Female Repro L2: Pregnancy disorders

Question 1

Glucose metabolism during pregnancy

Answer 1

Tendency towards hypoglycemia observed in normal as well as diabetic pregnant women

Diabetogenic effects of anti-insulin hormones observed in the second half of pregnancy

• – Human placental lactogen (hPL)
  
  • Lipolysis
  • Glucose uptake
  • Gluconeogenesis
• – Placental insulinase
  
  • Degrades insulin
  • Decreases insulin effect
• – Increased estrogen
• – Increased progesterone
• More insulin required to overcome resistance
  
  • – Insulin release by pancreatic islet cells increases
  • – Third trimester mean 24-hour insulin levels 50% higher than non-pregnant state
  • – Increased risk to ketoacidosis in type 1 diabetes
• Higher fasting and postprandial glucose levels facilitate glucose transfer from mother to fetus
• Carrier-mediated active transport system that saturates at 250 mg/dL

Question 2

Fetal response to hyperglycemia in GDM

Answer 2

• High levels of plasma glucose are embryotoxic
• Effects are in direct proportion to periconception glycemic levels
• HbA1C levels correlates with incidence of major congenital malformations
• Maternal hyperglycemia results in fetal hyperglycemia – Fetal glucose levels are 80% of maternal levels
• Fetal hyperglycemia stimulates fetal hyperinsulinemia – Insulin does not cross the placental barrier
• Hyperinsulinemia exerts global anabolic effects leading to fetal macrosomia

Question 3

Screening for and Diagnosis of GDM

Answer 3

Undiagnosed Type-2DM

– Pregnant women with risk factors for Type-2 DM at the first prenatal visit using standard criteria (non-pregnant criteria) (See risk assessment in box 1)

GDM
– All pregnant women not previously known to have

DM at 24-28 weeks

Persistent diabetes

– Women with GDM at 6-12 weeks postpartum using OGTT and standard criteria

“One-step”screening and diagnosis (IADPSG Consensus)

• – 75-g OGTT for women not previously diagnosed with DM at 24-28 weeks of gestation
• – Perform OGTT in the morning after an overnight fast of at least 8 hours
• – Plasma glucose measurements: Fasting, 1 hr and 2 hr
• – Diagnosis made when any (one) of the following values are exceeded:
  
  • Fasting: ≥ 92 mg/dL (5.1 mmol/L)
  • 1 hr: ≥ 180 mg/dL (10.0 mmol/L)
  • 2 hr: ≥ 153 mg/dL (8.5 mmol/L)

“Two-step” screening and diagnosis (NIH Consensus)

• Step 1: 50-g glucose load test (GLT) (non-fasting) -Women not previously diagnosed with DM at 24-28 weeks of gestation
  
  • Plasma glucose measured at 1 hr
  • Proceed to step 2 if ≥ 140 mg/dL (7.8 mmol/L)
• Step 2: 100-g OGTT (fasting)
  
  • Plasma glucose measurements: fasting, 1 hr, 2 hr and 3 hr after OGTT
  • GDM is diagnosed when at least 2 of the following values are met or exceeded:

Question 4

Complications of Diabetes in Pregnancy

Answer 4

EFFECTS OF DM ON FETUS AND NEONATE

• Fetal macrosomia
• Congenital malformations
• Birth trauma
• Perinatal mortality
• Hypoglycemia
• Hyaline membrane disease
• Hyperviscosity syndrome
• Electrolyte abnormalities

Question 5

PREECLAMPSIA

Answer 5

Dx

• Preeclampsia complicates 5-7% of all pregnancies
• A multiorgan system disease characterized by hypertension and proteinuria
• Edema no longer included as diagnostic criterion
• – Occurs in >80% of normal pregnancies
• – Edema in preeclampsia is rapid and non-dependent
• Urinary protein loss same in pregnancy and nonpregnancy states
• Proteinuria >300mg over 24 hours suggests renal disease
• Gestational age ≥ 20 weeks
• Sustained elevation in blood pressure
  
  • – Systolic BP ≥ 140mmHg or/and
  • – Diastolic BP ≥ 90mmHg, on 2 occasions at least 4 hours apart
  • Mild preeclampsia [140/90 – 159/109mmHg]
  • Severe preeclampsia [≥160/110mmHg]
• Proteinuria
  
  • – And proteinuria >300mg in 24-hour urine collection
  • – Protein/creatinine ratio ≥ 0.3 (both measured in mg/dL)
  • – Urine protein (+) used if quantitative method is not used
• In the absence of proteinuria, new onset hypertension with:
  
  • – Thrombocytopenia<100,000/mL
  • – Renalinsufficiency
  • – Impairedliverfunction
  • – Pulmonary edema
  • – Cerebral or visualsymptoms

Risk Factors

• Age <20 years or >35 years
• Nulliparity/Primipaternity
• Multiple gestation
• Hydatidiform mole
• Diabetes mellitus
• Thyroid disease
• Chronic hypertension
• Renal disease
• Collagen vascular disease
• Antiphospholipid syndrome
• Family history of preeclampsia

Etiology

A disease of unknown etiology but “a disease of many theories”

• Abnormal development of the placenta
• Immunologic theory
• Increased sensitivity to angiotensin II
• Genetic theory
• Role of diet theory
• Systemic endothelial dysfunction
• Systemic inflammation
• Systemic endothelial dysfunction theory
• – Most popular theory as all clinical features can be explained by this theory

Pathophysiology

• Maladaptations in preeclampsia
• – Failure of second wave of trophoblastic invasion
• – Impaired remodeling of spiral arteries
• Intact musculoelastic architecture of spiral arteries retains its ability to respond to endogenous vasoconstrictors e.g. angiotensin II
• – Absence of normal intravascular volume expansion and a reduction in normal circulating blood volume
• Reduced perfusion of the placenta leads to progressive placental hypoxia
• The placenta responds by releasing potentially vasoactive factors capable of damaging or altering the function of maternal endothelial cells
• Endothelial cell injury reduces PGI2 secretion and exposes subendothelial collagen
• Platelets aggregate to exposed collagen, are activated and release TXA2
• Clinical picture of the disease results from
• – Resultant destruction of the microcirculation
• – Widespread vasoconstriction in many organs

Question 6

Clinicopathogenetic correlation (partial)

Answer 6

• Right upper quadrant or epigastric pain: Stretching of the Glisson’s capsule by hepatic edema or hemorrhage
• HELLP (Hemolysis, Elevated Liver enzymes, Low Platelet) syndrome: Hepatic edema and/or ischemia leading to hepatocellular injury, and consumption of platelets in microthrombi
• Microangiopathic hemolysis and elevation of serum lactate dehydrogenase levels: Precipitation of soluble fibrin monomers produced by the coagulation cascade resulting in hemolysis in microcirculation

Question 7

Pre-eclampsia Labs

Answer 7

• Hematocrit – hemoconcentration unless there is hemolysis
• Platelet count – thrombocytopenia is indicative of severe disease
• Creatinine concentration – elevated serum levels indicate severe disease and renal affectation
• Serum uric acid concentration - elevated
• Serum ALT and AST – elevated in hepatic dysfunction
• Serum lactate dehydrogenase concentration – elevated in microangiopathic hemolysis and HELLP syndrome
• Urinary protein excretion (24 hour urine collection or protein- to-creatinine ratio on random specimen) – progressively elevated as disease worsens
• Coagulation function tests (PT, APTT, fibrinogen concentration) - usually normal unless thrombocytopenia or liver dysfunction is present

Question 8

HEMOLYTIC DISEASE OF THE NEWBORN

Answer 8

• Numerous blood group systems described: ABO, Rhesus, Kell, Duffy, Kidd, MNSs, Diego.P, Lutheran, Xg, etc.
• Rhesus blood group is the most complex and most relevant to obstetric practice
• ABO blood group most important for blood transfusion

Question 9

Rhesus Isoimmunization: Pathophysiology

Answer 9

• Fetomaternal transfusion occurs in most pregnancies
  
  • – During pregnancy, delivery, as a consequence of abortion, ectopic pregnancy, H. mole, or abdominal trauma
  • – Can complicate obstetric procedures such as external cephalic version(ECV), amniocentesis, chorionic villous sampling (CVS), termination of pregnancy
  • – Most are not sufficient to activate immune response
• Incidence and degree of such transfusion increase with gestation
  
  • – First trimester (7%), second trimester (16%) and third trimester (29%)
  • – Gynecological and obstetric complications and procedures increase the risk of fetomaternal transfusion
  • Most women are sensitized as a result of small undetectable hemorrhage
• Possibility of sensitization following maternofetal transfusion
• Following exposure to RhD-positive blood, B- lymphocyte clones that recognize the RBC antigen are established
• Ability to activate immune response depends on ABO blood group and critical sensitizing dose
• Primary maternal immune response is production of IgM isotype
• This primary response is dose dependent
• – 15% of pregnancies with 1mL of Rh-positive cells and 70% after 250mL
• Maternal IgG response occurs later
• Secondary immune response follows repeat exposure to as little as 0.03mL of Rh-positive cells
• Maternal anti-D antibodies cross the placenta and attach to Rh antigens on fetal RBCs
• Tagged RBCs form rosettes on macrophages in the reticuloendothelial system
• Mechanisms of red cell destruction
• – Lysis of antibody-coated RBCs by macrophage lysosomal enzymes
• – Activation of classical pathway of complement
  
  • Osmotic lysis by membrane attack complex (MAC), or
  • Opsonin-mediated phagocytosis
• Fetal response occurs in response to level of anemia and tissue hypoxia
  
  • – Initial response is reticulocytosis
  • – A rise in umbilical artery lactate indicates severe fetal anemia
• Extramedullary erythropoiesis occurs in the liver, spleen, placenta and skin
• Erythroblastosis fetalis results when RBC destruction exceeds production
• Displacement and destruction of the liver parenchyma by erythroid cells lead to hypoproteinemia
• Hydrops fetalis results from failure of compensatory mechanisms
• Destruction of RBCs with release of heme leads to unconjugated hyperbilirubinemia
• Excess fetal bilirubin is metabolized by the placenta and cleared by maternal kidneys
• Hyperbilirubinemia becomes apparent only when the immature/compromised liver of the newborn cannot cope with bilirubin load

Question 10

Rhesus Isoimmunization: Diagnosis

Answer 10

• Maternal rhesus negativity
• Paternal rhesus positivity or unknown
• History of a previous birth of an infant with hemolytic disease of the newborn
• Presence of rising antibody titers on indirect Coomb’s test
• – Generally accepted critical titer is 1: 32
• Prenatal diagnosis performed with cell-free fetal DNA (cffDNA) testing
• – Fetal RHD genotype detection
• Abnormal middle cerebral artery (MCA) Peak systolic velocity (PSV) Doppler waveform
  
  • – Has replaced the optical density (ΔOD450) measurement
  • – Accuracy 85%; Liley’s curve 76%; Queenan’s curve 81%
  • – Values >1.5 MoM indicates amniocentesis and possible transfusion
• Postnatal cord blood findings
  
  • – Severe anemia
  • – Neonatal ABO group (usually compartible)
  • – Rh-positivity
  • – High anti-Rh antibody (Direct Coomb’s test)
  • – Unconjugated hyperbilirubinemia
• Kleihauer-Betke test
• Neonatal jaundice and kernicterus

Question 11

Kleihauer-Betke Test

Answer 11

• Provides an estimate of fetal blood within the maternal circulation
• Helps determine the dose of Rhogam necessary to prevent sensitization
• Test is based on detection of fetal hemoglobin (HbF)
• – Resistance to elution when exposed to strong acid or alkali (stains red)
• – HbA-containing maternal cells appear as “ghosts”
• %HbF = No. of fetal cells x 100/Total number of cell
• With fetal RBC Hb concentration of 50% per mL
• – Volume of fetal blood (mL) = %HbF cells x 50
• Numbers of vials of Rh(D) Immune Globulin = Vol. of fetal blood/30
• – One vial neutralizes 30 mL of whole blood or 15 mL of RBCs

Question 12

THE FETOPLACENTAL UNIT

Answer 12

• Estrogens are synthesized by human placenta from C-19 steroids
• Principal precursor for placental estrogen synthesis is DHEA-S from fetal adrenal
• The placenta has abundance of 4 important enzymes
• – Sulfatase, 3-β hydroxysteroid dehydrogenase-1 (3- βHSD-1), and aromatase
• Sulfatase cleaves sulfate group (SO4-) off DHEA-S
• 3-βHSD-1 converts DHEA to androsteinedione
• Aromatase converts androsteinedione to estriol
• Estriol is not secreted by the ovaries in the non-pregnant state
• Estriol produced in the placenta is secreted into maternal circulation
• Conjugation to estriol sulfate and glucuronide occurs in maternal liver
• Estriol has lower affinity for SHBG than estradiol
  
  • – > 90% of estrogen in urine of pregnant women
  • – Excreted as sulfate and glucuronide conjugates
  • – Circulating levels of estradiol is greater than estriol
• Total estrogen increases many folds in pregnancy
• – More than a normal ovulating woman could produce in 150 years
• Estriol levels increase from 2 mg/24 hours at 26 weeks to 35-45 mg/24 hours at term
• Used as an index of fetal wellbeing since all maternal estriol comes from the fetus

Question 13

Infertility: Investigation

Answer 13

• Ovulatory functions
  
  • Day 3: FSH, LH, TSH, prolactin, DHEA, ± free testosterone
  • Day 3: Antimullerian hormone (AMH) – ovarian reserve
  • Day 21-23: serum progesterone (confirms ovulation)
  • Basal body temperature (biphasic)
  • Post-coital test (cervical mucus: clarity, spinnbarkeit)
• Tubo-peritoneal factors
  
  • Hysterosalpingography (HSG)
  • Laparoscopy
  • Hysteroscopy
• Other: Karyotype