Physiological Changes in Pregnancy (OG Assignment)

1. Changes in the Uterus

Size and Weight

• Non-pregnant uterus weighs 4-70 g with a volume of 10 mL
• At term: weight increases to 1100-1200 g, volume to 5 L
• A 10-fold increase in uterine blood flow occurs - from 2% of cardiac output in the non-pregnant state to 17% at term

Myometrial Changes

• Early pregnancy: Myometrial hyperplasia (increase in cell number)
• Latter half: Predominantly hypertrophy (increase in cell size) under endocrine and mechanical signals
• Accompanied by increase in fibrous connective tissue, blood vessels, and lymphatics

Lower Uterine Segment

• The isthmus does NOT undergo hypertrophy
• It becomes increasingly thin and distensible as pregnancy progresses, forming the lower uterine segment
• In the latter half, distension leads to gradual thinning of the uterine wall

Blood Flow Redistribution

• Non-pregnant: blood flow equally split between myometrium and endometrium
• During pregnancy: 80-90% of uterine blood flow goes to the placenta
• Remainder is equally distributed between endometrium and myometrium
• The increase in flow is related to uterine vascular sensitivity to estrogen, VEGF, angiotensin II, nitric oxide, and prostacyclin (PGI₂)

Cervix (Cervical Remodeling - 4 Phases)

1. Softening - begins in first trimester, maintained throughout; increased tissue compliance; changes in collagen fibril processing
2. Ripening - last 1-2 weeks of gestation; maximum increase in tissue viscoelasticity
3. Dilation - during active labor
4. Postpartum repair - after delivery

2. Changes in the Breast

First Trimester

• Ductal system expands and branches into adipose tissue in response to estrogen and progesterone from the corpus luteum
• hCG (produced ~8 weeks post-fertilization) prevents corpus luteum degradation, peaks at 9 weeks then declines
• Estrogen: causes adipose tissue involution, ductal proliferation and elongation; stimulates pituitary to raise prolactin levels
• Progesterone: stimulates lobule development
• Mononuclear inflammatory cell infiltration occurs

Second Trimester

• By 20th week of gestation: mammary glands sufficiently developed to produce milk components (due to prolactin stimulation)
• Lobule growth continues via cellular proliferation and increased cell size
• Myoepithelial cells become flattened and less prominent; epithelial cells enlarge
• Secretory substances accumulate in epithelial cells of lobule acini

Third Trimester

• Increased prolactin promotes alveolar cell differentiation and initiates lactogenesis
• Milk production is inhibited by high estrogen and progesterone levels during pregnancy
• Colostrum is produced during this time

Visible/External Changes

• Areola darkens
• Breast increases in size
• Areolar glands (Montgomery's glands) become more prominent
• Nipple discharge (bilateral) is physiologic; bloody bilateral nipple discharge can occur in up to 15% of nursing mothers

After Birth

• Rapid fall in estrogen and progesterone allows milk production and let-down
• Postlactation: massive apoptosis, acinar involution, basement membrane thickening, connective tissue shifts from loose to dense

3. Hematological Changes

Blood Volume

• Plasma volume expansion begins at 6-8 weeks' gestation
• Reaches maximum 4700-5200 mL at 32 weeks (increase of ~45%, i.e., 1200-1600 mL above non-pregnant values)
• Mechanism likely involves nitric oxide-mediated vasodilation → activates renin-angiotensin-aldosterone system → sodium and water retention

Red Blood Cell (RBC) Mass

• RBC mass increases by 250-450 mL (20-30%) by term
• Due to increased RBC production (not prolonged RBC life)
• Driven by: placental chorionic somatomammotropin, progesterone, and prolactin
• Maternal iron demand increases by 500 mg for erythropoiesis; an additional 300 mg transferred to fetus; 200 mg for daily losses → total iron requirement ~1000 mg during pregnancy
• Erythrocyte 2,3-DPG increases → lowers maternal Hb oxygen affinity → facilitates O₂ transfer to fetus

Physiologic Anemia of Pregnancy

• Plasma volume rises disproportionately to RBC mass → physiologic hemodilution
• Hematocrit mildly decreases, maximal in mid-third trimester
• Hb normally around 11.6 g/dL (values below this are concerning for true anemia)
• Hematocrit as low as 33% and Hb 11 g/dL if iron deficiency untreated
• Protective effects: decreases blood viscosity (reduces thromboembolic risk), improves intervillus perfusion

White Blood Cells

• Leukocytosis is normal in pregnancy (unrelated to infection)
• Normal WBC range extends to 13,000/mm³ (vs. 10,000/mm³ non-pregnant)
• WBC rises further during labor, proportional to duration of labor

Coagulation - Hypercoagulable State

• Increased: Fibrinogen (Factor I), Factor VII, and lesser increases in other factors; also increased plasma volume augments additional intravascular fluid by ~1000-1500 mL at term
• Decreased: Factors XI, XIII, antithrombin III, protein S
• Unchanged: Factors II, V, and protein C
• Net result: ~20% decrease in PT and PTT
• Platelet count: normal or slightly decreased (~10%) due to dilution; gestational thrombocytopenia (count rarely falls below 70,000/mm³) is a diagnosis of exclusion
• TEG/ROTEM at term shows hypercoagulable pattern: decreased R, decreased K, increased α angle, increased MA

4. Cardiovascular Changes

Hemodynamic Timeline

• Changes begin as early as 6th week of gestation
• Peripheral vascular resistance (PVR) decreases early → small drop in BP by 5-10 mmHg below baseline until third trimester
• BP returns to baseline by the third trimester

Heart Rate

• Increases by 10-20 beats/min above pre-pregnancy levels

Cardiac Output (CO)

• Increases by 30-50% (due to increased HR + stroke volume)
• Peaks between 20th-26th week; in the first trimester dominant factor is elevated stroke volume; later, increased HR predominates
• Twin pregnancy: CO increases by an additional 10-15%
• During labor/delivery and immediately postpartum: CO increases a further 60-80%
• Autotransfusion of at least 500 mL occurs with placental separation

Anatomic/Structural Changes (Echocardiographic)

• Ventricular wall muscle mass and end-diastolic volume increase
• No increase in end-systolic volume or end-diastolic pressure
• Cardiac compliance increases → physiologically dilated heart; ejection fraction maintained
• Left atrial diameter, volume, and function increase in parallel with blood volume rise
• General softening of collagen in the entire vascular system with smooth muscle hypertrophy → increased compliance of arteries and veins (evident by 5 weeks)
• Chest X-ray: cardiac silhouette often appears slightly enlarged (volume overload + elevated diaphragm)
• Small pericardial effusion is common and normal

Clinical Findings in Normal Pregnancy

• Collapsing arterial pulses
• Prominent jugular venous pulsations (no JVP elevation)
• Laterally displaced apical impulse
• Palpable right ventricle or pulmonary trunk
• Soft, short ejection systolic murmur over pulmonic area or left sternal border (normal finding)
• Symptoms: fatigue, dyspnea, light-headedness, palpitations (all can be normal)

Postpartum

• Many hemodynamic changes resolve in first 2 weeks after delivery; complete resolution may take up to 6 months
• Mobilization of fluid in the first week after delivery can precipitate heart failure in women with cardiomyopathy or severe outflow tract obstruction

5. Metabolic Changes

Glucose Metabolism and Insulin Resistance

• Pregnancy is characterized by: hyperinsulinemia, insulin resistance, relative fasting hypoglycemia, increased plasma lipids, and hypoaminoacidemia
• All directed by fetoplacental hormones to ensure uninterrupted fuel supply to the fetus
• Mechanism of insulin resistance: hCS (human chorionic somatomammotropin) and placental GH reduce insulin receptor sites and glucose transport in insulin-sensitive tissues
• Maternal islet cell hyperplasia accompanies insulin resistance
• Cortisol (free levels increase in late pregnancy), estrogen, and progesterone also contribute to the diabetogenic nature of pregnancy
• Fasting glucose is lower (~68 vs. 79 mg/dL), fasting insulin is higher (~16 vs. 10 µU/mL)

Lipid Changes

• Total plasma lipids increase significantly and progressively after 24 weeks of gestation
• Triglycerides, cholesterol, and free fatty acids show the most marked increases
• Pre-β-lipoprotein (VLDL) increases substantially
• HDL-cholesterol increases in early pregnancy; LDL-cholesterol increases later in pregnancy
• Plasma triglycerides increase more in response to oral glucose load in late pregnancy vs. non-pregnant state

Fasting Ketogenesis

• Prolonged fasting in pregnancy → exaggerated hypoglycemia, hypoinsulinism, and hyperketonemia
• Gluconeogenesis is not proportionally increased, meaning maternal homeostatic mechanisms cannot prevent hypoglycemia during extended fasting

Amino Acids

• Plasma amino acid levels (including alanine) are lower in late pregnancy as they are preferentially transferred to the fetus
• During fasting, fetal demands are met partly by accelerated maternal muscle breakdown

Key Concept - "Facilitated Anabolism" vs. "Accelerated Starvation"

• Fed state: facilitated anabolism (nutrients readily stored)
• Fasting state: accelerated starvation (rapid switch to ketones/lipids) to preserve glucose and amino acids for the fetus

• Creasy & Resnik's Maternal-Fetal Medicine: Principles and Practice - Chapters on Blood Volume, Anatomic Changes, CVS Changes, Endocrine-Metabolic Changes
• Braunwald's Heart Disease - Chapter 92: Cardiovascular Changes in Pregnancy
• Miller's Anesthesia 10e - Chapter 58: Hematologic Changes, Coagulation
• Current Surgical Therapy 14e - Pregnancy Changes to the Breast
• Goldman-Cecil Medicine - Laboratory Changes in Pregnancy