PHYSIOLOGICAL CHANGES OF PREGNANCY
This lecture we will outline the major maternal physiological adaptations to pregnancy. Pregnancy: it starts by the fertilization of the secondary oocyte by the male sperm forming the fertilized ovum which pass from the site of fertilization (ampulla of the tube) to the uterus, and Implantation: Occur in the 5-7th days after fertilization by the effect of proteolytic enzymes from the trophoblastic cells which digest the cells of the endometrium. The placenta is formed by proliferating cells from blastocyst, trophoblast, and the endometrium.
Function of the placenta:
The development of the placenta with its villi surrounded by lakes of maternal blood in the large blood sinuses serves many functions. Its main function is to carry nutrients from the mother to the fetus and the waste products from the fetus to the mother.
Oxygen is transmitted by simple diffusion, the dissolved O2 in the maternal blood pass to the fetal blood by means of pressure gradients between maternal and fetal blood (20mmHg).
CO2: which is formed in the fetus and excreted by diffusion through the placental membranes because of high solulability CO2 diffuse 20 times more rapid than O2.
GLUCOSE: TRANSFERRED BY FACILITATED DIFFUSION BY MEANS OF A CARRIER MOLECULES IN THE TROPHOBLASTIC CELLS. OTHER NUTRIENTS TRANSFERRED BY SIMPLE DIFFUSION ARE FATTY ACIDS, Na, K, Chloride…
Fetal waste products are excreted by simple diffusion through the fetal memb. Depending on a concentration gradient.
MATERNAL RESPONSE TO PREGNANCY
Major adaptations in maternal anatomy, physiology, and metabolism are required for successful pregnancy. Nearly every organ system is affected. Understanding these changes helps to distinguish normal physiology from pathological disease states. The changes that occur in the maternal body are numerous: Systemic, reproductive, urinary, respiratory, digestive and endocrinological: Systemic changes:
Volume homeostasis:
Pregnancy is a condition of chronic water overload (fluid retention), 8-10 kg of water is retained, the majority of it goes into the ECF ( MOST OF IT CONTRIBUTE TO THE PLASMA VOLUME EXPANSION) and this will lead to increased COP and increased urinary blood flow.
There is active Na and water retention:
1. Changes in osmoregulation.
2. Renin-angiotensin system. Osmoregulation: Na retention increases 900 mEq but serum Na decreases 3-4 mmol/l Plasma osmolality decreases 10mOsm/kg In the kidney: Enhanced tubular reabsorption of Na secondary to aldosterone, estrogen and deoxycorticosterone. Increased GFR and Atrial Natriuretic Peptide favor Na excretion.
CVS: Because of fluid retention:
1- Decrease Hb concentration.
2- Decrease HCT.
3- Decrease S.albumin.
4- Increased stroke volume.
5- Increased renal blood flow.
Heart : clinically *Displaced to the left and upward
*Apex is moved laterally
*Apparent cardiomegaly on chest x-ray
* systolic flow murmurs at left lower sternal border. 30-50% increase in CO (from 5 liters in the non pregnant state to 7 L)
*CO= SV x HR HR: *Increases as early as 5 weeks GA *Peaks at 32 weeks at 15-20 beats above baseline(20% increase)
SV:
*Increases as early as 8 weeks GA
*Peaks at 20 weeks with a 20-30% increase.
*BP= CO x SVR systemic vascular resistance SVR decreases to a minimum at midpregnancy with a gradual rise towards term but still 20% lower than nonpregnant the reduction in SVR due to: -Hormonal vasodilation due to progesterone, -NO, prostaglandins, others.
BP changes:
*maximum reduction in BP in midpregancy
*Increases to baseline in third trimester
*diastolic BP is measured by the 4th korotkoff sound(muffling) and nowadays they depend on the 5th sound (disappearance) which is more accurate. CO increased during labor between 17 – 35% of the normal value
Haematological changes:
*40-50% increase in blood volume beginning at 6 weeks and plateaus at 30 weeks
*both plasma volume and cell mass increase
*Physiologic anemia of pregnancy maximally at 30 weeks
*Increase in erythropoietin and reticulocyte count
The increase in plasma volume is by effect of fluid retention lead to:
Decreased red cell count Decreased Hb concentration (from 13.3 to 10.9g/dl
Decreased HCT
The platelet count slightly decreased
Other parameters are elevated during normal pregnancy:
WBC 9 ×10 9 /L may reach up to 20×10 9 /L mainly by neutophilia. Plasma fibrinogen increased and this contribute to the elevation of ESR during pregnancy There is reduction of the plasma fibrinolytic activity
Iron Metabolism:
*1000mg iron requirement, about 3.5 mg/d, 375 mg to form fetal blood, 600 mg for maternal blood.
*Requirements increase in third trimester
*Fetus receives Fe through active transport Fe supplementation:
*Fe supplemention usually not needed before 20 weeks
Coagulation System:
*Hypercoaguable state: Increased venous stasis
Changes in the coagulation cascade
Reproductive organs:
The ovary: change its position to become an abdominal organ when it is pulled up by the growing uterus, becomes hyperemic, and functionally ovulation is stopped.
Uterus: the rising E & P in the maternal blood lead to hyperplasia and hypertrophy of the myometrial cells which lead to increase in the weight from 50-60 g to 1000 g, 30 cm in length and 23 cm in width at term, with the formation of the upper and the lower segments. The growth in the early pregnancy is mainly by hyperplasia while in the 2nd half the growth is by hypertrophy which is stimulated by growing fetus and uterine distension. At term 500-700 ml of blood flow to the uterus and myometrial contraction is the 1st defense mechanism against bleeding after labor.
The cervix: becomes swollen, and softer by the effect of E &P E lead to the growth of the columnar epith. Of the endocervical canal which appear on the ectocervix as the ectropion which bleeds easily on touch. the mucous is more viscous and opaque to close the cervical canal against the ascending infection, The cervix becomes bluish in color because of high vascularity.
Vagina: E lead to thickening of the epith. Which desquamate leading to increased vaginal discharge and becomes more acidic PH( 4.5 – 5) because of the action of the lactobacilli on the glycogen this high acidity is protective against ascending infection but favored by candida albicans. The vagina also becomes more vascular (bluish in color). Ferning sign is completely absent during normal pregnancy.
Urinary System:
Anatomic Changes
*Renal hypertrophy
*Dilation of renal pelvis/calyces: -Predisposition to pyelonephritis in the presence of assymptomatic bacteriuria
*Dilatation of ureters to 2 cm because of compression by the gravid uterus and by the effect of Progesterone which induce smooth muscle relaxation.
Renal Hemodynamics and function:
*Renal blood flow is increase
*GFR increases.
*Serum Creatinine and BUN levels decrease
*Glycosuria occurs due to exceding of maximum tubular reabsorptive capacity
*No increase in proteinuria if proteinuria is present it indicates pathological condition
Respiratory Changes:
*Mechanical changes (earlier than mechanical pressure of rising uterus) Chest circumference expands Subcostal angle increases Transverse diameter increases Level of diaphragm rises Respiratory muscle function is not affected by pregnancy Pregnancy is a condition of:
*Chronic hyperventilation which is Progesterone induced
*Respiratory rate is unchanged. Gas Exchange
*Hyperventilation leads to deceased PCO² Increases CO² gradient between fetus and mother
Digestive Tract Changes:
*Stomach: Delayed gastric emptying time Gastro oesophageal reflux due to: Esophageal dysmotility Gastric compression due to enlarging uterus Decrease sphincter tone
Small bowel Motility is reduced due to progesterone allowing for more efficient absorption
Large bowel increased transit times allows for both water and sodium absorption
*LiverSize and histology are unchanged
*Spider angiomas and palmar erythema due to elevated estrogen level
Endocrinological changes of pregnancy:
Hormones produced from the uterus:
Placental hormones:
Human chorionic gonadotropin( hCG),
estrogen,
progesterone,
and human chorionic somatomamotropin (hPL) are all placental hormones and essential for normal pregnancy
hCG: is a glycoprotein produced by the syncytiotrophoblast cells into the maternal blood consist of 2 parts a and b subunits, and can be detected in the maternal blood from the 9th day of fertilization and its level in the plasma doubles every 2 days and reach maximum value at about 10-12 wks 50 000 -100 000 IU / L and then decrease toward the end of the pregnancy reaching half its level at 18 – 20 wks. hCG detectable in urine between 30 – 60 days Its main function is to maintain the corpus luteum of the pregnancy to secrete E & P; other function is to induce immunological tolerance in the mother. In the fetus the hCG stimulate the interstitial cells of the testes to secrete testosterone to enhance the development of the male sex organs and descent of the testes and stimulation of fetal adrenals. The b subunit is unique to pregnancy and used for the diagnosis of pregnancy by urine and blood tests, while a subunit is shared with other hormones like the FSH, LH, and TSH.
Estrogen:
produced by the placenta increasing toward the late part of the pregnancy to reach up to 30 times the normal female level. E produced by the placenta from precursors from maternal and fetal adrenals which secrete weak androgens that are converted by the placenta to E. E functions: enlargement of the mother uterus from 50gm to 1000 gm, angiogenesis, stimulation of protein synthesis ans cholesterol metabolism in the liver, Na and water retention, enlargement of the breast and development of the duct structure, enlargement of the mother external genitalia, relaxation of the maternal ligaments in preparation to labor in addition to many other functions.
Progesterone:
Its functions: Formation of the decidua, relaxation of the uterus maintaining the pregnancy, also help E in preparing the breast for lactation, vasodilatation, natriuretic, hyperventilation, thermogenic and increase thirst, appetite and fat deposition. Affect the nutrition and cleavage of cells in early embryo, it cross the placenta to be converted to cortisol in the fetal adrenals. P is synthesized from cholesterol which is derived from LDL. The placenta produces at term 250 mg P per day most of it bound to CSBG and only 5-15% is free. The increase in plasma level is 10 times quantitatively greater than the plasma level of E, but toward the end of pregnancy this ratio is inverted leading to initiation of labor.
Other hormones produced by the placenta are: like most of the hormones secreted from the pituitary and the hypothalamus
hPL is a polypeptide,and is a general metabolic hormone for the mother and the fetus, also have a prolactin like effect on the breasts.
Relaxin: produced by the C.L and the placenta causing relaxation of the maternal uterus and ligaments.
Prolactin: present in high concentration in the AF in early pregnancy till the 20 wks then decreases, is secreted from the decidua and its function is to regulate the electrolyte and fluid balance in the AF and the fetus, it increase myometrial contractility, the main source in the mother is the pituitary, its level is decreased in normal labor in the mother but surges 2 hours after labor.
Other endocrine effects of pregnancy:
Most of the maternal endocrine glands react to placental hormones and metabolic load on the mother, like the pitutary gland, thyroid and parathyroid gland enlarge by about 50% during pregnancy.
Diabetogenic effects of pregnancy
*hPL? lipolytic and anti-insulin it antagonize the action of insulin
*Cortisol which is elevated in normal pregnancy
*Prolactin
*Estrogen
and progesterone
Fetal glucose levels are 20 mg/dl less than maternal values Placental glucose transport is carrier mediated facilitated transport that is energy independent
Pancreas and Fuel Metabolism
*Physiologic glucose intolerance to insure continuous transport of nutrients from mother to fetus
*Fasting hypoglycemia
*Postprandial hyperglycremia
*Hyperinsulinemia due to insulin resistance induced by placental hormones
Thyroid Physiology
*Euthyroid state *Slight thyromegaly
*Free T4 and T3 remain normal but the total hormones are elevated because of the increased TBG.
*Fetal thyroid active by 12 weeks
Pituitary gland
*Enlarges due to proliferation of prolactin-secreting cells
*Prolactin levels are increased (ten times higher at term) to prepare breasts for lactation
Wt gain:
*Addition of 300 kcal/day
*the mother gain about 24 pounds during pregnancy mainly in the 2nd and 3rd trimesters of pregnancy
7 p by the baby
4 p by the placenta A.F, and membranes
9 p by the maternal body?
6 p ECF
?3 p by fat
2p by the uterus
2 p by the breasts
There is increased BMR especially in the 2nd half of pregnancy leading to increased calories requirements,
and increased sensation of heat.
Diet: the growth of the fetus mainly in the last 2 mo of pregnancy,
suppliments of iron, Ca, phosphate, proteins, vit. D, and vit K. Plasma lipids increased TG Is doubled LDL is increased Cholesterol incr. FFA is doubled
Skeletal and Postural Changes
*Lordosis of pregnancy? progressive increase in anterior convexity of the lumbar spine to Preserves center of gravity
*Ligaments of the symphysis and sacroiliac joints loosen during pregnancy due to relaxin which is secreted from the placenta in preparation for labor.
Skin changes:
*Hyperpigmentation of skin (cloasma), skin hyperemia, stria gravidarum on the abdomen, upper thigh and the breasts due to elevated level of cortisol which lead to weakness and breakdown of connective tissues on overstretching. Increased activity of sweat glands and sebaceous glands.
Physiology of Parturition
Means birth of the baby, toward the end of the pregnancy the uterus increase its excitability.
The mechanism responsible for initiation of labor is still unknown? due to hormonal and mechanical factors. Strong uterine contractions develop ended by expulsion of the fetus .
1- Hormonal factors: in the mother increase estrogen to progesterone ratio, and increased secretion of the oxytocin by the posterior pituitary. P inhibits uterine contractions during pregnancy but there is no evidence it decreases near term. E: a rising level of E during pregnancy sensitizes uterine muscles and makes it more easily responding to stimuli like oxytocin but there is no evidence of increased level prior to labor. Oxytocin it can induce and augment labor but there is no increase level prior to delivery. In the fetus: Fetal adrenal glands may play part in the initiation of labor there is evidence that anencephalic fetus has defective adrenal cortex, this pregnancy usually is prolonged.. Increased oxytocin, increased cortisol, increased prostaglandin from the fetal membrane, PG present in large amount in the decidua of late pregnancy, and synthetic PGs are used in induction of labor when placed vaginallyto stimulate uterine muscles contractions.
2- Mechanical factors: stretching of the smooth muscle lead to inccreased contractility, so contractions can be induced by fetal movements. But the question is why the uterus remains quiescent during the whole pregnancy and contracts only at its end?
*Over distended uterus: probably there is a limit for uterine distention that can be reached at term, which explain why twin pregnancy or polyhydramnios develop preterm labor? probably because of overstretching.
*Rupture of the amniotic membranes stimulate labor but labor can start without rupture of membranes
*The level of the intracellular Ca ion when raised leads to stimulation of contractions so we use the calicium chanel blockers and the beta adrenergic agonists to get uterine relaxation, while PG and oxytocin elevate Ca ion levels.
*The gap junction between myometrial cells increase in no and size near term which is stimulated by PG.
*The onset of parturition is thought to depend on interaction between fetal tissues(membranes and placenta) and maternal tissues(decidua) both contain increasing amounts of PG which initiate labor partly by stimulating uterine contraction and partly by ripening of the cervix.
*The baby is delivered and this process is called labour, and the contractions are called labour contractions
*Labor contractions continue to occur by a +ve feedback mechanism when the uterine cervix is stretched by the fetal head this will lead to contractions of the uterine body and increase the oxytocin secretion by the posterior Pituitary.
Breast changes and lactation:
The breast enlarge in size early in pregnancy and becomes lobular in texture with dilated veins under its skin.
The nipple enlarge in size, becomes darker in color and erectile.
The areola is enlarged and darkened.with the growth of Montgomery tubercle. Growth of the ductal system, role of estrogens: the placental estrogen cause ductal system of the breast to grow and branch, and the stroma increase in quantity with laying down of fat.
Other hormones essential for growth of ductal system are:
* G.H * Prolactin
* Adrenal glucocorticoid
* Insulin Development of the lobule alveolar system-role of progesterone: P work synergistically with E and other hormones leading to the development of the alveoli and lobules, with secretory changes in the alveoli Colostrum is secreted from the middle of pregnancy.
Initiation of lactation-function of prolactin: E and P ? breast growth but inhibit milk secretion, therefore no milk is produced in pregnancy.
Once the baby is born-? lowering of E and P and therefore removal of suppression on the milk production.
Ejection or let-down process in milk secretion-
function of oxytocin: Milk is secreted continually in the alveoli but not flow easily into the ducts and the nipples.
The milk ejection is both a neurogenic and hormonal process by the pit.
Oxytocin The 1st few sucks of the baby produce no milk flow but stimulation of the nippleàsensory impulses to the spinal cord to the hypothalamus to the pituitary gland to secrete both oxytocin and prolactin.
Oxytocin secreted in the blood reaching the breast leading to contraction of the myoepithelial cells surrounding the alveoli leading to ejection of the milk into the ducts then the baby can get milk after 30 sec. to 1 minute after starting of suckling leading to milk flow from both breasts