Willams ch. 7 Fetal growth and Development 부산백병원 산부인과 R2 박영미

Willams ch. 7 Fetal growth and Development

부산백병원 산부인과R2 박영미

PHYSILOLGY OF THE FETUS

Amnionic fluid (1) Amnionic fluid is composed

In early pregnancy : ultrafiltrate of maternal plasma

Second trimester : extracellular fluid which diffuses through the fetal ski

n

After 20weeks : fetal urine : the fetal kidneys start producing urine at 12wks, by 1

8wks are producing 7-14ml/d

Amnionic fluid (2) Amnionic fluid volume

Increaes by 10ml per week at 8weeks and up to 60ml per week at 21weeks Declines gradually back to a steady state by 33week

s

The usual amnionic volume 50ml at 12weeks 400ml at midpregnancy 1000ml at term

Amnionic fluid (3) Amnionic fluid serves to

Cushion – allowing musculoskeletal development Protecting from trauma Maintains temperature Minimal nutritive function

Epidermal growth factor, EGF-like growth factors (transforming growth factor-α) Ingestion of amnionic fluid into the lung and gastroint

estinal tract -> promote growth and differentiation of these tissues

Fetal circulation (1) Oxygenated blood is brought to the fetus by the umbilical

vein

The vein divides into the ductus venosus and the portal sinus

The ductus venosus is enter the inferior vena cava directly It carries well-oxygenated blood directly to the heart

The portal sinus carries blood to the hepatic veins

Relatively deoxygenated blood from the liver then flows back into the inferior vena cava

Fetal circulation (2)


The ventricles of the fetal heart work in parallel, not in series

Well-oxygenated blood enters the left ventricle through the foramen ovale -> supplies the heart and brain

Less oxygenated blood enters the right ventricle through the tricuspid valve -> supplies the rest of the body


Two separate circulations

by the structure of the right atrium depending on its oxygen content

The well-oxygenated blood -> along the medial aspect of the inferior vena cava

The less oxygenated blood -> along the lateral vessel wall

Fetal circulation (5) About 87% of blood exiting the right ventricle -> the ductus arteriosus -> descending aorta

only 13% of right ventricular output -> to the lung

The high pulmonary vascular resistance Lower resistance in the ductus arteriosus

One third of the blood passing through the ductus arteriosus -> to the body

The remaining output -> return to the placenta through the two hypogastric arteries -> distally become the umbilical arteries

Fetal blood (1) Hemopoiesis

Fetal blood (2) As fetal development progresses :

1. circulating erythrocytes are smaller and nonnucleated The first erythrocytes : nucleated,macrocytic

2. the volume of blood in the common fetoplacental circulation increase

3. Hemoglobin concentration rises Midpregnancy : 12g/dL By term : 18g/dL

Fetal blood (3)

Erythropoiesis

Controlled by erythropoietin made by the fetus Maternal erythropoietin does not cross the placenta

Produced in response to hypoxic stress Bleeding, labor, isoimmunization

Influenced by testosterone, estrogen, prostaglandins, thyroid hormone, lipoproteins

Fetal liver – may be an important source until renal production begins

Fetal blood (4) Fetal blood volume

Blood volume of term normal infants : average of 78 mL/kg when cord-clamping

The blood volume of fetal origin in the placenta : average 45 mL/kg

Fetoplacental blood volume at term : approximately 125 mL/kg

Fetal blood (5) Fetal hemoglobin

During embryonic and fetal life, a variety of a and b chain precursors

The timing of the production of each of these early hemoglobin version corresponds to the site of hemoglobin production Yolk sac : hemoglobin Gower 1, Gower 2, Portland Liver : hemoglobin F Bone marrow : normal hemoglobin A

Fetal blood (6)

The switch : various embryonic Hb -> Hb A methylation of the early globin genes

Diabetic women Persistence of Hb F Hypomethylation of the r-gene

Sickle cell anemia r-gene remains unmethylated Large quantities of fetal Hb

Fetal blood (7)

Hb F bind more oxygen than Hb A

Hb A binds 2,3-DPG more avidly than Hb F : lowers the affinity of Hb A for oxygen

Lower concentration of 2.3-DPG of fetal Hb : increased oxygen affinity of the fetal erythrocyte

The amount of Hb F in fetal erythrocytes falls during the latter weeks of pregnancy At term, about ¾ of the total Hb is Hb F

Fetal blood (8) Coagulation factors in the fetus

About 12 weeks Normal, adult-type, procoagulant, fibrinolytic, anticoagulant

proteins at appreciably reduced levels not cross the placenta

Factors : II, VII, IX, X, XI, XII, XIII, fibrinogen

Fetal fibnogen as early as 5 weeks differenet properites -> less compressible clot, lower degree aggregation compared with adult

Fetal blood (9)

Despite this reduced coagulation factors, the fetus seems to be protected from hemorrhage, and fetal bleeding is a rare event Cordocentesis : amnionic fluid thromboplastins and some fa

ctor in Wharton jelly combine to faciliate coagulation at the umbilical cord puncture site

Protein C, S, antithrombin III deficiency, or the Leiden (factor V) mutation : thrombosis, infarction

Stillbirth followed by maternal pulmonary embolism : protein S deficiency

Fetal blood (10) Fetal plasma proteins

Concentrations of plasma protein, albumin, lactic dehydrogenase, aspartate aminotransferase, r-glutamyl transpeptidase, alanine trasferase

-> all increase with gestational age

At birth, the mean total plasma protein, albumin concentrations in fetal blood

-> similar to maternal levels

Fetal blood (12)

Immunoglobulin G

IgG transport begins at about 16weeks

The bulk of IgG from the mother is during the last 4weeks of pregnancy Preterm infants : relatively poorly with maternal antibody

Adult values are not attained until 3years of age

Fetal blood (11) Immunocompetence of the fetus

In the absence of a direct antigenic stimulus (such as infection)

-> almost total immunoglobulins in the fetus is immunoglobulin G -> IgG synthesized in the maternal compartment and transferred across the placenta by receptor-mediated processes in syncytiotrophoblast

Fetal blood (13)

Immunoglobulin M

IgM is not transported from mother to ferus

Increased levels of IgM with congenital infection Rubella Cytomegalovirus Toxooplasmosis

Adult levels are attained by 9 months of age

Fetal blood (14)

Immunoglobulin A

IgA ingested in colostrum -> mucosal protection against enteric infection

IgA ingested with amnionic fluid before delivery

Fetal blood (15)

Lymphocytes

B lymphocytes : in liver by 9weeks : in blood & spleen by 12weeks

T lymphocytes : leave the thymus at 14weeks

The newborn responds poorly to immunization Deficient response of B cells to polyclonal activation Lake of T cell proliferation

Nervous system and sensory organs

The spinal cord extends In the embryo : entire vertebral column By 24 weeks : S1 At birth : L3 In the adult : L1

Myelination of the spinal cord Begins in the middle of gestation Continues through the first year of life

Synaptic function Developed by the eighth week


At 10 weeks Squinting Opening the mouth swallowing Incomplete finger closure

complete finger closure during the fourth lunar month

14-16 weeks Respiration

After 24 weeks The ability to suck

The third trimester Integration of nervous and muscular function proceeds


The development of internal, middle, external components of the ear -> by midpregnancy

The fetus hears some sounds in utero as early as 24-26 weeks

The eye sensitivity to light -> by 28 weeks

But, perception of form and color is not complete until long after birth

Gastrointestinal tract (1)

Swallowing begins at 10-12weeks Coincident with intestine peristalsis and glucose transport

What stimulates swallowing -> not clear The fetal neural analog of thirst Gastric emptying Change in the amnionic fluid composition Fetal taste buds

Late in pregnancy, the volume of amnionic fluid -> regulated by fetal swallowing Term fetus : 200-760mL per day


Movement of amnionic fluid through the gastrointestinal system Enhance growth and development of the alimentary canal

The swallowed amnionic fluid Contributes little to the caloric requirements Contributes essential nutrients Late in pregnancy, about 0.8g of soluble protein, approximately

half albumin, each day

Gastrointestinal tract (3) Meconium

Composition of meconium Undigested debris from swallowed amnionic fluid Glycerophospholipid from the lung Desquamated fetal cells Lanugo Scalp hair Vernix

Meconium passage Normal bowel peristalsis in the mature fetus Vagal stimulation due to cord compression Hypoxia -> arginine vasopressin -> stimulates the smooth m

uscle of the colon to contract


Liver liver enzyme levels increase with gestational age

Limited capacity for converting free bilirubin to bilirubin diglucuronoside Most of the bilirubin is transferred to the maternal circulatio

n through the placenta The small fraction conjugated bilirubin -> excreted through th

e biliary tract into the intestine Unconjugated bilirubin -> excreted into the amnionic fluid aft

er 12weeks -> transferred across the placent


Most of the cholesterol -> produced in fetal liver

Glycogen Second trimester : low concentration in fetal liver Near term : rapid and marked increase to levels

two- three times those in adult liver


Pancreas 9-10weeks : Insulin-containing granules 12weeks : insulin in fetal plasma

hyperglycemia -> increasing plasma insulin Newborns of diabetic mothers Large for gestational age infants

14weeks : amylase in amnionic fluid 16weeks : Most pancreatic enzymes are present

Trypsin, Chymotrypsin, Phospholipase A, lipase

Urinary system (1)

2weeks : pronephros

5weeks : mesonephros -> producing urine

11-12weeks : mesonephros -> degeneration

9-12weeks : ureteric bud and nephrogenic blastema -> metanephros

14weeks : loop of Henle -> functional & reabsorption occurs

Until 36weeks : new nephrons

Urinary system (2) The kidney receive 2-4% of the cardiac output

Renal vascular resistance is high

The glomerular filtration fraction is low

The filtration rate increases with gestational age 12weeks : less than 0.1mL/min 20weeks : 0.3mL/min

Urine production start at 12weeks 18weeks : 7-14mL/day At term : 27mL/hr, 650mL/day

Pulmonary system (1) Anatomical maturation of the fetal lung

Pseudoglandular stage 15-17weeks The growth of the intrasegmental bronchial tree

Canalicular stage 16-25weeks The peripheral extension of bronchial cartilage plates terminal bronchiole -> respiratory bronchioles -> multiple saccular ducts

Terminal sac stage The alveoli -> primative pulmonary alveoli (terminal sac)

Pulmonary system (2) An extracellular matrix develops from proximal to dist

al lung segments until term

Extensive capillary network & lymph system develops

The type II cells start to produce surfactant

At birth, only 15% of the adult number of alveoli

The lung continues to grow, adding more alveoli up to about 8 years

Pulmonary system (3) Surfactant

Formed in the type II pneumonocytes Multivesicular bodies -> Lamellar bodies -> surfactant

At birth, with the first breath Air-to-tissue interface in the lung

alveolus Surfactant to uncoil from the la

mellar bodies Prevent alveolar collapse during

expiration

Pulmonary system (4)

Surfactant compositon

80% : Phosphatidylcholines (lecithins)

8-15% : phosphatidylglycerol

Reducing surface tension in the alveolus


Corticosteroids and fetal lung maturation

Cortisol, produced in the fetal adrenal glands Natural stimulus for lung maturation Augmented surfactant synthesis

Glucocorticosteroids Administered in large amounts to the woman At certain critical times during gestation Effect an increase in the rate of fetal lung maturation


Respiration

Respiratory muscles movement of fetal chest wall Detected by USG as early as 11weeks

Respiratory movement intense to move amnionic fluid in and out of the respiratory tract

At the fourth month

Endocrine glands (1)

Pituitary gland : The fetal pituitary develops from two different sources

Adenohypophysis From the oral ectoderm – Rathke pouch

Neurohypophysis From the neuroectoderm

Endocrine glands (2) Anterior pituitary

: differnetiates into five cell types : secrete six protein hormones

Lactotropes -> prolactin (PRL) Somatotropes -> growth hormone (GH) Corticotropes -> corticotropin (ACTH) Thyrotropes -> thyroid stimulating hormone (TSH) Gonadotropes -> luteinizing hormone (LH) -> follicle stimulating hormone (FSH)

: 7weeks -> ACTH is first detected : 17weeks -> synthesize and store all pituitary hormones


Neurohypophysis

Well developed by 10-12weeks

Oxytocin, arginine vasopressin (AVP)

Conserve water by actions largely at the level of lung & placenta (rather than kidney)

Endocrine glands (4) Intermediate pituitary gland

Only in the fetal pituitary gland

Disappeared before term, absent in adult

a-melanocyte stimulating hormone (a-MSH)

b-endorphin

The levels of a-MSH decrease progressively with gestation

Endocrine glands (5) Thyroid

Hormone synthesis by 10-12weeks

The placenta actively concentrates iodide on the fetal side

The fetal thyroid concentrates iodide more avidly than the maternal thyroid Radioiodide, amount of ordinary iodide -> hazardous

Placental tissue and membranes Prevent substantial passage of maternal thyroid hormones t

o the fetus Rapidly deiodinating maternal T4 & T3 to reverse T3


The role of thyroid hormone Normal development of virtually all fetal tissues, especially b

rain

Congenital hyperhyroidism When maternal thyroid-stimulating antibody crosses the plac

enta Tachycardia, hepatosplenomegaly, hematological abnormalit

ies, craniosynostosis, growth restriction


Adrenal glands Fetal adrenal glands : much larger in relation to total

body size than in adults

Fetal zone of the adrenal cortex Hypertrophied fetal zone Involutes rapidly after birth

Aaldosterone Near term, the cord plasma levels exceed those in maternal

plasma Renal tubules : relatively insensitive to aldosterone

Fetal Gender

Sexual differentiation of the embryo-fetus

Gender differentiation is determined by

Chromosomal make-up

Gonad development

Phenotypic gender


Chromosomal sex Genetic sex, XX or XY At the time of fertilization of the ovum

Gonadal sex Primordial germ cells originate in the endoderm of th

e yolk sac -> migrate to the genital ridge -> form the indifferent gonad (ovary, testis)


Y chromosome At 6 weeks after conception

The gonad begins developing into a testis

Directed by a gene located on the short arm of Y

Testis-determining factor (TDF)

Sex-determining region (SRY)

The SRY gene is expressed in the human single-cell zygote immediately after ovum fertilization


Phenotypic sex Male phenotypic sexual differentiation

-> directed by the function of the fetal testis In the absence of the testis

-> female differentiation ensues The mullerian ducts

uterus, fallopian tubes, upper vagina The wolffian duct

epididymis, vas deferens, seminal vesicle Testosterone -> 5a-dihydrotestosterone

Act in Genital tubercle, labioscrotal folds -> penis, scrotum


Fetal testicular contributions to male sexual differentiation

Mullerian-inhibiting substance

Produced by the Sertoli cells of the seminiferous tubules

Secreted as early as 7 weeks

Regression of the mullerian duct

Prevent the development of uterus, fallopian tube, upper vagina

Mullerian duct regression is completed by 9-10weeks


Fetal testosterone secretion

Directly act on the wolffian duct

Development of the vas deferens, epididymidis, seminal vesicles

Converted to 5a-dihydrotestosterone in fetal blood

Amplifies the androgen action of testosterone

Virilization of the external genitalia


Genital ambiguity of the newborn

The abnormalities of sexual differentiation causing genital ambiguity can be assigned to one of four clinically defined categories

Female pseudohermaphroditism

Male pseudohermaphroditism

Dysgenetic gonads

True hermaphroditism

Category 1. female pseudohermaphroditism

Mullerian-inhibiting substance is not produced The uterus, fallopian tubes, upper vagina develop

Androgen exposure of the embryo-fetus is excessive, for a fetus destined to be female

Clitoral hypertrophy, posterior labial fusion Labioscrotal folds, development of a urogenital sinus Development of a penile urethra with scrotal formation

The karyotype is 46,XX

Ovaries are present

Category 1. Female Pseudohermaphroditism

The androgenic excess Congenital adrenal hyperplasia Transfer of androgen from the maternal compartment Drugs ingested in prgnancy

Congenital adrenal hyperplasia Life threatening, medical emergency Adrenal failure provokes nausea, vomiting, diarrhea,

dehydration, shock The neonate treated until appropriate tests confirm,

of rule it out

Category 2. Male Pseudohermaphroditism

Production of mullerian-inhibiting substance The uterus, fallopian tubes, upper vagina -> not develop

Incomplete but variable androgenic representation for a fetus destined to be male Inadequate production of testosterone by the testis Diminished responsiveness to normal quantities of androgen –

abnormal or absent androgen receptor protein Failure of the in situ formation of 5a-dihydrotestosterone in andr

ogen responsive tissue

The karyotype is 46, XY

The presence of testes or else no gonads

Category 3. Dysgenetic Gonads

Mullerian-inhibiting substance is not produced the uterus, fallopian tubes, upper vagina are present in all of th

e subjects of this category

Fetal androgen exposure is variable

The karyotype varies among subjects and is commonly abnormal

Neither normal ovaries nor testes are present-rarely, both ovarian and testicular tissues are found.

Category 3. Dysgenetic Gonads

Tuner syndrome (46X)

Most common form of dysgenesis

The phenotype is female

Secondary sex characteristics do not develop at the time of expected puberty

Sexual infantilism

Category 4. True Hermaphroditism

In most subjects, the guidelines for category 3 are met

In addition, both ovarian and testicular tissues are found

In particular, germ cells (ova and sperm) of both sexes are found in the abnormal gonads

Documents

Willams ch. 7 Fetal growth and Development 부산백병원 산부인과 R2 박영미