Accreditation Purpose and Value

Accreditation Purpose and Value

Biochemistry of Pregnancy and Fetal Well being Sameena Ghayur Associate Professor Shifa College of Medicine [email protected] Placenta and the Fetal membranes

Maternal and fetal circulation separate Nourishes the fetus Eliminates fetal wastes Produces hormones vital to pregnancy Placental Hormones Actions Placental Hormones Human chorionic gonadotropin(HCG)

Fertilization of the ovum prevents the regression of the corpus luteum (50 d) Enlarges, stimulated by the glycoprotein hormone, human chorionic gonadotropin (hCG), produced by the trophoblast (the developing placenta). Detected in maternal blood 6-9 days after conception and may be detectable in the urine 1-2 days later. The secretion of -hCG begins to fall by 10-12 weeks, although it remains detectable in the urine throughout pregnancy.

Placental Hormones Human chorionic gonadotropin(HCG) Steroidogenesis in pregnancy Hyperestrogenic state - unique and obligatory relationship with fetal adrenal secretion of C-19 steroids Syncitiotrophoblast utilize LDLcholesterol from maternal plasma for progesterone biosynthesis Steroidogenesis in pregnancy Composed of 3

compartments PLACENT AL FETAL Complementary forms complete unit utilizes MATERNAL COMPONENT Source of precursors, clearance of steroids Placental Hormones Placental steroids

Placental steroids 15-20mg/d 50-150mg/d Placental Hormones Human Human Placental lactogen

Help prepare breasts for lactation. Stimulates breast growth and development and stimulates the secretion of colostrum. Decrease the mother's use of glucose, so that it can be used by the fetus for growth and development Promotes breakdown of maternal fatsmaternal fatty acids in the plasma. "saving" the glucose for the fetus. Placental Hormones

Placental Hormones Parathyroid hormone (PTHrp) 40%, no change in plasma calcium A new set point for secretion of PTH No change in plasma free calcitonin

Vitamin 1,25-(OH) 2D3 increasing calcium absorption Placental Hormones Relaxin Expressed in: human corpus luteum, decidua, and placenta Structurally similar to insulin and insulin-like growth factor

Relaxin along with rising progesterone levels acts on myometrial smooth muscle to promote uterine relaxation and the quiescence observed in early pregnancy Relaxin and relaxin-like factors in the placenta and fetal membranes may play an autocrineparacrine role in regulation of extracellular matrix degradation in the puerperium Placental Hormones Inhibin

Produced by the testis, ovarian granulosa cells and the corpus luteum Placenta produces inhibin alpha-, and beta A and beta B-subunits Placental inhibin production together with large amounts of placental sex steroids inhibit FSH secretion and preclude ovulation during pregnancy Placental Hormones Endocrine changes Cortisol-CBG DHEAS

SHBG Estogen-Prolactin FSH and LH T4-TBG Chemical Changes in Pregnancy

Plasma triglycerides and cholesterol (40%) phospholipids and free fatty acids the glomerular filtration rate, plasma urea and creatinine. Glycosuria may be from a temporary hormonal impairment of glucose tolerance or a lowered renal threshold, Lactosuria is often present Plasma albumin and total protein

concentration of Metals and hormones caused by binding to transport globulin synthesized in excess, (TBG, CBG and SHBG) Placental synthesis of a specific isoenzyme Testing throughout pregnancy Antenatal Monitoring Why? What? How?

Antenatal Monitoring Why? Two thirds of fetal deaths occur before the onset of labor. Many antepartum deaths occur in women at risk for uteroplacental insufficiency. Ideal test: allows intervention before fetal

death or damage from asphyxia. Preferable: treat disease process and allow fetus to go to term. Antenatal Monitoring what? Conditions placing the fetus at risk for UPI Preeclampsia, chronic hypertension Collagen vascular disease diabetes mellitus Renal disease Fetal or maternal anemia, blood group sensitization, Hyperthyroidism Thrombophilia

Cyanotic heart disease Postdate pregnancy Antenatal Monitoring How? Methods for antepartum fetal assessment Fetal movement counting Assessment of uterine growth Antepartum fetal heart rate testing Biophysical profile Doppler velocimetry Antenatal Monitoring

How? Maternal and Fetal Health Assessment (Bichemical tests) Neural tube defects -16-18 weeks Downs syndrome -16-18 weeks Fetal lung maturity Rh immunization Gestational diabetes mellitus -24-28 weeks

HPL and Estriol- obsolete Maternal and Fetal Health Assessment Neural tube defects

Neural tube formation complete after 4 weeks after fertilization Failure of neural tube fusion leads to permanent developmental defects of the brain or spinal cord/both Anencephaly, meningomyelocele (spina bifida) and encephalocele All- 95% are open ,no overlying skin and in direct communication with the amniotic fluid Fetal serum proteins gain access AFP ( fetoprotein) appears in large Downs syndrome Risk Factors

Incidence (live births) 21: 1/6-800 Spontaneous and induced losses Maternal age Multiple gestation

Previous aneuploidy (patient or family) 70% have no identifiable risk factors Maternal and Fetal Health Assessment Downs syndrome Triple test (Kettering test or the Bart's test )

Usually performed at 15 to 18 weeks of gestation. fetoprotein Estriol, HCG Second-trimester maternal serum levels of AFP and unconjugated estriol are about 25 percent lower than normal levels and maternal serum hCG is approximately two times higher than the normal hCG level. Guidelines published by the American College of Obstetricians and Gynecologists state that maternal serum screening may be offered as an option for those women who do not accept the risk of amniocentesis or chorionic villus sampling or who wish to have this additional information prior to making a decision about

Maternal and Fetal Health Assessment Downs syndrome Maternal Alpha fetoprotein Recommended at 16 weeks of gestation Expressed as MoM Typical median is 35ng/ml (weight, race and for twins adjustment ) Maternal HCG

20,000-40,000IU/l at 16 weeks (weight adjustment ) 2.04 times higher Maternal and Fetal Health Assessment Downs syndrome Quad test Alpha-fetoprotein ( FP) Free -human chorionic gonadotrophin (free -hCG) Unconjugated oestriol (uE3 )

Recommended for women who: Inhibin-A Have family history of birth defects Are 35 yrs or older Used harmful medications or drugs during pregnancy Have diabetes and use insulin Had a viral infection during pregnancy Have been exposed to high levels of radiation Maternal and Fetal Health Assessment Downs syndrome

Pregnancy associated plasma protein A (PAPP-A) Produced by both embryo and placenta Zinc glycoprotein metalloproteinase and a member of the alpha-macroglobulin plasma protein family. Protease for IGF binding protein The gene for PAPPA is in chromosome band 9q33.1.

PAPPA has been used in prenatal genetic screening Women with low blood levels of PAPPA at 8 to 14 weeks of gestation have an increased risk of trisomy 21, premature delivery, preeclampsia, and stillbirth. Third trimester Glucose Screening: to test for gestational diabetes or glucose intolerance and assess the need for intervention (diet and meds) Amniotic Fluid testing Amniocentesis

Amniotic fluid obtained by inserting a needle through the abdominal and uterine walls Purpose Genetics - Abnormal AFP Fetal lung maturity Risks Infection (Sterile tech reqd) Pregnancy loss

Tests Triple tests AFP, hCG, and UE3 (unconjugated estriol/estrogen) L/S ratio- Lecithin/Sphingomyelin test for fetal lung maturation; 2:1 Fetal maturity index Phosphatidylglycerol- another phospholipid surfactant Amniocentesis Figure 149 Amniocentesis. The woman is scanned by ultrasound to determine the placental site and to locate a pocket of amniotic fluid. Then the needle is inserted into the uterine cavity to withdraw amniotic fluid. Amniotic fluid Fetal lung maturity

Respiratory distress syndrome Specialized alveolar cells type II granulocytes synthesize pulmonary surfactant storage granules -lamellar bodies Surfactant complex mixture of lipids and proteins with <3% CHO Lipid phospholipid and majority is lecithin Sphingomyelin present in very small amounts 2%

Tests L/S ratio DSPC Phosphotidylglycerol Foam stability Flourescent polarization Fetal lung maturity Lecithin Sphingomyelin ratio

Amniotic fluid sample collected via amniocentesis Spun down in a centrifuge at 1000 rpm for 3 to 5 minutes. Thin layer chromatography (TLC) performed on the supernatant, which separates out the components.

Lecithin and sphingomyelin are relatively easy to identify on TLC and the predictive value of the test is good Fetal lung maturity Foam Stability Index When pulmonary surfactant is present in amniotic fluid in sufficient concentrations , the fluid is able to form a highly stable surface film that can support the structure of a foam Method Centrifuge , mix supernatant by inverting several times Add 95% ethanol into tubes labelled 0.50, 0.48, 0.45, 0.44, add amniotic fluid to them , shake vigorously , allow to settle

A ring of bubbles at the air fluid meniscus in the is a positive test Highest concentration of ethanol at which aopositive readind g is obtained foam stability index Fetal lung maturity Lamellar body count . Am J Obstet Gynecol. 2002 Oct;187(4):908-12. Amniotic fluid Bilirubin

Amount of bilirubin is a marker of RBC hemolysis in the fetal circulation Most common Rh Incompatibility Feto maternal hemorrhage, repeat exposure causes an augmented response Liley degree of hemolysis is assessed by measuring the absorbance of bilirubin pigment

in amniotic fluid Classification into 3 zones based on gestational age A 450 Serial amniotic fluid estimations starting at 22 Amniotic fluid Bilirubin Absorption spectrophotometry Max absorption at

450nm Semilog scale , the degree which the curve deviates from a straight line at 450 nm is linearly proportional to the Liley method OD 450OD 450 Amniotic fluid spectrophotometric reading. Liley method OD 450 (0.256 in this OD 450 (0.256 in this example) falls into zone 3, indicating impending fetal death. A second pigment peak at 405 nm denotes the presence of heme pigment, further evidence of very severe erythroblastosis.(Bowman JM, Pollock JM: Amniotic fluid spectrophotometry and early delivery in the management of erythroblastosis fetalis. Pediatrics 35:815, 1965)

Other Fetal Diagnostic Tests Chorionic Villus Sampling performed at 10 12 weeks, off the placenta Percutaneous Umbilical Blood SamplingComputed Tomography- obtain maternal pelvic and fetal diameters Magnetic Resonance Imaging- confirm anamolies, placental assessment for location and size

Fetal Echocardiography- identify cardiac anomalies- during 2nd and 3rd trimester References Sher G, Statland BE, Freer DE, Kraybill EN Obstet Gynecol. 1978 Dec;52(6):673-7. Assessing fetal lung maturation by the foam stability index test. B J Trudinger, Y B Gordon, I G Grudzinskas, M G R Hull, P I

Lewis, Marie E Lozana Arrans. Fetal breathing movements and other tests of fetal wellbeing: a comparative evaluation. British Medical Journal, 1979, 2, 577-579 Pertl B, Pieber D, Lercher-Hartlieb A, Orescovic I, Haeusler M, Winter R, Kroisel P, Adinolfi M. Rapid prenatal diagnosis of aneuploidy by quantitative fluorescent PCR on fetal samples from mothers at high risk for chromosome disorders Mol Hum Reprod. 1999 Dec;5(12):1176-9. Gordon C. S. Smith, Emily J. Stenhouse, Jennifer A. Crossley, David A. Aitken, Alan D. Cameron and J. Michael Connor. Early Pregnancy Levels of PregnancyAssociated Plasma Protein A and the Risk of Intrauterine Growth Restriction, Premature Birth, Preeclampsia, and

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