Williams Chapter 4- Fetal Growth & Development

DETERMINATION OF GESTATIONAL AGE

Gestational Age(or menstrual age) o Time elapsed since the 1st day of the LMP, precedes conception o 2 weeks before ovulation & fertilization or 3 weeks before implantation of blastocyst o averages 280 days or 40 weeks b/t LMP & birth of fetus o quick estimate: add 7 days & subtract 3 months from LMP Ovulation Age- days or weeks from ovulation Post Conceptual Age- same as ovulation Women undergo 1st or early 2nd trimester ultrasound to determine gestational age Spontaneous abortion limited principally to 1st trimester; infant survival increases in pregnancy reaching 3rd trimester

MORPHOLOGICAL GROWTH
OVUM, ZYGOTE, & BLASTOCYST

Devt Phases (1st 2 weeks after ovulation) 1. Fertilization 2. Formation of free blastocyst 3. Implantation of blastocyst Chorionic villi formed soon after implantation

24 Weeks Gestation: o weight 630g o skin is wrinkled; fat deposition begins o head is still comparatively large; eyebrows & eyelashes are recognizable o canicular period of lung devt, where bronchi & bronchioles enlarge & alveolar ducts develop, is nearly completed 28 Weeks Gestation: o crown-rump length 25cm, weight 1100g o thin skin is red & covered w/vernix caseosa o papillary membrane disappears from eyes o infant born at this time has 90% chance of survival 32 Weeks Gestation: o crown-rump length 28cm, weight 1800g o skin is still red & wrinkled 36 Weeks Gestation: o crown-rump length 32cm, weight 2500g o body more rotund & wrinkled appearance of face is lost due to deposition of subcutaneous fat o excellent chance of survival 40 Weeks Gestation: o crown-rump length 36cm, weight 3400g

EMBRYO

Embryonic period starts @ beginning of the 3rd week after ovulation & fertilization (coincides with expected day that next menstruation wouldve started) Pregnancy tests hCG positive Embryonic disc well defined, body stalk is differentiated, chorionic sac is ~1cm diameter True intervillous space- contains maternal blood & villous cores in which angioblastic chorionic mesoderm can be distinguished By the end of the 4th week after ovulation: o Chorionic sac is 2-3cm in diameter, embryo is 4-5mm in length o Partitioning of the primitive heart (mid 4th week) o Arm & leg buds present o Amnion is beginning to unsheathe body stalk which becomes the umbilical cord End of the 6th week after fertilization: o Embryo is 22-24mm in length o Head is large compared with the trunk o Heart is completely formed o Fingers & toes are present, arms bend at the elbows o Upper lip is complete, external ears from definitive elevations on either side of head 8 weeks after fertilization or 10 weeks after onset of LMP o end of embryonic period & beginning of fetal period o embryo-fetus is 4cm long, lung devt has yet to cccur

FETUS- DEVT DURING FETAL PERIOD OF GESTATION 12 Weeks Gestation: o uterus is palpable above symphis pubis o crown-rump length- 6-7cm o centers of ossification in most bones o fingers & toes differentiated o skin & nails developed; rudiments of hair o external genitalia beginning to show definitive signs of male or female gender o begins spontaneous movements 16 Weeks Gestation: o crown-rump length 12cm, weight 110g o gender correctly determined by inspection of external genitalia by 14 weeks 20 Weeks Gestation (midpoint): o weight 300g, increases in a linear manner o skin is less transparent; downy lanugo covers entire body; scalp hair has developed

FETAL HEAD Skull is composed of o 2 frontal bones o 2 parietal bones o 2 temporal bones o occipital bone & wings of the sphenoid these bones are separated by membranous spaces termed sutures: o Frontal- b/t frontal bones o Sagittal- b/t parietal bones o Coronal(2)- b/t frontal & parietal bones o Lamboid(2)- b/t posterior margins of parietal bones & upper portion of the occipital bone Fontanel- irregular space formed where several sutures meet, covered by a membrane o Greater or Anterior- lozenge or diamond shaped; junction of the sagittal & coronal sutures o Lesser or Posterior- triangle shaped; intersection of the sagittal & lamboid sutures o Temporal or Casserian Fontanels- no clinical significance Critical Circumferences & Diameters: 1. Occipitofrontal (11.5cm)- point just above the root of the nose to the most prominent portion of the occipital bone 2. Biparietal (9.5cm)- greatest transverse diameter; from one parietal boss to the other 3. Bitemporal (8.0cm)- greatest distance between the two temporal sutures 4. Occipitomental (12.5cm)- chin to the most prominent portion of the occiput 5. Suboccipitobregmatic (9.5cm)- middle of the large fontanel to the undersurface of the occipital bone where it joins the neck Greatest circumference of the head, plane of the occipitofrontal diameter, averages 34.5cm; too large to fit through pelvis without flexion Smallest circumference, plane of the suboccipitobregmatic diameter, is 32cm FETAL BRAIN 6 Months- myelination of the ventral roots of the cerebrospinal nerves 7 brainstem begins; major portion of myelination occurs after birth

PLACENTAL ROLE IN FETAL GROWTH

Transfer of oxygen & nutrients from mother to fetus; transfer of carbon dioxide & metabolic wastes from fetus to mother No direct contact the fetal & maternal blood: o Fetal blood contained in fetal capillaries in the intravillous space of the chorionic villi o Maternal blood remains in the intervillous space o One exception occurs when breaks in the chorionic villi permit escape of fetal erythrocytes & leukocytes into the maternal circulation; mechanism by which some D-negative women become sensitized by the erythrocytes of their D-positive fetus

THE INTERVILLOUS SPACE: MATERNAL BLOOD Primary biological compartment of maternal-fetal transfer; directly bathes the trophoblasts

Substances from mother to fetus 1st enter intervillous space and are then transported to the syncytiotrophoblasts Substances from fetus to mother transferred from the syncytium into the syncytiotrophoblasts Chorionic villi & the intervillous space together function for the fetus as lung, git, & kidney Residual volume of intervillous space of the term placenta measures 140mL; before delivery the normal value may be twice this value Uteroplacental blood flow at term 700-900mL/min; most of the blood goes to the intervillous space Forceful uterine contractions of active labor cause a reduction in blood flow into the intervillous space depending on force of contraction Blood pressure within the intervillous space is less than the uterine arterial pressure but greater than uterine venous pressure Uterine venous pressure depends on several factors; when supine pressure in lower part of IVC is elevated as is pressure in the uterine & ovarian veins and in turn also in the intervillous space

Transfer of Oxygen & Carbon Dioxide o Placenta supplies 8 mL O2/min/kg of fetal weight o Oxygen saturation in intervillous space resembles that of maternal capillaries o Average oxygen saturation of intervillous blood is estimated to be 65-75%, with PO2 of 30-35 mmHg; similar in umbilical vein except for lower PO2 o Placenta is highly permeable to carbon dioxide, which traverses chorionic villus more rapidly than oxygen o Near term, PCO2 in umbilical arteries averages 48 mmHg or about 5mmHg more than in maternal intervillous blood o Fetal blood has less affinity for carbon dioxide than maternal blood, favors transfer of carbon dioxide to maternal blood Selective Transfer & Facilitated Diffusion o Trophoblasts & chorionic villus demonstrate enormous selectivity in transfer o Concentration of ascorbic acid is 2-4x higher in fetal plasma than in maternal plasma o Iron is lower in the plasma of pregnant women than in the fetus

PLACENTAL TRANSFER Chorionic Villus o Substances from maternal fetal blood traverse: Syncytiotrophoblasts Stroma of intravillous space Fetal capillary wall o Syncytiotrophoblasts- actively or passively permit, facilitate, & adjusts amount & rate of transfer of substances o Walls of venous capillaries become thinner; relative number of fetal vessels increase in relation to the villous connective tissue o Walls of fetal placenta surface vessels, which branch from truncal arteries, do not contain smooth muscle o Villous surface area of placenta is correlated with the fetal weight; approximately 10 m2 Regulation of Placental Transfer : o Syncytiotrophoblasts is fetal tissue interface: Maternal-facing surface is characterized by complex microvillous structure Fetal-facing(basal) cell membrane is site of transfer to intravillous space through which fetal capillaries traverse Fetal capillaries are additional site for transport from intravillous space into fetal blood o Variables which determine effectiveness of human placenta as a transport organ: 1. Concentration of substance under consideration in maternal plasma; extent to which it is bound to other compounds 2. Rate of maternal blood flow through intervillous space 3. Area available for exchange across the villous trophoblasts epithelium 4. Is substance is transferred by diffusion, the physical properties of the tissue barrier interposed b/t blood in the intervillous space & in fetal capillaries 5. If substance is actively transported, the capacity of the biochemical machinery of the placenta 6. Amount of substance metabolized by the placenta during transfer 7. Area for exchange across the fetal capillaries 8. Concentration of substances in the fetal blood 9. Specific binding or carrier proteins 10. Rate of fetal blood flow through the villous capillaries Mechanisms of transfer: o Substances w/ MW <500d readily diffuse placenta o Syncytiotrophoblasts actively facilitate transfer of small compounds o Simple diffusion mechanism of transfer for: oxygen, carbon dioxide, water, electrolytes, anesthetic gases o Insulin, steroid hormones, & thyroid hormones cross placenta at very slow rates o Concentrations of hCG and hPL are lower in fetal plasma

FETAL NUTRITION

1st 2 months of pregnancy: o embryo consists almost entirely of water o b/c of small amount of yolk the growth of fetus depends on nutrients from mother 1st few days after implantation: o nutrition of blastocysts comes from interstitial fluid of the endometrium & surrounding tissue o w/in a week forerunners of intervillous space are formed during 3rd week after fertilization: o fetal blood vessels in chorionic villi appear during 4th week: o cardiovascular system formed, true circulation is established both within the embryo & between embryo and chorionic villi Maternal diet is translated into storage depots made available to meet demand for energy, tissue repair, & new growth: o Liver, muscle, adipose tissue; insulin Insulin secretion sustained by increased serum levels of glucose & amino acids; net effect: o Storage of glucose as glycogen in liver & muscle o Retention of amino acids as protein o Storage of excess amino acids as fat Storage of maternal fat peaks in 2nd trimester then declines as fetal demands increase in late pregnancy During times of fasting: o Glucose is released from glycogen, but maternal glycogen stores cant provide adequate amount of glucose o Cleavage of triacyglycerols stored in adipose tissue provides mother w/energy in form of FFAs o Lipolysis is activated by: glucagons, NE, hPL, glucocorticosteroids, thyroxine

GLUCOSE & FETAL GROWTH At Mid-pregnancy fetal glucose concentration is independent of & may exceed maternal levels; it is the major nutrient for fetal growth & energy hPL-abundant in mother but not fetus o blocks peripheral uptake & use of glucose while promoting mobilization & use of FFAs by maternal tissues Glucose transport: o Transport of D-glucose across cell membrane accomplished by carrier-mediated, stereo-specific non-concentrating process of facilitated diffusion o GLUT-1 & GLUT-3 located in plasma membrane of microvilli of human syncytiotrophoblasts o GLUT-1: Expressed prominently in human placenta Increases as pregnancy advances Induced by almost all growth factors o GLUT-3 localized in human syncytiotrophoblasts

Fetal Macrosomia: o Excessive fetal growth o Hyperinsulinemic state o Increased levels of growth factors (i.e. insulin like growth factor, fibroblast like growth factor) o Increased expression of GLUT proteins Lactate o Transported via facilitated diffusion o Co-transported with hydrogen ions as lactic acid FFAs & Triglycerides o Large proportion of fetal body is fat (15%) o Neutral fat (triacylglycerols) do not cross placenta but glycerol does o Fatty acids are synthesized in the placenta; most cross the placenta via simple diffusion o Lipoprotein lipase is present on the maternal but not the fetal side of the placenta; favors the hydrolysis of triacylglycerols in the maternal intervillous space while preserving neutral lipids in fetal blood o Fatty acids transferred to the fetus can be converted to triacyglycerols in the fetal liver o Placental uptake & use of LDL is an alternative mechanism for fetal assimilation of essential fatty acids & amino acids o LDL from maternal plasma binds to specific receptors in the coated-pit regions of the microvilli on the maternal-facing side of the syncytiotrophoblasts; taken up by receptor mediated endocytosis o Apoprotein & cholesterol esters of LDL are hydrolyzed by lysosomal enzymes in syncytium to give: 1. Cholesterol from progesterone synthesis 2. Free amino acids 3. Essential fatty acids (linoleic acid) o Concentration of arachindonic acid is greater in fetal plasma

o o

Vitamin C (ascorbic acid)- transferred from mother to fetus by energy dependent, carrier-mediated process Vitamin D (cholecalciferol)- greater in maternal plasma than fetal

FETAL PHYSIOLOGY
Amniotic Fluid In early pregnancy- ultrafiltrate of maternal plasma

AMINO ACIDS Neutral amino acids from maternal plasma are taken up by trophoblasts Amino acids are concentrated in syncytiotrophoblasts and thence transferred to fetal side by diffusion Concentration of amino acids in the umbilical cord plasma is greater than in maternal venous or arterial plasms PROTEINS IgG crosses the placenta in large amounts via endocytosis Retinol-binding protein also crosses placenta IONS & TRACE METALS Iodide transport across the placenta is attributed to carrier-mediated, energy requiring active process Concentrations of zinc is higher in fetal plasma than maternal Concentration of copper is less in fetal plasma than maternal Placenta Sequestration of Heavy Metals: o Metallothionein-1- expressed in syncytiotrophoblasts, binds & sequesters zinc, copper, lead, cadmium o Cadmium levels increased with smoking; higher in maternal blood than cord blood & little or none found in fetal liver or kidney *cadmium acts to increase the transcription of the metallothionein gene; thus cadmium-induced increases in trophoblasts metallothionein levels result in placental cadmium accumulation by sequestration o Metallothionein also binds & sequesters copper in placental tissue; low levels of copper in cord blood o Deficiency in copper results in inadequate collagen cross linking & diminished tensile strength of tissues Calcium & Phosphorus o Actively transported from mother to fetus o PTH-rP activates adenylate cyclase & movement of calcium synthesized in fetal parathyroid, placenta, and fetal kidney expression in cytotrophoblasts modulated by extracellular concentration of calcium Vitamins o Vitamin A (retinol)- greater in fetal plasma than maternal; transferred from maternal compartment across syncytium

Beginning of 2nd Trimester- consists of largely extracellular fluid that diffuses through fetal skin After 20 Weeks- cornification of skin prevents diffusion & amniotic fluid composed mostly of fetal urine 12 Weeks- kidneys begin to produce urine 18 Weeks- producing 7-14 mL per day fetal urine contains: o urea o creatinine o uric acid o desquamated fetal cells o vernix o lanugo Urine is hypotonic, therefore decreasing amniotic fluid osmolality with advancing gestation Pulmonary fluid & fluid filtered through placenta account for rest of amniotic fluid At 8 weeks- volume increases up to 10mL per week At 21 weeks- volume increases up to 60mL per week By 33 weeks- volume gradually declines to steady state Functions of Amniotic Fluid: o Serves as cushion to the fetus o Allows musculoskeletal development o Protection from trauma o Maintains temperature o Minimal nutritive function EGF & EGF-like growth factors (TGF- ) are present Ingestion & inhalation of fluid may promote growth in the GIT & lungs

FETAL CIRCULATION