Per Vaginum (PV) Bleeding

Classification by Clinical Context

1. Pregnancy Status First

A. First-Trimester Bleeding (< 20 weeks)

Ectopic Pregnancy

• Prevalence: 1 in 28 to 1 in 200 pregnancies; accounts for the majority of first-trimester maternal deaths
• Over 40% are misdiagnosed on first presentation
• Classic triad: pain (97-100%) + amenorrhea (74-84%) + bleeding
• Risk factors (in descending significance):
  • IUD in place or recently used
  • Previous tubal/abdominal/pelvic surgery
  • Prior ectopic pregnancy
  • Prior STI / PID
  • Infertility
  • Recent therapeutic abortion
• Diagnosis: serial quantitative beta-hCG + transvaginal ultrasound (TVS)
  • An intrauterine gestational sac with fetal pole essentially excludes ectopic in most cases (heterotopic pregnancies are rare)

Threatened / Inevitable / Incomplete / Missed Abortion

• If fetal heartbeat is confirmed by Doppler, miscarriage risk falls to < 10%
• TVS is the first-line investigation from 5-7 weeks onward

B. Second Half of Pregnancy (> 20 weeks) - Antepartum Hemorrhage (APH)

Critical rule: Do NOT perform digital or speculum examination until TVS confirms placental location - mechanical disruption of placenta previa can cause catastrophic hemorrhage.

Placenta Previa

• Placenta extends near, partially over, or beyond the internal cervical os
• Presentation: painless, bright red vaginal bleeding, usually after 28 weeks
• Risk factors: previous cesarean scar, tobacco use, advanced maternal age, multiparity, multiple gestation
• The risk increases in a dose-dependent manner with number of prior cesareans
• Associated with uterine atony and placenta accreta
• Accreta risk escalates from 3% (primary cesarean with previa) to 61% with three prior cesareans
• Management:
  • Expectant if fetus immature + bleeding not profuse
  • Neuraxial anesthesia preferred if hemodynamically stable
  • Vaginal delivery is contraindicated
  • Cesarean if severe bleeding or fetal maturity

Placental Abruption (Abruptio Placentae)

• Premature separation of a normally implanted placenta
• Incidence: ~1% of deliveries, peak between 24-32 weeks
• Presentation: painful vaginal bleeding + uterine tenderness/hypertonus (dark, clotted blood)
• Bleeding may be concealed (revealed, concealed, or mixed)
• Risk factors: abdominal trauma, cocaine use, hypertension/preeclampsia, smoking, multiple gestation, oligohydramnios, chorioamnionitis, advanced maternal age/parity
• Severity spectrum:
  • Mild: mild tenderness, normal vitals, no coagulopathy, fetal distress absent
  • Severe: heavy or no visible bleeding, fetal distress, coagulopathy (DIC), maternal shock, continuous contractions
• When placental separation > 50%: stillbirth is the most likely outcome
• Investigations: CTG (100% negative predictive value when reassuring), TVS, CBC, coagulation panel (fibrinogen, FDPs), type & cross-match
• Complications: DIC, hemorrhagic shock, uterine rupture, multi-organ failure
• Management: maternal stabilization, obstetric consultation, large-bore IVs, RhoGAM if Rh-negative; emergency delivery for severe abruption

Vasa Previa

• Fetal vessels traverse the internal cervical os unsupported by placenta or cord
• Painless PV bleeding at time of membrane rupture = fetal blood loss (extremely high fetal mortality if unrecognized)

C. Postpartum Hemorrhage (PPH)

Primary PPH (within 24 hours) - The "4 T's"

Uterine Atony Management (stepwise):

1. Bimanual uterine massage (fist in anterior fornix + suprapubic compression)
2. Oxytocin 20-30 units in 1000 mL, rate ≤ 100 mU/min - avoid bolus IV (causes hypotension)
3. Methylergonovine / Ergonovine 0.2 mg IM - do NOT give IV (risk of hypertension, CNS vasospasm); contraindicated in hypertension
4. Carboprost (15-methyl PGF2α) 250 µg IM, repeatable - use with caution in cardiovascular disease or asthma
5. Misoprostol 800-1000 µg rectal/intrauterine - useful when conventional therapy fails
6. Uterine balloon tamponade (Bakri balloon, Foley catheter)
7. Uterine packing with sterile gauze
8. Pelvic vessel embolization (if facilities available)
9. Laparotomy: B-Lynch sutures, iliac artery ligation, peripartum hysterectomy

Secondary PPH (24 hours to 6 weeks postpartum)

D. Non-Pregnant PV Bleeding (Abnormal Uterine Bleeding - AUB)

PALM-COEIN Classification (FIGO)

• Polyp - intermenstrual bleeding; most common > 35 years
• Adenomyosis - ectopic endometrial glands in myometrium; heavy + painful periods
• Leiomyoma (fibroids) - submucosal fibroids most likely to bleed; common mid-30s onward
• Malignancy / hyperplasia - endometrial cancer (postmenopausal >> reproductive)

• Coagulopathy - von Willebrand disease is most common (accounts for up to 20% of AUB in adolescents); also myeloproliferative disorders, ITP, anticoagulants, liver disease
• Ovulatory dysfunction - anovulation in perimenarchal, perimenopausal, PCOS, thyroid disease, eating disorders, excessive exercise; increases risk of endometrial hyperplasia
• Endometrial causes - normal ovulation + normal cavity; bleeding from local endometrial disorder
• Iatrogenic - hormonal medications, IUDs, anticoagulants
• Not otherwise classified

Age-Based Differential

FIGO Bleeding Terminology (current)

Emergency Management of Massive PV Bleeding

Key Investigations

• Urine/serum beta-hCG - always first in reproductive-age women
• TVS - first-line imaging; do BEFORE any pelvic examination if placenta previa possible
• CBC - hemoglobin, hematocrit, platelets
• Coagulation panel - PT, APTT, fibrinogen, FDPs (especially in abruption/PPH)
• Type & cross-match - in significant bleeding
• Thyroid-stimulating hormone - if anovulatory bleeding of undetermined cause
• Hysteroscopy / saline infusion sonography - for structural causes (polyps, fibroids)
• Endometrial biopsy - mandatory in postmenopausal bleeding and in women > 45 with AUB to exclude malignancy

Rh Incompatibility

Overview

The Rh Blood Group System

• Two genes encode Rh erythrocyte membrane proteins: RhD and RhCE, both located on chromosome 1p, approximately 30 kb apart
• RhD-negative individuals are homozygous for a deletion of the D gene - no "d" antigen exists, so no anti-d antibody can be raised
• Rh-negative prevalence by ethnicity:
  • ~15% of Caucasians
  • ~5% of Africans
  • < 1% of Asians
• The D antigen is the primary culprit - it is the most immunogenic Rh antigen
• Other clinically relevant antigens in the Rh system: C/c, E/e (encoded by the RhCE gene)
  • E and e differ by a single point mutation in exon 5
  • C and c differ by four amino-acid substitutions in exons 1 and 2
• Other blood group systems that can also cause HDN: Kell, Duffy, Kidd, ABO

Pathophysiology

Step 1 - Sensitization (usually first pregnancy or prior transfusion)

• Fetal Rh(D)-positive RBCs cross the placenta into the maternal circulation during delivery (fetomaternal hemorrhage)
• Most women have < 1 mL of fetal blood in their circulation following delivery; however, fetomaternal hemorrhage > 30 mL occurs in ~1% of pregnancies
• The mother's immune system recognizes the foreign D antigen and mounts a primary immune response, producing IgM initially, then IgG anti-D antibodies
• Sensitization can also occur from incompatible blood transfusion (~50% of Rh-negative individuals are sensitized by Rh-positive transfusion)
• Rh(D) antigen is detectable as early as 5.5-6 weeks gestation
• Alloimmunization can occur with as little as 0.1 mL of fetal blood

Step 2 - Subsequent Pregnancy (second or later Rh-positive fetus)

• Fetal Rh-positive RBCs re-enter maternal circulation and trigger a rapid anamnestic (secondary) IgG antibody response with high titers
• Maternal IgG anti-D antibodies actively cross the placenta (IgM does NOT cross)
• In the fetus, IgG anti-D coats fetal RBCs - these are then destroyed by macrophages in the fetal spleen

Step 3 - Fetal/Neonatal Consequences

1. Hemolysis of fetal RBCs - releases hemoglobin
2. Hemoglobin converted to unconjugated bilirubin by fetal macrophages
3. In utero: bilirubin is cleared by the placenta - fetus does not become jaundiced
4. Bilirubin appears in amniotic fluid (measured as ΔOD450)
5. Fetal anemia - stimulates compensatory extramedullary erythropoiesis in liver and spleen
6. Extramedullary erythropoiesis damages hepatocytes → reduced serum albumin → reduced oncotic pressure
7. Severe cases: high-output cardiac failure + generalized fetal edema = Hydrops Fetalis

Incidence and Progression

Clinical Spectrum of Erythroblastosis Fetalis

Mild

• Mild jaundice only
• No significant anemia

Moderate

• Pallor at birth, then jaundice
• Hepatosplenomegaly (due to extramedullary erythropoiesis)
• Macrocytic anemia with reticulocytosis
• Elevated nucleated RBCs (erythroblasts) in peripheral blood - giving the disease its name

Severe

• Hydrops Fetalis: generalized fetal edema, ascites, pleural effusions, cardiac failure; very grave prognosis; without intrauterine transfusion, intrauterine death follows
• Kernicterus: unconjugated bilirubin crosses the immature blood-brain barrier, deposits in the basal ganglia and other brain cells → permanent neurological damage, mental impairment, motor deficits; results from high bilirubin production + immature conjugation system

Laboratory Findings in Newborn

• Nucleated RBCs up to 2.0 × 10⁹/L in term infants (normal: ~0.5 × 10⁹/L)
• Macrocytic anemia, elevated reticulocytes
• Elevated leukocyte count with immature forms
• Normoblastic hyperplasia of bone marrow
• In severe cases: thrombocytopenia, depression of prothrombin complex, DIC
• Direct Antiglobulin Test (DAT / direct Coombs) positive on fetal RBCs (detects IgG coating)

ABO vs. Rh Incompatibility

Monitoring the Sensitized Pregnancy

Initial Workup

1. Alloantibody screen at first prenatal visit for all women
2. If anti-D antibody identified: determine antibody titer
3. Paternal Rh phenotype/genotype - if father is homozygous Rh-negative, no risk; if D-positive, determine zygosity
4. If father is heterozygous or unavailable: fetal RhD genotyping from amniocytes OR now available via cell-free fetal DNA (cfDNA) in maternal blood

Surveillance of Sensitized Mother with At-Risk Fetus

• Serial anti-D antibody titers every month until 24 weeks, then every 2 weeks thereafter
• Critical titer = titer associated with risk of fetal hydrops: usually 1:8 to 1:32
• Once critical titer is reached: Middle Cerebral Artery (MCA) Doppler peak systolic velocity by ultrasound
  • Higher MCA velocity = strong indicator of fetal anemia
  • This has largely replaced amniocentesis for ΔOD450 measurement
• ΔOD450 (ΔA450) on amniotic fluid (Liley method) - spectrophotometric measurement of bilirubin at 450 nm - now mainly used as confirmatory tool

Treatment of Fetal Anemia

• Intrauterine percutaneous umbilical cord blood transfusion (IUBT) - Rh-negative, cross-matched RBCs transfused via umbilical vein
• Timing of delivery: balanced against risks of prematurity vs. continued in-utero hemolysis
  • If hydrops develops at ≥35 weeks or multiple transfusions required - delivery timing is individualized

Treatment of the Affected Neonate

1. Exchange Transfusion with Rh-negative blood
   • Neonate's Rh-positive blood is replaced with Rh-negative blood over ~1.5 hours
   • Repeated several times in first weeks of life
   • Purpose: keeps bilirubin low to prevent kernicterus
   • Rh-positive cells gradually repopulate over 6 weeks; by then maternal anti-D antibodies have degraded
2. Phototherapy - for hyperbilirubinemia
3. IVIG - may reduce hemolysis severity
4. Supportive care: respiratory support for hydrops, correction of coagulopathy

Prevention - Anti-D Immunoglobulin (RhoGAM)

Mechanism

• Exogenous anti-D IgG coats and clears fetal Rh-positive RBCs from maternal circulation before the mother can mount her own immune response
• Inhibits antigen-induced B-lymphocyte antibody production

Dosing

• 300 µg covers up to 15 mL of Rh-positive fetal RBCs (or 30 mL whole blood)
• Must be given to unsensitized (non-immunized) Rh-negative women only - no benefit once sensitized

Indications for Anti-D (Rh-negative women)

• Delivery of an Rh-positive baby
• Antenatal routine at 28 weeks
• Miscarriage / threatened abortion / ectopic pregnancy
• Amniocentesis, chorionic villus sampling (CVS), cordocentesis
• External cephalic version
• Antepartum hemorrhage
• Abdominal trauma in pregnancy

Kleihauer-Betke Test

• Detects fetal RBCs in maternal circulation after delivery
• Used to calculate the volume of fetomaternal hemorrhage
• If hemorrhage > 15 mL fetal RBCs: additional doses of anti-D required (1 vial/15 mL fetal RBCs)
• Flow cytometry is an effective alternative

Key Points Summary