the uctus arteriosus an the expansion o the lungs, bloo leaving the right ventricle preerentially
enters the pulmonary vasculature to become oxygenate beore
it returns to the let heart (Hillman, 2012). Virtually instantaneously, the ventricles, which ha worke in parallel in etal
lie, now eectively work in series. Te more istal portions
o the hypogastric arteries unergo atrophy an obliteration
within 3 to 4 ays ater birth. Tese become the umbilical ligaments, whereas the intraabominal remnants o the umbilical
vein orm the ligamentum teres. Te uctus venosus constricts
by 10 to 96 hours ater birth an is anatomically close by 2 to
3 weeks. Tis ultimately orms the ligamentum venosum (Fineman, 2014).
Fetoplacental Blood Volume
Although precise measurements o human etoplacental bloo
volume are lacking, Usher an associates (1963) reporte
values in term normal newborns to average 78 mL/kg when
immeiate cor clamping was conucte. Gruenwal (1967)
oun that the etal bloo volume containe in the placenta
ater prompt cor clamping average 45 mL/kg o etal weight.
Tus, etoplacental bloo volume at term is approximately 125
mL/kg o etal weight. Tis is important when assessing the
magnitue o etomaternal hemorrhage, which is iscusse in
Chapter 18 (p. 358).
■ Hemopoiesis
Embryo hemopoiesis begins in the yolk sac an enothelium, ollowe by the liver, an then spleen an bone marrow (Canu,
2021). ransitions are intricate an involve several genes an
protein complexes (Shao, 2018). Both myeloi an erythroi
cells are continually prouce by progenitors that erive rom
hemopoietic stem cells (Fanni, 2018; Heinig, 2015). Te rst
erythrocytes release into the etal circulation are nucleate an
macrocytic. Te mean cell volume is at least 180 L in the embryo
an ecreases to 105 to 115 L at term. Normal ault volume
ranges rom 80 to 95 L. Te erythrocytes o aneuploi etuses
generally o not unergo this maturation an maintain high
mean cell volumes, which average 130 L (Sipes, 1991). As etal
evelopment progresses, more an more circulating erythrocytes
are smaller an nonnucleate. With etal growth, both the bloo
volume in the common etoplacental circulation an hemoglobin
concentration increase. As shown in Table 7-1, etal hemoglobin
concentrations rise across pregnancy. For clinical purposes, the
Society or Maternal-Fetal Meicine (2015) recommens a cuto
etal hematocrit value o 30 percent to ene anemia.
Because o their large size, etal erythrocytes have a short lie
span, which progressively lengthens to approximately 90 ays
at term (Pearson, 1966). As a consequence, re bloo cell concentrations rise. Reticulocytes are initially present at high levels
but ecrease to 4 to 5 percent o the total at term. Fetal erythrocytes ier structurally an metabolically rom those in the
ault (Baron, 2012). Tey are more eormable, which serves
TABLE 7-1. Fetal Hemoglobin Concentrations Across
Pregnancy
Multiples of the Median
Weeks’
Gestation
1.16
(95th
percentile)
1.00
(median)
0.84
(5th
percentile)
grams per deciliter
18 12.3 10.6 8.9
20 12.9 11.1 9.3
22 13.4 11.6 9.7
24 13.9 12.0 10.1
26 14.3 12.3 10.3
28 14.6 12.6 10.6
30 14.8 12.8 10.8
32 15.2 13.1 10.9
34 15.4 13.3 11.2
36 15.6 13.5 11.3
38 15.8 13.6 11.4
40 16.0 13.8 11.6Embryogenesis and Fetal Development 129
CHAPTER 7
to oset their higher volume an viscosity. Tey also contain
several enzymes with appreciably ierent activities.
Erythropoiesis is controlle primarily by etal erythropoietin
because maternal erythropoietin oes not cross the placenta. Fetal
hormone prouction is infuence by testosterone, estrogen,
prostaglanins, thyroi hormone, lipoproteins, an importantly,
by etal hypoxia (eramo, 2018). Serum erythropoietin levels
rise with etal maturity.
Te etal liver is an important source until renal pro-
uction begins near term.
Te erythropoietin concentration in amnionic fui
correlates closely with that
in umbilical venous bloo
obtaine by corocentesis.
Ater birth, erythropoietin
normally may not be etectable or up to 3 months.
In contrast, platelet pro-
uction reaches stable levels
by mipregnancy, although
there is some variation across
gestation (Fig. 7-10). Te
etal an neonatal platelet
count is subject to various
agents, which are iscusse
in Chapter 18 (p. 359).
Fetal Hemoglobin
Tis tetrameric protein is
compose o two copies o
two ierent peptie chains,
95th
100,000
400,000
200,000
300,000
24 26 28 30 32 34 36 38 40 42
Gestational age (weeks)
Platelets (per µL)
50th
5th
FIGURE 7-10 Platelet counts by gestational age obtained the first
day of life. Mean values and 5th and 95th percentiles are shown.
(Data from Christensen RD, Henry E, Antonio DV: Thrombocytosis
and thrombocytopenia in the NICU: incidence, mechanisms and
treatments, J Matern Fetal Neonatal Med 25 Suppl 4:15, 2012.)
FIGURE 7-11 Hemoglobin types transition throughout pregnancy. Alpha (α) and zeta (ζ) globin chains
are interchangeable. The beta (β) globin chain can be replaced by epsilon (ε), gamma (γ), or delta ( δ)
globin chains. In embryonic life (stage I), ζ and ε globin chain production is gradually replaced by α
and γ globin chain production. Hemoglobin F is the main type in fetal life (stage II). After birth (stage III),
HbA1 predominates.
which etermine the type o hemoglobin prouce
(Fig. 7-11). Normal ault hemoglobin A1 is mae o α an
β chains. During embryonic an etal lie, various α an β
chain precursors are prouce. Tis results in the serial pro-
uction o several ierent embryonic hemoglobins. At least
17 genetic loci potentially regulate erythropoiesis (umburu,
2017). Genes or β-type chains are on chromosome 11, an
those or α-type chains on chromosome 16. Each o these
genes is turne on an then o uring etal lie, until α an
β genes, which irect the prouction o ault hemoglobin A1,
are permanently activate.
Te timing o prouction o each o these early hemoglobins
correspons to the site o hemoglobin prouction. Fetal bloo
is rst prouce in the yolk sac, where hemoglobins Gower 1,
Gower 2, an Portlan are mae. Erythropoiesis then moves
to the liver, where etal hemoglobin F is prouce. When
hemopoiesis nally moves to the bone marrow, ault-type
hemoglobin A1 appears in etal re bloo cells an is present
in progressively greater amounts as the etus matures (Lessar,
2018).
Te nal ault version o the α chain is prouce exclusively by 6 weeks. Ater this, there are no unctional alternative
versions, an the gene or the zeta (ζ) globin chain is ownregulate. I the gene coing the α globin chain unergoes
mutation, no alternate α-type chain can be substitute to orm
unctional hemoglobin. In contrast, at least two versions o the
β chain—δ an γ—remain in prouction throughout etal lie
an beyon. With a mutation in the gene coing the β globin
chain, these two other versions o the β chain oten continue
to be prouce, resulting in either hemoglobin A2 (α2δ2) or130 Placentation, Embryogenesis, and Fetal Development
Section 3
hemoglobin F (α2γ2), which substitute or the abnormal or
missing hemoglobin A1.
Genes are turne o by methylation o their control region,
which is iscusse in Chapter 13 (p. 322). In some situations,
methylation oes not occur. For example, in newborns o iabetic women, hemoglobin F may persist ue to hypomethylation o the γ gene (Perrine, 1988). With sickle-cell anemia,
the γ gene remains unmethylate, an large quantities o etal
hemoglobin continue to be prouce. As iscusse in Chapter
59 (p. 1053), elevate hemoglobin F levels are associate with
ewer sickle-cell isease symptoms, an pharmacological moi-
cation o these levels by hemoglobin F–inucing rugs is one
treatment approach (Pasricha, 2018).
Hemoglobins A an F unction ierently. At any given
oxygen tension an at ientical pH, etal erythrocytes that
contain mostly hemoglobin F bin more oxygen than o
those that contain nearly all hemoglobin A (Fig. 50-2, p.
886). Tis is because hemoglobin A bins 2,3-iphosphoglycerate (2,3-DPG) more avily than oes hemoglobin F.
Remember that 2,3-DPG is an intraerythrocyte phosphate,
an hemoglobin has a reciprocal anity or 2,3-DPG an
oxygen (Benesch, 1968). Tus, hemoglobin A’s greater
2,3-DPG bining lowers its oxygen anity compare with
hemoglobin F. Moreover, uring pregnancy, maternal 2,3-
DPG levels are greater, an because etal erythrocytes have
lower concentrations o 2,3-DPG, etal cells have increase
oxygen anity.
Te amount o hemoglobin F in etal erythrocytes begins
to ecrease in the last weeks o pregnancy. At term, approximately three ourths o total hemoglobin levels are hemoglobin
F. During the rst 6 to 12 months o lie, the hemoglobin F
proportion continues to ecline an eventually reaches the low
levels oun in ault erythrocytes (Pasricha, 2018).
Coagulation Factors
With the exception o brinogen, other hemostatic proteins o
not exist in embryonic orms. Te etus starts proucing normal, ault-type procoagulant, brinolytic, an anticoagulant
proteins by 12 weeks. Because they o not cross the placenta,
their concentrations at birth are markely below the levels that
evelop within a ew weeks o lie (Corrigan, 1992). In normal
neonates, the levels o actors II, VII, IX, X, an XI, an o protein S, protein C, antithrombin, an plasminogen, all approximate 50 percent o ault levels. In contrast, levels o actors V,
VIII, XIII, an brinogen are closer to ault values (Saracco,
2009). Maternal vitamin K eciency has been associate with
etal cerebral hemorrhage (Goto, 2018). Without prophylactic
treatment, the levels o vitamin K–epenent coagulation actors usually rop even urther uring the rst ew ays ater
birth. Tis ecline is amplie in breaste inants an may
lea to newborn hemorrhage (Chap. 33, p. 606). Schott (2018)
an Konstantinii (2019) an their colleagues have provie
thromboelastographic parameters or both healthy an sick
term newborns.
Fetal brinogen, which appears as early as 5 weeks, has the
same amino aci composition as ault brinogen but ierent properties (Klagsbrun, 1988). It orms a less compressible
clot, an the brin monomer has a lower egree o aggregation
(Heimark, 1988). Although plasma brinogen levels at birth are
less than those in nonpregnant aults, the protein is unctionally
more active than ault brinogen (Ignjatovic, 2011). Neonates
have higher cor plasma levels an bronectin-brinogen complexes compare with maternal levels (Lis-Kuberka, 2018).
Levels o unctional etal actor XIII (brin stabilizing actor)
are signicantly reuce compare with those in aults (Henriksson, 1974). Nielsen (1969) escribe low levels o plasminogen an elevate brinolytic activity in cor plasma compare
with that o maternal plasma. Platelet counts in cor bloo are
in the normal range or nonpregnant aults.
Despite this relative reuction in procoagulants, the etus
appears to be protecte rom hemorrhage, an etal bleeing is
rare. Even ater invasive etal proceures such as corocentesis,
excessive bleeing is uncommon. Ney an coworkers (1989)
have shown that amnionic fui thromboplastins an a actor(s)
in Wharton jelly combine to ai coagulation at the umbilical
cor puncture site.
Various thrombophilias may cause thromboses an pregnancy complications in aults (Chap. 55, p. 976). I the etus
inherits one o these mutations, thrombosis an inarction can
evelop in the placenta or etal organs. Tis is usually seen with
homozygous inheritance. One example is homozygous protein
C mutation, which causes purpura fulminans.
Plasma Proteins
Liver enzymes an other plasma proteins are prouce by the
etus, an these levels o not correlate with maternal levels
(Weiner, 1992). Concentrations o plasma proteins, which
inclue albumin, lactic ehyrogenase, aspartate an alanine aminotranserases, an γ-glutamyl transpeptiase, all
rise. Conversely, prealbumin levels ecline with gestational
age (Fryer, 1993). At birth, mean total plasma protein an
albumin concentrations in etal bloo are similar to maternal
levels. Tis is important because albumin bins unconjugate
bilirubin to prevent kernicterus in the newborn (Chap. 33,
p. 606).
■ Respiratory System
Lung maturation an biochemical inices o unctional etal
lung maturity are important preictors o early neonatal
outcome. Morphological or unctional immaturity at birth leas
to the evelopment o the respiratory distress syndrome (Chap.
34, p. 615). A sucient amount o surace-active materials—
collectively reerre to as surfactant—in the amnionic fui is
evience o etal lung maturity (Warburton, 2017). As Liggins
(1994) emphasize, however, the structural an morphological maturation o etal lung also is extraorinarily important to
proper lung unction.
Anatomical Maturation
Like the branching o a tree, lung evelopment procees along
an establishe timetable. As with other organ systems, gene
activation an eactivation control these unctions (Miller,
2019). Te lung primorium is an outgrowth rom oregut
enoerm at approximately 20 ays’ gestation. Te lung bu
arises at 25 ays an within this ramework, our essential lungEmbryogenesis and Fetal Development 131
CHAPTER 7
evelopment stages are escribe by Moore (2020). First, the
pseudoglandular stage entails growth o the intrasegmental bronchial tree between the 5th an 17th weeks. Te microvasculature begins to evelop, an the lung looks microscopically
like a glan. Secon, uring the canalicular stage, rom 16 to
25 weeks, the bronchial cartilage plates exten peripherally.
Each terminal bronchiole gives rise to several respiratory bronchioles, an each o these in turn ivies into multiple saccular ucts. Tir, the terminal sac stage begins ater 25 weeks.
During this stage, primorial alveoli give rise to primitive pulmonary alveoli, that is, the terminal sacs. Simultaneously, an
extracellular matrix evelops rom proximal to istal lung segments until term. Te ourth alveolar stage begins uring the
late etal perio an continues well into chilhoo. An extensive capillary network is built, the lymphatic system orms, an
type II pneumocytes begin to prouce suractant. At birth, only
approximately 15 percent o the ault number o alveoli is present. Tus, the lung continues to grow an a more alveoli or
up to 8 years.
Various insults can upset this process, an their timing
etermines the sequelae. During the embryonic phase, abnormalities in lung evelopment inclue esophageal an tracheal
atresia, tracheoesophageal stula, an pulmonary agenesis.
Another example is etal renal agenesis in which amnionic fui
is absent at the beginning o lung growth, an major eects
occur in all our evelopmental stages. Similarly, the etus with
membrane rupture an subsequent oligohyramnios beore 20
weeks usually exhibits nearly normal bronchial branching an
cartilage evelopment but has immature alveoli. In contrast,
membrane rupture ater 24 weeks may have minimal long-term
eect on pulmonary structure. Last, vitamin D is thought to be
important or several aspects o lung evelopment (Hart, 2015;
Ustun, 2020).
Pulmonary Surfactant
Ater the rst breath, the terminal sacs must remain expane
espite the pressure imparte by the tissue-to-air interace, an
suractant keeps them rom collapsing. Suractant is orme in
type II pneumocytes that line the alveoli. Tese cells are characterize by multivesicular boies that prouce the lamellar
boies in which suractant is assemble. During late etal lie,
at a time when the alveolus is characterize by a water-to-tissue
interace, the intact lamellar boies are secrete rom the lung
an swept into the amnionic fui uring respiratory-like
movements that are terme etal breathing. At birth, with
the rst breath, an air-to-tissue interace is establishe in the
lung alveolus. Suractant uncoils rom the lamellar boies an
spreas to line the alveolus to prevent alveolar collapse uring
expiration. Tus, the etal lungs’ capacity to prouce suractant establishes lung maturity.
Surfactant Composition. Gluck (1972) an Hallman (1976)
an their coworkers approximate that 90 percent o suractant
ry weight is lipi, specically glycerophospholipis. Proteins
account or the other 10 percent. Nearly 80 percent o the
glycerophospholipis are phosphatiylcholines (lecithins). Te
principal active component that constitutes hal o suractant
is a specic lecithin, which is ipalmitoyl phosphatiylcholine
(DPPC or PC). Phosphatiylglycerol (PG) accounts or another
8 to 15 percent. Its precise role is unclear because newborns
without PG usually o well. Te other major constituent is
phosphatiylinositol (PI).
Surfactant Synthesis. Biosynthesis takes place in the type II
pneumocytes. Te apoproteins are prouce in the enoplasmic reticulum, an the glycerophospholipis are synthesize
by cooperative interactions o several cellular organelles. Phospholipi is the primary surace tension–lowering component
o suractant, whereas the apoproteins ai the orming an
reorming o a surace lm.
Te major apoprotein is suractant A (SP-A), which is a glycoprotein with a molecular weight o 28,000 to 35,000 Da. It
is synthesize in the type II cells, an its content in amnionic
fui increases with gestational age an etal lung maturity.
SP-A gene expression is emonstrable by 29 weeks (Menelson,
2005). Specically, SP-A1 an SP-A2 are two separate genes on
chromosome 10, an their regulation is istinctive an ierent (McCormick, 1994).
Corticosteroids and Fetal Lung Maturation. Since Liggins
(1969) observe accelerate lung maturation in lamb etuses
given glucocorticosteroi prior to preterm elivery, many suggeste that etal cortisol stimulates lung maturation an suractant synthesis. It is unlikely, however, that corticosterois are the
only stimulus or augmente suractant ormation. But, when
these are aministere at certain critical times, they may improve
preterm etal lung maturation. Antenatal betamethasone an
examethasone or lung maturation an neonatal replacement
suractant therapy are iscusse in Chapter 34 (p. 617).
Breathing
Fetal respiratory muscles evelop early, an chest wall movements are etecte sonographically as early as 11 weeks (Koos,
2014). Breathing is essential or normal lung growth an
evelopment. From the beginning o the ourth month, the
etus engages in respiratory movement suciently intense to
move amnionic fui in an out o the respiratory tract. Some
extrauterine events have eects on etal breathing, or example,
maternal exercise stimulates it (Sussman, 2016).
■ Digestive System
Ater its embryogenic ormation rom the yolk sac as the primorial gut, the igestive system orms the intestines an various appenages. Te oregut gives rise to the pharynx, lower
respiratory system, esophagus, stomach, proximal uoenum,
liver, pancreas, an biliary tree. Te migut gives rise to the
istal uoenum, jejunum, ileum, cecum, appenix, an the
right colon. Te hingut evelops into the let colon, rectum,
an the superior portion o the anal canal that empties into the
cloaca (Kruepunga, 2018). Numerous malormations evelop
in these structures rom improper rotation, xation, an partitioning. A common example is one o the several types o
intestinal atresias (Moore, 2020; Stoll, 2017).
Swallowing begins at 10 to 12 weeks, coincient with
the ability o the small intestine to unergo peristalsis an132 Placentation, Embryogenesis, and Fetal Development
Section 3
to actively transport glucose (Kolovsky, 1965). As a correlate, neonates born preterm may have swallowing iculties
because o immature gut motility (Singenonk, 2014). Much
o the water in swallowe fui is absorbe, an unabsorbe
matter is propelle to the lower colon. Gitlin (1974) emonstrate that late in pregnancy, approximately 800 mg o soluble
protein is ingeste aily by the etus. Te stimulus or swallowing is unclear, but the etal neural analogue o thirst, gastric
emptying, an change in the amnionic fui composition are
potential actors (Boyle, 1992). Te etal taste bus may play
a role because saccharin injecte into amnionic fui increases
swallowing, whereas injection o a noxious chemical inhibits it
(Liley, 1972).
Fetal swallowing appears to have little eect on amnionic
fui volume early in pregnancy because the volume swallowe
is small compare with the total. However, term etuses swallow between 200 an 760 mL per ay—an amount comparable
to that o the term neonate (Pritchar, 1966). Tus at term,
amnionic fui volume regulation can be substantially altere
by etal swallowing. For example, as iscusse in Chapter 14
(p. 256), i swallowing is inhibite, hyramnios is common.
Hyrochloric aci an some igestive enzymes are present in the stomach an small intestine in minimal amounts
in the early etus. Intrinsic actor is etectable by 11 weeks,
an pepsinogen by 16 weeks. Te preterm neonate, epening
on its gestational age, may have transient eciencies o these
enzymes. Te small intestinal histological appearance is normal
(Meier, 2018).
Stomach emptying appears to be stimulate primarily by
volume. A ilate stomach suggests obstruction (McCormick,
2021). Movement o amnionic fui through the gastrointestinal system may enhance growth an evelopment o the
alimentary canal. Tat sai, other regulatory actors likely are
involve. For example, anencephalic etuses, in which swallowing is limite, oten have normal amnionic fui volume an
normal-appearing gastrointestinal tract.
Meconium
Fetal bowel contents consist o various proucts o secretion,
such as glycerophospholipis rom the lung, esquamate etal
cells, lanugo, scalp hair, an vernix. It also contains unigeste
ebris rom swallowe amnionic fui. Te ark greenishblack color orms rom bile pigments, especially biliverin.
Meconium can pass rom normal bowel peristalsis in the
mature etus or rom vagal stimulation. It can also pass when
hypoxia stimulates arginine vasopressin (AVP) release rom the
etal pituitary glan. AVP stimulates colonic smooth muscle
to contract, resulting in intraamnionic eecation (Rosenel,
1985). Meconium is toxic to the respiratory system, an its
inhalation can result in meconium aspiration syndrome.
Liver
Te hepatic iverticulum is an outgrowth o the enoermal
lining o the oregut. Epithelial liver cors an primorial cells
ierentiate into hepatic parenchyma. By 9 weeks, the liver
accounts or 10 percent o etal weight (Moore, 2020). Serum
liver enzyme levels increase with gestational age. As note, in
early gestation, etal hepatic hemopoiesis is a key source o
bloo an immune cells (p. 125) (Popescu, 2019).
Te etal liver has a gestational-age-relate capacity to conjugate bilirubin, which orms rom hemoglobin breakown
(Morioka, 2015). Because o hepatic immaturity, the preterm
newborn is at particular risk or unconjugate hyperbilirubinemia (Chap. 33, p. 606). An because the lie span o normal etal macrocytic erythrocytes is shorter than that o the
ault, relatively more unconjugate bilirubin is prouce. O
this unconjugate orm, only a small raction is conjugate
by the etal liver, an this is excrete into the intestine an
ultimately oxiize to biliverin. Instea, most o the unconjugate bilirubin is excrete into the amnionic fui ater
12 weeks an transerre across the placenta (Bashore, 1969).
Importantly, placental bilirubin transer is biirectional. Tus,
a woman with severe hemolysis has excess unconjugate bilirubin that reaily passes to the etus an then into the amnionic
fui. Conversely, conjugate bilirubin is not exchange to any
signicant egree between mother an etus.
Most etal cholesterol erives rom hepatic synthesis, which
satises the large eman or low-ensity lipoprotein (LDL)
cholesterol by the etal arenal glans. However, an estimate
20 to 50 percent o etal cholesterol originates rom the mother,
is transerre through the placenta, an release to circulating
etal apolipoproteins (Baarman, 2012; Pecks, 2014). Fetuses
with growth restriction have lower cholesterol levels ue to
iminishe etal synthesis rather than iminishe maternal
supply (Pecks, 2019).
Hepatic glycogen is present in low concentration uring the
secon trimester, but near term, levels rise rapily an markely to reach concentrations that are two- to threeol higher
than those in the ault liver. Ater birth, glycogen content alls
precipitously.
Pancreas
Tis glan arises rom orsal an ventral pancreatic bus rom
the enoerm o the oregut (Moore, 2020). Gene regulation o its evelopment has been reviewe (Jennings, 2015).
Insulin-containing granules can be ientie by 9 to 10 weeks,
an insulin is etectable in etal plasma at 12 weeks (Aam,
1969). Between 19 an 36 weeks, Kivilevitch an associates
(2017) were able to visualize the pancreas sonographically in
60 percent o etuses.
Te etal pancreas respons to hyperglycemia by secreting insulin (Obenshain, 1970). Islets o Langerhans are
enlarge in etuses o mothers with metabolic abnormalities
(Avagliano, 2019). Tese etuses likely can be ientie by
sonographic pancreatic hyperechogenicity (Akkaya, 2018).
Glucagon has been ientie in the etal pancreas at 8 weeks.
Although hypoglycemia oes not cause an increase in etal
glucagon levels, similar stimuli o so by 12 hours ater birth
(Chez, 1975).
Most pancreatic enzymes are present by 16 weeks. rypsin, chymotrypsin, phospholipase A, an lipase are oun in
the 14-week etus, an their concentrations increase with gestational age (Werlin, 1992). Amylase has been ientie in
amnionic fui at 14 weeks (Davis, 1986). Te exocrine unction o the etal pancreas is limite. Physiologically importantEmbryogenesis and Fetal Development 133
CHAPTER 7
secretion occurs only ater stimulation by a secretagogue such
as acetylcholine, which is release locally ater vagal stimulation (Werlin, 1992). Cholecystokinin normally is release
only ater protein ingestion an thus orinarily is not oun
in the etus.
■ Urinary System
Renal evelopment involves interaction between pluripotential
stem cells, unierentiate mesenchymal cells, an epithelial
components (Fanos, 2015). wo primitive urinary systems—
the pronephros an the mesonephros—precee evelopment o
the metanephros, which orms the nal kiney. Te pronephros
involutes by 2 weeks, an the mesonephros prouces urine at
5 weeks an egenerates by 11 to 12 weeks. Failure o these two
structures either to orm or to regress may result in anomalous
urinary system evelopment. Between 9 an 12 weeks, the ureteric bu an the nephrogenic blastema interact to prouce the
metanephros. Glomeruli evelop an ltration begins by week 9
(Moore, 2020). Te kiney an ureter evelop rom intermeiate mesoerm. Te blaer an urethra evelop rom the urogenital sinus. Te blaer also evelops in part rom the allantois.
Urogenital embryology is a ocus o Chapter 3.
By week 14, the loop o Henle is unctional an reabsorption occurs (Smith, 1992). New nephrons continue to be
orme until 36 weeks (Linström, 2018). In preterm neonates, their ormation continues ater birth. Although the etal
kineys prouce urine, their ability to concentrate an mo-
iy the pH is limite even in the mature etus. Fetal urine is
hypotonic with respect to etal plasma an has low electrolyte
concentrations.
Renal vascular resistance is high, an the ltration raction
is low compare with ault values (Smith, 1992). Fetal renal
bloo fow an thus urine prouction are controlle or infuence by the renin-angiotensin system, the sympathetic nervous system, prostaglanins, kallikrein, an atrial natriuretic
peptie. Te glomerular ltration rate increases with gestational age rom less than 0.1 mL/min at 12 weeks to 0.3 mL/
min at 20 weeks. In later gestation, the rate remains constant
when correcte or etal weight (Smith, 1992). Hemorrhage or
hypoxia generally ecreases renal bloo fow, glomerular ltration rate, an urine output.
Urine usually is oun in the blaer even in small etuses.
Te etal kineys start proucing urine at 12 weeks. By 18 weeks,
they are proucing 7 to 14 mL/, an at term, this increases
to 650 mL/ (Wlaimiro, 1974). Maternally aministere
urosemie augments etal urine ormation, whereas uteroplacental insuciency, etal-growth restriction, an other etal
isorers can lower it. Obstruction o the urethra, blaer, ureters, or renal pelves can amage renal parenchyma an istort
etal anatomy (Müller Brochut, 2014). Pathological correlates
an prenatal therapy o urinary tract obstruction are iscusse
in Chapter 19 (p. 376).
Kineys are not essential or survival in utero but infuence control o amnionic fui composition an volume. Tus,
abnormalities that cause chronic etal anuria are usually accompanie by oligohyramnios an pulmonary hypoplasia (Cotton, 2017).
■ Endocrine Gland Development
Te etal enocrine system is unctional or some time beore
the central nervous system reaches maturity (Mulchahey, 1987).
Pituitary Gland
Te anterior pituitary glan evelops rom oral ectoerm—the
Rathke pouch—whereas the posterior pituitary glan erives
rom neuroectoerm. Embryonic evelopment involves a
complex an highly spatiotemporally regulate network o
signaling molecules an transcription actors (Bancalari, 2012;
Montenegro, 2019).
Anterior and Intermediate Lobes. Te aenohypophysis, or
anterior pituitary, ierentiates into ve cell types that secrete
six protein hormones. O these types, lactotropes prouce prolactin (PRL), somatotropes prouce growth hormone (GH),
corticotropes prouce arenocorticotropic hormone (ACH),
thyrotropes prouce thyroi-stimulating hormone (SH), an
gonaotropes prouce luteinizing hormone (LH) an olliclestimulating hormone (FSH).
ACH is rst etecte in the etal pituitary glan at 7
weeks, an GH an LH have been ientie by 13 weeks. By
the en o the 17th week, the etal pituitary glan synthesizes
an stores all pituitary hormones. Moreover, the etal pituitary
is responsive to tropic hormones an is capable o secreting
these early in gestation (Grumbach, 1974). Te etal pituitary
secretes β-enorphin, an cor bloo levels o β-enorphin
an β-lipotropin rise with etal arterial partial pressure o carbon ioxie (Paco2) (Browning, 1983).
Te intermeiate lobe in the etal pituitary glan is well
evelope. Te cells o this structure begin to isappear beore
term an are absent rom the ault pituitary.
Neurohypophysis. Te posterior pituitary glan or neurohypophysis is well evelope by 10 to 12 weeks, an oxytocin an
arginine vasopressin are emonstrable. Both hormones probably
unction in the etus to conserve water by actions irecte largely
at the lung an placenta rather than kiney. Vasopressin levels in
umbilical cor plasma are strikingly higher than maternal levels
(Char, 1971).
Thyroid Gland
Te thyroi primorium arises rom the enoerm o the primorial pharynx (Moore, 2020). Te thyroi migrates to its
nal position, an the obliterate thyroglossal uct connects to
the oramen cecum o the tongue.
Te pituitary–thyroi system is unctional by the en o the
rst trimester. By 10 to 12 weeks, the thyroi glan is able to
synthesize hormones, an thyrotropin, thyroxine, an thyroi-
bining globulin (BG) have been etecte in etal serum as
early as 11 weeks (Bernal, 2007). Tyroi ollicles have orme
an colloi is present. Te placenta actively concentrates ioine
on the etal sie, an by 12 weeks an throughout pregnancy,
the etal thyroi concentrates ioine more avily than oes
the maternal thyroi. Tus, maternal aministration o either
raioioine or appreciable amounts o orinary ioine is hazarous ater this time (Chap. 66, p. 1174). Normal etal levels
o ree thyroxine (4), ree triioothyronine (3), an BG rise134 Placentation, Embryogenesis, and Fetal Development
Section 3
steaily throughout gestation (Ballabio, 1989). Compare with
ault levels, by 36 weeks, etal serum concentrations o SH
are higher, total an ree 3 concentrations are lower, an 4
is similar. Tis suggests that the etal pituitary may not become
sensitive to eeback until late pregnancy.
Fetal thyroi hormone plays a role in the normal evelopment o virtually all etal tissues, especially the brain (Anersen,
2018; Jansen, 2019). Congenital hypothyroiism is a heterogenous isorer or which several caniate genes have been ientie (Moore, 2020). With hypothyroiism, it was previously
believe that normal etal growth an evelopment provie
evience that 4 was not essential or etal growth. It is now
known, however, that growth procees normally because small
quantities o maternal 4 prevent antenatal cretinism in etuses
with thyroi agenesis (Forhea, 2014; Vulsma, 1989). As iscusse in Chapter 61 (p. 1098), the etus with congenital hypothyroiism typically oes not evelop stigmata o cretinism
until ater birth (Abuljabbar, 2012). Because aministration
o thyroi hormone will prevent this, by state law, all newborns
are teste or high serum levels o SH (Chap. 32, p. 594).
Te placenta prevents substantial passage o maternal thyroi hormones to the etus by rapily eioinating maternal
4 an 3 to orm reverse 3, a relatively inactive thyroi hormone. Several antithyroi antiboies cross the placenta when
present in high concentrations (Pelag, 2002). Tose inclue
the long-acting thyroi stimulators (LAS), LAS-protector
(LAS-P), an thyroi-stimulating immunoglobulin (SI).
Congenital hyperthyroiism evelops when maternal thyroi-
stimulating antiboy crosses the placenta to stimulate the etal
glan to secrete thyroxine (Donnelley, 2015). Tese etuses
evelop large goiters as shown in Figure 61-3 (p. 1092). Tey
also isplay tachycaria, hepatosplenomegaly, hematological
abnormalities, craniosynostosis, an growth restriction. As chil-
ren, they have perceptual motor iculties, hyperactivity, an
reuce growth (Johns, 2018).
Immeiately ater birth, thyroi unction an metabolism
unergo major change. Cooling to room temperature evokes
a suen an marke increase in SH secretion. Tis in turn
causes a progressive increase in serum 4 levels that are maximal
24 to 36 hours ater birth. Tere are nearly simultaneous elevations o serum 3 levels.
Adrenal Glands
Tese glans evelop rom two separate tissues. Te meulla
erives rom neural crest ectoerm, whereas the etal an
ault cortex arise rom intermeiate mesoerm. Te glan
grows rapily through cell prolieration an angiogenesis,
cellular migration, hypertrophy, an apoptosis (Ishimoto,
2011). Expression o the Kiss1R gene, alone or in concert
with corticotropin-releasing hormone, stimulates etal arenal growth (Katugampola, 2017). Fetal glans are enormous
in relation to boy size an are 10 to 20 times larger than
ault glans (Karsli, 2019; Moore, 2020). Te bulk is mae
up o the inner or etal zone o the arenal cortex an involutes rapily ater birth. Tis zone is scant to absent in rare
instances in which the etal pituitary glan is congenitally
absent. Te unction o the etal arenal glans is iscusse
in Chapter 5 (p. 102).
■ Immunological System
Inections in utero have provie an opportunity to examine
mechanisms o the etal immune response (Chap. 67, p. 1182).
Evience o immunological competence has been reporte as
early as 13 weeks (Stabile, 1988). In cor bloo at or near
term, the average level or most components approximates hal
that o the ault values.
B cells ierentiate rom pluripotent hemopoietic stem cells
that migrate to the liver (Berthault, 2017; Melchers, 2015).
Despite this, in the absence o a irect antigenic stimulus such
as inection, etal plasma immunoglobulins consist almost
totally o transerre maternal immunoglobulin G (IgG). Tus,
antiboies in the newborn most oten refect maternal immunological experiences (American College o Obstetricians an
Gynecologists, 2019). Te interaction between maternal an
etal cells is escribe in Chapter 5 (p. 93).
Immunoglobulin G
Maternal IgG transport correlates with placental Fc receptor
expression (Lozano, 2018). Fetal transport begins at approximately 16 weeks an increases thereater. Because the bulk o
IgG is acquire uring the last 4 weeks, preterm neonates are
poorly enowe with protective maternal antiboies. Newborns begin to slowly prouce IgG, an ault values are not
attaine until age 3 years. In certain situations, the transer o
IgG antiboies rom mother to etus can be harmul rather
than protective. Te classic example is hemolytic isease o the
etus an newborn resulting rom Rh-antigen alloimmunization (Chap. 18, p. 353).
Immunoglobulins M and A
In the ault, prouction o immunoglobulin M (IgM) in
response to an antigenic stimulus is supersee in a week or so
preominantly by IgG prouction. Similarly, very little IgM
is prouce by normal etuses not expose to inection, but
with inection, the IgM response preominates an remains so
or weeks to months in the newborn. An, because IgM is not
transporte rom the mother, any IgM in the etus or newborn is
that which it prouce. Tus, specic IgM levels in umbilical cor
bloo may be elevate in those with congenital inection. Accor-
ing to the American College o Obstetricians an Gynecologists
(2019), elevate IgM levels are usually oun in newborns with
congenital inection such as rubella, cytomegalovirus inection,
or toxoplasmosis. In inants, ault levels o IgM are normally
attaine by age 9 months.
Immunoglobulin A (IgA) ingeste in colostrum provies
mucosal protection against enteric inections. Tere is only a
small amount o etal secretory IgA oun in amnionic fui
(Quan, 1999).
Lymphocytes and Monocytes
Te immune system evelops early, an B lymphocytes are
erive rom primorial stem cells an appear in etal liver
by 9 weeks an in bloo an spleen by 12 weeks (Moore,
2020). lymphocytes begin to leave the thymus at approximately 14 weeks. Despite this, the newborn respons poorly
to immunization, an especially poorly to bacterial capsularEmbryogenesis and Fetal Development 135
CHAPTER 7
polysaccharies. Tis immature response may stem rom a
ecient response o newborn B cells to polyclonal activators
or rom a lack o cells that prolierate in response to specic stimuli (Haywar, 1983). In the newborn, monocytes are
able to process an present antigen when teste with maternal
antigen-specic cells. DNA methylation patterns are evelopmentally regulate uring monocyte-macrophage ierentiation an contribute to the antiinfammatory phenotype in
macrophages (Kim, 2012).
■ Musculoskeletal System
Te origin o most muscles an bones is mesoermal. MYOD
is a member o the amily o myogenic regulatory actors that
activates transcription o muscle-specic genes (Moore, 2020).
Te limb bus appear by the ourth week. Most skeletal muscle
erives rom myogenic precursor cells in the somites. Te skeleton arises rom conense mesenchyme—embryonic connective tissue—which eventually orms hyaline cartilage moels o
the bones. Osteoclasts arise rom erythro-myeloi progenitors
(Jacome-Galarza, 2019). By the en o the embryonic perio,
ossication centers have evelope, an bones haren by enochonral ossication.
ENERGY AND NUTRITION
Because o the small amount o yolk in the human ovum,
growth o the embryoetus is epenent on maternal nutrients uring the rst 2 months. During the rst ew ays ater
implantation, blastocyst nutrition comes rom the interstitial
fui o the enometrium an the surrouning maternal tissue.
Maternal aaptations to store an transer nutrients to the
etus are iscusse in Chapter 4 an summarize here. Tree
major maternal storage epots are the liver, muscle, an aipose
tissue. Tese maternal epots an the storage hormone insulin are intimately involve in the metabolism o the nutrients
absorbe rom the gut. Maternal insulin secretion is sustaine
by increase serum levels o glucose an amino acis. Te net
eect is maternal storage o glucose as glycogen primarily in
liver an muscle, retention o some amino acis as protein,
an storage o the excess as at (Abeysekera, 2016). Storage o
maternal at peaks in the secon trimester an then eclines as
etal energy emans rise in the thir trimester (Pipe, 1979).
Interestingly, the placenta appears to act as a nutrient sensor,
altering transport base on the maternal supply an environmental stimuli (Jansson, 2006b, Wesolowski, 2017).
During times o asting, glucose is release rom glycogen, but maternal glycogen stores cannot provie an aequate
amount o glucose to meet requirements or maternal energy
an etal growth. Augmentation is provie by cleavage o triacylglycerols, store in aipose tissue, which results in ree atty
acis an activation o lipolysis.
■ Glucose and Fetal Growth
Although epenent on the mother or nutrition, the etus also
actively participates in proviing its own nutrition. At mi-
pregnancy, etal serum glucose concentration is inepenent
o maternal levels an may excee them. Glucose is the major
nutrient or etal growth an energy. Logically, mechanisms
exist to minimize maternal glucose use so that the limite maternal supply is available to the etus. As one example, human placental lactogen (hPL) is a hormone normally abunant in the
mother but not the etus an has an insulin antagonist eect. It
blocks the peripheral uptake an use o glucose, while instea
promoting mobilization an use o ree atty acis by maternal
tissues (Chap. 5, p. 98). Tis hormone is also iabetogenic as
iscusse in Chapter 60 (p. 1068). Last, intrinsic epigenetic
changes play a role (Hansen, 2017). For example, nonalcoholic
atty liver isease (NAFLD) is associate with etal macrosomia
(Lee, 2019).
Glucose Transport
Te transer o d-glucose across cell membranes is accomplishe
by a carrier-meiate, stereospecic, nonconcentrating process
o acilitate iusion. Tere are 14 glucose transport proteins
(GLUs) encoe by the SLC2A gene amily an characterize
by tissue-specic istribution (Joshi, 2021). Several o these
are expresse by trophoblast (Stanirowski, 2017). GLU-1,
GLU-3, an GLU-4 primarily ai glucose uptake by the
placenta an are locate in the plasma membrane o the syncytiotrophoblast microvilli (Acosta, 2015; James-Allan, 2019).
DNA methylation regulates expression o placental GLUT
genes, with epigenetic moication across gestation (Novakovic, 2013). Methylation increases as pregnancy avances an
is inuce by almost all growth actors.
In aition to its transport role, the placenta uses glucose or
its metabolic unctions. Fetal an placental glucose consumption are inversely relate. Tus, placental glucose use is a key
moulator o maternal-etal transer (Michelsen, 2019).
Lactate is a prouct o glucose metabolism an transporte
across the placenta also by acilitate iusion. By way o
cotransport with hyrogen ions, lactate is probably transporte
as lactic aci.
Fetal Macrosomia
Te precise biomolecular events in the pathophysiology o
etal macrosomia are not ene. Nonetheless, etal hyperinsulinemia is clearly one riving orce (Luo, 2012). As iscusse
with etal-growth isorers in Chapter 47 (p. 824), insulin-like
growth actor an leptin an other aipokines are important
regulators o placental evelopment an unction (Gao, 2012).
Maternal obesity begets etal macrosomia. In aition, theories suggest that maternal obesity aects etal cariomyocyte
growth that may result in etal cariomyopathy or even congenital heart isease (Roberts, 2015).
■ Leptin
Tis polypeptie hormone was originally ientie as a pro-
uct o aipocytes an a regulator o energy homeostasis by
curbing appetite. It also contributes to angiogenesis, hemopoiesis, osteogenesis, pulmonary maturation, an neuroenocrine,
immune, an reprouctive unctions (Bria, 2015). Leptin is
prouce by the mother, etus, an placenta. It is expresse
in syncytiotrophoblast an etal vascular enothelial cells. O136 Placentation, Embryogenesis, and Fetal Development
Section 3
placental prouction, 5 percent enters the etal circulation,
whereas 95 percent is transerre to the mother (Hauguel-e
Mouzon, 2006).
Leptin concentrations peak in amnionic fui at mipregnancy (Scott-Finley, 2015). Fetal serum leptin levels begin
increasing at approximately 34 weeks an are correlate with
etal weight. Tis hormone is involve in the evelopment an
maturation o the heart, brain, kineys, an pancreas, an its
levels are ecrease with etal-growth restriction (Bria, 2015;
Yalinbas, 2019). Abnormal levels are associate with etalgrowth isorers, gestational iabetes, an preeclampsia, but
not maternal obesity (Allbran, 2018; Gurugubelli, 2018).
Postpartum, leptin levels ecline in both the newborn an
mother. Perinatal leptin is associate with the evelopment o
metabolic synromes later in lie (Bria, 2015).
■ Free Fatty Acids and Triglycerides
Te term newborn has a large proportion o at, which averages 15 percent o boy weight (Kimura, 1991). Tus, late in
pregnancy, a substantial part o the substrate transerre to the
human etus is store as at. Although maternal obesity raises
placental atty aci uptake an etal at eposition, it oes not
appear to aect etal organ growth (Dubé, 2012). Neutral at
in the orm o triglyceries oes not cross the placenta, but
glycerol oes. Despite this, evience supports that abnormal maternal concentrations o triglyceries—both low an
high levels—are associate with major congenital anomalies
(Neerlo, 2015).
Tere is preerential placental-etal transer o long-chain
polyunsaturate atty acis (Fonseca, 2018). Lipoprotein lipase
is present on the maternal but not on the etal sie o the placenta. Tis arrangement avors hyrolysis o triacylglycerols in
the maternal intervillous space yet preserves these neutral lipis
in etal bloo. Fatty acis transerre to the etus can be converte to triglyceries in the etal liver.
Te placental uptake an use o LDL is an alternative mechanism or etal assimilation o essential atty acis an amino
acis (Chap. 5, p. 100). LDL bins to specic receptors in the
coate-pit regions o the syncytiotrophoblast microvilli. Te
large LDL particle, measuring about 250,000 Da, is taken up
by a process o receptor-meiate enocytosis. Te apoprotein an cholesterol esters o LDL are hyrolyze by lysosomal
enzymes in the syncytium to yiel: (1) cholesterol or progesterone synthesis; (2) ree amino acis, incluing essential amino
acis; an (3) essential atty acis, primarily linoleic aci.
Interestingly, maternal cholesterol is obligatory or steroi hormone synthesis, but increasing levels are associate with etal
aortic atherogenesis (e Nigris, 2018).
■ Amino Acids
Te placenta concentrates many amino acis in the syncytiotrophoblast, which are then transerre to the etal sie by
iusion. In corocentesis bloo samples, the amino aci concentration in umbilical cor plasma is greater than in maternal
venous or arterial plasma. DNA methylation serves to regulate
transporter gene expression (Simner, 2017). ransport system
activity is infuence by gestational age an environmental actors. Tese inclue heat stress, hypoxia, uner- an overnutrition, an hormones such as glucocorticois, growth hormone,
an leptin (Bria, 2015). rophoblastic mammalian target o
rapamycin complex 1 (mORC1) regulates placental amino
aci transporters an moulates transer across the placenta
(Jansson, 2012). In vivo stuies suggest an upregulation o
transport or certain amino acis an a greater elivery rate o
these to the etuses o women with gestational iabetes associate with etal overgrowth (Jansson, 2006a).
■ Proteins
Placental transer o larger proteins is limite, but there are
exceptions. As iscusse, IgG crosses the placenta in large
amounts via enocytosis an trophoblast Fc receptors. IgG
transer epens on maternal levels o total IgG, gestational
age, placental integrity, IgG subclass, an antigenic potential
(Palmeira, 2012). Conversely, the larger immunoglobulins—
IgA an IgM—o maternal origin are eectively exclue rom
the etus.
■ Ions and Trace Metals
Calcium an phosphorus are actively transporte rom
mother to etus. Calcium is transerre or etal skeletal mineralization (Olausson, 2012). A calcium-bining protein is
prouce in placenta. Parathyroi hormone–relate protein
(PH-rP), as the name implies, acts as a surrogate PH in
many systems (Chap. 5, p. 99). PH is not oun in etal
plasma, but PH-rP is present, suggesting that PH-rP
is the etal parathormone (Martin, 2016). Te expression
o PH-rP in cytotrophoblasts is moulate by the extracellular concentration o Ca2+ (Hellman, 1992). It seems
possible that PH-rP synthesize in eciua, placenta, an
other etal tissues is important in etal Ca2+ transer an
homeostasis.
Another example is the uniirectional transer o iron. ypically, maternal plasma iron concentration is much lower than
that in her etus. Even with severe maternal iron-eciency
anemia, the etal hemoglobin mass is normal.
Ioine transport is clearly attributable to a carrier-meiate,
energy-requiring active process. An, as iscusse in Chapter
61 (p. 1097), the placenta concentrates ioine (Velasco, 2018).
Te concentrations o zinc in the etal plasma also are greater
than those in maternal plasma. Conversely, copper levels in
etal plasma are less than those in maternal plasma. Tis act
is o particular interest because important copper-requiring
enzymes are necessary or etal evelopment.
Placental Sequestration of Heavy Metals
Te heavy metal–bining protein metallothionein-1 is
expresse in human syncytiotrophoblast. Tis protein bins
an sequesters a host o heavy metals, incluing zinc, copper,
lea, an camium. Despite this, etal exposure is variable
(Caserta, 2013). For example, lea enters the etal environment at a level 90 percent o maternal concentrations. In contrast, placental transer o camium is limite (Kopp, 2012).Embryogenesis and Fetal Development 137
CHAPTER 7
Te most common source o environmental camium is cigarette smoke.
Metallothionein also bins an sequesters copper in placental tissue. Tis accounts or the low copper levels in cor
bloo (Iyengar, 2001). It is possible that camium provokes
metallothionein synthesis in the amnion. Tis may cause copper sequestration, a pseuocopper eciency, an in turn,
iminishe amnion tensile strength.
■ Vitamins
Te concentration o vitamin A (retinol) is greater in etal than
in maternal plasma an is boun to retinol-bining protein
an to prealbumin. Retinol-bining protein is transerre rom
the maternal compartment across the syncytiotrophoblast. Te
transport o vitamin C—ascorbic aci—rom mother to etus
is accomplishe by an energy-epenent, carrier-meiate
process. As a result, the concentration o ascorbic aci is two
to our times higher in etal plasma than in maternal plasma
(Morriss, 1994). Levels o principal vitamin D metabolites,
incluing 1,25-ihyroxycholecalcierol, are greater in maternal plasma than in etal plasma. Te 1β-hyroxylation o
25-hyroxyvitamin D3 is known to take place in placenta an
in eciua.
PLACENTAL ROLE IN EMBRYOFETAL
DEVELOPMENT
Te placenta is the organ o transer between mother an etus.
Within this biirectional maternal-etal interace, maternal
oxygen an nutrients transer to the etus, whereas CO2 an
metabolic wastes are irecte back to the mother. Fetal bloo,
which is containe in the etal capillaries o the chorionic villi,
has no irect contact with maternal bloo, which remains in
the intervillous space. Instea, biirectional transer epens
on processes that allow or ai the transport through the syncytiotrophoblast that lines chorionic villi (Michelsen, 2017).
With this system, breaks in the chorionic villi permit escape
o etal/placental cells an other bloo-borne material into the
maternal circulation. Tis leakage is the mechanism by which
some D-negative women become sensitize by the erythrocytes
o their D-positive etus (Chap. 18, p. 353). Te escape o
etal cells can also lea to etal microchimerism rom entrance
o allogeneic etal cells, incluing trophoblast, into maternal
bloo an other organs (Rijnink, 2015). Volumes are estimate
to range rom 1 to 6 cells/mL at mipregnancy. Some etal
cells become “immortal” in that they persist in the maternal
circulation an organs ollowing pregnancy. As iscusse in
Chapter 61 (p. 1109), the clinical corollary is that some maternal autoimmune iseases such as Hashimoto thyroiitis may be
provoke by such microchimerism.
Last, cell-ree DNA (cDNA) is release rom syncytiotrophoblast uring normal physiological cell turnover. Ater 10
weeks, 10 to 15 percent o all cDNA in maternal plasma is
trophoblastic DNA (Norton, 2015; Shaer, 2018). Tis phenomenon unerlies one maternal-serum screening metho or
etal aneuploiy, which is iscusse in Chapters 16 an 17
(pp. 327 an 335).
■ The Intervillous Space
Maternal bloo within the intervillous space is the primary
source o maternal–etal transer. Bloo rom the maternal spiral arteries irectly bathes the trophoblast layer that surrouns
the villi. Substances transerre rom mother to etus rst enter
the intervillous space an are then transporte to the syncytiotrophoblast. As such, the chorionic villi an intervillous space
unction together as the etal lung, gastrointestinal tract, an
kiney.
Circulation within the intervillous space is escribe in
Chapter 5 (p. 92). Intervillous an uteroplacental bloo fow
increases throughout pregnancy, an at term, the resiual volume o the intervillous space approximates 140 mL. Moreover, uteroplacental bloo fow near term ranges rom 700 to
900 mL/min, an most o this bloo apparently goes to the
intervillous space (Pates, 2010).
■ Placental Transfer
In the terminal villi, substances that pass rom maternal to
etal bloo must rst traverse the syncytiotrophoblast, the
attenuate cytotrophoblast layer, the thinne villous stroma,
an nally, the etal capillary wall. Although this histological barrier separates maternal an etal circulations, it is not
a simple physical barrier. First, throughout pregnancy, syncytiotrophoblast actively or passively permits, acilitates, an
ajusts the amount an rate o substance transer to the etus.
As iscusse in Chapter 5 (p. 92), the maternal-acing syncytiotrophoblast surace is characterize by a complex microvillus
structure. Te etal-acing basal cell membrane is the site o
transer to the intravillous space. Finally, the villous capillaries
are an aitional site or transport rom the intravillous space
into etal bloo, or vice versa. In etermining the eectiveness
o the human placenta as an organ o transer, several variables
are important an shown in Table 7-2. Epigenetic placental
changes brought about by methylation o genes engage in
nutrient transer also play a role (Kerr, 2018).
Mechanisms of Transfer
Most substances with a molecular mass <500 Da pass reaily
through placental tissue by simple iusion. Tese inclue
TABLE 7-2. Variables of Maternal-Fetal Substance
Transfer
Maternal plasma concentration
Maternal carrier-protein binding
Maternal blood flow rate through the intervillous space
Trophoblast surface area size available for exchange
Physical trophoblast properties to permit simple diffusion
Trophoblast biochemical machinery for active transport
Substance metabolism by the placenta during transfer
Fetal intervillous capillary surface area size for exchange
Fetal blood concentration of the substance
Fetal carrier-protein binding
Villous capillary blood flow rate
DNA methylation of transporter genes138 Placentation, Embryogenesis, and Fetal Development
Section 3
oxygen, CO2, water, most electrolytes, an anesthetic gases
(Carter, 2009). Some low-molecular-weight compouns
unergo transer acilitate by syncytiotrophoblast. Tese are
usually those that have low concentrations in maternal plasma
but are essential or normal etal evelopment.
Insulin, steroi hormones, an thyroi hormones cross
the placenta, but very slowly. Te hormones synthesize in
situ in the syncytiotrophoblast enter both the maternal an
etal circulations, but not equally (Chap. 5, p. 86). Examples
are hCG an hPL concentrations, which are much lower in
etal plasma than in maternal plasma. High-molecular-weight
substances usually o not traverse the placenta, but there are
important exceptions. As iscusse, one is IgG—molecular
weight 160,000 Da—which is transerre by way o a specic
trophoblast receptor–meiate mechanism (Stach, 2014).
Although simple iusion is an important metho o
placental transer, the trophoblast an chorionic villus unit
emonstrate enormous selectivity in transer. As iscusse,
important in this regar is DNA methylation o transporter
genes (Kerr, 2018; Simner, 2017). Te net results are ierent
metabolite concentrations on the two sies o the villus.
Transfer of Oxygen and Carbon Dioxide
Placental oxygen transer is bloo fow limite. Using estimate
uteroplacental bloo fow, Longo (1991) calculate oxygen
elivery to be approximately 8 mL O2/min/kg o etal weight.
Because o the continuous passage o oxygen rom maternal
bloo in the intervillous space to the etus, its oxygen saturation
resembles that in maternal capillaries. Te average oxygen saturation o intervillous bloo is estimate to be 65 to 75 percent,
with a partial pressure (Pao2) o 30 to 35 mm Hg. Te oxygen
saturation o umbilical vein bloo is similar but has a somewhat lower oxygen partial pressure (Ramsay, 1996). As note
earlier, etal hemoglobin has a higher oxygen anity than ault
hemoglobin.
Te placenta is highly permeable to CO2, which traverses
the chorionic villus by iusion more rapily than oxygen.
Near term, the partial pressure o carbon ioxie (Paco2) in the
umbilical arteries averages 50 mm Hg, which is approximately
5 mm Hg higher than in the maternal intervillous bloo. Fetal
bloo has less anity or CO2 than oes maternal bloo, thereby
avoring CO2 transer rom etus to mother. Also, mil maternal hyperventilation results in a all in Paco2 levels, avoring a transer o CO2 rom the etal compartment to maternal bloo.
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