8.1 - GI Disorders

Summary

GASTROINTESTINAL, HEPATIC, AND BILIARY DISORDERS IN PREGNANCY

GENERAL PRINCIPLES & PHYSIOLOGY

• Progesterone in pregnancy causes decreased GI motility and decreased LES tone, which can lead to constipation and GERD.
• Estrogen in pregnancy increases nausea and alters bile composition, predisposing the mother to gallstones.
• hCG peaks in the 1st trimester and is the primary hormone linked to pregnancy-related vomiting.
• Epigastric pain in the 3rd trimester is a "red flag" that requires checking blood pressure and liver enzymes to rule out preeclampsia/HELLP.
• Alkaline phosphatase levels naturally rise 3-4 fold during normal pregnancy due to placental production, not liver damage.
• AST, ALT, and Bilirubin levels do NOT change in a normal pregnancy; any elevation is considered pathologic.
• Serum Albumin and total protein concentrations decrease during normal pregnancy due to hemodilution.
• Gastrointestinal disorders in the Philippines are often complicated by high rates of anemia, malnutrition, and parasitic infections.

DIAGNOSTIC TECHNIQUES & NUTRITION

• Upper GI endoscopy is considered safe for diagnosis and management during pregnancy when indicated.
• Flexible sigmoidoscopy is the preferred method for visualizing the large bowel in pregnant women.
• Polyethylene glycol is used for bowel prep; maternal dehydration must be avoided to maintain uteroplacental perfusion.
• ERCP is useful for diagnosing and treating choledocholithiasis and pancreatic issues in pregnancy.
• Abdominal sonography is the ideal first-line technique for GI imaging due to its lack of radiation.
• Magnetic Resonance Imaging (MRI) is the preferred modality for viewing the retroperitoneal space and diagnosing appendicitis without radiation.
• Laparoscopy is the preferred surgical approach in the 1st and 2nd trimesters; it carries a risk of preterm labor in the 3rd trimester.
• Enteral nutrition (nasogastric tube) is always preferred over parenteral nutrition because it has fewer complications.
• Central Parenteral Nutrition (CPN) is reserved for conditions like short bowel syndrome and requires central venous access for hyperosmolar solutions.

UPPER GI DISORDERS: KEY FACTS

• Hyperemesis Gravidarum can cause Wernicke Encephalopathy due to thiamine deficiency, characterized by the triad of ocular signs, confusion, and ataxia.
• Vitamin K deficiency in hyperemesis can lead to maternal coagulopathy and fetal intracranial hemorrhage.
• Ondansetron (Zofran) should be reserved for cases after 8 weeks' gestation due to risks of prolonged QT interval and serotonin syndrome.
• Boerhaave Syndrome is a serious esophageal rupture caused by sustained, forceful retching in hyperemesis.
• Mallory-Weiss tears are small mucosal tears at the GE junction causing upper GI bleeding after persistent vomiting.
• Diaphragmatic hernia repair is recommended during pregnancy, even if asymptomatic, because the maternal mortality rate of rupture is approximately 45%.
• Vaginal delivery is generally contraindicated in unrepaired diaphragmatic hernias due to the risk of rupture from increased intraabdominal pressure.
• Hiatal hernias are found in 20% of multiparas in late pregnancy and may cause vomiting or epigastric pain.

INTESTINAL & COLONIC DISORDERS: KEY FACTS

• Acute diarrhea evaluation is required if it lasts >48 hours, involves fever >38°C, or grossly bloody stools.
• Loperamide (Imodium) should be avoided in acute diarrhea if the etiology is unknown, as it may prolong the presence of toxins.
• Clostridioides difficile is the most common nosocomial infection and is typically triggered by aminopenicillins or cephalosporins.
• Fecal calprotectin is a valid inflammatory biomarker used to identify IBD flares in pregnant patients.
• Toxic megacolon is a catastrophic complication of Ulcerative Colitis that may necessitate an emergency colectomy.
• Bowel obstruction in pregnancy is most commonly caused by the growing uterus exerting pressure on pre-existing adhesions.
• Tocolytics are not recommended for contractions following appendectomy due to the high risk of pulmonary edema in the setting of sepsis.

HEPATIC, BILIARY, & VIRAL DISORDERS: KEY FACTS

• Acute Liver Failure in the non-pregnant population is most commonly caused by Acetaminophen toxicity.
• Spider angiomata and palmar erythema occur in 2/3 of normal pregnancies due to high estrogen levels and are not necessarily signs of liver disease.
• Intrahepatic Cholestasis of Pregnancy (ICP) increases the risk of fetal death if bile acid levels exceed 100 µmol/L due to cardiotoxicity.
• Vaginal delivery is the preferred mode for liver failure patients to minimize incision-related bleeding, as the liver produces necessary coagulation factors.
• Hepatitis B screening should be done for ALL pregnant women at the first visit; it is a DNA virus.
• HBsAg is the first serologic marker to appear in an acute Hepatitis B infection.
• Vertical transmission of Hep B is highest (90%) if the mother is HBeAg positive at delivery.
• Neonatal intervention for Hep B involves giving the infant both HBIG and the Hep B vaccine series within 12 hours of birth.
• Hepatitis C vertical transmission is low (<5%) but higher if the mother is coinfected with HIV.
• Hepatitis A does NOT cause birth defects and maternal-fetal transmission has not been observed.
• Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common chronic liver disease and is linked to obesity and metabolic syndrome.
• Cholelithiasis (gallstones) is more common in pregnancy because gallbladder fasting and residual volumes double after the 1st trimester.
• Bile sludge often regresses spontaneously after delivery.
• Cholecystectomy is safe in all trimesters, but prophylactic removal of asymptomatic stones is NOT warranted.

DIFFERENTIAL COMPARISONS FOR EXAMS

• Hyperemesis Gravidarum vs. Normal Morning Sickness: HG involves weight loss >5% and ketonuria; morning sickness typically resolves by 16 weeks and doesn't cause dehydration.
• Acute Fatty Liver (AFLP) vs. HELLP Syndrome: AFLP is characterized by severe hypoglycemia and prolonged clotting times/hypofibrinogenemia; HELLP focus is on hemolysis and low platelets.
• ICP vs. Viral Hepatitis: ICP presents with pruritus and high bile acids with minimal transaminase elevation; Hepatitis presents with malaise and very high transaminases (>1000 U/L).
• Ulcerative Colitis vs. Crohn Disease: UC is continuous and involves only the mucosa/submucosa of the colon; Crohn's is patchy, transmural, and can affect the small bowel (distal ileum).
• pANCA vs. ASCA: pANCA is associated with Ulcerative Colitis (70%); ASCA (Anti-S. cerevisiae) is associated with Crohn Disease (50%).
• Boerhaave Syndrome vs. Mallory-Weiss Tear: Boerhaave is a full-thickness esophageal rupture (emergency); Mallory-Weiss reflects linear mucosal tears (usually self-limiting bleeding).
• Epigastric Pain in 3rd Trimester: If BP is high, think Preeclampsia/HELLP; if BP is normal and patient has fatty food intolerance, think Cholecystitis.
• Progesterone Effects vs. Mechanical Effects: Progesterone causes decreased LES tone (GERD) and slow GI transit; the enlarging uterus increases pressure on the stomach and displaces the appendix.
• HBsAg vs. Anti-HBs: HBsAg indicates infection (active/carrier); Anti-HBs indicates immunity (previous infection or vaccination).
• HBeAg vs. Anti-HBe: HBeAg indicates high viral replication and high infectivity; Anti-HBe suggests lower viral titers.
• Enteral vs. Parenteral Nutrition: Enteral is via the GI tract (preferred); Parenteral is via the veins (used only if the GI tract must remain "quiescent").
• PPN vs. CPN: PPN is short-term and peripheral; CPN is long-term, uses 24-40 kcal/kg/day, and requires high-flow central veins for hypertonic solutions.
• Appendicitis Diagnosis: Ultrasound is first-line to rule out OB causes; MRI is the gold standard for definitive diagnosis in pregnancy.
• Treatment of C. diff: Oral Vancomycin is 1st line; avoid Loperamide which can worsen the infection.
• Hepatitis Transmission: Hep A is fecal-oral; Hep B and C are parenteral (blood/body fluids).
• Management of Bile Stones: Symptomatic gallstones = Laparoscopic Cholecystectomy; Asymptomatic gallstones = Observation until postpartum.
• Achalasia Appearance: Barium swallow shows a "bird beak" narrowing; GERD does not show this specific narrowing unless a stricture has formed.
• Methotrexate: Excellent for ectopic pregnancy but strictly contraindicated for IBD management in a viable pregnancy due to teratogenicity.
• Delivery in IBD: Vaginal delivery is the goal; Cesarean is only preferred if active perianal disease (fistulas/abscesses) is present in Crohn's.
• Delivery in ICP: Routine induction at 38 weeks; if jaundice or bile acids are >100, deliver at 36 weeks.
• Management of HG: Diclegis is the 1st step; if intractable, use IV fluids with Thiamine before any glucose-containing fluids to avoid Wernicke's.

QA

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1. What hormones contribute to the pathogenesis of Hyperemesis Gravidarum? | hCG, estrogen, progesterone
2. Which bacterium is possibly linked to Hyperemesis Gravidarum? | Helicobacter pylori
3. What is the weight loss criteria for Hyperemesis Gravidarum? | >5% weight loss
4. Enumerate the metabolic/electrolyte imbalances in Hyperemesis Gravidarum (3). | Ketonuria, hypokalemia, alkalosis
5. What is the first-line pharmacologic treatment for Hyperemesis Gravidarum? | Diclegis
   (Doxylamine + Pyridoxine)
6. Which nutrient is given to prevent Wernicke Encephalopathy in Hyperemesis Gravidarum? | Thiamine (100mg)
7. What is the primary pathogenesis of GERD in pregnancy? | Progesterone-induced LES relaxation
8. What is the clinical term for heartburn often seen in GERD? | Pyrosis
9. When does the prevalence of GERD symptoms typically increase? | 3rd trimester
10. Which class of drugs is safe for GERD but must avoid Misoprostol? | PPIs and H2 blockers
11. Why is pregnancy considered gastroprotective against Peptic Ulcer Disease? | Low gastric acid/High mucus
12. List the components of Triple Therapy for H. pylori PUD (3). | Amoxicillin/Metronidazole,
    Clarithromycin,
    PPI
13. Which plexus is destroyed in the pathogenesis of Achalasia? | Myenteric (Auerbach) plexus
14. What classic finding is seen on a barium swallow for Achalasia? | "Bird beak" narrowing
15. What is the confirmatory diagnostic test for Achalasia? | Manometry
16. How does the position of the appendix change in Appendicitis during pregnancy? | Upward and outward
17. What is the most common site of pain in Appendicitis, even in pregnancy? | Right Lower Quadrant (RLQ)
18. What is the diagnostic modality of choice for Appendicitis in pregnancy? | MRI
19. What is the preferred surgical approach for Appendicitis in the 1st/2nd trimester? | Laparoscopy
20. Describe the extent of inflammation in Ulcerative Colitis. | Continuous, superficial mucosal inflammation
21. Where does Ulcerative Colitis inflammation always begin? | Rectum
22. Which serologic marker is found in 70% of Ulcerative Colitis cases? | pANCA
23. What medication is strictly contraindicated in Ulcerative Colitis due to teratogenicity? | Methotrexate
24. Describe the inflammatory pattern of Crohn Disease. | Transmural and patchy/segmental
25. Which specific GI complications are characteristic of Crohn Disease? | Perianal fistulas/abscesses
26. Which antibody is associated with 50% of Crohn Disease cases? | ASCA
27. What is the folic acid recommendation for patients with Crohn Disease? | 4mg
28. What causes Intrahepatic Cholestasis of Pregnancy (ICP)? | Impaired bile salt transport
29. What is the hallmark clinical manifestation of ICP? | Pruritus (palms/soles)
30. What lab result is diagnostic for ICP? | Elevated total serum bile acids
31. What is the first-line medication for ICP? | Ursodeoxycholic acid
32. When is delivery recommended for severe ICP or jaundice? | 36 weeks
33. What mitochondrial abnormality is linked to Acute Fatty Liver of Pregnancy (AFLP)? | LCHAD mutation
34. What metabolic emergency is a hallmark of AFLP? | Hypoglycemia
35. Which criteria are used to diagnose AFLP? | Swansea Criteria
36. What is the definitive management for AFLP? | Immediate delivery
37. How does Progesterone affect GI motility in pregnancy? | Decreases motility
38. How does Estrogen affect the gallbladder in pregnancy? | Predisposes to gallstones
39. When does hCG peak in pregnancy? | 1st trimester
40. Epigastric pain in the 3rd trimester is a "red flag" for which condition? | Preeclampsia/HELLP
41. Which liver enzyme rises naturally in pregnancy due to placental production? | Alkaline phosphatase
42. Which liver labs do NOT change in a normal pregnancy (3)? | AST, ALT, Bilirubin
43. Why do serum albumin levels decrease during normal pregnancy? | Hemodilution
44. Name three factors complicating Gastrointestinal disorders in the Philippines. | Anemia, malnutrition, parasitic infections
45. Which diagnostic procedure is the preferred method for viewing the large bowel in pregnancy? | Flexible sigmoidoscopy
46. Why must maternal dehydration be avoided during bowel prep with Polyethylene glycol? | Maintain uteroplacental perfusion
47. What is ERCP used for in pregnancy? | Choledocholithiasis/Pancreatic issues
48. What is the first-line imaging technique for GI issues in pregnancy? | Abdominal sonography
49. Why is MRI preferred for diagnosing appendicitis in pregnancy? | No radiation/Good retroperitoneal view
50. What is a risk of Laparoscopy performed in the 3rd trimester? | Preterm labor
51. Why is Enteral nutrition preferred over parenteral nutrition? | Fewer complications
52. Which condition specifically warrants Central Parenteral Nutrition (CPN)? | Short bowel syndrome
53. What is the classic triad of Wernicke Encephalopathy? | Ocular signs, confusion, ataxia
54. What are the neonatal risks of maternal Vitamin K deficiency? | Fetal intracranial hemorrhage
55. Why is Ondansetron reserved until after 8 weeks' gestation? | QT interval/Serotonin syndrome risk
56. Define Boerhaave Syndrome. | Full-thickness esophageal rupture
57. Define Mallory-Weiss tears. | Mucosal GE junction tears
58. What is the maternal mortality rate of a ruptured Diaphragmatic hernia? | Approximately 45%
59. Why is vaginal delivery contraindicated in unrepaired Diaphragmatic hernias? | Risk of rupture
60. What percentage of multiparas have Hiatal hernias in late pregnancy? | 20%
61. When is evaluation for Acute diarrhea required? | Duration >48 hours/Fever/Bloody stools
62. Why should Loperamide be avoided if the diarrhea etiology is unknown? | Prolongs toxin presence
63. Which antibiotics typically trigger Clostridioides difficile? | Aminopenicillins or Cephalosporins
64. What biomarker is used to identify IBD flares in pregnancy? | Fecal calprotectin
65. What is Toxic megacolon? | Catastrophic UC complication
66. What is the most common cause of Bowel obstruction in pregnancy? | Pressure on pre-existing adhesions
67. Why are tocolytics avoided after an appendectomy in septic patients? | Risk of pulmonary edema
68. What is the most common cause of Acute Liver Failure in the general population? | Acetaminophen toxicity
69. What skin signs occur in 2/3 of pregnancies due to high estrogen? | Spider angiomata/Palmar erythema
70. At what bile acid level does the risk of fetal death increase in ICP? | >100 µmol/L
71. What is the preferred mode of delivery for Liver failure patients? | Vaginal delivery
72. When should Hepatitis B screening be performed? | First prenatal visit
73. Which serologic marker appears first in acute Hepatitis B? | HBsAg
74. What HBeAg status in the mother correlates with 90% vertical transmission of Hep B? | HBeAg positive
75. What two interventions are given to Hep B exposed neonates within 12 hours? | HBIG and Hep B vaccine
76. What increases the risk of vertical transmission for Hepatitis C? | HIV coinfection
77. Is Hepatitis A associated with birth defects? | No
78. What is the most common chronic liver disease? | NAFLD
79. How do gallbladder volumes change after the 1st trimester? | They double
80. What is the management for Asymptomatic gallstones in pregnancy? | Observation/Expectant management
81. Compare Hyperemesis Gravidarum vs. Morning Sickness regarding weight loss. | HG has >5% loss; Morning sickness does not.
82. Compare AFLP vs. HELLP regarding glucose and coagulation. | AFLP: Hypoglycemia/Prolonged clotting
    HELLP: Hemolysis/Low platelets
83. Compare ICP vs. Viral Hepatitis regarding transaminases. | ICP: Minimal elevation
    Hepatitis: Very high (>1000 U/L)
84. Compare Ulcerative Colitis vs. Crohn Disease regarding thickness of inflammation. | UC: Mucosal/superficial
    Crohn's: Transmural
85. Which antibody is for UC and which is for Crohn's? | pANCA (UC); ASCA (Crohn's)
86. Compare Boerhaave vs. Mallory-Weiss severity. | Boerhaave: Rupture (Emergency)
    Mallory-Weiss: Tear (Self-limiting)
87. Epigastric pain in 3rd trimester + High BP Suggests? | Preeclampsia/HELLP
88. Epigastric pain in 3rd trimester + Normal BP + Fatty food intolerance suggests? | Cholecystitis
89. Contrast HBsAg vs. Anti-HBs. | HBsAg: Infection
    Anti-HBs: Immunity
90. Contrast HBeAg vs. Anti-HBe. | HBeAg: High infectivity
    Anti-HBe: Lower viral titers
91. Contrast Enteral vs. Parenteral Nutrition route. | Enteral: GI tract
    Parenteral: Veins
92. Contrast PPN vs. CPN duration and flow. | PPN: Short-term/Peripheral
    CPN: Long-term/Central/Hypertonic
93. What is the first-line drug for C. diff? | Oral Vancomycin
94. Contrast the transmission of Hep A vs. Hep B/C. | Hep A: Fecal-oral
    Hep B/C: Parenteral
95. Contrast Achalasia vs. GERD on barium swallow. | Achalasia: Bird beak
    GERD: No narrowing
96. When is Cesarean delivery preferred in Crohn Disease? | Active perianal disease
97. What is the routine induction timing for ICP? | 38 weeks
98. What must be given BEFORE glucose in intractable Hyperemesis Gravidarum? | Thiamine
99. What are the clinical signs of Achalasia (3)? | Dysphagia, chest pain, regurgitation
100. What is the pathogenesis of AFLP? | Microvesicular fat accumulation
101. What is the "Gold Standard" for diagnosing Appendicitis in pregnancy? | MRI
102. Which IBD type has a 1%/year risk for colon cancer? | Ulcerative Colitis
103. What are the characteristics of NAFLD? | Obesity and metabolic syndrome

8.2 - Hematologic Disorders

Summary

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PHYSIOLOGIC ADAPTATION IN PREGNANCY

• (Maternal Physiology) Plasma volume expansion by 40-50% disproportionately exceeds the 15-25% increase in red cell mass, resulting in hemodilution and physiologic anemia.
• (Maternal Physiology) Hematocrit levels typically decrease during pregnancy to an average of 34% in singleton pregnancies and 30% in multifetal gestations.
• (Maternal Physiology) Oxygen-carrying capacity remains normal during pregnancy despite hemodilution and physiologic anemia.
• (Maternal Physiology) Whole blood viscosity decreases during pregnancy due to the decline in hemoglobin and hematocrit concentrations.
• (Maternal Physiology) Hemoglobin concentration at term is normally 12.5 g/dL; values below 11.0 g/dL are considered abnormal and usually signify iron deficiency.
• (Maternal Physiology) Maternal blood volume expansion reaches a plateau during the last weeks of pregnancy after rising most rapidly during the midtrimester.
• (Maternal Physiology) Iron requirements increase from 1 mg/day in non-pregnant women to approximately 7 mg/day in the third trimester to support the fetus, placenta, and expanded maternal red cell mass.
• (Maternal Physiology) Total iron requirement for a healthy normal pregnancy is approximately 1000 mg, with 300 mg transferred to the fetus/placenta and 200 mg lost through normal excretion.
• (Maternal Physiology) Maternal hepcidin levels are suppressed 10-fold in the second trimester compared to the first to facilitate greater iron absorption via ferroportin in enterocytes.
• (Maternal Physiology) Coagulation factors VII, VIII, IX, and X increase during pregnancy, creating a physiologic hypercoagulable state to prevent hemorrhage.
• (Maternal Physiology) Fibrinogen levels double by term (reaching up to 600+ mg/dL), while fibrinolysis is simultaneously inhibited.
• (Maternal Physiology) Protein S functional activity significantly decreases during pregnancy (dropping from ~65-140% to ~16-42% by the 3rd trimester), contributing to the prothrombotic state.
• (Maternal Physiology) Platelet counts decrease from the mid-second to third trimester due to dilution, increased spleen size (50% increase), and pooling in the intervillous space.
• (Maternal Physiology) Left ventricular mass increases throughout pregnancy, beginning at 26 to 30 weeks' gestation.
• (Maternal Physiology) Arterial blood pressure usually declines to a nadir at 24 to 26 weeks, with diastolic pressure decreasing more than systolic pressure.

ANEMIA: DIAGNOSIS AND GENERAL CAUSES

• (Anemia Diagnosis) Anemia is defined as a decreased blood concentration of hemoglobin, regardless of cause, morphology, or RBC function.
• (Anemia Diagnosis) Anemia thresholds for pregnant women differ by trimester: <11 g/dL in the first/third and <10.5 g/dL in the second trimester according to the CDC.
• (Anemia Diagnosis) Microcytic anemia evaluation requires measuring serum ferritin and performing hemoglobin electrophoresis to differentiate iron deficiency from hemoglobinopathies.
• (Anemia Diagnosis) Macrocytic anemia evaluation primarily involves checking serum folate and vitamin B12 levels.
• (Acute Blood Loss) Oral iron therapy can be provided for three months to a moderately anemic woman (Hgb ~7 g/dL) who is hemodynamically stable, able to ambulate, and not septic.
• (Chronic Anemia) Anemia of chronic disease is characterized by slightly hypochromic/microcytic cells, low transferrin saturation, high serum ferritin, and elevated hepcidin which restricts iron export.
• (Chronic Anemia) Recombinant erythropoietin is considered in pregnancies with chronic renal insufficiency when the hematocrit approximates 20 percent.

IRON DEFICIENCY ANEMIA (IDA)

• (Iron Deficiency Anemia) Iron deficiency anemia is the most common cause of anemia in pregnancy, resulting from an inability to meet the 1000 mg requirement.
• (Iron Deficiency Anemia) Serum ferritin levels below 10–15 μg/L specifically confirm iron-deficiency anemia in gravidas.
• (Iron Deficiency Anemia) Ferritin acts as an acute phase reactant, so levels up to 100 ng/mL may still be compatible with IDA in the presence of inflammation or infection.
• (Iron Deficiency Anemia) Erythropoietin (EPO) synthesis increases in pregnancy due to hypoxia sensed by the kidneys, supporting RBC mass expansion.
• (Iron Deficiency Anemia) Erythroferrone (ERFE) is upregulated by EPO to sequester hepcidin-inducer BMP6, thereby lowering hepcidin and increasing iron flow.
• (Iron Deficiency Anemia) Red cell distribution width (RDW) is high in IDA, reflecting significant anisopoikilocytosis on a peripheral smear.
• (Iron Deficiency Anemia) Bone marrow iron stores (absent) is the most sensitive and specific criterion for iron deficiency erythropoiesis, though bone marrow exam is rarely needed.
• (Iron Deficiency Anemia) Maternal complications of IDA include increased risk of infections, preterm labor, PPROM, postpartum hemorrhage, and increased mortality.
• (Iron Deficiency Anemia) Fetal complications of maternal IDA include low birth weight (LBW), IUGR, and impaired long-term neurodevelopment.
• (Iron Deficiency Anemia) Hydrops fetalis or intrauterine death can result from severe fetal anemia leading to high-output heart failure.

MEGALOBLASTIC AND APLASTIC ANEMIA

• (Megaloblastic Anemia) Folate deficiency is essential for DNA synthesis; deficiency is common in poor nutritional states or users of anticonvulsants.
• (Megaloblastic Anemia) Vitamin B12 deficiency is typically seen in vegetarians, vegans, or patients with malabsorption/GI surgery.
• (Megaloblastic Anemia) Megaloblasts are large RBC precursors caused by impaired nuclear division with relatively normal cytoplasmic maturation (asynchronous maturation).
• (Aplastic Anemia) Aplastic anemia is a grave complication characterized by pancytopenia and a markedly hypocellular bone marrow.
• (Aplastic Anemia) Diamond-Blackfan anemia is a pure red cell hypoplasia that responds well to glucocorticoid therapy but increases risk of preeclampsia and FGR.
• (Aplastic Anemia) Gaucher disease is an autosomal recessive lysosomal deficiency of acid β-glucosidase that causes anemia and thrombocytopenia worsening in pregnancy.
• (Aplastic Anemia) Red cell transfusions in aplastic anemia are indicated to maintain a hematocrit above 20 percent.

HEMOLYTIC ANEMIA AND HEMOGLOBINOPATHIES

• (Hemolytic Anemia) Evans syndrome refers to autoimmune hemolysis comorbid with thrombocytopenia.
• (Hemolytic Anemia) Paroxysmal Nocturnal Hemoglobinuria (PNH) carries a high risk of venous thromboembolism (40% of cases) and is treated with eculizumab.
• (Hemolytic Anemia) G6PD deficiency leads to episodic anemia triggered by drugs (e.g., Macrodantin) or infections; it is an X-linked recessive disorder.
• (Hemoglobinopathies) Sickle-cell crisis is a diagnosis of exclusion in pregnancy and is managed with IV fluids, prompt opioid analgesia, and oxygen.
• (Hemoglobinopathies) Acute chest syndrome in sickle cell patients presents with pleuritic chest pain, fever, and new lung infiltrates; it occurs in ~6% of pregnant women.
• (Hemoglobinopathies) Sickle-cell trait (Hb AS) occurs in ~8% of African Americans and is NOT a deterrent to pregnancy but increases risk for asymptomatic bacteriuria.
• (Hemoglobinopathies) Hemoglobin E is common in Southeast Asia; homozygous state (Hb EE) shows marked microcytosis but little anemia.
• (Thalassemia) Alpha-thalassemia major (Hb Bart disease) involves deletion of all 4 alpha genes and is incompatible with survival, often resulting in hydrops fetalis.
• (Thalassemia) Beta-thalassemia minor is characterized by elevated Hemoglobin A2 (>3.5%) and mild hypochromic microcytic anemia.
• (Polycythemia) Polycythemia vera is a myeloproliferative neoplasm associated with the JAK2 mutation and requires aggressive management with aspirin and LMWH.

PLATELET AND MICROANGIOPATHIC DISORDERS

• (Platelet Disorders) Gestational thrombocytopenia accounts for 75% of thrombocytopenia cases in pregnancy and usually requires no treatment.
• (Thrombotic Microangiopathy) Thrombotic microangiopathy (TMA) is characterized by microangiopathic hemolytic anemia (MAHA), schizocytes on smear, and end-organ damage.
• (TTP) Thrombotic thrombocytopenic purpura (TTP) is confirmed by an ADAMTS13 activity level <10% and is treated primarily with plasmapheresis.
• (TTP) TTP clinical pentad includes thrombocytopenia, hemolytic anemia, fever, neurologic manifestations, and renal injury.
• (HELLP vs TTP) HELLP syndrome is reversed by delivery, whereas delivery does NOT improve thrombotic microangiopathies like TTP.
• (TMA treatment) Eculizumab is the preferred treatment for complement-mediated TMA (aHUS) and PNH.

INHERITED COAGULATION DEFECTS

• (Hemophilia) Hemophilia A and B are X-linked recessive conditions; female carriers usually have ~50% factor activity due to lyonization but can experience bleeding if levels are <20%.
• (Hemophilia) Desmopressin can be used to stimulate factor VIII release in patients with Hemophilia A.
• (von Willebrand Disease) von Willebrand disease (VWD) is the most common inherited bleeding disorder; Type 1 is a partial quantitative deficiency, while Type 3 is a complete deficiency.
• (von Willebrand Disease) VWF levels rise appreciably during normal pregnancy for Type 1, but women with Type 2 or 3 remain at high risk for postpartum hemorrhage (PPH).
• (Thrombophilia) Inherited thrombophilias (e.g., Factor V Leiden, Prothrombin G20210A) increase the risk of venous thromboembolism (VTE) in pregnancy.
• (Thrombophilia) Antithrombin deficiency is considered a high-risk inherited thrombophilia requiring management during pregnancy.

PHILIPPINE CONTEXT AND PUBLIC HEALTH

• (Philippine Health Sector) 8-Point Action Agenda (2023-2028) aims to ensure every Filipino experiences health and well-being through humanistic leadership and good governance.
• (Philippine Diet) Rice dependence and lack of dietary diversity contribute significantly to widespread iron and zinc deficiencies among Filipinos.
• (Public Health Strategy) Biofortification is an effective approach to enrich rice with micronutrients to target vulnerable populations in the Philippines.
• (Hemophilia in PH) Hemophilia prevalence in the Philippines may be 10 times higher than the 1604 cases currently diagnosed based on worldwide estimates.

HIGH-YIELD DIFFERENTIATION AND COMPARISON

• (Comparison: Physiologic vs. Pathologic) Physiologic anemia results from expanded plasma volume (40-50%) exceeding RBC mass increase (20%), whereas iron deficiency anemia is confirmed when Hgb falls below 11 g/dL.
• (Comparison: Sickle Cell SS vs. SC) Hb SS disease has significantly higher maternal mortality (OR 11-23) compared to Hb SC disease, though both increase stillbirth risk.
• (Comparison: TTP vs. HELLP) Transaminitis (High AST/ALT) is characteristic of HELLP syndrome, whereas it is usually absent or mild in TTP.
• (Comparison: TTP vs. HELLP) ADAMTS13 deficiency (&lt10%) is the hallmark of TTP, while it is only mild-to-moderately reduced in HELLP.
• (Comparison: Delivery effect) Delivery reverses the pathology of HELLP and Preeclampsia, but has no effect on the progression of TMA/TTP.
• (Comparison: Thalassemia Types) Alpha-thalassemia is more common in Asian Americans, while Beta-thalassemia is diagnosed by elevated HbA2 levels.
• (Comparison: Hemophilia vs. vWD) Hemophilia is X-linked (mostly males affected), whereas von Willebrand disease is autosomal (affects males and females equally).
• (Comparison: Thalassemia major vs. trait) Alpha-thalassemia major (Hb Bart) leads to hydrops fetalis and stillbirth, while Alpha-thalassemia trait (2 gene deletion) presents as mild microcytic anemia with no major maternal issues.
• (Comparison: Ferritin) Low ferritin (&lt15) is specific for IDA, but Ferritin can be falsely elevated up to 100 in patients with IDA who also have liver disease or infection.
• (Comparison: Thrombophilia risk) Heterozygous Factor V Leiden is a low-risk thrombophilia, while Homozygous Factor V Leiden is a high-risk condition.
• (Comparison: Relative vs. Absolute Polycythemia) Relative polycythemia is caused by volume loss (dehydration/diuretics), while Absolute polycythemia (Polycythemia Vera) involves a JAK2 mutation and increased RBC mass.
• (Comparison: B12 vs. Folate) B12 deficiency is common in vegans/gastric surgery; Folate deficiency is common in malnutrition or anticonvulsant use.
• (Comparison: Spherocytosis vs. G6PD) Hereditary spherocytosis shows increased osmotic fragility; G6PD deficiency shows episodic hemolysis after oxidant triggers (drugs/infection).
• (Comparison: Hemophilia A vs. B) Hemophilia A is a deficiency of Factor VIII; Hemophilia B (Christmas Disease) is a deficiency of Factor IX.
• (Comparison: Schizocytes) Schizocytes are present in all TMAs (TTP, HUS, HELLP), but the severity of fragmentation is most marked in TTP.

QA

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PHYSIOLOGIC ADAPTATION IN PREGNANCY

1. Under Physiologic Adaptation, what is the pathogenesis of hemodilution? | Plasma volume expansion (40-50%) exceeds red blood cell mass increase (15-25%).
2. What are the clinical manifestations (3) of Physiologic Adaptation? | 1) Physiologic anemia
   2) Decreased blood viscosity
   3) Increased heart rate/stroke volume
3. What are the laboratory findings (2) for Physiologic Adaptation hematocrit? | 1) ~34% (singleton)
   2) ~30% (multifetal)
4. What happens to Maternal hepcidin to augment iron absorption? | Profoundly decreased.
5. Why does Plasma volume expansion result in physiologic anemia? | It disproportionately exceeds red cell mass increase.
6. What is the typical Hematocrit level in a singleton pregnancy? | 34 percent.
7. What is the typical Hematocrit level in a multifetal gestation? | 30 percent.
8. How is Oxygen-carrying capacity affected by physiologic anemia? | Remains normal.
9. Why does Whole blood viscosity decrease during pregnancy? | Decline in hemoglobin and hematocrit.
10. What Hemoglobin concentration at term is considered abnormal/iron deficient? | Values below 11.0 g/dL.
11. When does Maternal blood volume expansion reach a plateau? | Last weeks of pregnancy.
12. What are the Iron requirements in the third trimester? | 7 mg/day. (Compared to 1 mg/day in non-pregnant).
13. What is the Total iron requirement for a healthy normal pregnancy? | Approximately 1000 mg.
14. How much total iron is transferred to the Fetus/Placenta? | 300 mg.
15. By how much is Maternal hepcidin suppressed to facilitate iron absorption? | 10-fold (in second trimester).
16. Which Coagulation factors (4) increase creating a hypercoagulable state? | Factors VII, VIII, IX, and X.
17. What happens to Fibrinogen levels by term? | They double (up to 600+ mg/dL).
18. What happens to Protein S functional activity in the 3rd trimester? | Significantly decreases (to ~16-42%).
19. What are the causes (3) of decreased Platelet counts in pregnancy? | 1) Dilution
    2) Splenic pooling
    3) Pooling in intervillous space.
20. When does Left ventricular mass begin to increase? | 26 to 30 weeks' gestation.
21. When does Arterial blood pressure reach its nadir? | 24 to 26 weeks.

ANEMIA: DIAGNOSIS AND GENERAL CAUSES

22. What is the Hemoglobin threshold for anemia in the 1st trimester? | < 11.0 g/dL.
23. What is the Hemoglobin threshold for anemia in the 2nd trimester? | < 10.5 g/dL.
24. What is the Hemoglobin threshold for anemia in the 3rd trimester? | < 11.0 g/dL.
25. How is Anemia broadly defined? | Decreased blood hemoglobin concentration.
26. What tests (2) are required for Microcytic anemia evaluation? | 1) Serum ferritin
    2) Hemoglobin electrophoresis.
27. What levels (2) are checked for Macrocytic anemia evaluation? | 1) Serum folate
    2) Vitamin B12.
28. When is Oral iron therapy indicated for moderate anemia (Hgb ~7 g/dL)? | Hemodynamically stable, ambulating, and non-septic.
29. What are the laboratory characteristics (4) of Anemia of chronic disease? | 1) High ferritin
    2) Elevated hepcidin
    3) Hypochromic/microcytic
    4) Low transferrin saturation.
30. When is Recombinant erythropoietin considered in renal insufficiency? | Hematocrit approximates 20 percent.

IRON DEFICIENCY ANEMIA (IDA)

31. What is the pathogenesis of Iron Deficiency Anemia (IDA)? | Insufficient iron to meet 1000 mg demand.
32. What are the diagnostic findings (4) for Iron Deficiency Anemia (IDA)? | 1) MCV < 80 fL
    2) Ferritin ≤ 10–15 μg/L
    3) Increased TIBC
    4) Decreased Transferrin Sat.
33. What is the oral treatment dose for Iron Deficiency Anemia (IDA)? | 200 mg elemental iron/day.
34. What is the Most common cause of anemia in pregnancy? | Iron deficiency anemia.
35. What Serum ferritin level specifically confirms iron-deficiency? | Below 10–15 μg/L.
36. Why might Ferritin be as high as 100 ng/mL in IDA? | It acts as an acute phase reactant.
37. Why does Erythropoietin (EPO) synthesis increase in pregnancy? | Renal hypoxia.
38. What is the role of Erythroferrone (ERFE) in iron metabolism? | Lowers hepcidin (via BMP6 sequestration).
39. What does a high Red cell distribution width (RDW) reflect in IDA? | Anisopoikilocytosis.
40. What is the most sensitive/specific criterion for Iron deficiency erythropoiesis? | Absent bone marrow iron stores.
41. What are the maternal complications (5) of Iron Deficiency Anemia? | 1) Infections
    2) Preterm labor
    3) PPROM
    4) Postpartum hemorrhage
    5) Increased mortality.
42. What are the fetal complications (3) of Maternal Iron Deficiency Anemia? | 1) Low birth weight
    2) IUGR
    3) Impaired long-term neurodevelopment.
43. What is the result of severe fetal anemia on the Fetal heart? | High-output heart failure (Hydrops).

MEGALOBLASTIC AND APLASTIC ANEMIA

44. What is the pathogenesis of Megaloblastic Anemia? | Impaired DNA synthesis (Folate/B12 deficiency).
45. What are the hallmark findings (2) of Megaloblastic Anemia? | 1) Megaloblasts in marrow
    2) Hypersegmented neutrophils.
46. What is the treatment for Megaloblastic Anemia? | 5-15 mg oral folic acid with iron.
47. What is the pathogenesis of Aplastic Anemia? | Decline in committed marrow stem cells.
48. What is the clinical hallmark of Aplastic Anemia? | Pancytopenia.
49. What is the management (3) for Aplastic Anemia? | 1) Immunosuppression
    2) Antimicrobials
    3) Bone marrow transplant.
50. Which vitamin deficiency is common in users of Anticonvulsants? | Folate deficiency.
51. Which population is typically affected by Vitamin B12 deficiency? | Vegetarians/Vegans or malabsorption patients.
52. How are Megaloblasts formed? | Impaired nuclear division with normal cytoplasm maturation.
53. What marrow finding characterizes Aplastic anemia? | Markedly hypocellular bone marrow.
54. What are the pregnancy risks associated with Diamond-Blackfan anemia? | Preeclampsia and Fetal Growth Restriction.
55. What is the enzyme deficiency in Gaucher disease? | Acid β-glucosidase.
56. What is the target hematocrit for Red cell transfusions in aplastic anemia? | Above 20 percent.

HEMOLYTIC ANEMIA AND HEMOGLOBINOPATHIES

57. What is the diagnostic finding for Autoimmune Hemolysis? | Positive Direct and Indirect Coombs tests.
58. What is the mutation and risk in Paroxysmal Nocturnal Hemoglobinuria (PNH)? | 1) PIG-A mutation
    2) 40% Thrombosis risk.
59. What is the hallmark lab finding for Hereditary Spherocytosis? | Increased osmotic fragility.
60. What is the protein substitution in Sickle Cell (Hb SS)? | Beta-globin glutamic acid to valine.
61. What hemoglobin markers (2) define Thalassemia types? | 1) Hb Bart (Alpha major)
    2) High HbA2 (Beta minor).
62. What is Evans syndrome? | Autoimmune hemolysis with thrombocytopenia.
63. What drug is used to treat Paroxysmal Nocturnal Hemoglobinuria (PNH)? | Eculizumab.
64. What triggers episodic anemia in G6PD deficiency? | Drugs (e.g., Macrodantin) or infections.
65. What is the management (3) for Sickle-cell crisis in pregnancy? | 1) IV fluids
    2) Opioid analgesia
    3) Oxygen.
66. What are the symptoms (3) of Acute chest syndrome? | 1) Pleuritic chest pain
    2) Fever
    3) New lung infiltrates.
67. What is the primary risk of Sickle-cell trait (Hb AS) in pregnancy? | Asymptomatic bacteriuria.
68. What is the state of anemia in Hemoglobin E homozygotes (Hb EE)? | Marked microcytosis but little anemia.
69. What is the outcome of Alpha-thalassemia major (Hb Bart disease)? | Incompatible with survival (hydrops fetalis).
70. What Hemoglobin A2 level indicates Beta-thalassemia minor? | Greater than 3.5%.
71. What mutation is associated with Polycythemia vera? | JAK2 mutation.

PLATELET AND MICROANGIOPATHIC DISORDERS

72. What is the hallmark of Gestational Thrombocytopenia? | Platelets > 70,000.
73. What deficiency confirms Thrombotic thrombocytopenic purpura (TTP)? | ADAMTS13 activity < 10%.
74. What are the laboratory hallmarks (2) of HELLP? | 1) High AST/ALT
    2) LDH > 600.
75. What causes Complement-mediated TMA (aHUS)? | Complement gene mutations (Auto-FH antibodies).
76. What percentage of pregnancy thrombocytopenia is Gestational thrombocytopenia? | 75 percent.
77. What are the general features (3) of Thrombotic microangiopathy (TMA)? | 1) MAHA
    2) Schizocytes
    3) End-organ damage.
78. What is the primary treatment for Thrombotic thrombocytopenic purpura (TTP)? | Plasmapheresis.
79. Name the components of the TTP clinical pentad (5). | 1) Thrombocytopenia 2) Hemolytic anemia 3) Fever 4) Neuro symptoms 5) Renal injury.
80. Does delivery improve Thrombotic thrombocytopenic purpura (TTP)? | No. (Delivery reverses HELLP).
81. What is the preferred treatment for aHUS and PNH? | Eculizumab.

INHERITED COAGULATION DEFECTS

82. Why can female carriers of Hemophilia A and B experience bleeding? | Factor levels <20% (due to lyonization).
83. What drug stimulates Factor VIII release in Hemophilia A? | Desmopressin.
84. Compare von Willebrand Disease Type 1 vs Type 3. | Type 1: Partial quantitative deficiency
    Type 3: Complete deficiency.
85. Which von Willebrand Disease types have high risk for postpartum hemorrhage? | Type 2 or 3.
86. Give examples (2) of Inherited thrombophilias that increase VTE risk. | 1) Factor V Leiden
    2) Prothrombin G20210A.
87. Why is Antithrombin deficiency significant in pregnancy? | It is a high-risk inherited thrombophilia.

PHILIPPINE CONTEXT AND PUBLIC HEALTH

88. What is the goal of the 8-Point Action Agenda (2023-2028)? | Ensure every Filipino health and well-being.
89. How does the Philippine Diet contribute to iron/zinc deficiency? | Rice dependence and lack of diversity.
90. What is Biofortification? | Enriching rice with micronutrients for vulnerable populations.
91. How does actual Hemophilia prevalence in PH compare to diagnosed cases? | May be 10 times higher than diagnosed.

HIGH-YIELD DIFFERENTIATION AND COMPARISON

92. Contrast Physiologic vs Iron Deficiency Anemia. | Physiologic: Hemodilution
    IDA: Hgb < 11 g/dL with iron lack.
93. Compare Hb SS vs Hb SC disease mortality. | Hb SS: Significantly higher maternal mortality (OR 11-23).
94. Compare TTP vs HELLP liver enzymes. | HELLP: Transaminitis (High AST/ALT)
    TTP: Absent/mild.
95. Compare TTP vs HELLP ADAMTS13 activity. | TTP: <10% activity
    HELLP: Mildly reduced.
96. How does Delivery affect HELLP vs TTP? | Delivery reverses HELLP but has no effect on TTP.
97. How is Beta-thalassemia diagnosed? | Elevated HbA2 levels.
98. Contrast the inheritance of Hemophilia vs von Willebrand Disease. | Hemophilia: X-linked
    vWD: Autosomal.
99. Contrast Alpha-thalassemia major vs trait. | Major: Hydrops fetalis
    Trait: Mild microcytic anemia.
100. When can Ferritin be falsely elevated in IDA? | Liver disease or infection (up to 100 ng/mL).
101. Compare Heterozygous vs Homozygous Factor V Leiden risk. | Heterozygous: Low-risk
     Homozygous: High-risk.
102. Contrast Relative vs Absolute Polycythemia. | Relative: Volume loss
     Absolute: JAK2 mutation/increased RBC mass.
103. Contrast the causes of B12 vs Folate deficiency. | B12: Vegan/Gastric surgery
     Folate: Malnutrition/Anticonvulsants.
104. Contrast Spherocytosis vs G6PD deficiency labs. | Spherocytosis: Osmotic fragility
     G6PD: Episodic (oxidant triggered).
105. Contrast Hemophilia A vs B factor deficiency. | A: Factor VIII
     B: Factor IX.
106. In which condition is Schizocyte fragmentation most marked? | Thrombotic thrombocytopenic purpura (TTP).

8.3 - DM in Pregnancy

Summary

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DIABETES MELLITUS IN PREGNANCY: OVERVIEW AND COMPARISON

EPIDEMIOLOGY AND RISK FACTORS

• Filipino women are considered a high-risk ethnic group for hyperglycemia in pregnancy, with an estimated prevalence of 6-20% in the Philippines.
• Southeast Asian race is a significant risk factor as this population has the highest global risk for hyperglycemia.
• History of Macrosomia (defined as a birthweight of $\geq$ 9 lbs or 4 kg) is a major risk factor for Gestational Diabetes Mellitus and may indicate undiagnosed GDM in previous pregnancies.
• Advanced Maternal Age (e.g., 36 years old) increases the risk of developing glucose intolerance during pregnancy.
• Obesity (BMI $\geq$ 30 or BMI $\geq$ 25 in Asians) contributes to GDM through central adiposity and the release of leptin and proinflammatory cytokines.
• Polycystic Ovary Syndrome (PCOS) is a pertinent risk factor for GDM due to its underlying insulin resistance.
• History of unexplained stillbirths or abortions is a clinical indicator for screening, as increased sugar can cause a lack of oxygen and sudden cessation of the fetal heartbeat.
• Persistent glycosuria (measured as +3 or +4 glucose in urine) warrants immediate investigation for diabetes in pregnancy.
• Strong family history of diabetes is a critical factor; if a direct relative has DM, the chance of the patient developing it is significantly high.

MATERNAL AND FETAL PATHOPHYSIOLOGY

• Pregnancy-related hormones (Progesterone, Placentally derived Growth Hormone, Prolactin, Cortisol) are elevated in the 2nd trimester and naturally increase insulin resistance to maintain fetal growth.
• Maternal metabolic adaptations to pregnancy include fasting hypoglycemia, postprandial hyperglycemia, and hyperinsulinemia.
• Proinflammatory cytokines (TNF-alpha, IL-6, IGF-1) evoke insulin resistance during pregnancy, contributing to the pathogenesis of GDM.
• Maternal hyperglycemia leads to the transfer of excess glucose to the fetus, which stimulates the fetal pancreas to secrete its own insulin.
• Fetal hyperinsulinemia acts as a growth hormone, promoting fat deposition and excessive anabolism, leading to Fetal Macrosomia.
• Aerobic metabolism of glucose consumes oxygen; extreme maternal hyperglycemia can lead to fetal hypoxemia because the baby uses excessive oxygen to process high glucose levels.
• Placental development is usually fully established by the 24-28th week, which is why screening is most effective at this interval to detect placentally-derived glucose elevation.

SCREENING AND DIAGNOSTIC CRITERIA (IADPSG)

• Universal screening for GDM is recommended for all pregnant women, regardless of risk, because the Filipino race itself is a high-risk factor.
• First prenatal visit screening aims to categorize patients: FBS $\leq$ 92 mg% is normal, 92-125 mg% is GDM, and $\geq$ 126 mg% is overt DM.
• Low-risk patients should undergo a 75-g OGTT at 24-28 weeks gestation.
• High-risk patients (obese, family history) should receive an immediate 75-g OGTT at the first visit, even if the initial FBS is normal.
• 75-g OGTT Procedure (IADPSG) requires 6-8 hours of fasting, blood collection at baseline, 1 hour, and 2 hours after drinking the glucose solution.
• IADPSG Diagnostic Thresholds for GDM (75-g OGTT) require only ONE value to be met or exceeded:
  1. Fasting Blood Sugar (FBS) $\geq$ 92 mg/dL
  2. 1-hour postprandial $\geq$ 180 mg/dL
  3. 2-hour postprandial $\geq$ 153 mg/dL
• Overt Diabetes in pregnancy is diagnosed if any of the following are met: FBS $\geq$ 126 mg/dL, HbA1c $\geq$ 6.5%, or Random Plasma Glucose $\geq$ 200 mg/dL.
• 75-g OGTT at 32 weeks should be repeated if signs of DM appear, such as polyhydramnios, macrosomia, polyphagia, polydipsia, or polyuria.

MANAGEMENT AND GLYCOSE TARGETS

• Medical Nutrition Therapy (MNT) is the first-line management for 2 weeks; it was formerly known as Diet Restriction Management.
• Pinggang Pinoy and small, frequent meals are encouraged to decrease the incidence of glucose spikes.
• MNT Dietary Composition (ACOG) suggests 33–40% carbohydrates, ~20% protein, and ~40% fat. Note that low carbohydrate intake may lead to IUGR.
• Insulin is the "Gold Standard" for pharmacological management and is initiated if target glucose levels are not achieved through MNT and exercise.
• Insulin safety in pregnancy is high because it does NOT cross the placenta.
• Self-Monitored Capillary Blood Glucose (CBG) Targets:
  • Fasting $\leq$ 95 mg/dL
  • 1-hour postprandial $\leq$ 140 mg/dL
  • 2-hour postprandial $\leq$ 120 mg/dL
• Metformin is considered a second-line option for pharmacological management in selected cases.
• Folic Acid supplementation should be 5 mg/day (lecturer) or 400 $\mu$g/day (book) given periconceptionally to reduce the risk of neural tube defects.
• Weight Gain Guidelines are based on BMI: Obese (BMI $\ge$ 30) should only gain 5-9 kg total (0.21 kg/week in 2nd/3rd trimesters).

ANTENATAL SURVEILLANCE AND COMPLICATIONS

• Congenital Heart Defects are the most common congenital anomaly affected by high maternal blood sugar before conception.
• Congenital Anomaly Scan (CAS) with fetal ECHO is specifically indicated at 20-24 weeks for diabetic pregnancies to monitor for cardiac and CNS anomalies.
• Fetal Kick Counting should begin at 26-28 weeks every night; a normal count is 10 movements in 2 hours.
• Biophysical Profile (BPS) should be performed every 2 weeks starting at 28-37 weeks, increasing to twice a week if the patient is on insulin.
• Aspirin (60-150 mg/day) is given from 12-16 weeks until delivery as prophylaxis for preeclampsia.
• Shoulder Dystocia and birth trauma (e.g., Clavicular fracture) are major labor complications due to fetal macrosomia and enlargement of the fetal trunk.
• Respiratory Distress Syndrome (RDS) in neonates occurs because elevated sugar levels delay the formation of lung surfactant.
• Neonatal metabolic complications include hypoglycemia, hypocalcemia, and hypomagnesemia.
• Neonatal polycythemia (increased hematocrit) is caused by hyperglycemia-induced increases in blood cell formation.
• Hydramnios / Polyhydramnios is caused by hyperglycemia increasing osmolality, which leads to a transfer of fluids and increased amniotic fluid.

DELIVERY AND POSTNATAL CARE

• Timing of delivery for well-controlled GDM is usually planned at 39 to 39 6/7 weeks.
• Timing of delivery for insulin-treated GDM is recommended at 38-39 weeks.
• Poorly controlled GDM requires earlier delivery at 37-38 weeks.
• Elective Cesarean Section should be considered if the estimated fetal weight is $\geq$ 4500 g to prevent brachial plexus injury.
• Postpartum glucose metabolism assessment involves a repeat 75-g, 2-hr OGTT at 6-12 weeks after delivery.
• Postpartum classification uses non-pregnant thresholds: DM if FBS $\geq$ 126 mg/dL or 2-hr $\geq$ 200 mg/dL.
• GDM recurrence risk is significant, with a 50-75% likelihood of developing Type 2 DM within 15-25 years.

DIFFERENTIATING SIMILAR ENTITIES IN EXAMS

1. GDM vs. Overt DM (AOG): GDM is recognized later in pregnancy (typically after 20 weeks/2nd trimester), while Overt DM is discovered in the 1st trimester (before 20 weeks).
2. GDM vs. Overt DM (FBS criteria): Overt DM requires an FBS $\geq$ 126 mg/dL; GDM is diagnosed with an FBS between 92-125 mg/dL.
3. IADPSG vs. ADA Screening: IADPSG requires only ONE abnormal value on the 75-g OGTT, whereas ADA criteria traditionally require TWO abnormal values.
4. GDM FBS vs. Non-pregnant FBS: The cutoff for fasting glucose in pregnancy is lower ($\geq$ 92 mg/dL) compared to the non-pregnant cutoff ($\geq$ 100 mg/dL/126 mg/dL).
5. Macrosomia vs. LGA: Macrosomia usually refers to an absolute birth weight (e.g., >4000g), while Large for Gestational Age (LGA) refers to a weight above the 90th percentile for a specific AOG.
6. Fetal Kick Counting (Normal vs. Abnormal): 10 movements within 2 hours is normal; fewer movements require further biophysical evaluation.
7. Insulin vs. Glucose Placental Transfer: Glucose crosses the placenta easily (facilitated diffusion), causing fetal hyperglycemia; Insulin does NOT cross the placenta.
8. Maternal Hypoglycemia vs. Neonatal Hypoglycemia: Maternal hypoglycemia occurs due to the continuous glucose draw by the fetus; Neonatal hypoglycemia occurs post-delivery because the baby still has high insulin levels but the maternal glucose supply is cut off.
9. Insulin Regimens (Parkland vs. UAB): Parkland uses a split-dose mix (Breakfast: 2/3 total dose; Dinner: 1/3 total dose), while UAB uses a Basal-Bolus approach (50% long-acting at bedtime; 50% split rapid-acting before meals).
10. Hypertension in Pregnancy Types: Pregnancy-induced hypertension and preeclampsia are both associated with GDM due to shared vascular damage mechanisms.
11. Polyhydramnios vs. Polyphagia: Polyhydramnios is an objective sign of excess amniotic fluid; Polyphagia is a subjective symptom of excessive hunger.
12. Postpartum screening timing: Persistent overt diabetes is checked at 1-3 days post-delivery; GDM re-classification is performed at 6-12 weeks postpartum.
13. CAS vs. Fetal ECHO: The Congenital Anomaly Scan (CAS) is a general head-to-toe survey; the Fetal ECHO is a specialized view looking specifically for cardiac defects (the #1 anomaly).
14. MODY 1-6 (Obese vs. Autosomal Dominant): One form of Maturity-Onset Diabetes of the Young is common in obese adolescents, while the other is a rare autosomal dominant condition in thin young adults.
15. Glycolysis vs. Hypoxemia: Excessive glucose metabolism (Glycolysis) in the fetus consumes oxygen; if disproportionate, it leads to fetal hypoxemia and potential stillbirth.

QA

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DIABETES MELLITUS IN PREGNANCY: OVERVIEW AND COMPARISON

1. What is the pathogenesis of Type 1 Diabetes? | Pancreatic $\beta$-cell destruction
   Leading to absolute insulin deficiency.
2. What is the pathogenesis of Type 2 Diabetes? | Insulin resistance
   Ranges from resistance to secretory defect with resistance.
3. What is the pathogenesis of Gestational Diabetes (GDM)? | Pregnancy-induced insulin resistance
   Accompanied by inadequate $\beta$-cell compensation.
4. What is the pathogenesis of Overt Diabetes? | Pre-existing Type 2 DM
   Likely undocumented before pregnancy.
5. When is the typical onset of Type 1 Diabetes? | Before age 30
   Usually clinically apparent.
6. What lifestyle factors relate to the onset of Type 2 Diabetes? | Lifestyle, obesity, heredofamilial factors.
7. When is Gestational Diabetes (GDM) typically recognized? | 24-28 weeks
   Onset or first recognition during pregnancy.
8. When is Overt Diabetes discovered during pregnancy? | 1st trimester
   Discovered for the 1st time during pregnancy.
9. When is typical screening performed for Type 1 Diabetes? | Before reproductive age
   Identified early in life.
10. When is Type 2 Diabetes identified relative to pregnancy? | Before or early pregnancy.
11. What is the universal screening interval for Gestational Diabetes (GDM)? | 24-28 weeks
    Can be earlier if patient is high risk.
12. How is Overt Diabetes screened at the first prenatal visit? | Fasting Blood Sugar (FBS).
13. What diagnosis criteria are used for Type 1 and Type 2 Diabetes? | Standard non-pregnant criteria.
14. What are the IADPSG 75-g OGTT diagnostic values for Gestational Diabetes (GDM)? (3) | FBS $\geq$ 92, 1h $\geq$ 180, 2h $\geq$ 153.
15. What are the diagnosis criteria for Overt Diabetes? (3) | FBS $\geq$ 126, HbA1c $\geq$ 6.5%, RPG $\geq$ 200.
16. What is the management requirement for Type 1 Diabetes? | Insulin always required.
17. What is the initial management for Type 2 Diabetes? | Medical Nutrition Therapy (MNT).
18. How long is the trial of MNT for Gestational Diabetes (GDM)? | 2 weeks
    Insulin is added if uncontrolled.
19. What is the immediate pharmacological management for Overt Diabetes? | Insulin or Metformin.

EPIDEMIOLOGY AND RISK FACTORS

20. What is the GDM prevalence for Filipino women? | 6-20%
    Filipinos are considered a high-risk ethnic group.
21. Which global population has the highest risk for hyperglycemia? | Southeast Asian race.
22. How is History of Macrosomia defined by birthweight? | $\geq$ 9 lbs or 4 kg.
23. What may a History of Macrosomia indicate? | Undiagnosed GDM
    Refers to previous pregnancies.
24. At what age is Advanced Maternal Age a risk factor for glucose intolerance? | 36 years old.
25. How does Obesity contribute to GDM pathologically? | Central adiposity
    Release of leptin and proinflammatory cytokines.
26. What is the BMI cutoff for Obesity in Asians? | BMI $\geq$ 25.
27. Why is Polycystic Ovary Syndrome (PCOS) a risk factor for GDM? | Underlying insulin resistance.
28. In unexplained stillbirths, what causes sudden cessation of fetal heartbeat? | Lack of oxygen
    Caused by increased sugar levels.
29. What level of Persistent glycosuria warrants immediate investigation? | +3 or +4 glucose
    Measured in urine.
30. How does Strong family history affect DM risk? | Significantly high risk
    Applies if a direct relative has Diabetes Mellitus.

MATERNAL AND FETAL PATHOPHYSIOLOGY

31. Name the Pregnancy-related hormones that increase insulin resistance. (4) | Progesterone, Growth Hormone, Prolactin, Cortisol.
32. When do Pregnancy-related hormones peak to maintain fetal growth? | 2nd trimester.
33. List the Maternal metabolic adaptations to pregnancy. (3) | Fasting hypoglycemia, postprandial hyperglycemia, hyperinsulinemia.
34. Name the Proinflammatory cytokines that evoke insulin resistance. (3) | TNF-alpha, IL-6, IGF-1.
35. How does Maternal hyperglycemia affect the fetal pancreas? | Stimulates insulin secretion
    Due to transfer of excess glucose to the fetus.
36. What is the role of Fetal hyperinsulinemia in macrosomia? | Growth hormone
    Promotes fat deposition and excessive anabolism.
37. How does Aerobic metabolism of glucose lead to fetal hypoxemia? | Consumes oxygen
    Baby uses excessive oxygen to process high glucose.
38. Why is GDM screening most effective at 24-28 weeks? | Placental development established
    Placentally-derived glucose elevation is detectable.

SCREENING AND DIAGNOSTIC CRITERIA (IADPSG)

39. Why is Universal screening recommended for all Filipina women? | High-risk ethnic group.
40. Under First prenatal visit screening, what FBS is considered normal? | $\leq$ 92 mg%.
41. Under First prenatal visit screening, what FBS indicates GDM? | 92-125 mg%.
42. Under First prenatal visit screening, what FBS indicates overt DM? | $\geq$ 126 mg%.
43. When should Low-risk patients undergo OGTT? | 24-28 weeks gestation.
44. When should High-risk patients receive a 75-g OGTT? | First prenatal visit
    Even if the initial FBS is normal.
45. What is the fasting requirement for the 75-g OGTT Procedure? | 6-8 hours.
46. When is blood collected during a 75-g OGTT? (3) | Baseline, 1 hour, 2 hours.
47. How many abnormal values are needed for GDM diagnosis under IADPSG Thresholds? | One value.
48. What is the IADPSG Fasting Blood Sugar threshold for GDM? | $\geq$ 92 mg/dL.
49. What is the IADPSG 1-hour postprandial threshold for GDM? | $\geq$ 180 mg/dL.
50. What is the IADPSG 2-hour postprandial threshold for GDM? | $\geq$ 153 mg/dL.
51. What HbA1c level diagnoses Overt Diabetes in pregnancy? | $\geq$ 6.5%.
52. What Random Plasma Glucose diagnoses Overt Diabetes? | $\geq$ 200 mg/dL.
53. When should 75-g OGTT be repeated if signs like polyhydramnios appear? | 32 weeks gestation.
54. List symptoms that warrant a repeat OGTT at 32 weeks. (5) | Polyhydramnios, macrosomia, polyphagia, polydipsia, polyuria.

MANAGEMENT AND GLUCOSE TARGETS

55. What is the first-line management for GDM for 2 weeks? | Medical Nutrition Therapy (MNT).
56. What dietary model is encouraged for GDM? | Pinggang Pinoy
    Small, frequent meals decrease glucose spikes.
57. In MNT Dietary Composition, what is the recommended carbohydrate %? | 33–40%.
58. In MNT Dietary Composition, what are the protein and fat %? | Protein ~20%; Fat ~40%.
59. What may result from very low carbohydrate intake in GDM management? | intrauterine growth restriction (IUGR).
60. What is the "Gold Standard" for GDM pharmacological management? | Insulin.
61. Why is Insulin safety high in pregnancy? | Does NOT cross placenta.
62. What is the CBG Target for Fasting? | $\leq$ 95 mg/dL.
63. What is the CBG Target for 1-hour postprandial? | $\leq$ 140 mg/dL.
64. What is the CBG Target for 2-hour postprandial? | $\leq$ 120 mg/dL.
65. What is the second-line pharmacological option for GDM? | Metformin.
66. What dose of Folic Acid is recommended by the lecturer? | 5 mg/day.
67. What dose of Folic Acid is recommended by the book? | 400 $\mu$g/day.
68. What is the total weight gain guideline for Obese patients (BMI $\ge$ 30)? | 5-9 kg total.
69. What is the weekly weight gain for Obese patients in the 2nd/3rd trimesters? | 0.21 kg/week.

ANTENATAL SURVEILLANCE AND COMPLICATIONS

70. What are the most common congenital anomalies in Diabetic pregnancies? | Congenital Heart Defects.
71. When is a CAS with fetal ECHO indicated for diabetic pregnancies? | 20-24 weeks.
72. When should Fetal Kick Counting begin? | 26-28 weeks.
73. What is a normal Fetal Kick Count? | 10 movements in 2 hours.
74. How often is a Biophysical Profile (BPS) performed for general GDM? | Every 2 weeks
    Starting at 28-37 weeks.
75. How often is BPS performed if the patient is on insulin? | Twice a week.
76. What is the dose and timing for Aspirin prophylaxis? | 60-150 mg/day
    12-16 weeks until delivery.
77. Aspirin is used as prophylaxis for which condition? | Preeclampsia.
78. List common labor complications of Fetal Macrosomia. (2) | Shoulder Dystocia, Clavicular fracture.
79. Why does RDS occur in neonates of diabetic mothers? | Delayed lung surfactant formation
    Caused by elevated sugar levels.
80. List the Neonatal metabolic complications. (3) | Hypoglycemia, hypocalcemia, hypomagnesemia.
81. What causes Neonatal polycythemia in GDM? | Hyperglycemia-induced blood cell formation
    Results in increased hematocrit.
82. What causes Hydramnios in diabetic pregnancies? | Hyperglycemia increasing osmolality
    Leads to fluid transfer and increased amniotic fluid.

DELIVERY AND POSTNATAL CARE

83. What is the delivery timing for well-controlled GDM? | 39 to 39 6/7 weeks.
84. What is the delivery timing for insulin-treated GDM? | 38-39 weeks.
85. What is the delivery timing for poorly controlled GDM? | 37-38 weeks.
86. At what fetal weight is Elective Cesarean Section considered? | $\geq$ 4500 g.
87. Why is Elective C-section done for macrosomia? | Prevent brachial plexus injury.
88. When is Postpartum glucose assessment performed? | 6-12 weeks after delivery
    Uses a repeat 75-g, 2-hr OGTT.
89. What 2-hr OGTT value defines Postpartum DM? | $\geq$ 200 mg/dL.
90. What is the long-term risk of GDM recurrence as Type 2 DM? | 50-75% likelihood
    Within 15-25 years.

DIFFERENTIATING SIMILAR ENTITIES

91. Compare GDM vs. Overt DM by typical AOG. | GDM: after 20 weeks.
    Overt DM: before 20 weeks (1st trimester).
92. Compare GDM vs. Overt DM by FBS diagnosis. | GDM: 92-125 mg/dL.
    Overt DM: $\geq$ 126 mg/dL.
93. Compare IADPSG vs. ADA OGTT requirements. | IADPSG: One abnormal value.
    ADA: Two abnormal values.
94. Compare Pregnant vs. Non-pregnant Fasting cutoffs. | Pregnancy: $\geq$ 92 mg/dL.
    Non-pregnant: $\geq$ 100/126 mg/dL.
95. Compare Macrosomia vs. LGA. | Macrosomia: Absolute weight (>4000g).
    LGA: >90th percentile for AOG.
96. Compare Normal vs. Abnormal Kick Count. | Normal: 10 movements in 2 hours.
    Abnormal: Fewer movements.
97. Compare Insulin vs. Glucose placental transfer. | Glucose: Crosses (facilitated diffusion).
    Insulin: Does NOT cross.
98. What causes Neonatal hypoglycemia post-delivery? | High fetal insulin levels
    Maternal glucose supply is suddenly cut off.
99. Contrast Parkland vs. UAB insulin regimens. | Parkland: Split-dose mix (2/3 AM, 1/3 PM).
    UAB: Basal-Bolus approach.
100. Why is Hypertension associated with GDM? | Shared vascular damage mechanisms.
101. Define Polyhydramnios vs. Polyphagia. | Polyhydramnios: Excess amniotic fluid.
     Polyphagia: Excessive hunger.
102. Compare Postpartum screening timing for overt DM vs. GDM. | Overt DM: 1-3 days.
     GDM re-classification: 6-12 weeks.
103. Define CAS vs. Fetal ECHO scope. | CAS: General survey.
     Fetal ECHO: Cardiac specific (anomaly #1).
104. Contrast the two presentations of MODY. | Type 1: Obese adolescents.
     Type 2: Rare autosomal dominant in thin adults.
105. How does excessive Glycolysis lead to stillbirth? | Consumption of oxygen
     Leads to fetal hypoxemia.

8.4 - Endocrine Disorders

Summary

text

SYSTEMATIC SUMMARY OF ENDOCRINE DISORDERS IN PREGNANCY

ENDOCRINE PHYSIOLOGY BULLET POINTS

• Maternal endocrine physiology is constantly changed across pregnancy, partially due to the development of the maternal-fetal unit in the placenta which acts as a temporary gland.
• First trimester hCG acts as a strong stimulator for TSH receptors, resulting in increased thyroid function and a mirroring decrease in TSH levels.
• Gestational thyrotoxicosis is the clinical condition where TSH is decreased because of high hCG levels; TSH typically increases back to normal after 12 weeks as hCG decreases.
• Total thyroxine (T4) increases early in pregnancy due to increased liver synthesis of thyroxin-binding globulin (TBG) stimulated by high placental estradiol.
• Free thyroxine (fT4) should be maintained at the upper limit of the nonpregnant reference range to be considered normal for healthy pregnant women.
• Maternal thyroid hormones pass through the placenta in small amounts as early as 6 weeks and are critical for embryogenesis and fetal brain development.
• Biologically inactive rT3 is produced by type III deiodinase in the placenta, which inactivates maternal T4; this activity increases in the second half of pregnancy.
• Maternal Thyrotropin-releasing hormone (TRH) can cross the placenta and is also synthesized by the placenta to stimulate fetal pituitary thyroid function.
• Maternal TSH does not cross the placenta and has no direct effect on the fetus.
• Fetal thyroid gland starts functioning after 12 weeks of gestation but remains dependent on maternal thyroxine for 30% of its needs at term.
• Thyroxine-binding globulin (TBG) levels are affected by maternal nutrition; TBG binds fT4, decreasing its bioavailability.
• The Pituitary Gland is considered the "Master Gland," while the thyroid is the central gland in metabolic regulation.
• Regulatory positive feedback in the HPO axis occurs when a mid-cycle surge in estrogen stimulates LH release, triggering ovulation.

HYPERTHYROIDISM AND THYROID STORM

• Most common cause of thyrotoxicosis in pregnancy is Graves' Disease, an autoimmune disorder featuring TSH-receptor antibodies.
• Clinical hyperthyroidism diagnosis is suggested by excessive tachycardia, thyromegaly, exophthalmos, and weight loss despite adequate intake.
• Adverse pregnancy outcomes linked to poorly controlled hyperthyroidism include miscarriage, preterm birth, preeclampsia, and heart failure.
• Offspring of hyperthyroid mothers face higher risks of epilepsy and autism spectrum disorders.
• Growth restriction occurs in hypermetabolic mothers because the mother consumes massive energy for her own metabolic processes, leaving insufficient nutrients/oxygen for the fetus.
• Fetal goiter can occur even if the mother is euthyroid because testing only captures maternal levels and not fetal thyroid status.
• Subclinical hyperthyroidism is characterized by low TSH and normal T4; it generally requires no antithyroid treatment due to potential fetal risks.
• Rare but life-threatening Thyroid Storm is a hypermetabolic state that can lead to pulmonary hypertension and heart failure (cardiomyopathy).
• Propylthiouracil (PTU) is the preferred thionamide for the first trimester because it has less placental transfer and inhibits T4 to T3 conversion, despite the FDA warning for hepatotoxicity.
• Methimazole (MMI) is preferred after 16 weeks of gestation; its use in the first trimester is avoided due to rare embryopathy like aplasia cutis or choanal atresia.
• Switching from PTU to MMI is done at a 20:1 dose ratio.
• Thyroidectomy in pregnancy is only recommended in the 2nd trimester if medical therapy is toxic or fails (e.g., doses >450mg/day PTU).
• Radioactive iodine (RAI) is strictly contraindicated in pregnancy as it can destroy the fetal thyroid gland.
• Management of thyroid storm (Parkland Hospital protocol) involves loading PTU (1000 mg), followed by iodine (e.g., Sodium iodide/Lugol's) after 1-2 hours, and potential dexamethasone.
• Gestational Transient Thyrotoxicosis (GTT) is caused by hCG stimulating TSH receptors; it requires no antithyroid drug treatment and normalizes by mid-pregnancy.
• Molar pregnancy causes T4 elevation in 25-65% of cases because the excess hCG overstimulates TSH receptors; normalization follows molar evacuation.

HYPOTHYROIDISM AND IODINE

• Hashimoto thyroiditis is the most common cause of hypothyroidism in pregnancy, evidenced by anti-TPO antibodies.
• Overt hypothyroidism is confirmed by an abnormally high TSH and an abnormally low T4.
• Severe maternal hypothyroidism is associated with infertility, higher miscarriage rates, and a twofold greater risk of severe preeclampsia.
• Metabolic syndrome is found in 36% of adult Filipinos with hypothyroidism, significantly increasing the presence of DM and hypertension.
• Levothyroxine dosing for overt hypothyroidism is 1-2μg/kg/d (approx 100μg/day), with higher requirements starting as early as 5 weeks' gestation.
• Monitoring of TSH during hypothyroidism treatment should occur every 4 weeks in the first half of pregnancy and at least once in the third trimester.
• Isolated maternal hypothyroxemia features normal TSH but low free T4; current guidelines recommend against routine treatment.
• Euthyroid autoimmune thyroid disease (positive anti-TPO with normal TSH/T4) is associated with a 2-5x increased risk of early pregnancy loss and preterm birth.
• Iodine requirements are higher in pregnancy (220-250 μg/day) due to increased thyroid hormone production, renal losses, and fetal needs.
• Severe iodine deficiency is associated with endemic cretinism; the ATA advises against exceeding 500 μg/day (twice the recommended intake).
• Early thyroxine replacement is critical for newborns with Congenital Hypothyroidism to prevent neurological damage.

THYROIDITIS, NODULES, AND CANCER

• Postpartum thyroiditis occurs in 5-10% of women within the first year after childbirth; it presents initially as a thyrotoxic phase followed by a hypothyroid phase.
• Thyrotoxic phase of postpartum thyroiditis (1-4 months PP) is caused by hormone release from glandular disruption and is treated with beta-blockers if symptoms are severe.
• Hypothyroid phase of postpartum thyroiditis (4-8 months PP) is more symptomatic and requires levothyroxine (25-75 μg/day) for 6-12 months.
• Palpable thyroid nodules found in pregnancy require Fine-needle aspiration (FNA) under ultrasound guidance as pregnancy does not affect cytological diagnosis.
• Solitary thyroid nodules are 90-95% benign; biopsy is recommended for nodules >5 mm persistent at 3 months post-delivery.
• Surgery for thyroid cancer is deferred until postpartum if the cancer is non-aggressive or diagnosed in the third trimester; surgery is performed in the 1st/2nd trimester for aggressive cases.
• Papillary thyroid cancer is the most common thyroid cancer; it is usually slow-growing and non-invasive.

PARATHYROID DISORDERS

• Calcium homeostasis during pregnancy is maintained by Parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D (calcitriol).
• Elemental calcium requirement is 1.5-2 g daily from the 20th week of gestation until the end of pregnancy (WHO).
• Primary hyperparathyroidism (PHPT) is mostly caused by a single parathyroid adenoma; in the Philippines, it is predominantly diagnosed when overtly symptomatic.
• Hypercalcemic crisis (Ca >14 mg/dL) is a postpartum risk of hyperparathyroidism characterized by nausea, vomiting, and mental status changes.
• Maternal hyperparathyroidism suppresses the fetal parathyroid gland, leading to a 15-25% incidence of severe neonatal hypocalcemia/tetany after birth.
• Surgical removal of a symptomatic parathyroid adenoma is the preferred treatment, ideally performed in the 2nd trimester.
• Emergency treatment for severe hypercalcemia involves IV normal saline diuresis, furosemide, and calcitonin to decrease skeletal calcium release.
• Hypoparathyroidism symptoms include neuromuscular manifestations like numbness, tingling, and muscle cramps.

ADRENAL AND DISORDERS

• Cushing's syndrome symptoms like hypertension and DM overlap with pregnancy findings, making late detection common.
• Active Cushing's syndrome carries a 66% risk of preterm birth and a 52% risk of cesarean delivery.
• Adrenalectomy surgery remains the definitive cure for Cushing's syndrome caused by an adrenal adenoma.
• Addison disease (Adrenal Insufficiency) requires increased corticosteroid replacement (stress doses) during labor and delivery to match the normal adrenal response.

PITUITARY DISORDERS

• Pituitary gland enlarges by approximately one-third during normal pregnancy due to estrogen-induced lactotrophic hyperplasia.
• Sheehan syndrome is postpartum pituitary necrosis caused by severe hemorrhage/hypovolemic shock; the earliest sign is failure of lactation.
• Prolactinoma is the most common pituitary tumor in women of childbearing age; complications include amenorrhea, galactorrhea, and visual field defects.
• Microadenomas (pituitary) are ≤10 mm, while Macroadenomas are >10 mm.
• Visual field testing (bitemporal hemianopia) is used to detect tumor expansion impinging on the optic chiasm.
• Bromocriptine is a dopamine-receptor agonist used to restore ovulation in hyperprolactinemic women and to treat symptomatic tumor enlargement during pregnancy.
• MRI imaging is considered safe for pregnant women needing visualization of pituitary tumors.
• Acromegaly diagnosis is confirmed by elevated IGF-1 and lack of GH suppression after a glucose load (GH <1 ug/L is normal).
• Octreotide and pegvisomant are somatostatin and GH analogues used to treat pregnant women with acromegaly.
• Lymphocytic hypophysitis is a rare autoimmune pituitary disorder that presents close to delivery with headaches and visual disturbances.
• Desmopressin (dDAVP) is the standard treatment for Central Diabetes Insipidus and is considered safe for the fetus and lactating mothers.
• Water deprivation test is used to differentiate DI types; nothing by mouth is advised during the test, with hourly measurement of urine tests/body weight.

COMPARISON AND DIFFERENTIATION FOR EXAMS

• PTU vs. Methimazole: PTU is used in the 1st trimester due to lower placental transfer but has hepatotoxicity risk; MMI is used in 2nd/3rd trimester due to higher potency but is avoided in the 1st trimester due to aplasia cutis risk.
• TRH vs. TSH: TRH is produced in the placenta and crosses to the fetus; TSH does not cross the placenta.
• Thyroid Storm vs. Hyperemesis Gravidarum: Both feature tachycardia and vomiting, but Thyroid Storm is a life-threatening hypermetabolic state with decompensation (heart failure), while HG is often transient and TSH/T4 normalize by mid-pregnancy.
• Graves' Disease vs. Gestational Thyrotoxicosis (GTT): Graves' usually has a pre-pregnancy history, thyromegaly, or exophthalmos and requires thionamides; GTT is transient, hCG-mediated, requires no antithyroid medications, and improves after 12 weeks.
• Overt Hypothyroidism vs. Subclinical Hypothyroidism: Overt has high TSH and low fT4 and must be treated with levothyroxine (100μg); Subclinical has high TSH but normal fT4 and is treated selectively (e.g., if antibodies present or TSH >10).
• Central vs. Nephrogenic DI: Central DI responds to Desmopressin (dDAVP) with increased urine osmolality; Nephrogenic DI is resistant to Desmopressin and involves the renal tubules.
• Diabetes Insipidus vs. Primary Polydipsia: Both feature polyuria/polydipsia, but primary polydipsia is psychogenic and shows a higher response in urine osmolality during Desmopressin testing compared to organic DI.
• Sheehan Syndrome vs. Prolactinoma: Sheehan syndrome presents with lactation failure and breast atrophy (low prolactin); Prolactinoma features galactorrhea and secondary amenorrhea (high prolactin).
• Cushing's Syndrome vs. Normal Pregnancy: Both feature weight gain and striae; however, Cushing's is distinguished by more severe hypertension, hyperglycemia, and suppressed ACTH with high UFC.
• Cushing's Syndrome: Pregnant vs. Non-pregnant: In pregnancy, it is mostly an adrenal adenoma; in non-pregnant adults, 60% is caused by ACTH-dependent pituitary-dependent adrenal hyperplasia.
• Neonatal Hyperparathyroidism vs. Hypoparathyroidism: Maternal hyperparathyroidism suppresses the fetal gland, leading to transient neonatal hypoparathyroidism (severe hypocalcemia) after birth.
• Bitemporal Hemianopia vs. Normal Vision: A patient with bitemporal hemianopia (seen in pituitary tumors) can see the medial/central portion but has lost peripheral vision.
• dDAVP vs. Insulin: dDAVP is safe for the fetus in DI treatment; insulin for DM is also safe but requires closer management for maternal-fetal metabolic side effects.
• Prolactinoma: Micro vs. Macro: Microadenomas are ≤10mm and rarely enlarge symptomatically in pregnancy (2.4%); Macroadenomas are >10mm and have a 21% risk of symptomatic enlargement.
• Postpartum Thyroiditis Phases: The Thyrotoxic phase occurs 1-4 months PP (treated with Beta-blockers); the Hypothyroid phase occurs 4-8 months PP (treated with Levothyroxine).
• TSH-hCG mirroring: In early pregnancy, as hCG rises (peaks at 12 wks), TSH falls; as hCG falls after 12 wks, TSH rises back to baseline.

QA

SYSTEMATIC SUMMARY - THYROID DISORDERS

1. What is the pathogenesis of Hyperthyroidism (Graves')? | TSH-receptor antibodies.
   Stimulate the thyroid; worsened by hCG in the 1st trimester.
2. What is the pathogenesis of Hypothyroidism (Hashimoto's)? | Anti-TPO antibodies.
   Causes autoimmune glandular destruction.
3. What are the diagnostic laboratory findings for Hyperthyroidism (Graves')? | Suppressed TSH, elevated fT4.
4. What are the diagnostic laboratory findings for Hypothyroidism (Hashimoto's)? | Elevated TSH, low fT4.
5. What are the high-yield clinical findings (4) for Hyperthyroidism (Graves')? | 1) Exophthalmos
   2) Thyromegaly
   3) Weight gain failure
   4) Tachycardia
6. Why is Hypothyroidism (Hashimoto's) difficult to diagnose clinically in pregnancy? | Symptom overlap.
   Fatigue and weight gain are common in normal pregnancy.
7. What are the maternal risks (3) of Hyperthyroidism (Graves')? | 1) Preeclampsia
   2) Heart failure
   3) Thyroid storm
8. What are the maternal risks (3) of Hypothyroidism (Hashimoto's)? | 1) Preeclampsia
   2) Placental abruption
   3) Cardiac dysfunction
9. What are the fetal risks (4) of Hyperthyroidism (Graves')? | 1) Preterm birth
   2) FGR
   3) Stillbirth
   4) Neonatal Graves'
10. What are the fetal risks (4) for Hypothyroidism (Hashimoto's)? | 1) Infertility
    2) Miscarriage
    3) Stillbirth
    4) Low birthweight
11. What is the trimester-specific management for Hyperthyroidism (Graves')? | 1st: PTU; 2nd/3rd: Methimazole.
    Goal is high-normal fT4.
12. What is the management and TSH goal for Hypothyroidism (Hashimoto's)? | Levothyroxine (1-2μg/kg/d).
    Goal is TSH ~2.5 mU/L.

SYSTEMATIC SUMMARY - ADRENAL DISORDERS

13. What is the primary cause of Cushing's Syndrome in pregnancy? | Autonomous Adrenal Adenoma.
14. What are the primary causes (2) of Adrenal Insufficiency (Addison's)? | Autoimmune (Global) and Tuberculosis (Philippines/Poor areas).
15. What are the clinical features (4) of Cushing's Syndrome? | 1) Hypertension
    2) DM
    3) Preeclampsia
    4) Cushingoid facies
16. What are the clinical features (4) of Adrenal Insufficiency (Addison's)? | 1) Hypotension
    2) Nausea
    3) Weakness
    4) Hyperpigmentation
17. How is Cushing's Syndrome diagnosed? | Elevated 24-hr UFC.
    Accompanied by suppressed ACTH.
18. How is Adrenal Insufficiency (Addison's) diagnosed? | Blunted cortisol response.
    Occurs after insulin hypoglycemia or ACTH stimulation.
19. What is the definitive treatment for Cushing's Syndrome? | Surgical Adrenalectomy.
20. What is the treatment for Adrenal Insufficiency (Addison's) during labor? | Stress dose corticosteroids.
    Must increase dose to match labor stress.

SYSTEMATIC SUMMARY - DIABETES INSIPIDUS (DI)

21. What is the etiology of Central Diabetes Insipidus? | ADH deficiency.
    Due to hypothalamus or pituitary lesions.
22. What is the etiology of Nephrogenic Diabetes Insipidus? | Renal resistance to ADH.
23. What is the etiology of Gestational Diabetes Insipidus? | Increased ADH degradation.
    Caused by placental vasopressinase.
24. How does Central Diabetes Insipidus respond to Desmopressin? | Increased urine osmolality.
25. How does Nephrogenic Diabetes Insipidus respond to Desmopressin? | No change.
    Urine osmolality remains the same.
26. When does Gestational Diabetes Insipidus typically occur? | Late 3rd trimester.
    It is a transient condition.
27. What are the associated conditions (3) for Central Diabetes Insipidus? | trauma, tumor, infection.
28. What is the primary population for hereditary Nephrogenic Diabetes Insipidus? | Mostly males.
    It is rare in females.
29. What conditions (3) are associated with Gestational Diabetes Insipidus? | 1) Preeclampsia
    2) HELLP
    3) AFLP

ENDOCRINE PHYSIOLOGY BULLET POINTS

30. Why does maternal endocrine physiology change during pregnancy? | Maternal-fetal unit development.
    The placenta acts as a temporary gland.
31. How does hCG affect thyroid function in the first trimester? | Stimulates TSH receptors.
    Results in increased thyroid function and decreased TSH.
32. Define Gestational thyrotoxicosis. | Decreased TSH via high hCG.
    TSH typically normalizes after 12 weeks.
33. Why does total thyroxine (T4) increase early in pregnancy? | Increased TBG synthesis.
    Stimulated by high placental estradiol in the liver.
34. What is the target level for free thyroxine (fT4) in healthy pregnant women? | Upper limit.
    Target is the upper limit of the nonpregnant reference range.
35. When do maternal thyroid hormones first cross the placenta? | As early as 6 weeks.
    Crucial for fetal brain development.
36. What is the function of rT3 (reverse T3) in the placenta? | Inactivating maternal T4.
    Produced by type III deiodinase.
37. Does maternal Thyrotropin-releasing hormone (TRH) cross the placenta? | Yes.
    Also synthesized by the placenta to stimulate fetal thyroid.
38. Does maternal TSH cross the placenta? | No.
    It has no direct effect on the fetus.
39. At what week does the fetal thyroid gland start functioning? | After 12 weeks.
    Still depends on mother for 30% of thyroxine at term.
40. How does maternal nutrition affect Thyroxine-binding globulin (TBG)? | Affects TBG levels.
    TBG binds fT4, decreasing its bioavailability.
41. Which gland is considered the Pituitary Gland vs. the thyroid? | Pituitary is "Master Gland".
    Thyroid is central for metabolic regulation.
42. When does positive feedback occur in the HPO axis? | Mid-cycle estrogen surge.
    Stimulates LH release to trigger ovulation.

HYPERTHYROIDISM AND THYROID STORM

43. What is the most common cause of thyrotoxicosis in pregnancy? | Graves' Disease.
44. What clinical signs (4) suggest hyperthyroidism? | 1) Tachycardia
    2) Thyromegaly
    3) Exophthalmos
    4) Weight loss
45. List pregnancy outcomes of poorly controlled hyperthyroidism. (4) | 1) Miscarriage
    2) Preterm birth
    3) Preeclampsia
    4) Heart failure
46. What neurodevelopmental risks do offspring of hyperthyroid mothers face? | Epilepsy and Autism.
47. Why does fetal growth restriction occur in hypermetabolic mothers? | Maternal energy consumption.
    Mother consumes nutrients leaving insufficient amounts for the fetus.
48. Can a fetal goiter occur if the mother is euthyroid? | Yes.
    Maternal testing may not reflect fetal thyroid status.
49. What labs define subclinical hyperthyroidism? | Low TSH, normal T4.
50. What life-threatening state leads to Thyroid Storm complications? | Hypermetabolic state.
    Leads to pulmonary hypertension and heart failure.
51. Why is Propylthiouracil (PTU) preferred in the 1st trimester? | Less placental transfer.
    Inhibits T4 to T3 conversion.
52. Why is Methimazole (MMI) avoided in the 1st trimester? | Rare embryopathy.
    Risk of aplasia cutis or choanal atresia.
53. What is the dose ratio for switching PTU to MMI? | 20:1 ratio.
54. When is thyroidectomy recommended during pregnancy? | 2nd trimester.
    Only if medical therapy fails or is toxic.
55. Why is radioactive iodine (RAI) contraindicated in pregnancy? | Destroys fetal thyroid.
56. What is the first-line drug and dose for thyroid storm management? | PTU 1000 mg (loading).
    Followed by iodine after 1-2 hours.
57. What causes Gestational Transient Thyrotoxicosis (GTT)? | hCG stimulating TSH receptors.
58. Why does molar pregnancy cause T4 elevation? | Excess hCG.
    Overstimulates TSH receptors; normalizes after evacuation.

HYPOTHYROIDISM AND IODINE

59. What is the most common cause of Hashimoto thyroiditis? | Anti-TPO antibodies.
60. What lab values confirm overt hypothyroidism? | High TSH, low T4.
61. What risks (3) are associated with severe maternal hypothyroidism? | 1) Infertility
    2) Miscarriage
    3) Severe preeclampsia
62. What percentage of hypothyroid Filipinos have metabolic syndrome? | 36%.
63. What is the standard levothyroxine dosing for overt hypothyroidism? | 1-2μg/kg/d (approx 100μg/day).
64. How often should TSH monitoring occur during treatment? | Every 4 weeks.
    In the first half of pregnancy.
65. Define isolated maternal hypothyroxemia. | Normal TSH, low fT4.
66. What are the risks of euthyroid autoimmune thyroid disease? | Pregnancy loss and preterm birth.
    (Positive anti-TPO with normal TSH/T4).
67. What are the iodine requirements in pregnancy? | 220-250 μg/day.
68. What condition results from severe iodine deficiency? | Endemic cretinism.
69. Why is early thyroxine replacement critical in newborns? | Prevents neurological damage.
    Used for Congenital Hypothyroidism.

THYROIDITIS, NODULES, AND CANCER

70. When does postpartum thyroiditis typically occur? | Within the first year.
    Features a thyrotoxic phase then a hypothyroid phase.
71. How is the thyrotoxic phase of postpartum thyroiditis treated? | Beta-blockers.
    Treats symptoms of hormone release.
72. How long is levothyroxine given for the hypothyroid phase of thyroiditis? | 6-12 months.
    (Dose: 25-75 μg/day).
73. What is the preferred diagnostic test for thyroid nodules in pregnancy? | Fine-needle aspiration (FNA).
74. A biopsy is recommended for solitary thyroid nodules if they are what size? | >5 mm persistent at 3 months PP.
75. When is surgery for thyroid cancer performed if diagnosed in the 3rd trimester? | Deferred until postpartum.
    Unless it is aggressive.
76. What is the most common and non-invasive type of thyroid cancer? | Papillary thyroid cancer.

PARATHYROID DISORDERS

77. Which two factors maintain calcium homeostasis? | PTH and Calcitriol (1,25-dihydroxyvit D).
78. What is the WHO recommendation for elemental calcium daily intake? | 1.5-2 g daily.
    From 20th week until term.
79. What is the most common cause of primary hyperparathyroidism? | Single parathyroid adenoma.
80. What are the symptoms (3) of a hypercalcemic crisis? | Nausea, vomiting, mental status changes.
81. Maternal hyperparathyroidism causes neonatal hypocalcemia via what mechanism? | Suppression of fetal parathyroid gland.
82. When is surgical removal of a parathyroid adenoma best performed? | 2nd trimester.
83. Name the emergency treatment for severe hypercalcemia. (3) | 1) IV Saline diuresis
    2) Furosemide
    3) Calcitonin
84. What are the neuromuscular symptoms of hypoparathyroidism? | Numbness, tingling, muscle cramps.

ADRENAL DISORDERS

85. Why is Cushing's syndrome detection often late in pregnancy? | Symptom overlap.
    Hypertension and DM overlap with normal pregnancy findings.
86. Active Cushing's syndrome increases the risk of what? (2) | Preterm birth (66%) and Cesarean (52%).
87. What is the cure for Cushing's syndrome via adrenal adenoma? | Adrenalectomy.
88. Addison disease management during labor requires what? | Stress dose corticosteroids.

PITUITARY DISORDERS

89. Why does the pituitary gland enlarge in pregnancy? | Lactotrophic hyperplasia.
    Induced by estrogen.
90. What is the earliest sign of Sheehan syndrome? | Failure of lactation.
    Caused by postpartum pituitary necrosis.
91. What are the complications (3) of a prolactinoma? | 1) Amenorrhea
    2) Galactorrhea
    3) Visual field defects
92. Differentiate Microadenomas vs Macroadenomas by size. | Micro ≤10 mm; Macro >10 mm.
93. What specific visual defect is seen in pituitary tumor expansion? | Bitemporal hemianopia.
94. Use of Bromocriptine in hyperprolactinemic women. | Restores ovulation.
    Also treats symptomatic tumor enlargement.
95. Is MRI imaging safe for visualizing pituitary tumors in pregnancy? | Yes.
96. How is Acromegaly diagnosis confirmed? | Elevated IGF-1.
    Lack of GH suppression after glucose load.
97. Name the drugs used for acromegaly in pregnant women. | Octreotide and pegvisomant.
98. When does lymphocytic hypophysitis usually present? | Close to delivery.
    Presents with headaches and visual disturbances.
99. Why is Desmopressin (dDAVP) used in DI? | ADH replacement.
    Standard treatment for Central DI.
100. What is mandatory during a water deprivation test? | Nothing by mouth (NPO).
     Hourly urine/weight monitoring.

COMPARISONS

101. Compare PTU vs. Methimazole trimester use. | PTU (1st Tri); MMI (2nd/3rd Tri).
102. Compare TRH vs. TSH placental transfer. | TRH crosses; TSH does not.
103. Differentiate Thyroid Storm vs. Hyperemesis Gravidarum. | Storm is life-threatening/decompensated.
     HG is transient; TSH normalizes mid-pregnancy.
104. Differentiate Graves' vs. Gestational Thyrotoxicosis (GTT). | Graves' needs thionamides/history.
     GTT is hCG-mediated/transient.
105. Overt vs. Subclinical Hypothyroidism labs. | Overt: High TSH, Low fT4.
     Subclinical: High TSH, Normal fT4.
106. Central vs. Nephrogenic DI Desmopressin response. | Central responds; Nephrogenic is resistant.
107. DI vs. Primary Polydipsia. | Polydipsia is psychogenic.
     Shows higher urine osmolality response to dDAVP.
108. Sheehan Syndrome vs. Prolactinoma prolactin levels. | Sheehan: Low prolactin.
     Prolactinoma: High prolactin.
109. Cushing's vs. Normal Pregnancy symptoms. | Cushing's is more severe.
     Features high UFC and suppressed ACTH.
110. Cushing's Syndrome Cause: Pregnant vs Non-pregnant. | Pregnant: Adrenal Adenoma.
     Non-pregnant: Pituitary-dependent hyperplasia.
111. Neonatal Hyper- vs Hypoparathyroidism. | Maternal Hyper causes Neonatal Hypo.
112. Define Bitemporal Hemianopia vision loss. | Loss of peripheral vision.
     Medial/central vision remains intact.
113. dDAVP vs. Insulin safety. | Both are generally safe.
114. Prolactinoma risk of enlargement: Micro vs Macro. | Micro (2.4%); Macro (21%).
115. Timing of Postpartum Thyroiditis Phases. | Thyrotoxic: 1-4 months PP.
     Hypothyroid: 4-8 months PP.
116. Explain TSH-hCG mirroring. | As hCG rises, TSH falls.
     As hCG falls, TSH rises back.

8.5 - Connective Tissue Disorders

Summary

text

CONNECTIVE TISSUE DISORDERS (CTDs) IN PREGNANCY

I. GENERAL EPIDEMIOLOGY AND FILIPINO CONTEXT

II. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

III. ANTIPHOSPHOLIPID SYNDROME (APS)

IV. RHEUMATOID ARTHRITIS (RA) & SYSTEMIC SCLEROSIS

V. INHERITED DISORDERS (MARFAN, OI, EDS)

COMPREHENSIVE BULLET POINTS (REPRESENTATIVE FOR FLASHCARDS)

• In Mixed Connective Tissue Disease (MCTD), the Alarcon-Segovia Criteria is used for diagnosis, and high titers of anti-U1RNP are characteristic findings.
• Patients with Systemic Lupus Erythematosus (SLE) have placentas that are typically smaller with vascular lesions like decidual vasculopathy, thrombosis, and infarction.
• Neonatal Lupus Erythematosus (NLE) is caused by the transplacental passage of maternal anti-SSA (Ro) or anti-SSB (La) autoantibodies.
• The most common manifestation of Neonatal Lupus (NLE) is a photosensitive skin rash, which usually resolves within 3 to 6 months as maternal antibodies clear.
• A permanent and serious complication of Neonatal Lupus (NLE) is congenital heart block (CHB), though the lecturer notes this was not seen in the specific Filipino study reviewed.
• Hydroxychloroquine (HCQ) is the only maternal treatment for SLE that has been shown to lower the risk of Neonatal Lupus.
• For pregnant women with Systemic Lupus Erythematosus (SLE), non-fluorinated corticosteroids (Prednisone, Hydrocortisone) are preferred because they are inactivated by the placenta.
• Aspirin at 81mg/day should be initiated at 12 weeks of gestation in all SLE patients to decrease the occurrence of preeclampsia.
• Lupus flares in pregnancy are often difficult to distinguish from preeclampsia; however, decreased complement levels (C3, C4) and increased anti-dsDNA titers strongly suggest a flare.
• The Lupus Anticoagulant (LAC) is the only antiphospholipid antibody consistently associated with adverse pregnancy outcomes despite being named an "anticoagulant" due to its in vitro effects.
• Annexin V is a natural anticoagulant expressed by the syncytiotrophoblast that may be targeted by pathogenetic antibodies in Antiphospholipid Syndrome (APS).
• Catastrophic Antiphospholipid Antibody Syndrome (CAPS), also known as Asherson Syndrome, involves a "cytokine storm" affecting three or more organ systems and has a high mortality rate.
• Heparin (UFH or LMWH) is the mainstay for thrombosis prevention in Antiphospholipid Syndrome (APS) because it prevents cellular damage by binding to beta-2-glycoprotein-I.
• Warfarin is strictly avoided during pregnancy in Antiphospholipid Syndrome (APS) management because it is a Vitamin K antagonist that is teratogenic and causes fetal bleeding.
• Symptom improvement in Rheumatoid Arthritis (RA) during pregnancy is correlated with higher serum levels of pregnancy-associated alpha2-glycoprotein (PAG).
• In Systemic Sclerosis, Labetalol must be avoided for hypertension management because it can cause peripheral vasospasm.
• Captopril (ACE inhibitor) is the treatment of choice if a Scleroderma Renal Crisis (SRC) is suspected, though typically used post-natally unless life-threatening.
• Polyarteritis Nodosa (PAN) is a necrotizing vasculitis of small and medium-sized arteries that may present peripartum with tender subcutaneous nodules and myositis.
• Marfan Syndrome risk is highest during the third trimester and postpartum due to cardiovascular changes like increased stroke volume and hormonal wall changes.
• In Ehlers-Danlos Syndrome (EDS), patients are at high risk for postpartum hemorrhage (PPH) and should receive prompt episiotomies to prevent irregular perineal tears.
• Osteogenesis Imperfecta (OI) patients may experience a fracture rate increase in the third trimester due to pregnancy-induced bone loss and transient decreases in bone mineral density.
• Pregnancy is generally discouraged in patients with severe CTD manifestations, specifically those with pulmonary hypertension or recent stroke.
• Methotrexate and Mycophenolate Mofetil must be discontinued 1-3 months and 6 weeks respectively before attempting pregnancy due to high teratogenic risk.

DIFFERENTIATING SIMILAR ENTITIES (FOR EXAMS)

• Lupus Flare vs. Preeclampsia: In Lupus Flare, complement levels (C3/C4) are decreased and anti-dsDNA is increased; in Preeclampsia, complements are usually normal and anti-dsDNA is negative.
• Lupus Flare vs. Preeclampsia: Urinary cellular casts and hematuria are highly characteristic of an SLE renal flare, whereas they are absent in pure preeclampsia.
• Lupus Flare vs. Preeclampsia: Uric acid is typically elevated in preeclampsia but remains normal in an SLE flare.
• Chronic Arterial vs. Venous Insufficiency: Arterial insufficiency presents with decreased/absent pulses and pale skin on elevation; Venous insufficiency has normal pulses and brown skin pigmentation.
• Arterial vs. Venous Ulcers: Arterial ulcers occur on toes or trauma points; Venous ulcers occur at the medial ankle.
• SLE vs. RA: SLE is multisystemic with hallmark malar rash and nephritis; RA is primarily an inflammatory synovitis of peripheral joints.
• APS Lab Markers: Lupus Anticoagulant (LAC) is the most predictive of pregnancy loss, while Anticardiolipin (ACA) is directed specifically against mitochondrial/platelet membranes.
• OI Type I vs. Type II: Type I is the mildest form and compatible with successful pregnancy; Type II is typically lethal in the neonatal period or in utero.
• EDS vs. Marfan: Both involve connective tissue, but Marfan is primarily a fibrillin-1 defect with aortic risks, while EDS is a collagen defect with skin/joint fragility risks.
• Heparin vs. Aspirin: Heparin inhibits the coagulation cascade (common pathway); Aspirin inhibits platelet aggregation by blocking Thromboxane A2.
• Systemic Sclerosis (Limited vs. Diffuse): Limited (CREST) is more benign and slow; Diffuse features rapid skin and GI fibrosis.
• Neonatal Lupus vs. SLE: Neonatal Lupus is a passive transfer of antibodies that resolves (except heart block); SLE is an endogenous autoimmune disease of the patient.
• Prednisone vs. Dexamethasone: Prednisone is preferred for maternal SLE treatment (placenta inactivates it); Dexamethasone is used only if the goal is to treat the fetus (crosses placenta).
• Labetalol in CTDs: Preferred in preeclampsia but contraindicated in Scleroderma due to potential to worsen Raynaud's/vasospasm.
• Thrombosis (APS): Arterial thrombosis often presents as stroke or MI; Venous thrombosis typically presents as DVT or PE.

QA

1. How is Hereditary Connective Tissue Disorder typically inherited? | Autosomal dominant trait.

2. Which sexes are equally affected by Hereditary Connective Tissue Disorder? | Males and females.

3. Contrast the origin of Autoimmune Connective Tissue Disorder vs Hereditary types. | Acquired (not inherited).

4. What triggers Autoimmune Connective Tissue Disorder in genetically predisposed individuals? | External factors.

5. In Filipinos, which sex predominantly develops Mixed Connective Tissue Disease (MCTD)? | Females.

6. What is the median age of onset for Mixed Connective Tissue Disease (MCTD) in Filipinos? | 30.5 years.

7. What is the most common chief complaint (67%) in Filipino Mixed Connective Tissue Disease (MCTD)? | Joint pain.

8. What is the second most common complaint (13%) in Filipino Mixed Connective Tissue Disease (MCTD)? | Skin tightness.

9. What was the most frequent initial diagnosis in Filipino patients later confirmed with Mixed Connective Tissue Disease (MCTD)? | Systemic lupus erythematosus (SLE).

10. What is the musculoskeletal hallmark (100%) of Mixed Connective Tissue Disease (MCTD)? | Arthritis.

11. What is the vascular hallmark (93%) of Mixed Connective Tissue Disease (MCTD)? | Raynaud’s phenomenon.

12. What is the cutaneous hallmark (71%) of Mixed Connective Tissue Disease (MCTD)? | Skin tightness.

13. How is Systemic Lupus Erythematosus (SLE) defined regarding its clinical course? | Relapses (flares) and remissions.

14. What is the mandatory entry criterion for Systemic Lupus Erythematosus (SLE) classification? | Antinuclear antibodies (ANA).

15. What ANA titer on HEp-2 cells is required to classify Systemic Lupus Erythematosus (SLE)? | ≥1:80.

16. What total score is required for Systemic Lupus Erythematosus (SLE) classification after ANA positivity? | 10 points or more.

17. Which renal findings carry the highest weight (10 points) in Systemic Lupus Erythematosus (SLE) classification? | Class III/IV lupus nephritis.

18. What cardiac criterion for Systemic Lupus Erythematosus (SLE) yields 6 points? | Acute pericarditis.

19. What serosal criterion for Systemic Lupus Erythematosus (SLE) yields 5 points? | Pleural/pericardial effusion.

20. What specific photosensitive skin manifestation is seen in Systemic Lupus Erythematosus (SLE)? | Malar rash.

21. What hair-related manifestation is a criterion for Systemic Lupus Erythematosus (SLE)? | Non-scarring alopecia.

22. What mucosal finding is part of the Systemic Lupus Erythematosus (SLE) clinical criteria? | Oral ulcers.

23. How is Antiphospholipid Syndrome (APS) defined? | Acquired thrombophilia.

24. What are the two core clinical features of Antiphospholipid Syndrome (APS)? | Thrombosis or pregnancy morbidity.

25. How many occasions must Lupus anticoagulant (LAC) be present for APS diagnosis? | ≥2 occasions.

26. What is the minimum time interval between positive Lupus anticoagulant (LAC) tests? | 12 weeks.

27. What titers of Anticardiolipin antibodies (ACA) IgG/IgM are required for APS? | Medium-high (>40 GPL/MPL).

28. How many weeks apart must Anticardiolipin antibodies (ACA) be measured? | 12 weeks.

29. What percentile threshold is used for Anti-beta-2 glycoprotein I antibody in APS? | >99th percentile.

30. Define the fetal death criterion for Antiphospholipid Syndrome (APS). | ≥1 death (≥10 weeks).

31. Define the preterm birth criterion for Antiphospholipid Syndrome (APS). | <34 weeks.

32. What causes preterm birth in Antiphospholipid Syndrome (APS) criteria? | Preeclampsia/placental insufficiency.

33. Define the abortion criterion for Antiphospholipid Syndrome (APS). | ≥3 consecutive (<10 weeks).

34. Where is Beta-2 Glycoprotein-I expressed in high concentrations during pregnancy? | Syncytiotrophoblast.

35. How do antibodies affect Beta-2 Glycoprotein-I in APS? | Reverse natural anticoagulant activity.

36. What process is inhibited by Antiphospholipid Syndrome (APS) in the placenta? | Syncytiotrophoblast differentiation (SYNCI).

37. What may be considered the definitive treatment for Antiphospholipid Syndrome (APS)? | Delivery.

38. What percentage of Rheumatoid Arthritis (RA) patients improve during pregnancy? | 70%.

39. What is the likely cause of Rheumatoid Arthritis (RA) improvement in pregnancy? | HLA disparity (mother-fetus).

40. What percentage of Rheumatoid Arthritis (RA) women experience a postpartum flare-up? | 40-50%.

41. What is the minimum score required for Rheumatoid Arthritis (RA) classification? | Score ≥6.

42. Which joints are weighted higher in the Rheumatoid Arthritis (RA) scoring system? | Small joints.

43. Which lab titers are part of Rheumatoid Arthritis (RA) classification? | RF and ACPA.

44. Which inflammatory markers are used in Rheumatoid Arthritis (RA) diagnosis? | ESR and CRP.

45. Why must Methotrexate be strictly avoided in Rheumatoid Arthritis (RA) pregnancy? | Causes abortion.

46. What screening must be done before starting a Rheumatoid Arthritis (RA) patient on Methotrexate? | Pregnancy screen.

47. What is the pathognomonic feature of Systemic Sclerosis? | Overproduction of normal collagen.

48. Enumerate the components of CREST Syndrome. (5) | 1) Calcinosis
    2) Raynaud’s
    3) Esophageal involvement
    4) Sclerodactyly
    5) Telangiectasia

49. What is the leading cause of death in Systemic Sclerosis? | Pulmonary Arterial Hypertension (PAH).

50. What percentage of Systemic Sclerosis patients are affected by Pulmonary Arterial Hypertension? | 15%.

51. Marfan Syndrome is caused by a mutation in which gene? | FBN1 gene.

52. On which chromosome is the gene for Marfan Syndrome located? | 15q21.

53. The FBN1 gene in Marfan Syndrome encodes for which protein? | Fibrillin-1.

54. What is the most serious pregnancy complication in Marfan Syndrome? | Aortic Dissection (AoD).

55. How is Ehlers-Danlos Syndrome (hEDS) Types I-III generally tolerated in pregnancy? | Well-tolerated.

56. What are the two main risks for Ehlers-Danlos Syndrome (hEDS) patients in pregnancy? | Joint hypermobility; skin fragility.

57. Which type of Ehlers-Danlos Syndrome (EDS) is high-risk for maternal vessel/uterine rupture? | Type IV (Vascular).

58. Enumerate the classic features of Osteogenesis Imperfecta (OI). (3) | 1) Brittle bones
    2) Blue sclerae
    3) Hearing loss

59. Which type of Osteogenesis Imperfecta (OI) is typically lethal in utero? | Type II.

60. Which criteria are used for Mixed Connective Tissue Disease (MCTD) diagnosis? | Alarcon-Segovia Criteria.

61. Which antibody is characteristic of Mixed Connective Tissue Disease (MCTD)? | Anti-U1RNP.

62. Describe the typical placenta in Systemic Lupus Erythematosus (SLE). | Smaller than normal.

63. Enumerate the vascular lesions found in Systemic Lupus Erythematosus (SLE) placentas. (3) | 1) Decidual vasculopathy
    2) Thrombosis
    3) Infarction

64. What causes Neonatal Lupus Erythematosus (NLE)? | Transplacental maternal antibodies.

65. Which specific antibodies (2) cause Neonatal Lupus Erythematosus (NLE)? | Anti-SSA (Ro); anti-SSB (La).

66. What is the most common manifestation of Neonatal Lupus (NLE)? | Photosensitive skin rash.

67. When does the skin rash in Neonatal Lupus (NLE) usually resolve? | 3 to 6 months.

68. What permanent cardiac complication can occur in Neonatal Lupus (NLE)? | Congenital heart block (CHB).

69. Which maternal SLE treatment reduces the risk of Neonatal Lupus? | Hydroxychloroquine (HCQ).

70. Why are non-fluorinated corticosteroids preferred for SLE in pregnancy? | Inactivated by the placenta.

71. Enumerate the preferred non-fluorinated corticosteroids for SLE. (2) | 1) Prednisone
    2) Hydrocortisone

72. What dosage of Aspirin is used in SLE to prevent preeclampsia? | 81mg/day.

73. At what gestational age should Aspirin be initiated for SLE patients? | 12 weeks.

74. Distinguish Lupus Flare vs. Preeclampsia based on complement (C3, C4). | Flare: Decreased;
    Preeclampsia: Normal.

75. Distinguish Lupus Flare vs. Preeclampsia based on anti-dsDNA. | Flare: Increased;
    Preeclampsia: Negative.

76. Which APS antibody is most consistently associated with adverse pregnancy outcomes? | Lupus Anticoagulant (LAC).

77. Which natural syncytiotrophoblast anticoagulant is targeted in Antiphospholipid Syndrome (APS)? | Annexin V.

78. What is the alternative name for Catastrophic Antiphospholipid Antibody Syndrome (CAPS)? | Asherson Syndrome.

79. How many organ systems must be affected for Catastrophic APS (CAPS)? | Three or more.

80. What is the main treatment for thrombosis prevention in Antiphospholipid Syndrome (APS)? | Heparin (UFH or LMWH).

81. How does Heparin prevent damage in APS? | Binds to beta-2-glycoprotein-I.

82. Why is Warfarin strictly avoided in APS during pregnancy? | Teratogenic (fetal bleeding).

83. Which protein's high serum levels correlate with Rheumatoid Arthritis (RA) improvement? | Pregnancy-associated alpha2-glycoprotein (PAG).

84. Why is Labetalol avoided in Systemic Sclerosis? | Causes peripheral vasospasm.

85. What is the treatment of choice for Scleroderma Renal Crisis (SRC)? | Captopril (ACE inhibitor).

86. Define Polyarteritis Nodosa (PAN). | Necrotizing vasculitis.

87. Enumerate findings of peripartum Polyarteritis Nodosa (PAN). (2) | 1) Subcutaneous nodules
    2) Myositis

88. When is the risk of Marfan Syndrome complication highest? | Third trimester and postpartum.

89. Ehlers-Danlos Syndrome (EDS) patients are at high risk for which delivery complication? | Postpartum hemorrhage (PPH).

90. What is the recommended management for Ehlers-Danlos Syndrome (EDS) at delivery? | Prompt episiotomy.

91. Why does Osteogenesis Imperfecta (OI) fracture rate increase in the 3rd trimester? | Pregnancy-induced bone loss.

92. Severe CTD manifestations (e.g. stroke) result in what recommendation regarding pregnancy? | Pregnancy is discouraged.

93. How long before attempting pregnancy should Methotrexate be discontinued? | 1-3 months.

94. How long before attempting pregnancy should Mycophenolate Mofetil be discontinued? | 6 weeks.

95. Distinguish Lupus Flare vs. Preeclampsia based on urinary findings. | Flare: Cellular casts/hematuria;
    Preeclampsia: Absent.

96. Distinguish Lupus Flare vs. Preeclampsia based on uric acid levels. | Flare: Normal;
    Preeclampsia: Elevated.

97. Distinguish Insufficiency (Arterial vs. Venous) based on pulses. | Arterial: Decreased/absent;
    Venous: Normal.

98. Distinguish Ulcers (Arterial vs. Venous) based on location. | Arterial: Toes/trauma points;
    Venous: Medial ankle.

99. Compare SLE vs. RA primary pathology. | SLE: Multisystemic/Nephritis;
    RA: Inflammatory synovitis.

100. Contrast OI Type I vs. Type II pregnancy compatibility. | Type I: Successful pregnancy;
     Type II: Lethal in utero.

101. Compare Marfan vs. EDS structural defects. | Marfan: Fibrillin-1 (Aortic risk);
     EDS: Collagen (Skin/Joint risk).

102. Compare Heparin vs. Aspirin inhibition targets. | Heparin: Coagulation cascade;
     Aspirin: Platelet aggregation.

103. Contrast Systemic Sclerosis (Limited vs. Diffuse) progression. | Limited: Benign/Slow;
     Diffuse: Rapid skin/GI fibrosis.

104. Contrast Neonatal Lupus vs. SLE origin. | Neonatal: Passive antibody transfer;
     SLE: Endogenous autoimmune.

105. Compare Prednisone vs. Dexamethasone fetal effect. | Prednisone: Inactivated (maternal use);
     Dexamethasone: Crosses (fetal use).