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MICROBIOLOGY & IMMUNOLOGY — MRCOG Part 1 Deep-Dive Study Document

Target: MRCOG Part 1 Estimated reading time: 20,000+ words Last updated: May 2026

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TABLE OF CONTENTS

MICROBIOLOGY 1. Bacterial Pathogens in O&G 2. Viral Pathogens in O&G 3. Fungal Pathogens 4. Parasitic Infections 5. Sexually Transmitted Infections 6. Surgical Site Infections & Puerperal Sepsis 7. Vaginal Microbiome

IMMUNOLOGY 8. Basic Immunology 9. Immunology of Pregnancy 10. Immunological Disorders in Pregnancy

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PART I — MICROBIOLOGY

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1. BACTERIAL PATHOGENS IN OBSTETRICS & GYNAECOLOGY

1.1 Classification of Bacteria

Bacteria are classified by multiple criteria relevant to clinical practice:

By Gram stain: - Gram-positive: Thick peptidoglycan layer, stain purple/violet. Includes Staphylococcus, Streptococcus, Listeria, Clostridium, Gardnerella (variable). - Gram-negative: Thin peptidoglycan + outer membrane, stain pink/red. Includes E. coli, Neisseria, Bacteroides, Treponema (too thin to stain — best seen with darkfield microscopy).

By morphology: - Cocci (spherical): Staphylococcus (clusters), Streptococcus (chains), Neisseria (diplococci). - Bacilli (rod-shaped): E. coli, Gardnerella, Listeria, Clostridium, Mycobacterium (acid-fast bacillus). - Spirochaetes: Treponema pallidum. - Others: Chlamydia (intracellular), Mycoplasma (no cell wall).

By oxygen requirement: - Aerobes: Require O₂ for growth. E.g., Neisseria, Mycobacterium tuberculosis. - Anaerobes: Cannot grow in O₂. E.g., Bacteroides fragilis, Clostridium perfringens, Mobiluncus. - Facultative anaerobes: Can grow with or without O₂. E.g., E. coli, Staphylococcus, Streptococcus. - Microaerophilic: Require low O₂. E.g., Campylobacter, Gardnerella.

By spore formation: - Clostridium species form spores (resistant to heat, drying, disinfectants).

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1.2 Group B Streptococcus (GBS) — Streptococcus agalactiae

Microbiology: - Gram-positive coccus in chains. - Lancefield group B (cell wall carbohydrate antigen). - Polysaccharide capsule — serotypes Ia, Ib, II, III, IV, V (type III causes most neonatal meningitis). - Normal commensal of lower GI tract and vagina (10–30% of women colonised).

Clinical Significance in Obstetrics: - Leading cause of early-onset neonatal sepsis in the UK/USA. - Transmission: ascending infection from vagina to amniotic fluid → fetal aspiration. - Also causes: chorioamnionitis, postpartum endometritis, UTI, wound infection.

GBS Screening (UK — RCOG Green-top Guideline): - Risk-based screening (UK practice): Offer IAP if any risk factor present. - Risk factors: Previous infant with GBS disease, GBS bacteriuria in current pregnancy, preterm labour (<37 weeks), prolonged ROM (≥18 hours), maternal intrapartum pyrexia (≥38°C). - A universal screening programme (like USA — rectovaginal swab at 35–37 weeks) is NOT currently recommended by UK NSC (National Screening Committee), though many women opt for private testing.

Intrapartum Antibiotic Prophylaxis (IAP): - First-line: Benzylpenicillin 3 g IV stat, then 1.5 g IV 4-hourly until delivery. - Penicillin-allergic (low-risk anaphylaxis): Cefazolin 2 g IV stat, then 1 g IV 8-hourly. - Penicillin-allergic (high-risk anaphylaxis): Clindamycin 900 mg IV 8-hourly if isolate sensitive (>20% resistance reported). If resistant → vancomycin 1 g IV 12-hourly. - IAP reduces early-onset GBS disease by ~80%.

Neonatal GBS Disease: - Early-onset (0–6 days): Pneumonia, septicaemia, meningitis. Risk ~1 in 300 births from colonised mothers without IAP. - Late-onset (7–90 days): Meningitis, bacteraemia. Often serotype III. Vertical + horizontal transmission. - Management: IV benzylpenicillin + gentamicin (neonatal sepsis protocol).

Penicillin G Resistance: Not yet reported in GBS (remains universally sensitive). Clindamycin resistance ~20%.

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1.3 Group A Streptococcus (GAS) — Streptococcus pyogenes

Microbiology: - Gram-positive coccus in chains. - Lancefield group A. - M protein (surface virulence factor — antiphagocytic). - Produces exotoxins: streptolysin O & S (haemolysins), pyrogenic exotoxins (SpeA, SpeB, SpeC — superantigens → toxic shock), hyaluronidase, DNase, streptokinase.

Clinical Significance in O&G: - Puerperal sepsis: Historically "childbed fever" (Semmelweis, 1847). Life-threatening postpartum uterine infection. - Necrotising fasciitis: Surgical emergency. Rapid spread along fascial planes. Mortality 30–50%. - Streptococcal toxic shock syndrome (STSS): Multi-organ failure, hypotension, rash. Mortality >50%. - Impetigo, cellulitis, erysipelas, pharyngitis, scarlet fever.

Puerperal Sepsis — Key Points: - Sudden onset high fever, rigors, abdominal pain, tender uterus, foul-smelling lochia (may be absent in GAS — lochia may be serous). - Rapid deterioration → hypotension, multi-organ failure. - Management: High-dependency care, IV clindamycin (reduces toxin production) + IV benzylpenicillin (or piperacillin-tazobactam), source control (surgical debridement, hysterectomy if needed). - Contact tracing: Household contacts + healthcare workers.

Why Clindamycin? - Clindamycin suppresses M-protein and exotoxin synthesis (protein synthesis inhibitor), whereas β-lactams don't. Even if the organism is resistant, clindamycin is added for its anti-toxin effect.

Notifiable disease: In the UK, confirmed GAS is notifiable to UKHSA.

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1.4 Escherichia coli

Microbiology: - Gram-negative bacillus (rod). - Facultative anaerobe. - Part of normal gut flora. - Has O (somatic), H (flagellar), K (capsular) antigens. - Pili/fimbriae for adhesion (type 1, P pili).

Clinical Significance in O&G: - Most common cause of UTI in pregnancy (cystitis, pyelonephritis). Pyelonephritis in pregnancy → increased risk of preterm labour, sepsis, ARDS. - Chorioamnionitis: Especially after prolonged ROM, ascending infection. - Neonatal sepsis: Gram-negative rod — second most common cause after GBS. High mortality. Can cause meningitis (K1 capsular antigen). - Postoperative infection: After caesarean section, hysterectomy, pelvic surgery. - PID: Mixed infection including E. coli.

Antibiotic Resistance: - ESBL (Extended-Spectrum β-Lactamase) producing E. coli — increasing concern. - Resistance to ampicillin ~50%; to co-amoxiclav ~15–20%; to ciprofloxacin ~20–30%. - Pregnancy-safe options: Nitrofurantoin (avoid at term — risk of haemolytic anaemia in G6PD-deficient neonates), oral cephalexin, IV cefuroxime/ceftriaxone.

Uropathogenic E. coli (UPEC): Express P pili that bind to glycolipid receptors on uroepithelial cells. Causes ~80% of community-acquired UTIs.

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1.5 Staphylococcus aureus

Microbiology: - Gram-positive coccus in clusters ("grape-like"). - Coagulase-positive (distinguishes from S. epidermidis which is coagulase-negative). - Produces: Protein A (binds IgG Fc — antiphagocytic), coagulase, haemolysins, leukocidins, enterotoxins, TSST-1 (toxic shock syndrome toxin). - Biofilm-forming on surgical implants.

Clinical Significance in O&G: - Breast abscess: Most common cause of lactational mastitis/abscess. Milk stasis → infection. Treatment: needle aspiration/incision and drainage + IV flucloxacillin. MRSA considered if risk factors. - Toxic shock syndrome (TSS): Associated with tampon use and surgical wounds. TSST-1 acts as superantigen → massive cytokine release → fever, hypotension, diffuse rash, multi-organ failure. Management: IV clindamycin + IV flucloxacillin/vancomycin. - Surgical site infection: Post-CS, post-hysterectomy. - Neonatal sepsis: S. aureus skin infections, omphalitis (umbilical infection).

MSSA vs MRSA: - MSSA: Treat with flucloxacillin (or cefazolin). - MRSA (Meticillin-resistant S. aureus): Resistant to all β-lactams. Treat with vancomycin, teicoplanin, daptomycin, linezolid. Colonisation screening (nose, throat, perineum) in high-risk admissions. Decolonisation: nasal mupirocin + chlorhexidine body wash. - MRSA in obstetrics: Higher risk in women with hospitalisation, previous surgery, IVDU, recent antibiotics.

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1.6 Bacteroides fragilis

Microbiology: - Gram-negative bacillus. - Obligate anaerobe — dies in presence of oxygen. - Part of normal gut flora (most numerous anaerobe in colon). - Polysaccharide capsule — major virulence factor.

Clinical Significance in O&G: - Pelvic abscess: Most common anaerobe isolated. Mixed infection with other bowel flora (E. coli, enterococci). - Postoperative infection: After gynaecological surgery, CS, hysterectomy — especially if bowel involvement. - PID (Pelvic Inflammatory Disease): Part of the mixed flora. - Bacterial vaginosis: Anaerobic overgrowth (including Bacteroides species, but Gardnerella is more common).

Antibiotic Therapy: - Metronidazole — drug of choice for anaerobes (IV/oral/PR). Excellent bioavailability, penetrates abscesses well. - Co-amoxiclav, piperacillin-tazobactam, carbapenems (meropenem, ertapenem) also cover. - Resistance to clindamycin ~20–40%.

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1.7 Clostridium perfringens

Microbiology: - Gram-positive, spore-forming rod. - Obligate anaerobe. - Produces at least 12 toxins; α-toxin (lecithinase/phospholipase C) — causes haemolysis, tissue necrosis, increased capillary permeability. - Spores survive in soil, dust, and on skin.

Clinical Significance in O&G: - Gas gangrene (clostridial myonecrosis): Rare but catastrophic. History of septic abortion (illegal "back-street" terminations), uterine instrumentation, or necrotic tissue after CS. Rapid onset: severe pain, crepitus (gas in tissues), foul-smelling "sweet" discharge, bronze skin discolouration. Mortality >50%. - Septic abortion: Now rare in UK (safe abortion laws) but seen in resource-limited settings. - As part of "the sixes" — classic puerperal sepsis organisms.

Management: - Surgical debridement — emergency hysterectomy often required. - IV clindamycin + benzylpenicillin (clindamycin suppresses toxin production). - Hyperbaric oxygen (inhibits spore germination, limits toxin production) — supportive role. - Clostridial antitoxin used historically, limited role now.

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1.8 Gardnerella vaginalis & Mobiluncus spp.

Gardnerella vaginalis: - Gram-variable bacillus (often appears Gram-positive or Gram-indeterminate). - Facultative anaerobe. - Part of normal vaginal flora in small numbers. - Overgrows when lactobacilli are depleted → bacterial vaginosis (BV). - Produces adherence factor (adheres to vaginal epithelial cells → "clue cells" on microscopy).

Mobiluncus spp.: - Gram-variable, curved rod ("comma-shaped"). - Obligate anaerobe. - Highly specific for BV. - Detected on wet mount by characteristic tumbling motility.

Role in BV: Both organisms flourish in the polymicrobial biofilm of BV. BV is not a single infection but a shift in vaginal microbiome away from Lactobacillus dominance.

Treatment: Metronidazole (oral or intravaginal) or clindamycin (intravaginal cream). Male partners do NOT require treatment (not sexually transmitted in the classical sense).

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1.9 Neisseria gonorrhoeae

Microbiology: - Gram-negative diplococcus ("kidney bean" shape, intracellular). - Fastidious — requires CO₂ for growth (chocolate agar + CO₂ or Thayer-Martin selective medium). - Pili — major virulence factor (adhesion, antigenic variation). - Porin proteins (PorA, PorB) — antiphagocytic. - Produces β-lactamase (penicillinase) — many strains resistant. - Has outer membrane lipooligosaccharide (LOS — similar to endotoxin).

Clinical Significance in O&G: - Pelvic Inflammatory Disease (PID): Ascending infection from cervix → uterus → fallopian tubes → peritoneal cavity. Leads to tubal factor infertility, ectopic pregnancy, chronic pelvic pain. Fitz-Hugh-Curtis syndrome (perihepatitis) — "violin string" adhesions. - Cervicitis: Mucopurulent discharge, cervical friability, contact bleeding. - Ophthalmia neonatorum: Purulent neonatal conjunctivitis acquired during vaginal delivery. Can cause blindness if untreated. Prophylaxis: topical tetracycline/erythromycin or silver nitrate (historical). Caused by N. gonorrhoeae OR C. trachomatis. - Disseminated gonococcal infection: Vesiculopustular rash, tenosynovitis, arthritis, rarely endocarditis/meningitis. - Neonatal sepsis (rare). - Preterm delivery, PROM — association with untreated gonorrhoea in pregnancy.

Screening & Diagnosis: - NAAT (Nucleic Acid Amplification Test) — first-line. High sensitivity/specificity. Can be done on urine, vulvovaginal swab (self-taken), endocervical swab. - Culture — for antibiotic sensitivity testing (increasing resistance to ceftriaxone and azithromycin). - Gram stain with intracellular diplococci in PMNs — diagnostic in symptomatic men; less sensitive in women.

Treatment: - Uncomplicated genital infection: Ceftriaxone 1 g IM/IV single dose (resistance emerging in some regions). Previously azithromycin 1 g PO was dual therapy; now monotherapy with higher-dose ceftriaxone is preferred by BASHH/UK guidelines (azithromycin resistance increasing). - Alternatives: Cefixime 800 mg PO (oral option), spectinomycin 2 g IM. - PID: Ceftriaxone 1 g IM/IV + doxycycline 100 mg PO BD + metronidazole 400 mg PO BD for 14 days. Or IV therapy (e.g., IV ceftriaxone + IV metronidazole + PO doxycycline).

Pregnancy: - Ceftriaxone is safe in pregnancy. - Azithromycin can be added (safe in pregnancy). - Quinolones (ciprofloxacin, ofloxacin) and tetracyclines (doxycycline) are CONTRAINDICATED. - Test of cure recommended (NAAT 2 weeks post-treatment). - Retesting at 3 months (high reinfection rate).

Contact tracing: All sexual partners within 3 months.

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1.10 Chlamydia trachomatis

Microbiology: - Obligate intracellular bacterium — cannot replicate extracellularly. - Unique biphasic life cycle: 1. Elementary body (EB): Small (0.3 µm), metabolically inactive, infectious form. Survives extracellularly. Attaches to and enters host cells. 2. Reticulate body (RB): Larger (1 µm), metabolically active, intracellular replicative form. Divides by binary fission inside cytoplasmic inclusion. - Has a Gram-negative-like cell wall but lacks muramic acid (peptidoglycan). - Serovars: A-C (trachoma), D-K (genital infection), L1-L3 (lymphogranuloma venereum — LGV).

Clinical Significance in O&G: - Most common bacterial STI in the UK. Peak prevalence in under-25s. - PID: C. trachomatis causes ~50% of PID cases. Often "silent" — subclinical upper tract infection still causes tubal damage. Leads to: tubal factor infertility (most common cause worldwide), ectopic pregnancy, chronic pelvic pain. - Mucopurulent cervicitis: Often asymptomatic (70% women, 50% men). Discharge, contact bleeding, "strawberry cervix" (follicular cervicitis). - Ophthalmia neonatorum: Inclusion conjunctivitis (5–21 days after birth). Less acute than gonococcal. Treated with oral erythromycin. - Neonatal pneumonia: Afebrile, staccato cough, bilateral infiltrates. Presents 2–19 weeks after birth. - Endometritis, salpingitis, perihepatitis (Fitz-Hugh-Curtis syndrome). - Reactive arthritis (Reiter's syndrome): Urethritis, conjunctivitis, arthritis. - LGV: Tropical/subtropical. Painful inguinal lymphadenopathy (buboes), proctocolitis.

Diagnosis: - NAAT — gold standard. High sensitivity. First-void urine (men), self-taken vaginal swab (women), endocervical swab. - ELISA/direct immunofluorescence — older methods, less sensitive. - Cell culture — for medicolegal cases (rape). Low sensitivity but 100% specificity. - LGV serology — MIF (microimmunofluorescence) for serovar-specific antibodies.

Treatment: - Uncomplicated: Doxycycline 100 mg PO BD for 7 days (first-line). Azithromycin 1 g single dose (less effective for LGV). - Pregnancy: Azithromycin 1 g PO single dose OR amoxicillin 500 mg TDS for 7 days (less effective than azithromycin). Doxycycline CONTRAINDICATED. - LGV: Doxycycline 100 mg PO BD for 21 days. - Ophthalmia neonatorum / neonatal pneumonia: Oral erythromycin 50 mg/kg/day in divided doses for 14 days.

Test of cure: Not routine for uncomplicated genital C. trachomatis treated with doxycycline (high efficacy). Recommended in pregnancy (NAAT 5 weeks after treatment end) or if LGV suspected.

Contact tracing: All sexual partners within 6 months.

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1.11 Treponema pallidum (Syphilis)

Microbiology: - Spirochaete — thin, helical (6–14 µm × 0.2 µm), too thin to see on Gram stain. - Visualised by darkfield microscopy (live organisms from chancre/lesion exudate) or silver stain. - Cannot be cultured in vitro — propagated in rabbit testes. - Extremely sensitive to penicillin (but requires prolonged therapy due to slow division time — 30 h). - Surface antigens: TpN47, TpN17, TpN15.

Clinical Stages:

Stage	Timing	Features
Primary	9–90 days post-exposure	Painless chancre (genital/anal/oral), regional lymphadenopathy. Heals spontaneously in 3–6 weeks.
Secondary	2–8 weeks later	Rash (palms/soles "copper-coloured"), condylomata lata (moist, flat papules), lymphadenopathy, fever, malaise, alopecia.
Latent	Asymptomatic	Early (<2 years): infectious relapses possible. Late (>2 years): non-infectious.
Tertiary	10–30+ years	Gummatous (skin/bone), cardiovascular (aortitis, aortic regurgitation, aneurysm), neurosyphilis (tabes dorsalis, general paresis).

Congenital Syphilis: - Transplacental transmission at any stage, but highest in primary/secondary (70–100%) vs early latent (40%) vs late latent (10%). - Early congenital (first 2 years): Hepatosplenomegaly, rash (vesiculobullous "syphilitic pemphigus"), osteochondritis, periostitis ("sabre tibia"), rhinitis ("snuffles"), anaemia, jaundice. - Late congenital: Hutchinson's triad — Hutchinson incisors (notched, peg-shaped), interstitial keratitis, eighth nerve deafness. Also: saddle nose, Clutton's joints (painless knee effusion).

Diagnosis: - Screening (non-treponemal): VDRL (Venereal Disease Research Laboratory) or RPR (Rapid Plasma Reagin) — quantitative, used for monitoring treatment response. Can be falsely positive (pregnancy, autoimmune, TB, malaria). - Confirmation (treponemal): TPHA (T. pallidum haemagglutination assay), TPPA, FTA-Abs (fluorescent treponemal antibody absorption) — remain positive for life. - Algorithm: EIA (enzyme immunoassay) first → if positive, confirm with TPPA and/or RPR. - PCR can detect treponemal DNA from lesions. - Darkfield microscopy for primary chancre.

Treatment: - Early syphilis (primary/secondary/early latent <2 years): Benzathine benzylpenicillin 2.4 million units IM single dose. - Late latent or unknown duration: Benzathine benzylpenicillin 2.4 million units IM weekly × 3 doses. - Pregnancy: Procaine benzylpenicillin 600,000 units IM daily for 10 days (or benzathine penicillin as above). Penicillin is the only recommended treatment in pregnancy. Erythromycin/azithromycin do NOT adequately cross the placenta. - Penicillin allergy in pregnancy: Desensitisation is mandatory. - Neurosyphilis: IV benzylpenicillin 2.4 million units 4-hourly for 14 days.

Jarisch-Herxheimer Reaction: - Acute febrile reaction (fever, rigors, myalgia, hypotension) occurring 2–8 hours after starting treatment. - Caused by massive release of treponemal lipoproteins after spirochaete killing → cytokine release. - More common in primary/secondary syphilis. - In pregnancy, can precipitate preterm labour or fetal distress (transient). Therefore: tell the pregnant woman, monitor in hospital for 24 hours, consider pre-treatment with prednisolone (though evidence limited). - Management: Supportive (bed rest, antipyretics). NOT an allergic reaction to penicillin. - Advise the woman that the reaction is expected, self-limiting, and does NOT mean treatment failure.

Contact tracing: All sexual partners within 3 months (primary), 6–12 months (secondary), 5 years (early latent).

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1.12 Mycobacterium tuberculosis (TB)

Microbiology: - Acid-fast bacillus (AFB) — mycolic acid-rich cell wall resists decolourisation (retains carbolfuchsin → Ziehl-Neelsen stain). - Aerobic, non-spore-forming, slow-growing (division time 15–20 hours; cultures take 4–8 weeks). - Obligate intracellular — survives within macrophages by preventing phagosome–lysosome fusion. - Muramyl dipeptide + adjuvant → granuloma formation (caseating).

Clinical Significance in O&G: - Genital TB: Major cause of infertility in developing countries. M. tuberculosis usually reaches genital tract via haematogenous spread from lungs (primary infection). Affects fallopian tubes (most common → tubal infertility, hydrosalpinx), endometrium (menstrual irregularities, Asherman's syndrome), ovaries, cervix. - Pulmonary TB in pregnancy: Increased risk of active TB in pregnant/postpartum women (immunological changes). Presents with cough, haemoptysis, night sweats, weight loss, lymphadenopathy. - Congenital TB: Rare. Transplacental transmission via haematogenous route. Presents in first weeks of life with hepatosplenomegaly, respiratory distress, fever, poor feeding. High mortality.

Diagnosis: - IGRA (Interferon-γ Release Assay): Quantiferon-TB Gold or T-SPOT.TB. Preferred over Mantoux (which can be falsely positive due to BCG). Measures T-cell response to ESAT-6 and CFP-10 (specific to M. tuberculosis, not BCG). - Chest X-ray (with abdominal shielding in pregnancy): apical infiltrates, cavities, Ghon focus. - Sputum AFB smear + culture + GeneXpert (PCR for TB + rifampicin resistance). - Endometrial biopsy + culture for genital TB (histology: caseating granulomas, AFB). Hysterosalpingography may show tubal calcification or "tobacco pouch" appearance.

Treatment: - Standard regimen (RIPE): Rifampicin, Isoniazid, Pyrazinamide, Ethambutol for 2 months (intensive), then Rifampicin + Isoniazid for 4 months (continuation). - In pregnancy: All first-line drugs are safe (Rifampicin, Isoniazid, Pyrazinamide, Ethambutol). Pyridoxine (vitamin B₆) MUST be given with Isoniazid to prevent peripheral neuropathy. Streptomycin is CONTRAINDICATED (ototoxic to fetus). - BCG vaccine: Live attenuated vaccine — contraindicated in pregnancy. Given to neonates in high-prevalence settings.

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1.13 Listeria monocytogenes

Microbiology: - Gram-positive rod (bacillus) — can be confused with diphtheroids/contaminants. - Facultative intracellular — can survive and replicate in macrophages and epithelial cells. - Psychrophile — can grow at refrigeration temperatures (4°C). This is unique among major pathogens and explains food-borne transmission via refrigerated, ready-to-eat foods. - Beta-haemolytic on blood agar. - Tumbling motility at 25°C (not at 37°C) — diagnostic clue. - Produces: internalin (invasion), listeriolysin O (LLO — hemolysin, escapes phagosome), ActA (actin polymerisation → cell-to-cell spread).

Clinical Significance in Pregnancy: - Listeriosis in pregnancy: Pregnant women are 10–20 times more susceptible due to cell-mediated immunosuppression (Th2 shift). - Presentation: Usually flu-like illness (fever, myalgia, headache, GI symptoms — nausea, vomiting, diarrhoea). Can be mild or subclinical in mother. - Impact on fetus: Transplacental transmission → fetal loss (miscarriage/stillbirth), preterm labour, early-onset sepsis, granulomatosis infantiseptica (disseminated granulomas with microabscesses in liver, spleen, lungs, brain). - Neonatal listeriosis: Two patterns: - Early-onset (<5 days): Severe sepsis, pneumonia, respiratory distress. High mortality (20–50%). Gram-positive bacilli seen on neonatal gastric aspirate. - Late-onset (5 days–3 weeks): Meningitis. Lower mortality.

Food Sources: - Unpasteurised dairy products (soft cheeses: brie, camembert, blue cheese, feta). - Ready-to-eat meats (deli meats, pâté, hot dogs). - Cold smoked fish. - Pre-prepared coleslaws, salads. - Advice in pregnancy: Avoid high-risk foods. Reheat all leftovers until steaming hot.

Treatment: - IV Ampicillin + Gentamicin (synergistic, bactericidal). - Penicillin-allergic: IV trimethoprim-sulfamethoxazole (co-trimoxazole) or IV erythromycin. - Duration: 14–21 days (≥14 days for bacteraemia, ≥21 days for meningitis).

Prevention: Food hygiene advice to all pregnant women as part of antenatal care.

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1.14 Mycoplasma genitalium

Microbiology: - Smallest self-replicating bacterium (~0.2 µm). - No cell wall (therefore: no Gram stain reaction; β-lactams ineffective). - Obligate intracellular parasite. - Flask-shaped with terminal tip (adhesion organelle). - Extremely fastidious — one of the hardest bacteria to culture (weeks to months).

Clinical Significance: - Emerging cause of non-gonococcal urethritis (NGU) in men. - Cervicitis, PID, endometritis in women. - Subfertility — association with tubal factor infertility. - Preterm birth — emerging evidence of association.

Diagnosis: NAAT (multiplex PCR for STI panels). Culture not routinely available.

Treatment: - Increasing resistance to azithromycin (macrolide resistance >50% in some regions). - First-line: Doxycycline 100 mg PO BD for 7 days (reduces bacterial load) → THEN Azithromycin 1 g day 1, then 500 mg days 2–4 (extended course). - If macrolide-resistant: Moxifloxacin 400 mg PO daily for 7–14 days. (Not first-line due to tendonopathy/QTc prolongation risk.) - Pregnancy: No clearly safe/effective regimen. Azithromycin (extended course) if susceptible. Doxycycline and moxifloxacin contraindicated. Refer to specialist.

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1.15 Ureaplasma urealyticum

Microbiology: - No cell wall (like Mycoplasma). - Hydrolyses urea to generate ATP (unique — contains urease enzyme). This distinguishes it from Mycoplasma. - Tiny colonies ("fried egg" appearance on agar). - Part of normal genital flora in many women (40–80% colonised).

Clinical Significance (Controversial): - Chorioamnionitis: Can cause subclinical infection → preterm labour, PPROM. - Neonatal lung disease: U. urealyticum colonisation of preterm neonates is associated with chronic lung disease (bronchopulmonary dysplasia). Also neonatal pneumonia, meningitis (especially in very low birth weight infants). - NGU: Minor cause in men. - Infertility: Weak association. - Role in adverse pregnancy outcomes is debated — many colonised women have normal pregnancies.

Treatment: - Doxycycline (non-pregnant), Azithromycin, Erythromycin. - Pregnancy: Erythromycin (safe but GI side effects), azithromycin. - Clarithromycin preferred in neonates.

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2. VIRAL PATHOGENS IN OBSTETRICS & GYNAECOLOGY

2.1 Herpes Simplex Virus (HSV-1 & HSV-2)

Virology: - DS DNA virus, enveloped. - Herpesviridae family — shares with VZV, CMV, EBV, HHV-6/7/8. - HSV-1: Typically orolabial; HSV-2: Typically genital. But increasing overlap (HSV-1 now causes ~50% of first-episode genital herpes in the UK). - Latency: HSV establishes lifelong latent infection in sensory ganglia (trigeminal for oral, dorsal root ganglia S2-S4 for genital). Reactivation triggers: stress, illness, immunosuppression, UV light, menstruation.

Clinical Features: - Primary infection: More severe. Vesicles on erythematous base → painful ulcers. Fever, myalgia, lymphadenopathy. Viral shedding 12–24 days. Duration 2–3 weeks. - Recurrent infection: Shorter, milder. Prodrome (tingling, burning). Shedding 3–5 days.

HSV in Pregnancy: - Neonatal herpes: Devastating. Incidence ~1 in 60,000 births (UK). 60% mortality with disseminated disease; high neurological morbidity in survivors. - Transmission routes: - Intrauterine (5%): Transplacental → congenital HSV. Features: skin lesions/scarring, chorioretinitis, microcephaly, IUGR. - Peripartum (85%): Exposure to HSV in genital tract during vaginal delivery → neonatal herpes. - Postnatal (10%): Oral HSV-1 from parents/carers (cold sores). - Highest risk: Primary HSV in third trimester (30–50% neonatal transmission) due to no protective maternal antibodies crossing placenta. Recurrent disease: <1% transmission.

Management in Pregnancy:

Scenario	Management
Primary HSV (any trimester)	Oral aciclovir 400 mg TDS × 5–10 days (or valaciclovir). Reduces duration, severity, viral shedding.
Primary HSV in 3rd trimester	Suppressive aciclovir 400 mg TDS from 36 weeks → delivery. Elective C-section at term (before ROM or within 4 hours of ROM).
Recurrent HSV in pregnancy	Suppressive aciclovir from 36 weeks reduces outbreaks and need for C-section.
Recurrent lesion at term	If active lesions or prodrome → elective C-section. If no lesions, vaginal delivery is safe.
Baby born to mother with active lesion	Paediatric review. Consider IV aciclovir if signs. Avoid scalp electrodes/fetal blood sampling if active infection.

Aciclovir in Pregnancy: - Safe in pregnancy (no teratogenicity in registries). - Penetrates placenta. Secreted in breast milk (safe).

Neonatal Herpes Types: 1. Skin/eye/mouth (SEM) — 45%: Localised vesicles, keratitis. Good prognosis if treated. 2. CNS (30%): Encephalitis, seizures. High morbidity. 3. Disseminated (25%): Hepatitis, pneumonitis, DIC. 60% mortality.

Treatment: IV aciclovir 20 mg/kg TDS for 14–21 days.

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2.2 Varicella Zoster Virus (VZV)

Virology: - DS DNA virus, enveloped (Herpesviridae). - Pathogen of primary varicella infection (chickenpox) and secondary reactivation (herpes zoster/shingles). - Infectivity: Very high (>90% in susceptible contacts). Airborne transmission (droplet + aerosol).

Chickenpox in Pregnancy: - Incidence: ~3/1000 pregnancies in UK (most women immune). - Increased severity in pregnancy: Higher risk of varicella pneumonia (most common cause of VZV-related maternal death). Mortality 10–40% in pregnancy vs <1% in non-pregnant adults. - Other complications: Hepatitis, encephalitis, haemorrhagic varicella.

Fetal Effects:

1. Congenital Varicella Syndrome (CVS) — <20 weeks:
2. Risk ~0.4–2% in first 20 weeks (highest 8–20 weeks).
3. Features: Skin scarring (cicatricial lesions in dermatomal distribution), limb hypoplasia (muscular atrophy, syndactyly), eye defects (chorioretinitis, cataracts, microphthalmia), CNS (microcephaly, mental retardation, hydrocephalus), GI/GU abnormalities.
4. Diagnosis: Prenatal USS (limb defects, hydrops, microcephaly), PCR on amniotic fluid (controversial — risk of fetal loss ~1%).

5. Proruptive: Aciclovir may reduce risk if given early.

6. Neonatal Varicella — peripartum (day –7 to day +7 from delivery):

7. Most severe form: Maternal chickenpox from 5 days before to 2 days after delivery.
8. Baby born before protective maternal IgG crosses placenta.
9. Disseminated neonatal varicella — high mortality (20–30%).
10. Management: VZIG (Varicella Zoster Immunoglobulin) as soon as possible after birth + IV aciclovir.

Prevention & Management:

Scenario	Action
Pregnant woman with chickenpox exposure, no history of varicella/chickenpox	Check VZV IgG urgently. If IgG-negative, give VZIG within 10 days of exposure (ideally <96 h). VZIG attenuates but does not prevent infection.
Pregnant woman develops chickenpox	Oral aciclovir 800 mg 5×/day for 7 days if <24 h rash onset (reduces maternal complications). Admit if respiratory symptoms.
Varicella pneumonia	IV aciclovir 10 mg/kg TDS. High-dependency care.
Labour within 7 days of onset	Consider elective C-section if active lesions in genital area. Delay delivery if possible to allow VZIG/aciclovir.

VZIG (Varicella Zoster Immunoglobulin): - Human pooled immunoglobulin with high VZV antibody titre. - Indications: Pregnant VZV IgG-negative women with significant exposure (face-to-face contact with infectious case >15 min, same room >15 min, next bed in hospital). - Given IM. Does not prevent infection but reduces severity. - Available from UKHSA/Blood Transfusion Service.

Shingles in Pregnancy: - Reactivation of VZV from dorsal root ganglia. - Localised, dermatomal, painful vesicular rash. - Minimal fetal risk if shingles (maternal IgG already present). No CVS risk. - Treat with oral aciclovir. Avoid live-attenuated zoster vaccine (Zostavax — contraindicated in pregnancy). Recombinant vaccine (Shingrix) is non-live and can be given if needed (though not routinely recommended in pregnancy).

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2.3 Cytomegalovirus (CMV)

Virology: - DS DNA virus, enveloped (Herpesviridae). - Largest herpesvirus genome (~235 kb). - Most common congenital infection worldwide (0.3–2.3% of live births). - Latency in monocytes, macrophages, CD34+ stem cells. Reactivation under immunosuppression. - "Owl's eye" inclusion bodies on cytology.

Transmission: - Horizontal: Bodily fluids (urine, saliva, sexual contact, blood transfusion, organ transplant). - Vertical: Transplacental (most common), intrapartum (cervical shedding), postpartum (breast milk).

CMV in Pregnancy:

Type	Risk of Vertical Transmission	Fetal Severity
Primary maternal CMV	~30–40% overall (highest in 3rd trimester ~45–50%)	Most severe — 10–15% of infected neonates have symptomatic disease at birth
Recurrent/non-primary	~1–3%	Usually mild or asymptomatic

Congenital CMV: - Symptomatic at birth (10–15%): Petechiae/purpura ("blueberry muffin baby"), hepatosplenomegaly, jaundice, IUGR, microcephaly, chorioretinitis, pneumonitis, haemolytic anaemia, SNHL (sensorineural hearing loss). - Late sequelae: SNHL (most common — 50% of symptomatic, 5–15% of asymptomatic → progressive, can present months–years after birth), developmental delay, cerebral palsy, visual impairment, dental defects.

Diagnosis in Pregnancy: - Serology: CMV IgM + IgG avidity index. - Low IgG avidity (early infection): Recent primary. - High IgG avidity (mature): Past infection or >12–16 weeks ago. - Amniocentesis: CMV PCR on amniotic fluid (best after 21 weeks + >6 weeks post-primary). Sensitivity 70–80%. - Pre-conception counselling: No routine CMV screening in the UK (not recommended by UK NSC).

Management: - Prevention: Hand hygiene (wash after changing nappies, avoid sharing cups/cutlery, avoid kissing toddlers on the lips) — most effective intervention. Primary prevention counselling at booking. - Valganciclovir: 900 mg PO BD for maternal treatment of primary CMV. May reduce vertical transmission risk. Specialist use only. Side effects: neutropenia, thrombocytopenia. - IV hyperimmune globulin (CMVIG): Historically studied but no clear proven benefit (future trials ongoing). - Neonatal treatment: Valganciclovir 6 mg/kg BD for 6 months in symptomatic congenital CMV (improves hearing and neurodevelopmental outcomes).

Recurrent CMV: Risk of transmission is very low. No intervention routinely needed. Serial USS for fetal growth and anomalies.

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2.4 Rubella

Virology: - RNA virus (togavirus). Single-stranded, positive sense, enveloped. - "Minor rash, major defects" — classic teaching. - MMR vaccine (measles, mumps, rubella) — live attenuated. Contraindicated in pregnancy.

Clinical Features (Postnatal rubella): - Incubation 14–21 days. - Prodrome: fever, malaise, coryza, headache. - Maculopapular rash starting on face → trunk → limbs. Lasts 3 days. - Lymphadenopathy (suboccipital, postauricular, cervical — pathognomonic). - Arthralgia/arthritis (especially in women — 70%, can persist). - Mild and self-limiting in adults/children.

Rubella in Pregnancy: - Highest risk: Primary infection in first 16 weeks of pregnancy. - Congenital Rubella Syndrome (CRS): - <8 weeks: Risk of CRS ~85–90%. Multiple defects. - 9–12 weeks: ~50%. - 13–16 weeks: ~10–20% (mainly SNHL). - >20 weeks: Minimal/no risk (0–1%).

Congenital Rubella Syndrome Triad: 1. Congenital cataract (or microphthalmia). 2. Sensorineural deafness (most common single defect). 3. Patent ductus arteriosus (PDA) — also: pulmonary artery stenosis, septal defects. - Plus: IUGR, meningoencephalitis, microcephaly, "blueberry muffin" rash (dermal erythropoiesis), hepatitis, osteitis, thrombocytopenia, hepatosplenomegaly. - Late-onset: Diabetes mellitus, thyroid disorders, progressive panencephalitis (rare).

Screening & Prevention: - Rubella IgG check at booking (first antenatal visit). All pregnant women in UK are screened. - If non-immune: Counsel about avoiding exposure (stay away from children with rash). Offer MMR postpartum (after delivery, before discharge). Advise avoiding pregnancy for 1 month after MMR. - MMR is contraindicated in pregnancy (live vaccine — theoretical risk of fetal infection, though no cases of CRS from accidental vaccination reported). - If exposure in pregnancy: Check rubella IgG urgently. If non-immune and confirmed rubella in first 16 weeks → discuss termination of pregnancy. No antiviral treatment. No rubella immunoglobulin proven to prevent infection.

Elimination: Rubella and CRS declared eliminated in the UK (2015) thanks to MMR vaccination. However, imported cases still occur from countries without vaccination programmes.

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2.5 Parvovirus B19

Virology: - SS DNA virus. Smallest DNA virus known. - Parvoviridae family. - Targets erythroid progenitor cells (binds P antigen on RBCs → lytic infection). - Also known as "Slapped cheek" / Fifth disease / Erythema infectiosum.

Clinical Features: - Children: Mild febrile illness, "slapped cheek" rash (bright red cheeks), then lacy reticular rash on trunk/limbs. - Adults: Arthralgia/arthritis (especially in women — 80%), rash may be absent. - Aplastic crisis: In haemolytic anaemia patients (sickle cell, thalassaemia, hereditary spherocytosis) — sudden severe anaemia due to arrest of erythropoiesis. - Immunocompromised: Persistent infection → chronic anaemia.

Parvovirus B19 in Pregnancy: - Vertical transmission rate: ~30–50% after maternal infection. - Fetal effects depend on gestational age: - <20 weeks: Highest risk of hydrops fetalis (~3–10% of infected fetuses). Parvovirus B19 is the most common cause of non-immune hydrops fetalis in developed countries. - Mechanism of hydrops: Infection of fetal erythroid precursors → severe fetal anaemia → high-output cardiac failure → hydrops (generalised oedema, ascites, pleural effusion, pericardial effusion). - Miscarriage: Risk increased (but data variable). - >20 weeks: Risk of hydrops much lower. Isolated anaemia possible. - No known teratogenic effect (no structural defects).

Diagnosis: - Maternal: Parvovirus B19 IgM + IgG serology. IgM appears ~3 days post-symptoms, lasts 2–3 months. IgG appears ~7 days post-infection, persists for life. - Fetal: Serial USS monitoring for hydrops (first sign: increased MCA-PSV — middle cerebral artery peak systolic velocity >1.5 MoM indicates fetal anaemia). Amniocentesis for fetal PCR (not routinely done).

Management: - Maternal infection: No specific antiviral. - Fetal hydrops: Intrauterine transfusion (IUT) of RBCs via cordocentesis (umbilical vein). Survival >85% in treated hydropic fetuses. - Spontaneous resolution: Up to 30% of mild hydrops resolves without IUT. - Serial USS (weekly for 8–12 weeks after maternal infection) to monitor for hydrops. - No immunoglobulin/preventive therapy for exposed contacts.

Workplace: Pregnant healthcare workers are at risk if exposed to children with aplastic crisis (high viral load). Advise to avoid caring for patients with confirmed parvovirus B19 infection.

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2.6 Human Immunodeficiency Virus (HIV)

Virology: - RNA retrovirus (ssRNA + reverse transcriptase → dsDNA → integrates into host genome). - HIV-1 (pandemic, common worldwide) vs HIV-2 (West Africa, less virulent, slower progression). - Targets CD4+ T cells (and macrophages, dendritic cells) via gp120 binding to CD4 + co-receptors (CCR5, CXCR4). - Destroys CD4+ T cells → immunodeficiency → AIDS-defining illnesses. - Viral load (copies/mL) and CD4 count are key monitoring parameters.

Vertical Transmission (Mother-to-Child — MTCT): - Without intervention: 25–30% transmission rate. - With optimal intervention (cART, C-section, avoid breastfeeding): <1%.

Routes of Transmission: 1. Antepartum (intrauterine): 5–10%. Transplacental. Associated with high maternal viral load, low CD4. 2. Intrapartum (during labour/delivery): 60–70%. Exposure to maternal blood/genital secretions. 3. Postpartum (breastfeeding): 10–15%. Risk increases with duration of breastfeeding, high maternal viral load, mastitis.

Vertical Transmission Prevention:

Intervention	Effect
Combination ART (cART) in pregnancy	Viral load undetectable (<50 copies/mL) → <1% transmission
Elective CS at 38–39 weeks	Reduces intrapartum exposure. Indicated if viral load >1000 copies/mL at 36 weeks or unknown VL at delivery
Avoid breastfeeding	Eliminates post-natal transmission in well-resourced settings
Neonatal prophylaxis	Zidovudine (AZT) for 4 weeks (low-risk) or dual/triple ART (high-risk)
Avoid: scalp electrodes, fetal blood sampling, instrumental delivery unless urgently indicated	Reduces fetal exposure to maternal blood

cART in Pregnancy: - Goal: Viral load undetectable by delivery. - First-line regimens in pregnancy: - Tenofovir disoproxil fumarate (TDF) + Emtricitabine (FTC) + Dolutegravir (DTG) — preferred. Dolutegravir was previously associated with neural tube defects (NTD) in early pregnancy (Botswana study, 2018 — small increased risk). However, subsequent data show NTD risk is very low (<0.2%). BHIVA guidelines now recommend DTG throughout. - Alternatives: Darunavir/ritonavir + TDF/FTC. - Avoid: Efavirenz (first trimester neurodevelopmental concerns — though safe after), stavudine, didanosine. - Start ART as soon as possible (including first trimester). Do NOT delay for fear of teratogenicity — untreated HIV poses far greater risk to mother and fetus. - Test-and-treat: All pregnant women offered HIV testing at booking (opt-out screening). If positive → start ART same day.

Delivery: - Viral load <1000 copies/mL at 36 wks → vaginal delivery is safe (IV zidovudine infusion not needed). - Viral load 1000–10,000 → consider elective CS at 38–39 wks. - Viral load >10,000 or unknown → elective CS at 38 wks + IV AZT infusion. - Preterm rupture of membranes: If viral load undetectable, can wait for spontaneous labour (standard ROM management). If detectable → expedite delivery.

Neonatal Management: - Low-risk (maternal VL <50 at delivery, adherent): Zidovudine (AZT) monotherapy for 4 weeks. - High-risk (maternal VL >1000, no ART, preterm): Triple ART (AZT + lamivudine + nevirapine). - Avoid breastfeeding: Formula feeding recommended in the UK. - HIV PCR testing: At birth, 6 weeks, 12 weeks, and 18 months (antibody testing). Two negative PCRs off prophylaxis = uninfected.

PrEP & Pre-Exposure Prophylaxis: - PrEP: Tenofovir/emtricitabine (Truvada or generic). For HIV-negative pregnant women at high risk (serodiscordant couple, high-prevalence area). - Safe in pregnancy and breastfeeding. - PEP (Post-Exposure Prophylaxis): 28-day course of ART after potential exposure (e.g., needlestick, sexual assault in pregnancy). Start within 72 hours.

HIV in Non-Pregnant O&G: - Higher risk of cervical neoplasia (HPV co-infection). Annual cervical screening. - PID may present atypically (less pain, more tubo-ovarian abscess). - Menopause may occur earlier.

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2.7 Hepatitis B Virus (HBV)

Virology: - DS DNA virus (Hepadnaviridae). Partially double-stranded, enveloped. - HBsAg (surface antigen) — first marker of infection; vaccine antigen. - HBcAg (core antigen) — not measurable in blood; anti-HBc indicates past/current infection. - HBeAg (e antigen) — marker of active replication, high infectivity. - Viral DNA — direct measure of replication.

Serology Interpretation:

HBsAg	Anti-HBs	Anti-HBc	Interpretation
+	–	+ IgM	Acute infection
+	–	+ IgG	Chronic infection
–	+	+ IgG	Resolved infection (immunity)
–	+	–	Vaccinated (immunity)
–	–	–	Susceptible

Vertical Transmission: - High risk: HBeAg-positive, high viral DNA. - Transmission routes: - Intrapartum (90%): Exposure to maternal blood/genital secretions during delivery. This is preventable. - Intrauterine (5%): Transplacental (higher if acute hepatitis in pregnancy). - Postnatal (5%): Close contact. - Without prophylaxis: 70–90% of HBeAg-positive mothers transmit to baby; 10–40% of HBeAg-negative. - Chronicity: 90% of infected neonates become chronic carriers (vs 5% of adults).

Prevention of Vertical Transmission: 1. Antenatal screening: All pregnant women offered HBsAg testing at booking. If positive → check HBeAg and HBV DNA. 2. Antiviral therapy in pregnancy: Tenofovir disoproxil fumarate (TDF) 300 mg daily from 28–32 weeks if HBV DNA >200,000 IU/mL (or >6–8 log₁₀ copies/mL). Reduces viral load → reduces breakthrough transmission despite passive-active immunisation. 3. Immunoprophylaxis at birth (within 24 hours): - HBV vaccine (recombinant, 0.5 mL IM) — active. - HBIG (Hepatitis B Immunoglobulin) 200 IU IM — passive. - Given at different sites. Both within 24 hours of birth (ideally <12 h). 4. Completion of vaccine course: Doses at 1 month and 6–12 months. 5. Breastfeeding: Safe once baby immunised (no contraindication). Prophylaxis TDF in mother is safe.

Effectiveness: With full immunisation (vaccine + HBIG), transmission is <5%. Without HBIG, vaccine alone ~75% effective.

Acute Hepatitis B in Pregnancy: - Manage supportively. Tenofovir can be used if severe. - Higher risk of preterm delivery, low birth weight. - Needs urgent HBIG + vaccine for baby at birth.

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2.8 Hepatitis C Virus (HCV)

Virology: - RNA virus (Flaviviridae). Enveloped, single-stranded (+) RNA. - 6 major genotypes (Genotype 1 most common in UK/US, Genotype 3 in South Asia). - High mutation rate → evades immune system, no vaccine, no passive immunoglobulin.

HCV in Pregnancy: - Vertical transmission: ~5–10% (higher if co-infected with HIV ~20%, or high maternal viral load). - Timing: Usually intrapartum. Intrauterine rare. - No specific antenatal intervention to reduce transmission. C-section does NOT reduce risk (different from HIV/HBV). Therefore vaginal delivery is safe. - Breastfeeding: Considered safe (no evidence of transmission via breast milk). Avoid if cracked/bleeding nipples.

Screening: - Risk-based screening in UK (not universal). Offer to: IVDU, blood transfusion before 1991, from high-prevalence country, HIV-positive, partner with HCV, multiple piercings/tattoos. - Anti-HCV antibody → confirm with HCV RNA PCR.

Treatment: - DO NOT treat with ribavirin in pregnancy (contraindicated — teratogenic, embryocidal). - DO NOT treat with direct-acting antivirals (DAAs) in pregnancy (insufficient safety data). DAAs are avoided in pregnancy. - Treat after delivery: DAA combinations (sofosbuvir/velpatasvir, glecaprevir/pibrentasvir) cure >95%. - Monitor: Liver function, HCV RNA, USS for hepatocellular carcinoma if cirrhotic.

Congenital HCV: - Baby will have passive maternal anti-HCV (clears by 12–18 months). - HCV RNA PCR at 2–3 months (or anti-HCV at 18 months) for diagnosis. - Most children spontaneously clear HCV. - No specific treatment in infancy unless progressive disease.

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2.9 SARS-CoV-2 / COVID-19 in Pregnancy

Virology: - RNA virus (Coronaviridae). ssRNA (+) sense, enveloped, ~30 kb genome. - Spike (S) protein binds to ACE2 receptor on host cells → TMPRSS2-mediated entry. - Variants of concern: Alpha, Delta, Omicron (and sub-lineages).

COVID-19 in Pregnancy: - Pregnant women are at increased risk of severe COVID-19 compared to non-pregnant women of the same age (especially in third trimester). - Increased ICU admission, need for ventilation, preterm birth, pre-eclampsia-like syndrome. - Vertical transmission: Possible but uncommon (~2% of neonates test positive). May be transplacental or intrapartum. No evidence of congenital anomalies. - Neonatal outcomes: Increased preterm birth (iatrogenic), lower birth weight. Most infected neonates are asymptomatic or mild.

Vaccination: - COVID-19 vaccines (mRNA: Pfizer/BioNTech, Moderna; Viral vector: AstraZeneca) are recommended in pregnancy. No safety concerns identified. All major UK and international societies (RCOG, ACOG, WHO) recommend vaccination or booster in pregnancy. - Highest uptake and earliest vaccination recommended — third trimester is NOT too late; it maximises neonatal passive antibody transfer. - No evidence of fertility impairment from COVID-19 vaccines.

Management of COVID-19 in Pregnancy: - Mild: Symptomatic management, self-isolation. - Moderate-severe: Admit, monitor oxygen saturations, multidisciplinary care (obstetric + medical + critical care). - Dexamethasone 6 mg daily for 10 days (or until discharge) for oxygen requirement (same as non-pregnant — ARDS protocol). - Remdesivir (IV antiviral): Authorised for use in pregnancy if clinical need. - Corticosteroids for fetal lung maturity: Betamethasone can be given if preterm delivery risk (22–35+6 weeks). Do NOT withhold because of COVID-19 — benefits outweigh risks. - Mode of delivery: Based on obstetric indications, not COVID-19 status alone. Vaginal delivery is safe. C-section reserved for obstetric indications + respiratory compromise needing ICU.

Post-COVID condition (Long COVID): Affects women of reproductive age. Management is supportive and multidisciplinary.

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2.10 Zika Virus

Virology: - RNA virus (Flaviviridae). Enveloped, ssRNA (+). - Transmitted by Aedes aegypti and Aedes albopictus mosquitoes. - Also sexual transmission (male to female, female to male), vertical transmission, blood transfusion.

Clinical Features: - 80% asymptomatic. Symptomatic: mild fever, maculopapular rash, arthralgia, conjunctivitis, headache. - Self-limiting (2–7 days). No specific antiviral.

Zika in Pregnancy — Congenital Zika Syndrome (CZS): - Microcephaly (most striking feature — severe, with partial skull collapse). - Intracranial calcifications (periventricular, parenchymal), ventriculomegaly, brain atrophy, lissencephaly, pachygyria. - Ocular abnormalities (chorioretinal atrophy, optic nerve hypoplasia). - Arthrogryposis (joint contractures due to neurological damage). - IUGR, fetal loss. - Risk: Highest in first trimester (~1–5%) but also second/third. - Pathophysiology: ZIKV is neurotropic, infects neural progenitor cells, causes cell death and disrupted neurogenesis.

Management: - Travel advice: All pregnant women should avoid travel to Zika-affected areas. If unavoidable, strict mosquito bite prevention (DEET, long sleeves, mosquito nets, screens, air conditioning). - Screening: Not routine in UK. Consider if symptomatic or exposure. - Diagnosis: RT-PCR on serum/urine (within 14 days of symptoms). IgM after. - Pregnant women with confirmed Zika: Serial USS at 3–4 weekly intervals for fetal growth and brain anatomy. Amniocentesis for Zika PCR (limited utility). - No specific treatment. No vaccine yet (several in development).

Sexual transmission prevention: Condoms for 3 months (male) or 2 months (female) after return from endemic area, even if asymptomatic.

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2.11 Human Papillomavirus (HPV)

Virology: - DS DNA virus (Papillomaviridae). ~55 nm, non-enveloped (resistant to heat/desiccation). - Capsid proteins: L1 (major), L2 (minor). E6, E7 (early oncoproteins). - >200 types classified as: - Low-risk (LR): 6, 11 — cause genital warts (condylomata acuminata). Rarely cancer. - High-risk (HR): 16, 18 (cause 70% of cervical cancer), 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68 — cause cervical, anal, vulvar, vaginal, penile, oropharyngeal cancers.

Clinical Significance in O&G: - Genital warts: HPV 6 & 11. Cauliflower-like lesions. Can grow rapidly in pregnancy (hormonal influence). Treatment: cryotherapy, trichloroacetic acid, topical imiquimod (safe in pregnancy?), surgical excision. Regress postpartum. Podophyllin CONTRAINDICATED in pregnancy. - Cervical cancer: Persistent HR HPV infection → CIN → invasive cancer. HPV 16 & 18 account for ~70% of cervical cancers worldwide. - Abnormal cervical screening in pregnancy: Manage with colposcopy. Biopsy if suspicious (limited — risk of bleeding). Defer treatment until postpartum. Repeat smear at 12 weeks postnatal.

HPV Vaccines: - Gardasil 9 (9-valent): Covers HPV 6, 11, 16, 18, 31, 33, 45, 52, 58. Given as 2-dose schedule (9–14 years) or 3-dose (≥15 years). - Cervarix (bivalent): HPV 16, 18 — no longer used in UK NHS programme (replaced by Gardasil 9 from 2022). - Vaccination in pregnancy: Not recommended (insufficient data). If inadvertently given, no harm found. Complete schedule after delivery. - Vaccination postpartum: Safe in breastfeeding. - Efficacy: >90% reduction in cervical cancer (from HPV 16/18). NHSCSP data confirms significant reduction in CIN3 in vaccinated cohorts.

Vertical transmission: Rare (<1%) — HPV can be transmitted to neonate via vaginal delivery. Usually clears spontaneously. Rarely → juvenile-onset recurrent respiratory papillomatosis (RRP — HPV 6/11 in larynx). This is extremely rare. C-section not indicated to prevent RRP.

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3. FUNGAL PATHOGENS

3.1 Candida Species

Microbiology: - Yeast (dimorphic — can form pseudohyphae/hyphae in tissue). - Candida albicans — most common (80–90% of vulvovaginal candidiasis, VVC). - C. glabrata — second most common (azole-resistant). - C. parapsilosis, C. tropicalis, C. krusei. - Normal commensal of GI tract, vagina (20–30% of women asymptomatic carriers).

Vulvovaginal Candidiasis (VVC): - Symptoms: Pruritus (itching), burning, thick white "cottage cheese" discharge, vulval erythema, dyspareunia, dysuria. - Triggers: Pregnancy, antibiotics, diabetes, immunosuppression, oral contraceptives (oestrogen promotes adherence), tight synthetic clothing. - Diagnosis: Wet mount (KOH preparation) → pseudohyphae, budding yeasts. Culture (Sabouraud agar) for species identification.

Treatment: - Uncomplicated VVC: Clotrimazole 500 mg vaginal pessary single dose (or 1% cream × 6 days). Oral fluconazole 150 mg single dose. - Pregnancy: Avoid oral fluconazole (linked to spontaneous miscarriage at low doses, and rare cardiac/seletal anomalies with high-dose long-term use). Use intravaginal clotrimazole (pessary/cream) — safe in pregnancy. - Recurrent VVC (≥4 episodes/year): Induction (clotrimazole × 14 days or fluconazole 150 mg 72-hourly × 3 doses) then maintenance (fluconazole 150 mg weekly × 6 months). Check for diabetes, HIV. - Candida glabrata: Often azole-resistant. Treat with intravaginal boric acid (600 mg daily × 14 days) or amphotericin B suppositories.

Neonatal Thrush: - Oral candidiasis in neonates (white patches on oral mucosa, difficult to wipe off). Treat with nystatin oral suspension or miconazole gel. - Avoid oral fluconazole in term and late preterm neonates unless refractory. - Risk factors: Vaginal candidiasis at delivery, prolonged antibiotic therapy, prematurity, immunodeficiency.

PCP (Pneumocystis jirovecii pneumonia): - Formerly P. carinii, reclassified as a fungus (genetically, but behaves like a protozoan). - Opportunistic infection in immunocompromised (HIV with CD4 <200, organ transplant, long-term steroids). - Pregnancy: PCP can present in late pregnancy with profound hypoxia. Treat with high-dose trimethoprim-sulfamethoxazole (co-trimoxazole). Prophylaxis if CD4 <200 in HIV+ pregnant women. - P. jirovecii is not responsive to standard antifungal therapies (triazoles, amphotericin).

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3.2 Dermatophyte Infections (Tinea)

• Tinea cruris: "Jock itch" — fungal groin infection. Pruritic annular plaques. Causative: Trichophyton rubrum, Epidermophyton floccosum.
• Treatment: Topical terbinafine, clotrimazole. If severe: oral terbinafine or itraconazole (avoid in pregnancy — teratogenic).
• Tinea corporis (ringworm), Tinea pedis (athlete's foot). All treated topically.

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4. PARASITIC INFECTIONS

4.1 Trichomonas vaginalis

Microbiology: - Flagellate protozoan (~10 × 7 µm). No cyst form — only trophozoite. - Pear-shaped, amoeboid motility (j jerky/tumbling movement), 4–6 flagella + undulating membrane. - Not a normal commensal — when found, is pathogenic.

Clinical Features: - Women (50% symptomatic): Profuse frothy, yellowish-green, malodorous discharge, vulvovaginal pruritus, dysuria, dyspareunia. - Strawberry cervix (colpitis macularis) — punctate haemorrhages on cervix. Pathognomonic but only seen in 2–5%. - Men (usually asymptomatic): Mild urethritis, prostatitis. - Associated with: Preterm birth, PROM, low birth weight, postpartum endometritis. - Increased HIV susceptibility (mucosal inflammation).

Diagnosis: - Wet mount (saline microscopy): Motile flagellates — immediate diagnosis (sensitivity ~60–70%). - NAAT: Gold standard — high sensitivity (>95%). Can be done on vaginal swab, urine. - Culture (Diamond's medium): Still used for medicolegal/resistance testing.

Treatment: - Metronidazole 400–500 mg PO BD × 5–7 days (or 2 g single dose — less effective). - Pregnancy: Metronidazole is safe in pregnancy (all trimesters). Treat to reduce symptoms and prevent adverse pregnancy outcomes. The 2 g single dose is often used to improve adherence, though the multi-day regimen may be more effective. - Alcohol: No alcohol while taking metronidazole + 48 hours after (disulfiram-like reaction). - Partner treatment: Essential. Treat all sexual partners within preceding 6 weeks. - Tinidazole: 2 g single dose — alternative (also safe in pregnancy, but less safety data than metronidazole).

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4.2 Toxoplasma gondii

Microbiology: - Obligate intracellular protozoan (Apicomplexa). - Definitive host: Domestic cats (and other felidae) — only cats shed oocysts in faeces. - Intermediate hosts: Humans, sheep, cattle, birds, rodents. - Life cycle forms: 1. Oocyst (from cat faeces → ingested by intermediate host). 2. Tachyzoite (rapidly dividing, active infection — found in acute phase). 3. Bradyzoite (slowly dividing, in tissue cysts — latent/chronic infection in muscle, brain, retina).

Transmission to Humans: - Ingestion of oocysts: Contact with cat litter, contaminated soil (gardening without gloves), contaminated raw vegetables. - Ingestion of bradyzoites: Eating undercooked/raw meat containing tissue cysts (lamb, pork, game). - Vertical (congenital): Transplacental transmission of tachyzoites from pregnant woman to fetus.

Toxoplasmosis in Pregnancy: - Primary infection in pregnancy: Usually asymptomatic (80–90%). Some develop: lymphadenopathy (cervical, suboccipital — non-tender), fever, malaise, myalgia. - Vertical transmission risk: - Before conception: Minimal (if infected >3 months before conception, fetal immunity protects). - First trimester: 10–25% transmission; but most severe fetal disease. - Second trimester: 25–50% transmission. - Third trimester: 50–80% transmission; but 80-90% of infected infants asymptomatic at birth.

Congenital Toxoplasmosis:

Classic Triad (Sabin's triad)
1. Chorioretinitis (bilateral, posterior pole)
2. Hydrocephalus (or microcephaly)
3. Intracranial calcifications (diffuse, scattered)

Other features: Seizures, developmental delay, hepatosplenomegaly, jaundice, rash, fever, pneumonitis, thrombocytopenia.

Diagnosis in Pregnancy: - Serology: Toxoplasma IgM + IgG. - Negative IgM + negative IgG → susceptible. - Positive IgM + positive IgG → acute/recent infection (check IgG avidity — low avidity = recent). - Negative IgM + positive IgG → past infection (immune). - Amniocentesis: PCR for Toxoplasma gondii DNA in amniotic fluid (>18 weeks, >4 weeks after acute infection). - Ultrasound: hydrocephalus, intracranial calcifications, hepatosplenomegaly, IUGR, ascites, placental thickening.

Treatment in Pregnancy:

Indication	Treatment
Confirmed acute toxoplasmosis in pregnancy (first 18 weeks)	Spiramycin 1 g TDS PO (macrolide antibiotic). Reduces vertical transmission by 50–60%. Does NOT treat established fetal infection.
Fetal infection confirmed (amniotic PCR +) or infection acquired >18 weeks	Pyrimethamine + Sulfadiazine + Folinic acid (leucovorin). More effective at treating fetal infection.
Fetal infection with severe features on USS	Consider termination of pregnancy after counselling.

• Spiramycin: Available from specialist centres (imported in UK). Safe in pregnancy.
• Pyrimethamine: Teratogenic in first trimester — avoid before 18 weeks. Contraindicated only in first trimester. Supplement with folinic acid to prevent bone marrow suppression.

Prevention: Advise pregnant women: - Avoid raw/undercooked meat. - Wash hands thoroughly after handling raw meat. - Wear gloves when gardening. - Avoid changing cat litter (or wear gloves + wash hands). - Wash fruit/vegetables thoroughly. - Avoid feeding cats raw meat.

Screening in Pregnancy: - NOT routine in the UK (low incidence ~2/1000). - Offered in some European countries (France, Austria) with high prevalence.

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4.3 Malaria (Plasmodium species)

Microbiology: - Apicomplexan protozoan. - Species causing human disease: - P. falciparum — most severe. High parasitaemia. Cerebral malaria, severe anaemia, multi-organ failure. Dominant in sub-Saharan Africa. - P. vivax — hypnozoite stage (relapse). Common in Asia, Latin America. - P. ovale — hypnozoite stage. West Africa. - P. malariae — causes nephrotic syndrome. - P. knowlesi — zoonotic (macaque), SE Asia.

Life Cycle: - Anopheles mosquito injects sporozoites → liver (hepatocytes) → exo-erythrocytic schizogony → merozoites → RBCs (erythrocytic schizogony) → gametocytes → mosquito.

Malaria in Pregnancy: - Pregnant women are more susceptible to malaria (partially due to immunological changes). - Highest risk: Primigravidae, teenage pregnancies, first half of pregnancy (before immunity develops). - Mechanisms: - Placental malaria: P. falciparum expresses VAR2CSA protein which binds to chondroitin sulphate A (CSA) on placental syncytiotrophoblast → sequestration of infected RBCs in placental intervillous spaces → placental inflammation, impaired nutrient/oxygen transfer.

Maternal Effects: - Severe anaemia (haemolysis + dyserythropoiesis + folate deficiency). - High parasitaemia, cerebral malaria, ARDS. - Increased mortality than non-pregnant women.

Fetal Effects: - Miscarriage, stillbirth. - Intrauterine growth restriction (IUGR) / low birth weight. - Preterm delivery. - Congenital malaria (rare — 1–4% of deliveries, presents at 2–8 weeks of life with fever, anaemia, hepatosplenomegaly).

Prevention in Pregnancy (in endemic areas): - Intermittent Preventive Treatment in Pregnancy (IPTp): Sulfadoxine-pyrimethamine (SP/Fansidar) — 3 doses in second and third trimester (at least 1 month apart). Safe in pregnancy. Reduces maternal anaemia, placental malaria, LBW. - Contraindicated in first trimester (can cause kernicterus in G6PD-deficient neonates? — actually SP is avoided only due to theoretical risk of neural tube defects from folate antagonism; most guidelines now consider it safe in 2nd/3rd trimester). - Insecticide-treated bed nets (ITNs). - Avoid mosquito bites: DEET-containing repellent, long sleeves, mosquito coils.

Treatment in Pregnancy: - Uncomplicated P. falciparum malaria: - First trimester: Quinine + Clindamycin (7 days). Avoid artemisinin derivatives (limited safety data in first trimester — animal studies show embryotoxic at high doses; however, WHO now recommends artemisinin-based combination therapy [ACT] for all trimesters including first, as the risk of severe malaria outweighs theoretical risk). - Second/third trimester: Artemether-Lumefantrine (Coartem) — safe and effective. Alternatives: Quinine + Clindamycin. - Severe malaria (any trimester): IV Artesunate* (superior to quinine — reduces mortality by 30% in adults). Switch to oral ACT when tolerated. - P. vivax / P. ovale: Treat acute infection with ACT (or chloroquine if sensitive). Primaquine (for hypnozoite eradication) is contraindicated in pregnancy* (G6PD-haemolysis risk). Postpone radical cure until after delivery and avoid breastfeeding (or check G6PD first). Consider chloroquine prophylaxis for rest of pregnancy.

Key drugs in pregnancy: - Safe: Chloroquine, Quinine, Artemether-Lumefantrine, Artesunate (IV for severe), Sulfadoxine-Pyrimethamine (IPTp), Clindamycin. - Contraindicated: Doxycycline, Primaquine, Tetracycline, Halofantrine (cardiotoxic).

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5. SEXUALLY TRANSMITTED INFECTIONS (STIs)

5.1 Comprehensive Screening Approach

Booking Antenatal Screen (UK — all offered): - HIV (opt-out). - Syphilis (TPPA/VDRL). - Chlamydia (if <25 years or risk factors — varies by area). - Hepatitis B (HBsAg). - Hepatitis C (risk-based). - Rubella IgG (part of antenatal infection screen).

STI Screen in Sexual Health Clinic (any stage in pregnancy): - Chlamydia trachomatis — NAAT. - Neisseria gonorrhoeae — NAAT + culture (for resistance). - Trichomonas vaginalis — NAAT or wet mount. - HIV antigen/antibody (fourth-generation test — detects p24 antigen + anti-HIV-1/2). - Syphilis serology. - Mycoplasma genitalium — NAAT (if symptoms/indication). - HSV PCR (if lesions present). - HBV/HCV serology (if not done).

Annual Screening Recommendations (Non-pregnant): - Under 25: Annual chlamydia screen (National Chlamydia Screening Programme in UK). - HIV, Syphilis: Annually in sexually active individuals at risk. - HPV: Cervical screening (3–5 yearly depending on age).

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5.2 Effect of STIs on Pregnancy Outcomes

STI	Effect on Pregnancy
Chlamydia	Preterm labour, PROM, LBW, ophthalmia neonatorum, neonatal pneumonia
Gonorrhoea	Preterm labour, PROM, chorioamnionitis, ophthalmia neonatorum, disseminated infection
Syphilis	Congenital syphilis, stillbirth, preterm birth, LBW
Trichomoniasis	Preterm birth, PROM, LBW
HSV	Neonatal herpes (severe)
HIV	Vertical transmission (preventable)
Hepatitis B	Vertical transmission (preventable)
HPV	Genital warts (may grow rapidly in pregnancy), rarely RRP
BV (not strictly STI)	Preterm birth, mid-trimester loss

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5.3 Contact Tracing Principles

• Partner notification is a key public health intervention.
• Done by the index patient (patient referral), healthcare provider (provider referral), or health advisor (third-party referral).
• Time frame for partner tracing:
• Chlamydia: Partners within 6 months.
• Gonorrhoea: Partners within 3 months.
• Syphilis: Primary — 3 months; Secondary — 6–12 months; Early latent — 5 years.
• HIV: As far back as index can recall or last negative test.
• Trichomonas: Partners within 6 weeks.
• Epidemiological treatment: Partners treated empirically before test results (especially for chlamydia, gonorrhoea, syphilis).
• Chaperone and treat for under-16s and vulnerable persons.

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6. SURGICAL SITE INFECTIONS & PUERPERAL SEPSIS

6.1 Surgical Site Infections (SSI)

Definition (CDC): Infection occurring within 30 days of surgery (or up to 1 year if implant) and involving: 1. Superficial incisional — skin/subcutaneous only. 2. Deep incisional — deep soft tissues (fascia, muscle). 3. Organ/space — any organ/space opened during surgery (e.g., uterus, peritoneal cavity, vagina).

Common Organisms in Gynaecological Surgery: - Gram-negative aerobes: E. coli, Klebsiella, Proteus. - Anaerobes: Bacteroides fragilis, Peptostreptococcus, Clostridium. - Gram-positive: Enterococcus faecalis, Group B Streptococcus, Staphylococcus aureus (including MRSA). - Skin flora: S. epidermidis (coagulase-negative staphylococci — especially with implants).

Prevention Strategies: 1. Antibiotic prophylaxis: - C-section: Single dose before skin incision (e.g., cefazolin 2 g IV + azithromycin if ROM/preterm). Reduces SSI by 60%. Repeat dose if >150 minutes or blood loss >1500 mL. - Hysterectomy (vaginal/abdominal/LH): Single dose cefazolin 2 g IV (or co-amoxiclav). If penicillin-allergic → clindamycin + gentamicin. 2. Skin preparation: 2% chlorhexidine in 70% alcohol (superior to povidone-iodine). 3. Normothermia (active warming during surgery). 4. Glycaemic control (maintain blood glucose <10 mmol/L). 5. Oxygenation: Maintain SpO₂ >95%, consider high FiO₂. 6. Hair removal: Clippers (not razors — micro-abrasions increase infection). 7. Surgical technique: Gentle tissue handling, haemostasis, minimal dead space.

Management of SSI: - Superficial: Wound swab, open and drain, antibiotics only if cellulitis. - Deep/Organ space: CT/USS to localise collection, percutaneous drainage or surgical re-exploration, IV broad-spectrum antibiotics (e.g., piperacillin-tazobactam or meropenem + vancomycin if MRSA risk).

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6.2 Puerperal Sepsis

Definition: Sepsis arising from the genital tract during pregnancy, labour, or up to 42 days postpartum.

Epidemiology: - Leading cause of maternal death globally (WHO). In the UK, sepsis accounts for ~10–15% of direct maternal deaths (MBRRACE-UK). - Preventable with early recognition and treatment.

Causative Organisms — "The Sixes" (mnemonic): 1. Group A Streptococcus (S. pyogenes) 2. Group B Streptococcus (S. agalactiae) 3. E. coli 4. C. perfringens (and other clostridia) 5. S. aureus 6. Bacteroides (and other anaerobes)

Also: Listeria, Mycoplasma, Ureaplasma, Klebsiella, Pseudomonas.

Risk Factors: - C-section (5–20× increased risk vs vaginal delivery). - Prolonged ROM, chorioamnionitis. - Multiple vaginal examinations in labour. - Retained products of conception. - Wound haematoma/infection. - Immunosuppression, diabetes, obesity. - Inadequate antibiotic prophylaxis.

Diagnosis:

Sepsis in Pregnancy — Modified qSOFA (quick SOFA): - Respiratory rate ≥22/min - Systolic BP ≤90 mmHg - GCS <15 (or altered mentation) - ≥2 criteria → check lactate and escalate.

Early Warning Scores: - MEOWS (Modified Early Obstetric Warning System) — tracks HR, BP, RR, temperature, SpO₂, consciousness, urine output. - Rising MEOWS is a red flag. - Don't underestimate tachycardia: Physiological increase in pregnancy means HR >100 is abnormal; >120 is concerning.

Sepsis Six (1-hour bundle): 1. Give high-flow oxygen — target SpO₂ ≥94%. 2. Take blood cultures. 3. IV antibiotics (within 1 hour of recognition). 4. Check lactate (venous or arterial). 5. Measure urine output (catheterise). 6. IV fluids — give 30 mL/kg crystalloid if hypotensive/lactate >2 mmol/L.

Antibiotic Regimens for Puerperal Sepsis: - Community-acquired / mild-moderate: Co-amoxiclav 1.2 g IV TDS + Gentamicin (5–7 mg/kg IV once daily). - Hospital-acquired / severe / MRSA risk: Piperacillin-tazobactam 4.5 g IV QDS + Gentamicin. Add vancomycin (or teicoplanin) if MRSA suspected. - Penicillin allergy: Clindamycin 900 mg IV QDS + Gentamicin + Ciprofloxacin 400 mg IV BD (or aztreonam 2 g IV TDS if severe). - Group A Strep suspected (toxic shock): Add Clindamycin 900 mg IV QDS (toxin suppression) + high-dose benzylpenicillin 2.4 g IV 4-hourly. - Necrotising fasciitis: Emergency surgical debridement + antibiotics as above + ICU.

Definitive treatment: Source control — identify and treat the source. May require: - Removal of retained products (evacuation/ERPC). - Drainage of wound abscess. - Laparotomy, hysterectomy (for clostridial or group A strep with uterine necrosis/abscess).

"Why" puerperal sepsis is so dangerous: - Uterus is a large, highly vascular, and necrotic post-delivery wound — ideal culture medium for bacteria. - Reduced immune surveillance (Th2 shift, lymphocyte suppression in pregnancy). - Facilitating factors: lochia, blood clots, retained products, trauma from delivery.

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7. VAGINAL MICROBIOME

7.1 Normal Vaginal Flora

• Lactobacillus dominance: L. crispatus, L. jensenii, L. gasseri, L. iners.
• Lactobacillus produces lactic acid (maintaining vaginal pH 3.5–4.5) + hydrogen peroxide (H₂O₂ — bactericidal) + bacteriocins (antimicrobial proteins).
• Döderlein's bacillus (historical term for Lactobacillus acidophilus in the vagina — credited to Albert Döderlein, 1892).
• Normal flora also includes small numbers of: Gardnerella, Atopobium, Prevotella, Peptostreptococcus, Candida, Ureaplasma, Mycoplasma — all kept in check by lactobacilli.
• pH change with menstruation: Menstrual blood (pH ~7) raises vaginal pH transiently, allowing overgrowth of anaerobes.

Factors Maintaining Lactobacillus Dominance: - Oestrogen → glycogen deposition in vaginal epithelial cells → glycogen breakdown to glucose → lactic acid (via lactobacilli). - Protective microecology disrupted by: antibiotics (especially clindamycin/cephalosporins), douching, spermicides (nonoxynol-9), sexual activity (semen pH ~7.4), smoking, and loss of oestrogen (menopause).

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7.2 Bacterial Vaginosis (BV)

Definition: Replacement of Lactobacillus-dominant flora by polymicrobial overgrowth of Gardnerella vaginalis, Atopobium vaginae, Prevotella, Mobiluncus, Bacteroides, Megasphaera, Sneathia and other anaerobes.

Not a typical STI — but associated with sexual activity, new/multiple partners, and IUD use. Men can be colonised but treatment of male partners does NOT reduce recurrence.

Diagnosis:

Amsel Criteria (≥3 of 4): 1. Thin, homogenous, white/grey discharge (adherent to vaginal walls). 2. Vaginal pH >4.5 (use narrow-range pH paper). 3. Fishy odour (amine test): on addition of 10% KOH. 4. Clue cells >20% of epithelial cells on saline wet mount (epithelial cells stippled with bacteria, borders obscured).

Nugent Score (Gram stain): - Scores 0–10 based on: - Lactobacillus morphotypes (large Gram+ rods) — scored 0–4. - Gardnerella/Bacteroides morphotypes (small Gram-variable/-negative rods) — scored 0–4. - Mobiluncus morphotypes (curved Gram-variable rods) — scored 0–2. - Score 0–3: Normal (Lactobacillus dominant). - Score 4–6: Intermediate. - Score 7–10: BV. - Nugent Score is the gold standard for research but rarely used in routine clinical practice (Amsel criteria + point-of-care molecular tests are more common).

Complications of BV in O&G: - Preterm birth / PPROM: Strongest association among all vaginal dysbioses. BV in early pregnancy (OR 2–3 for preterm birth). Treating asymptomatic BV in pregnancy does NOT consistently reduce preterm birth (controversial — screening and treatment not recommended by UK NSC). - Second trimester miscarriage. - Postpartum endometritis (post-CS, post-vaginal delivery). - Post-hysterectomy vaginal cuff infection. - Post-abortion PID. - Increased HIV susceptibility (loss of protective H₂O₂/Lactobacillus barrier + increased inflammation).

Treatment: - Symptomatic BV: Metronidazole 400–500 mg PO BD × 5–7 days (or 2 g single dose — less effective). Intravaginal metronidazole gel 0.75% or clindamycin cream 2% for 7 days. - Pregnancy: Oral metronidazole is safe. Treat if symptomatic. Asymptomatic BV in pregnancy with prior preterm birth may be treated at clinician discretion (limited evidence). - Recurrent BV (>3/year): Suppressive therapy — metronidazole gel twice weekly for 4–6 months, or oral metronidazole 500 mg BD for 7 days at the start of each menstrual cycle. Add Lactobacillus probiotic (adjunctive — limited evidence). - Lactobacillus for BV: Oral L. rhamnosus GR-1 + L. reuteri RC-14 (or intravaginal) may help restore flora (weak evidence as adjunct, not replacement for antibiotics).

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PART II — IMMUNOLOGY

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8. BASIC IMMUNOLOGY

8.1 Innate vs Adaptive Immunity

Feature	Innate (Natural)	Adaptive (Acquired)
Speed	Immediate (0–4 h)	Delayed (days — clonal expansion)
Specificity	Broad (PAMPs via PRRs)	Highly specific (antigen-specific)
Memory	No (same response each time)	Yes (immunological memory)
Cells	Neutrophils, macrophages, NK cells, dendritic cells, complement	T cells, B cells
Receptors	Pattern recognition receptors (TLR, NLR, RLR)	TCR, BCR/surface immunoglobulin
Major components	Physical barriers, phagocytes, complement, acute phase proteins, NK cells	Antibodies, cytotoxic T cells

PAMPs & PRRs: - PAMP: Pathogen-Associated Molecular Pattern (e.g., LPS from Gram-negative bacteria, peptidoglycan, flagellin, dsRNA, CpG DNA). - PRR: Pattern Recognition Receptor (e.g., Toll-like receptors — TLRs expressed on macrophages, dendritic cells, epithelial cells). - TLR4: LPS. - TLR3: dsRNA. - TLR5: Flagellin. - TLR9: CpG DNA (unmethylated).

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8.2 Cells of the Immune System

Phagocytes

Neutrophils (polymorphonuclear leukocytes — PMNs): - Most abundant white blood cell (40–70% of total leukocytes). - First responders to infection. Short-lived (6–8 hours in circulation). - Effector functions: Phagocytosis (engulf and kill via reactive oxygen species — respiratory burst), degranulation (myeloperoxidase, lysozyme, defensins, proteases), NET formation (neutrophil extracellular traps — DNA + antimicrobial peptides that trap and kill bacteria). - IL-8 (CXCL8) is the major chemoattractant. - Marginated pool: Many neutrophils are adherent to endothelium (spleen, lungs, bone marrow). Stress/steroids → demargination → increased WCC. - Neutrophilia: Bacterial infection, inflammation, stress, steroids, smoking. - Neutropenia: Viral infection, chemotherapy, autoimmune, drug-induced.

Macrophages (mononuclear phagocytes): - Derived from circulating monocytes. Tissue-resident macrophages: Kupffer cells (liver), alveolar macrophages (lung), microglia (brain), osteoclasts (bone), peritoneal macrophages, decidual macrophages (uterus in pregnancy). - M1 (classical activation): Pro-inflammatory, kill intracellular pathogens. TNF-α, IL-1, IL-12, iNOS (NO production). - M2 (alternative activation): Anti-inflammatory, tissue repair, fibrosis. IL-10, TGF-β, arginase.

Dendritic Cells (DCs): - Professional antigen-presenting cells (APCs). Express high levels of MHC class II. - Subtypes: Conventional DCs (myeloid), Plasmacytoid DCs (produce Type I interferons — anti-viral), Langerhans cells (skin), follicular DCs (in lymph node germinal centres — present antigen to B cells). - Immature DCs in tissues capture antigen → migrate to draining lymph nodes → mature (upregulate costimulatory molecules CD80/86, MHC) → present antigen to naïve T cells → activate adaptive immune response.

Natural Killer (NK) Cells

• Innate lymphoid cells (ILCs). Do NOT require prior sensitisation.
• Recognise absence of "self" MHC class I ("missing self" hypothesis).
• Activating receptors: NKG2D, NKp46, NKp44 (natural cytotoxicity receptors — NCRs).
• Inhibitory receptors: KIR (Killer-cell Immunoglobulin-like Receptors) — bind to HLA-A, HLA-B, HLA-C, HLA-G.
• If MHC-I is downregulated (e.g., viral infection, tumour cells), inhibitory signal is lost → NK cell activation.
• Effector mechanisms:
• Cytotoxic granules: Perforin (pores in target cell membrane) + Granzymes (induce apoptosis).
• Antibody-dependent cellular cytotoxicity (ADCC): CD16 (FcγRIII) binds antibody-coated target cells.
• Cytokine secretion: IFN-γ, TNF-α.

Decidual NK (dNK) cells: - Unique subset — CD56^bright CD16^- KIR+. Found in pregnant uterus. - NOT cytotoxic (despite high granularity). Instead, secrete cytokines, chemokines, angiogenic factors (VEGF, PIGF, TGF-β, IL-8, IP-10) for spiral artery remodelling and trophoblast invasion. - Recognise HLA-C, HLA-E, HLA-G on extravillous trophoblast → regulates depth of trophoblast invasion.

T Lymphocytes

T Cell Development: - Thymus: Positive selection (MHC restriction — only T cells that recognise self-MHC survive) and Negative selection (elimination of self-reactive T cells — central tolerance). - CD3 = pan-T cell marker (part of TCR complex).

CD4+ Helper T Cells (Th): - Recognise peptide presented on MHC class II by APCs. - Th1: IFN-γ, TNF-α, IL-2. Defend against intracellular pathogens (viruses, mycobacteria). Activates macrophages (cell-mediated immunity). Associated with pregnancy loss (excessive Th1). - Th2: IL-4, IL-5, IL-13. Defend against extracellular pathogens (parasites, helminths). Drives humoral immunity (B cell activation, IgE class switching). Th2 dominance in normal pregnancy. - Th17: IL-17A, IL-17F, IL-22. Defend against extracellular bacteria and fungi. Role in: mucosal immunity, autoimmunity (psoriasis, RA), neutrophil recruitment. Th17 in pregnancy: involved in trophoblast invasion and placental development. Excessive Th17 linked to pre-eclampsia. - Treg (Regulatory T cells): CD4+CD25+FOXP3+. Produce IL-10, TGF-β. Essential for maintaining maternal-fetal tolerance. Suppress effector T cells that recognise fetal antigens (paternal). Depletion of Treg causes fetal rejection in animal models. Lower Treg seen in pre-eclampsia, recurrent miscarriage. - Tfh (Follicular helper): Help B cells in germinal centres (antibody class switching, affinity maturation).

CD8+ Cytotoxic T Cells (CTLs): - Recognise peptide presented on MHC class I (all nucleated cells). - Kill virus-infected cells and tumour cells. - Effector mechanisms: Perforin/granzyme, Fas-FasL (induces apoptosis), IFN-γ, TNF-α. - CD8+ T cell exhaustion: Chronic viral infection (HIV, HCV, HBV) leads to PD-1 upregulation, decreased effector function.

γδ T Cells: - Minor subset (<5% of T cells). Bridge innate and adaptive immunity. - Recognise non-peptide antigens (phospholipids, stress molecules — MICA/B). - Enriched at mucosal surfaces (including endometrium and decidua — role in implantation and immune surveillance).

B Lymphocytes

• Develop in bone marrow.
• B Cell Receptor (BCR): Surface immunoglobulin (IgM + IgD) on naïve B cells.
• Activation: Requires antigen binding + help from CD4+ Tfh cells (for T-dependent antigens). T-independent antigens (polysaccharides, TLR ligands) activate B cells without T cell help (rapid but limited).
• Germinal centre reaction: Activated B cells proliferate and undergo somatic hypermutation (increases antibody affinity — affinity maturation) and class switching (IgM → IgG, IgA, IgE).
• Differentiation:
• Plasma cells: Antibody factories (short-lived + long-lived in bone marrow).
• Memory B cells: Long-lived, rapid response on re-exposure.

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8.3 Major Histocompatibility Complex (MHC / HLA)

Human Leukocyte Antigen (HLA) System: - Located on chromosome 6 (short arm). - Class I: HLA-A, HLA-B, HLA-C. Expressed on all nucleated cells (+ platelets). Presents endogenous peptides (cytosolic) → CD8+ T cells. - Class II: HLA-DP, HLA-DQ, HLA-DR. Expressed on professional APCs (dendritic cells, macrophages, B cells). Presents exogenous peptides (processed in endosomes) → CD4+ T cells. - Class III: Complement proteins (C2, C4, Factor B), TNF-α, lymphotoxin.

MHC Polymorphism: - Most polymorphic genes in the human genome — >20,000 alleles for some loci. - This diversity ensures a population can present a wide range of pathogen peptides. - HLA-B*57:01: Associated with hypersensitivity to abacavir (HIV drug); testing mandatory before use. - HLA-DRB104:01, 07:01, *09:01: Associated with rheumatoid arthritis, type 1 diabetes.

Antigen Processing & Presentation: - Class I pathway (endogenous): Protein → proteasome → peptide (8–10 aa) → TAP transporter → ER → MHC-I → cell surface. - Class II pathway (exogenous): Engulf → endosome → peptide (13–25 aa) → MHC-II compartment → cell surface. - Cross-presentation: Dendritic cells can also present exogenous antigens on MHC-I (necessary for CD8+ response against viruses that don't infect DCs).

Trophoblast HLA Expression (key for pregnancy immunology): - Trophoblast does NOT express classical MHC-I (HLA-A, HLA-B) — prevents recognition by maternal CD8+ cytotoxic T cells. - Trophoblast DOES express: - HLA-C (polymorphic — interacts with maternal NK cell KIRs). - HLA-E (non-classical — ligand for NKG2A/CD94 on NK cells → inhibitory signal). - HLA-G (non-classical — limited polymorphism, very restricted expression to trophoblast. Interacts with dNK cells LILRB1/2 and KIR2DL4 → inhibitory/immunomodulatory. Promotes Treg, blocks T cell cytotoxicity, induces apoptosis of activated CD8+ T cells). - Trophoblast does NOT express MHC-II (no CD4+ T cell activation).

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8.4 Antibody Structure & Function

Basic Structure: - Y-shaped monomer. 4 polypeptide chains: 2 heavy (H) chains + 2 light (L) chains. - Constant (C) region: Determines isotype (class). - Variable (V) region: Antigen-binding site (Fab — Fragment antigen binding). - Fc region: Fragment crystallisable — determines effector function (binding to Fc receptors on immune cells, complement activation, placental transfer).

Antibody Classes:

Class	Structure	Serum half-life	Placental Transfer	Key Functions
IgG	Monomer	21–28 days	Yes (active via FcRn on syncytiotrophoblast)	Neutralisation, opsonisation, ADCC, complement activation. Most abundant in serum. 4 subclasses (IgG1,2,3,4).
IgA	Monomer (serum), Dimer (secretory)	5–6 days	No	Mucosal immunity (GI, respiratory, GU tracts). Secretory IgA (sIgA): dimer + J chain + secretory component (prevents proteolysis). Present in breast milk (colostrum), tears, saliva, vaginal secretions.
IgM	Pentamer	5 days	No	First antibody produced in primary immune response. Potent complement activation. Natural IgM (pre-immune) — first line defence.
IgE	Monomer	2 days	No (minimal)	Allergic reactions (type I hypersensitivity — mast cell degranulation), defence against helminths. Bound to FcεRI on mast cells/basophils.
IgD	Monomer	3 days	No	Co-expressed with IgM on naïve B cells (BCR). Function unclear.

Placental Transfer of IgG: - Only IgG crosses the placenta (via FcRn — neonatal Fc receptor). - Transfer increases with gestational age: First trimester — low; third trimester ~38 weeks — maternal IgG equal or exceeds fetal IgG. - Transfer: IgG1 > IgG4 > IgG3 > IgG2. - This is why term infants have protective maternal IgG against many pathogens (measles, tetanus, etc.) for the first 3–6 months. - It's also why maternal autoimmune IgG (e.g., anti-Ro/La in SLE → neonatal lupus/CHB; anti-D in Rh disease → HDFN) affects the fetus.

Opsonisation: IgG coating pathogen → FcγR on phagocytes → enhanced phagocytosis.

Complement activation: - IgG and IgM (both via classical pathway) — IgM is most potent. - IgA alternative pathway (not classical).

Neutralisation: IgG and IgA block pathogen binding to host cells (e.g., neutralising antibodies to SARS-CoV-2, HPV).

ADCC: IgG bound to infected cell → FcγRIII (CD16) on NK cells → killing.

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8.5 Complement System

A cascade of plasma proteins forming a host defence system. Three activation pathways converge on a common terminal pathway.

Classical Pathway: - Activated by: Antigen-antibody complex (IgM, IgG1, IgG3). IgG2 is poor. - C1q (binds Fc region) → C1r → C1s → C4 → C2 → C3 convertase (C4bC2a).

Alternative Pathway: - Spontaneous/tickover activation of C3 (hydrolysis). Provides rapid, antibody-independent defence. - Maintained by Factor D, properdin (stabilises C3bBb). - C3 convertase (C3bBb) = alternative pathway.

Lectin Pathway: - Mannose-binding lectin (MBL) binds to mannose residues on pathogen surfaces (bacteria, yeast, viruses). - Activates MASP1/MASP2 (MBL-associated serine proteases) → cleaves C4 and C2 → same as classical pathway from C4 onwards. - C3 convertase (C4bC2a) — same as classical.

C3 Convertase → C5 Convertase → MAC: - C3 convertase cleaves C3 → C3a (anaphylatoxin — chemotaxis, mast cell degranulation) + C3b (opsonin — coats pathogens for phagocytosis). - C3b + C3 convertase → C5 convertase. - C5 convertase cleaves C5 → C5a (potent anaphylatoxin — neutrophil chemotaxis, monocyte activation, increased vascular permeability) + C5b. - C5b, C6, C7, C8, C9 → Membrane Attack Complex (MAC — C5b-9) — forms pores in bacterial cell membranes → osmotic lysis.

Regulation of Complement: - DAF (Decay Accelerating Factor / CD55): Accelerates decay of C3 convertases. Expressed on host cells (including placenta). - MCP (Membrane Cofactor Protein / CD46): Cofactor for Factor I-mediated cleavage of C3b/C4b. Expressed on host cells. - CD59 (Protectin): Inhibits MAC formation (binds C8, prevents C9 polymerisation). Expressed on host cells. - C1-inhibitor: Regulates classical pathway (C1r, C1s). - Factor H: Regulates alternative pathway (displaces Bb from C3b). - Factor I: Inactivates C3b and C4b with cofactors (MCP, Factor H, CR1).

Complement Deficiencies: - C1-C4 deficiencies → increased risk of SLE (impaired clearance of immune complexes). - MBL deficiency → increased risk of infections in children. - C5-C9 deficiency → increased risk of Neisseria (meningococcal, gonococcal) infections. MAC is essential for killing Neisseria.

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8.6 Cytokines

Small glycoproteins that mediate cell-to-cell communication in the immune system.

Interleukins (IL):

Cytokine	Source	Primary Function
IL-1	Macrophages, many cells	Fever (endogenous pyrogen), inflammation, T cell activation, acute phase response
IL-2	T cells	T cell proliferation (autocrine), NK cell activation
IL-4	Th2 cells	Th2 differentiation, B cell class switching → IgE, IgE production
IL-5	Th2 cells	Eosinophil activation, eosinophilia
IL-6	Macrophages, T cells, endothelial cells	B cell maturation, acute phase response (CRP), fever, Th17 differentiation
IL-8 (CXCL8)	Macrophages, epithelial cells	Neutrophil chemoattractant
IL-10	Treg, macrophages, Th2	Anti-inflammatory — inhibits Th1, macrophage activation
IL-12	Dendritic cells, macrophages	Th1 differentiation, NK activation, IFN-γ production
IL-13	Th2 cells	Mucus production, allergic inflammation, fibrosis
IL-17	Th17 cells	Neutrophil recruitment, mucosal defence, autoimmunity
IL-22	Th17, ILC3	Epithelial repair, antimicrobial peptides
IL-23	DCs, macrophages	Maintenance of Th17 cells
IL-35	Treg	Suppression of effector T cells
IL-37	Various	Anti-inflammatory — suppresses innate immunity

Interferons (IFN): - Type I IFN (IFN-α, IFN-β): Produced by virus-infected cells and plasmacytoid DCs. Induce antiviral state in neighbouring cells (MHC upregulation, activation of RNase L, protein kinase R). Key in innate response to viruses. - Type II IFN (IFN-γ): Produced by Th1 cells, CD8+ T cells, NK cells. Potent macrophage activator, MHC upregulation, Th1 polarisation. - Type III IFN (IFN-λ): Mucosal antiviral defence.

TNF-α (Tumor Necrosis Factor-alpha): - Produced by macrophages, T cells, NK cells. - Pro-inflammatory: Endothelial activation, fever, septic shock (high levels → myocardial depression, DIC, multi-organ failure). - Anti-TNF therapy (infliximab, adalimumab) used for RA, IBD.

TGF-β (Transforming Growth Factor-beta): - Produced by Treg, many cell types. - Anti-inflammatory — suppresses T cell proliferation, promotes Treg differentiation, fibrosis, wound healing. - Important in pregnancy for trophoblast invasion and immune regulation.

Chemokines: - Chemotactic cytokines — direct leukocyte migration. - CCL2 (MCP-1): Monocyte recruitment. - CCL3 (MIP-1α), CCL4 (MIP-1β): Macrophage, NK, T cell recruitment. - CXCL8 (IL-8): Neutrophil recruitment. - CXCL10 (IP-10): Th1 cell recruitment. - CX3CL1 (Fractalkine): NK, monocyte adhesion.

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8.7 Acute Phase Response

Systemic inflammatory response to infection/tissue injury, mediated by IL-1, IL-6, TNF-α.

Positive Acute Phase Proteins (increase): - CRP (C-Reactive Protein): Produced by liver in response to IL-6. Binds to phosphocholine on bacteria (opsonin). Rises within 6–12 hours, peaks at 48 h. Used clinically to monitor inflammation/infection (e.g., chorioamnionitis, postpartum sepsis, PID). - Serum Amyloid A (SAA): Apoprotein of HDL; very sensitive acute phase marker. - Haptoglobin: Binds free haemoglobin (prevents iron loss). - Ferritin: Iron storage — increased in inflammation. - Fibrinogen: Coagulation — increased → ESR raised. - Complement proteins (C3, C4, MBL). - α1-antitrypsin, α1-acid glycoprotein, ceruloplasmin, hepcidin.

Negative Acute Phase Proteins (decrease): - Albumin (hypoalbuminaemia in inflammation). - Transferrin (iron transport — decreases to limit iron availability to bacteria). - Transthyretin (prealbumin).

Systemic Effects: - Fever: IL-1, IL-6, TNF-α act on hypothalamus → PGE2 production → temperature set point raised. - Leukocytosis: Increased WBC (demargination + increased bone marrow production). - Lethargy, anorexia, myalgia, malaise. - Anaemia of chronic disease: Hepcidin (acute phase) blocks iron export from macrophages → hypoferraemia.

CRP in Obstetrics: - CRP rises mildly in normal pregnancy (up to 20 mg/L). - Marked rise >30–50 mg/L suggests infection (chorioamnionitis, endometritis, pyelonephritis). - Procalcitonin (PCT) — more specific for bacterial infection vs viral/inflammatory, but less studied in pregnancy.

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9. IMMUNOLOGY OF PREGNANCY

9.1 The Immunological Paradox of Pregnancy

The fetus is semi-allogeneic (inherits 50% paternal antigens). The maternal immune system must: 1. Tolerate the fetus (not reject as foreign graft). 2. Maintain immune competence against pathogens. 3. Allow trophoblast invasion and remodelling of spiral arteries.

Key mechanisms:

Immunological adaptation at the maternal-fetal interface: - Trophoblast does NOT express classical MHC class I (HLA-A/B) → avoids CD8+ T cell recognition. - Trophoblast expresses HLA-C, HLA-E, HLA-G → protects from NK cell killing. - Decidual NK cells (CD56^bright CD16^-) are NOT cytotoxic; they secrete angiogenic factors (VEGF, PIGF, TGF-β, IL-8) to facilitate spiral artery remodelling. - Treg cells accumulate in the decidua and suppress alloreactive T cells.

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9.2 HLA-C, HLA-E, HLA-G in Pregnancy

HLA-G: - Non-classical MHC class Ib. Very limited polymorphism. - Expression almost exclusively on extravillous trophoblast (EVT). - Binds to inhibitory receptors on NK cells and macrophages: LILRB1 (ILT2), LILRB2 (ILT4), KIR2DL4 (CD158d). - Functions: - Inhibits NK cell cytotoxicity. - Induces Treg differentiation. - Suppresses CD8+ T cell cytotoxicity. - Modulates dendritic cell function. - Promotes angiogenesis. - Soluble HLA-G (sHLA-G) found in maternal serum and amniotic fluid. Low levels associated with pre-eclampsia, recurrent miscarriage, and failed IVF implantation.

HLA-C: - Polymorphic classical MHC-I. Expressed on EVT. - KIR-HLA-C interaction: Maternal NK cells express KIRs (Killer-cell Immunoglobulin-like Receptors) that recognise fetal HLA-C. - KIR AA (inhibitory only) + HLA-C2 (ligand for inhibitory KIR) → strong NK inhibition → good pregnancy. - KIR AA + HLA-C1 → weaker inhibition → possible pregnancy complications. - KIR B (activating KIRs present) → NK activation promotes trophoblast invasion. - Specific KIR/HLA-C combinations are associated with: - Pre-eclampsia (Risk increased with KIR AA + fetal HLA-C2). - Recurrent miscarriage. - IUGR. - Birth weight (KIR-HLA-C interaction influences placentation).

HLA-E: - Expresses on EVT. - Presents leader peptides from other HLA molecules. - Ligand for NKG2A/CD94 (inhibitory) and NKG2C/CD94 (activating) on NK cells. - HLA-E expression protects trophoblast from NK-mediated lysis (NKG2A binding → inhibitory signal).

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9.3 Decidual NK Cells (dNK)

• Phenotype: CD56^bright CD16^- KIR^+ NKp44^+ NKp46^+. This contrasts with peripheral blood NK cells (CD56^dim CD16^+).
• Location: Decidua basalis (maternal side of the placental bed). Abundant in first trimester (up to 70% of decidual leukocytes).
• NOT cytotoxic — despite having abundant cytotoxic granules (perforin, granzymes), the granules are recycled, not released.
• Functions:
• Angiogenesis: Secrete VEGF, PIGF, TGF-β, IL-8, IP-10, ANG2 → spiral artery remodelling.
• Trophoblast invasion control: Regulate depth of EVT invasion via IFN-γ and TNF-α (trophoblast expresses MHC-C → interacts with KIR).
• Immune regulation: Secrete IL-10, IL-22, GM-CSF.
• Selective maternal tolerance: Interact with dendritic cells and Treg.
• Mechanism of non-cytotoxicity: High expression of inhibitory receptors (KIR, LILRB1, NKG2A), lack of activating receptor signalling, and presence of TGF-β in the decidual microenvironment.

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9.4 Th1/Th2/Th17/Treg Balance in Pregnancy

Classic "Th2 shift" model in pregnancy: - Normal pregnancy is characterised by a shift from Th1 → Th2 dominance (placentally induced). - Th2 cytokines (IL-4, IL-5, IL-10, IL-13) dominate — favouring humoral immunity, reducing cell-mediated Th1 responses. - Th1 cytokines (IFN-γ, TNF-α, IL-2) are harmful to the fetus — they promote: - Macrophage activation → trophoblast damage. - NK cell activation → fetal rejection. - Coagulation abnormalities. - Excessive Th1 response is linked to: - Recurrent miscarriage (↑ IFN-γ, TNF-α in decidua). - Pre-eclampsia (↑ TNF-α, IL-6, Th1 shift). - IUGR, preterm labour.

Th17 in Pregnancy: - Th17 cells (IL-17, IL-22) are important for mucosal defence and neutrophil recruitment. - Involved in trophoblast invasion and placental development. - Excessive Th17 (with low Treg) is pro-inflammatory: - Associated with pre-eclampsia (↑ IL-17 in decidua). - Associated with recurrent miscarriage. - IL-17 induces anti-angiogenic factors (sFlt-1, sEng).

Treg in Pregnancy: - CD4+CD25+FOXP3+ Treg are the most critical cells for maternal-fetal tolerance. - Treg accumulate in decidua (CXCL10/CXCR3 mediated recruitment). - Functions: - Suppress alloreactive T cells (via IL-10, TGF-β, IL-35, CTLA-4). - Inhibit Th1 and Th17 responses. - Promote M2 macrophage polarisation. - Induce tolerogenic dendritic cells. - Treg expand during normal pregnancy (peak in 2nd trimester, decline postpartum). - Deficient Treg is linked to: Recurrent miscarriage, pre-eclampsia, IUGR, and possibly preterm labour.

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9.5 Trophoblast Invasion & Spiral Artery Remodelling

Stages of Remodelling: 1. Interstitial EVT invades through decidual stroma → periarterial cuff. 2. Endovascular EVT migrates into spiral artery lumen. 3. Replaces endothelial cells + smooth muscle → large-calibre, low-resistance vessels. 4. This ensures maximal blood flow to the intervillous space for fetal nutrition and oxygenation. 5. Remodelling should extend through the decidua and into the inner myometrium (complete transformation).

Failure of remodelling → high-resistance spiral arteries, placental hypoxia, oxidative stress → Pre-eclampsia, IUGR, miscarriage.

Regulation of Invasion: - Promoters: Trophoblast-derived MMPs (matrix metalloproteinases), integrins, VEGF, PIGF, uPAR, TGF-β (at early stages). - Inhibitors: TIMPs, TGF-β (late stages), IL-10, HLA-G, decidual NK cell interactions. - Oxygen tension: Low O₂ in early pregnancy (before 10 weeks — trophoblast plugs occlude spiral arteries, creating a low-oxygen environment that promotes proliferation and invasion). After 10–12 weeks, plugs dislodge → onset of maternal blood flow → increased O₂ → trophoblast differentiates from proliferative → invasive phenotype.

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9.6 Complement Regulation at the Maternal-Fetal Interface

Complement activation is tightly regulated at the placenta to prevent fetal damage.

Regulatory proteins on trophoblast: - DAF (CD55 / Decay Accelerating Factor): Accelerates decay of C3 and C5 convertases. - MCP (CD46 / Membrane Cofactor Protein): Cofactor for Factor I-mediated cleavage of C3b and C4b. - CD59 (Protectin): Inhibits MAC formation by blocking C9 polymerisation.

Importance of complement regulation: - Animal models: Deficiency of complement regulatory proteins → complement deposition → placental inflammation → fetal loss. - In antiphospholipid syndrome (APS): Antiphospholipid antibodies activate complement → trophoblast injury. Heparin is therapeutic partly because it inhibits complement activation. - Low C3/C4 in pregnancy can indicate complement consumption (e.g., SLE flare, severe pre-eclampsia, HELLP).

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9.7 Immunomodulatory Proteins in Pregnancy

Progesterone: - PIBF (Progesterone-Induced Blocking Factor): Produced by lymphocytes in response to progesterone. Promotes Th2 dominance, inhibits NK cell activity, boosts Treg differentiation. - Progesterone itself suppresses T cell activation, reduces pro-inflammatory cytokine production (IL-1β, TNF-α), and promotes IL-10. - Progesterone supplementation has been studied for prevention of preterm birth in at-risk women.

Human Chorionic Gonadotropin (hCG): - Produced by syncytiotrophoblast. - Immunomodulatory effects: Promotes Treg, induces M2 macrophage polarisation, inhibits NK cytotoxicity, enhances IL-10 production, suppresses T cell proliferation.

Alpha-fetoprotein (AFP): - Produced by fetal liver, crosses placenta into maternal circulation. - Immunosuppressive: Inhibits T cell and B cell responses. - Low levels in maternal serum are a marker for trisomy 21 (not an immunological effect).

TGF-β: - Produced by trophoblast, decidual stromal cells, Treg. - Potent immunosuppressive: inhibits T cell proliferation, NK activation, promotes Treg. - Crucial for trophoblast invasion (regulatory — early promotion, later inhibition).

IL-10: - Anti-inflammatory cytokine. Produced by trophoblast, decidual macrophages, Treg, Th2 cells. - Suppresses Th1 responses, reduces macrophage TNF-α/IL-1, inhibits NK cytotoxicity. - Found in high concentrations in amniotic fluid.

Galectins: - Galectin-1 (Gal-1): Produced by trophoblast and decidual stromal cells. Promotes Treg, induces T cell apoptosis, suppresses Th1/Th17 responses. - Galectin-3, Galectin-9, Galectin-13 (PP13): Each has distinct immunomodulatory roles at the interface. PP13 (placental protein 13) is being investigated as a biomarker for pre-eclampsia.

Fas-FasL Interactions: - FasL (CD95L) is expressed on trophoblast (especially EVT). - Activated maternal T cells express Fas (CD95). - Fas-FasL binding → apoptosis of activated T cells (activation-induced cell death). This eliminates maternal T cells that recognise fetal antigens. - Mechanism of "immune privilege" at the maternal-fetal interface (like eye, testis, brain).

Tryptophan Catabolism — IDO (Indoleamine 2,3-dioxygenase): - IDO is expressed by trophoblast and decidual macrophages/dendritic cells. - IDO degrades tryptophan (essential amino acid) → depletes local tryptophan needed for T cell proliferation. - Also produces kynurenine metabolites that suppress T cell activation and promote Treg. - Animal model: IDO inhibition with 1-methyl-tryptophan → fetal rejection in mice.

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10. IMMUNOLOGICAL DISORDERS IN PREGNANCY

10.1 Antiphospholipid Syndrome (APS)

Definition: Systemic autoimmune disorder characterised by thrombosis (arterial/venous) and/or pregnancy morbidity in the presence of persistent antiphospholipid antibodies (aPL).

Diagnostic Criteria (Revised Sapporo / Sydney Criteria):

Clinical: - Thrombosis — ≥1 confirmed episode of arterial, venous, or small-vessel thrombosis. - Pregnancy morbidity: - ≥1 unexplained death of morphologically normal fetus ≥10 weeks gestation. - ≥1 premature birth <34 weeks due to severe pre-eclampsia, eclampsia, or placental insufficiency. - ≥3 unexplained consecutive miscarriages <10 weeks (excluding chromosomal, anatomical, hormonal causes).

Laboratory (≥2 positive tests ≥12 weeks apart): 1. Lupus anticoagulant (LA) — functional coagulation assay (dRVVT, PTT-LA). 2. Anticardiolipin antibodies (aCL) — IgG/IgM medium-high titre. 3. Anti-β2 glycoprotein I antibodies (β2GPI) — IgG/IgM medium-high titre.

Pathophysiology: - aPL bind to β2-glycoprotein I (β2GPI) on cell surfaces (endothelial cells, platelets, trophoblast) → activation: - Thrombotic: Endothelial activation → increased tissue factor, decreased prostacyclin, increased PAI-1 → procoagulant state. - Pregnancy loss: aPL bind to β2GPI on trophoblast → disrupted trophoblast adhesion, invasion, differentiation; increased apoptosis; inhibition of hCG production. - Complement activation: aPL activate complement (C3, C5) → placental inflammation → fetal loss.

Treatment in Pregnancy: - Low-dose Aspirin (LDA) — 75–150 mg daily (start preconception or as soon as pregnancy confirmed). - Low Molecular Weight Heparin (LMWH) — e.g., enoxaparin 40 mg (or 0.5 mg/kg BD if higher risk). Start as soon as pregnancy confirmed. - LDA + LMWH reduces live birth from ~40% (no treatment) to ~70% (with treatment). - If failed on LDA + LMWH: Consider adding hydroxychloroquine (HCQ) 200–400 mg daily, or low-dose prednisolone, or IVIG. These are second-line and require specialist input. - Postpartum: Continue LMWH for 6 weeks (thrombosis prophylaxis). Warfarin can be reintroduced. - High-risk features (triple positive aPL, previous thrombosis): Higher-dose LMWH, closer surveillance.

Catastrophic APS (CAPS): - Rare (<1% of APS). Rapid multi-organ failure from widespread thrombosis. Mortality >50%. - Trigger: Infection, surgery, pregnancy/postpartum. - Treatment: Anticoagulation + IV corticosteroids + plasma exchange/IVIG.

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10.2 Systemic Lupus Erythematosus (SLE) in Pregnancy

Overview: - Chronic autoimmune disease affecting women of reproductive age (F:M 9:1). - Multi-system: skin (malar rash, discoid), joints (arthritis), kidneys (lupus nephritis), blood (cytopenias), serosal (pleurisy, pericarditis), CNS (seizures, psychosis). - Autoantibodies: ANA (anti-nuclear antibody — sensitive but not specific), anti-dsDNA (specific — correlates with disease activity), anti-Smith (Sm — highly specific), anti-Ro/SSA, anti-La/SSB, anti-RNP.

SLE & Pregnancy: - Fertility: Normal (unless severe nephritis, cyclophosphamide-induced ovarian failure). - Pregnancy outcomes: Higher risk of: - Miscarriage, IUFD, IUGR, preterm birth, pre-eclampsia. - SLE flare (especially renal — 20–60%). - Neonatal lupus (transplacental anti-Ro/La).

SLE Flare in Pregnancy: - Differentiating from pre-eclampsia can be difficult (both have hypertension, proteinuria, oedema, thrombocytopenia). - Clues for SLE flare: Low complement (C3/C4), rising anti-dsDNA, extra-renal features (rash, arthritis, fever), active urine sediment (RBC casts), no evidence of placental insufficiency (normal Dopplers). - Clues for pre-eclampsia: New-onset hypertension after 20 weeks, elevated sFlt-1/PIGF ratio, placental Dopplers abnormal, resolution postpartum.

Management of SLE in Pregnancy: - Preconception counselling: Delay pregnancy until disease quiescent for ≥6 months. - Contraindications to pregnancy: Severe pulmonary hypertension, severe renal disease (Cr >2.8), severe heart failure, recent stroke. - Medications: - Hydroxychloroquine (HCQ) 200–400 mg daily — SAFE and RECOMMENDED throughout pregnancy. Reduces SLE flares and neonatal lupus. - Prednisolone: Use lowest effective dose. Avoid high doses (increased risk of preterm PROM, gestational diabetes, osteoporosis). - Azathioprine: Safe in pregnancy (lowest dose effective). - Cyclophosphamide, mycophenolate mofetil (MMF), methotrexate — CONTRAINDICATED (teratogenic). - NSAIDs: Avoid after 20 weeks (risk of fetal ductal constriction, oligohydramnios). - Monitoring: Every 2–4 weeks (BP, urinalysis, urine protein:creatinine ratio, serum Cr, complement, LFTs, anti-dsDNA, FBC). Serial USS for fetal growth (4-weekly from 28 weeks). - Delivery: Aim for term (37+ weeks). C-section for obstetric indications.

Neonatal Lupus & Congenital Heart Block (CHB):

Issue	Details
Maternal autoantibody	Anti-Ro/SSA (most common), Anti-La/SSB
Fetal effect	Congenital heart block (CHB) — irreversible; neonatal lupus rash — transient
CHB timing	Usually develops 18–24 weeks (critical window). Complete heart block (3rd degree) is permanent.
Pathophysiology	Anti-Ro antibodies bind to fetal cardiac conducting tissue (cross-reactive with L-type calcium channels, SERCA, laminin) → inflammation, fibrosis, scarring of AV node
Risk	~2% for anti-Ro-positive mothers (if previous child with CHB → risk ~18%)
Management of exposed pregnancy	Serial fetal echo/Doppler from 16–26 weeks (weekly). Look for first-degree block (prolonged PR interval — but intermittent; difficult to reliably detect).
Prevention of CHB	HCQ reduces risk by 50%. High-dose corticosteroids (fluorinated steroids — dexamethasone/betamethasone) for reversing incomplete block? Controversial, limited efficacy. IVIG not proven.
Treatment of established CHB	No reversal. Monitor for hydrops fetalis (heart rate <55 bpm → risk of hydrops). If hydrops → deliver if viable. If not viable → maternal fluorinated steroid + β-agonist (salbutamol/terbutaline) to increase fetal HR.
Postnatal management	Pacemaker insertion (usually in infancy/childhood). Transient neonatal lupus rash resolves without treatment.

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10.3 Alloimmunisation: RhD & Kell

Background: - RhD is the most immunogenic red cell antigen after ABO. - RhD-negative mother carrying an RhD-positive fetus → fetal RBCs enter maternal circulation (fetomaternal haemorrhage — FMH) → maternal immune system produces anti-D IgG. - In subsequent pregnancies, anti-D crosses placenta → haemolytic disease of the fetus and newborn (HDFN). - Kell is the next most immunogenic. Anti-Kell can cause severe HDFN even at low titres (attacks erythroid progenitor cells — reduces RBC production + haemolysis).

Rhesus D Prophylaxis: - Routine antenatal anti-D prophylaxis (RAADP): All RhD-negative pregnant women in UK offered anti-D 1500 IU at 28 weeks (single dose) or 500 IU at 28 and 34 weeks (two doses). - Post-partum anti-D: Given within 72 hours of delivery of an RhD-positive baby (dose depends on FMH size — Kleihauer test to quantify FMH). - Additional anti-D for sensitising events: - Miscarriage (≥12 weeks), termination of pregnancy (any gestation), ectopic pregnancy, chorionic villus sampling, amniocentesis, external cephalic version, abdominal trauma, antepartum haemorrhage, intrauterine death, stillbirth. - Dose: 250 IU (for <12 weeks) or 500 IU (≥12 weeks) plus Kleihauer if ≥20 weeks. - Mechanism: Passive anti-D binds to fetal RhD-positive RBCs → removed by maternal reticuloendothelial system before mother can mount an active immune response.

Kleihauer-Betke Test / Flow Cytometry: - Quantifies FMH (fetal HbF-containing cells in maternal blood after acid elution — adult HbA is eluted, fetal HbF remains). - Performed after delivery (or sensitising event >20 weeks) to determine if additional anti-D is needed. - RhD-negative mother: Standard 1500 IU (or 500 IU) covers up to 4 mL fetal RBCs (8 mL whole blood). If FMH >4 mL → give additional anti-D (calculated as 500 IU per 4 mL FMH or equivalent).

Alloimmunised Pregnancy (Anti-D, Anti-Kell, etc.): - Monitoring: Serial maternal antibody titres (critical titre: 1:8 or 1:16 — varies by centre; if ≥1:16 → refer to fetal medicine). - MCA-PSV Dopplers: Middle cerebral artery peak systolic velocity (MCA-PSV) measured 1–2 weekly from 20–24 weeks until delivery. MCA-PSV >1.5 MoM (multiples of median) indicates severe fetal anaemia. - IUT (Intrauterine transfusion): If MCA-PSV >1.5 MoM or hydrops. Volume and haematocrit of donor blood calculated. IUT is via umbilical vein (cordocentesis). Repeated every 1–3 weeks. - Delivery: Usually at 34–37 weeks (or earlier if hydrops/abnormal Dopplers).

Kell Sensitisation: - Anti-Kell is more severe because Kell antigen appears on erythroid progenitor cells (early RBC precursors). - Therefore, anti-Kell can cause profound fetal anaemia with lower antibody titres than anti-D. - Kell typing of partner: If partner is Kell-negative, no risk. If partner is Kell-positive (heterozygous 50% chance of fetal Kell), the mother requires antibody monitoring.

Other Alloantibodies: - Anti-c, Anti-E (Rhesus system) — can cause HDFN. - Anti-Fya, Anti-Fyb, Anti-Jka, Anti-Jkb, Anti-S, Anti-s — less common, can cause mild-moderate HDFN. - ABO incompatibility: Most common cause of neonatal jaundice (maternal anti-A/anti-B IgG). Usually mild (haemolysis limited to extravascular). Does NOT cause hydrops.

Non-Invasive Prenatal Diagnosis (NIPT) for Fetal RhD: - Cell-free fetal DNA (cffDNA) from maternal blood can determine fetal RhD genotype from 11 weeks. - Used to: Identify RhD-negative women carrying an RhD-positive fetus (so RAADP can be targeted — "targeted" prophylaxis avoids unnecessary anti-D for women carrying RhD-negative fetus). Being rolled out in UK (NHS).

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10.4 Autoimmune Thyroid Disease in Pregnancy

Graves' Disease (Autoimmune Hyperthyroidism): - Autoantibodies: - TSI (Thyroid-Stimulating Immunoglobulin) — stimulates TSH receptor → hyperthyroidism. - TBII (TSH-Receptor Binding Inhibitory Immunoglobulin) — can also block. - In pregnancy: Disease may improve (immune suppression) or worsen (HCG cross-reactivity with TSH receptor in first trimester). - Monitoring: Check TSH every 4–6 weeks. Target: TSH 0.3–2.5 mIU/L (1st trimester), 0.3–3.0 (2nd/3rd). - Treatment: Propylthiouracil (PTU) first-line in first trimester (preferred over carbimazole due to risk of carbimazole-associated embryopathy — aplasia cutis, choanal atresia, tracheo-oesophageal fistula). Switch to carbimazole from 2nd trimester. β-blockers (propranolol) for symptomatic control. - Fetal effects: Transplacental TSI → fetal/neonatal hyperthyroidism (risk 1–5%). Monitor fetal HR (tachycardia >160 bpm → fetal thyrotoxicosis). Check cord blood T4/TSH at birth. - Postpartum: Graves' often flares 3–6 months postpartum.

Hashimoto's Thyroiditis (Autoimmune Hypothyroidism): - Anti-TPO (thyroid peroxidase) antibodies — present in >90%. - In pregnancy: Oestrogen increases TBG → increased total T4/T3. Free T4 may fall. Most women with known hypothyroidism need increased levothyroxine dose (30–50% increase) in 1st trimester. - Monitoring: TSH every 4 weeks until stable, then 8-weekly. Target: TSH <2.5 mIU/L (1st trimester), <3.0 (2nd/3rd). - Postpartum thyroiditis: Autoimmune thyroid destruction 3–6 months postpartum. Tends to follow classic pattern: transient thyrotoxicosis (destructive release of preformed hormone) → hypothyroid phase → euthyroid (or permanent hypothyroidism). Common in women with TPO antibodies.

TPO Antibodies in Euthyroid Women: - Anti-TPO positive but euthyroid → increased risk of: - Miscarriage (OR 1.5–2). - Preterm birth. - Postpartum thyroiditis (50%). - Gestational diabetes? Possible association. - Screening: Not routinely done in UK (controversial). If found, check TSH throughout pregnancy every 6–8 weeks.

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10.5 Immune Thrombocytopenia (ITP) in Pregnancy

Definition: Acquired immune-mediated destruction of platelets (antiplatelet IgG to GPIIb/IIIa, GPIb/IX). Platelet count <100 × 10⁹/L.

Background: - Incidence: ~1–3 in 10,000 pregnancies. - Usually pre-existing but can be diagnosed in pregnancy. - Important to differentiate from gestational thrombocytopenia (most common cause of low platelets in pregnancy — 5–8% of pregnancies; mild, >70 × 10⁹/L, asymptomatic, resolves postpartum).

Risks: - Maternal: Bleeding at delivery (especially if platelets <50 × 10⁹/L). Risk of epidural haematoma (platelets need >50–80 × 10⁹/L for epidural). - Fetal/neonatal: Maternal antiplatelet IgG crosses the placenta → neonatal thrombocytopenia (5–15% risk of severe <20 × 10⁹/L). Risk of intracranial haemorrhage (ICH) during vaginal delivery is very low (<1%).

Management: - Preconception: Optimise platelet count. Avoid splenectomy before pregnancy (spleen is important for fetal immunoprotection? Actually, splenectomy can be done but increases infection risk). - During pregnancy: - Monitor maternal platelets every 2–4 weeks. - Indications for treatment: - Platelets <20–30 × 10⁹/L (any gestation). - Platelets <50 × 10⁹/L in third trimester (to allow for safe delivery and epidural). - Active bleeding. - First-line: Oral prednisolone 0.25–0.5 mg/kg/day (gradual taper). Side effects: gestational diabetes, hypertension, osteoporosis, weight gain. - Second-line: IVIG (intravenous immunoglobulin) 1 g/kg × 1–2 doses. Faster response (24–48 h) but short-lived (3–4 weeks). Used if corticosteroid-resistant or pre-delivery. - Third-line: Azathioprine (safe in pregnancy). Rituximab (limited data but probably safe). Splenectomy (avoid in pregnancy — best in second trimester if unavoidable). - Avoid: Vinca alkaloids, cyclophosphamide, danazol (androgen). - Platelet transfusion: Only for life-threatening bleeding or emergency C-section when platelets cannot be raised (transient effect because antiplatelet antibodies rapidly destroy transfused platelets). - Delivery: - Aim for platelets >50 × 10⁹/L for vaginal delivery, >80 × 10⁹/L for C-section. - Epidural anaesthesia: Need platelets >80 × 10⁹/L (some centres accept >50–70 × 10⁹/L if no other bleeding risk). - Avoid: Fetal scalp electrodes, fetal blood sampling, rotational delivery, ventouse (elective low-cavity forceps may be considered). - Neonatal management: - Cord blood platelets at birth. - If severe thrombocytopenia → IVIG. Avoid IM injections (Vitamin K can be given oral/subcutaneous). Check cranial USS for ICH. - Usually resolves spontaneously in 1–4 weeks.

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10.6 Myasthenia Gravis (MG) in Pregnancy

Definition: - Autoimmune disorder — antibodies to acetylcholine receptor (AChR) at neuromuscular junction → impaired neuromuscular transmission → muscle weakness. - 10–15% have anti-MuSK antibodies (muscle-specific tyrosine kinase). - Incidence: 1–5 in 10,000 pregnancies.

Clinical Features: - Fluctuating muscle weakness (worse with use, improves with rest). - Ocular: Ptosis, diplopia. - Bulbar: Dysphagia, dysphonia, choking. - Generalised: Proximal limb weakness, neck weakness. - Respiratory: Diaphragm weakness → myasthenic crisis (medical emergency).

Management in Pregnancy: - Pre-pregnancy counselling: Disease should be in remission/stable for ≥6 months before conception. Thymectomy (if thymoma) should be done before pregnancy. - Medications: - Pyridostigmine (acetylcholinesterase inhibitor) — first-line, safe in pregnancy. - Prednisolone — safe in pregnancy, lowest effective dose. - Azathioprine — safe (lowest effective dose). - Mycophenolate mofetil and methotrexate — CONTRAINDICATED (teratogenic). - IVIG / plasma exchange — safe if severe exacerbation/myasthenic crisis in pregnancy. - Labour and delivery: - Mode of delivery: Vaginal is safe. Shorten second stage (assisted delivery). Epidural recommended (reduces pain/fatigue, allows for C-section if needed). - Avoid: Magnesium sulphate (contraindicated — blocks neuromuscular transmission → precipitates crisis). Use phenytoin/levetiracetam for eclampsia. - Avoid: Aminoglycoside antibiotics, quinolones, macrolides — can exacerbate weakness. - Avoid: Muscle relaxants (suxamethonium, non-depolarising NMBDs — prolonged effect). - C-section: For obstetric indications only. - Neonatal: - Transient neonatal myasthenia: Occurs in 10–15% of infants. Maternal AChR antibodies cross placenta. Presents hours to days after birth: weak cry, poor sucking, hypotonia, respiratory difficulty. Lasts 2–4 weeks. Treat with oral pyridostigmine. Supportive care ± ventilation. - Risk correlates with maternal antibody titre, not disease severity.

Myasthenic Crisis: - Respiratory failure requiring ventilation. - Triggers: Infection, surgery, stress, pregnancy, certain drugs. - Management: ICU, IVIG 1 g/kg × 2 days or plasma exchange × 5–7 exchanges, pyridostigmine (IV via NG tube), corticosteroids.

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10.7 Other Immunological Disorders in Pregnancy

Rheumatoid Arthritis (RA): - 70% improve in pregnancy (Th2 shift, increased anti-inflammatory cytokines). - Flares postpartum (up to 90% within 1–3 months). - Safe drugs: Hydroxychloroquine, sulfasalazine, prednisolone, TNF-α inhibitors (certolizumab has minimal placental transfer — active transport via FcRn is lacking in certolizumab because it's a PEGylated Fab fragment; others like adalimumab, infliximab cross placenta — especially in third trimester). - Contraindicated: Methotrexate, leflunomide, tofacitinib. - Effect on pregnancy: Minimal if disease controlled. Mild increase in preterm birth, IUGR.

Inflammatory Bowel Disease (IBD): - Crohn's disease (most commonly) and ulcerative colitis can affect pregnancy. - Active disease at conception → higher risk of preterm birth, LBW, disease flare. - Safe drugs: Mesalazine, sulfasalazine (add folate), azathioprine, prednisolone, anti-TNF biologics. - Contraindicated: Methotrexate. - Mode of delivery: C-section for active perianal Crohn's disease (to avoid perineal damage/formation of fistula). Otherwise vaginal delivery is safe.

Autoimmune Hepatitis (AIH): - Type 1: ANA + anti-smooth muscle antibody. - Type 2: Anti-LKM1 (liver kidney microsomal) antibody. - Treatment: Prednisolone + azathioprine — both safe in pregnancy. - Contraindicated: Mycophenolate mofetil (teratogenic).

Celiac Disease: - Autoimmune enteropathy triggered by gluten. - Associated with: Recurrent miscarriage, IUGR, preterm birth, subfertility (undiagnosed). - Screening: Anti-tTG (tissue transglutaminase) IgA + total IgA (to exclude IgA deficiency). - Treatment: Strict gluten-free diet before and during pregnancy → outcomes normalise.

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QUICK REVISION TABLES (Key Facts for MRCOG Part 1)

TORCH Infections

Organism	Key Feature	Fetal Effect	Treatment in Pregnancy
Toxoplasma	Cat faeces, undercooked meat	Chorioretinitis, hydrocephalus, intracranial calcifications	Spiramycin (maternal); Pyrimethamine+sulfadiazine (fetal)
Other (Syphilis)	T. pallidum	Congenital syphilis, stillbirth	Penicillin (desensitise if allergic)
Rubella	MMR vaccine-preventable	Cataract, deafness, PDA	Termination discussion if <16 weeks
CMV	Most common congenital infection	SNHL, microcephaly, petechiae	Valganciclovir (specialist)
HSV	Neonatal herpes	Disseminated neonatal HSV, encephalitis	Aciclovir; C-section if primary in 3rd trimester
HIV	Vertical transmission <1% with treatment	Paediatric HIV	cART, C-section if VL>1000, avoid BF

Vaccination in Pregnancy

Vaccine	Type	Recommended?
Influenza	Inactivated	Yes — all trimesters
Pertussis (Tdap/IPV)	Inactivated	Yes — 16–32 weeks (boost maternal Ab)
COVID-19 (mRNA)	mRNA	Yes — all trimesters
MMR	Live attenuated	No — contraindicated (give postpartum)
Varicella	Live attenuated	No — contraindicated (give postpartum)
HPV	Recombinant	No — insufficient data (but safe if given accidentally)
Hepatitis B	Recombinant	Yes — if high risk
BCG	Live attenuated	No — contraindicated
Yellow Fever	Live attenuated	No — contraindicated (but may be given if high risk/outbreak)

Antibiotic Safety in Pregnancy

Antibiotic	Safety	Notes
Penicillins	Safe	First-line for most infections
Cephalosporins	Safe	Cross-allergy with penicillin ~10%
Metronidazole	Safe	All trimesters
Clindamycin	Safe	GI side effects common
Erythromycin	Safe	GI side effects; avoid estolate salt (hepatotoxicity)
Azithromycin	Safe	Better tolerated than erythromycin
Nitrofurantoin	Safe	Avoid at term (haemolytic anaemia — G6PD)
Gentamicin	Caution	Ototoxicity risk with prolonged use; short courses safe
Vancomycin	Safe	Monitor levels
Fluconazole (oral)	Avoid in 1st trimester	Low-dose single dose probably safe, but avoid high-dose/long-term
Quinolones	Avoid	Cartilage damage (animal studies)
Tetracyclines (doxycycline)	Avoid	Tooth discolouration, bone growth suppression
Co-trimoxazole	Avoid in 1st trimester	Folate antagonist — NTD risk; also kernicterus risk at term
Rifampicin	Safe	Give with pyridoxine if with isoniazid
Isoniazid	Safe	Give pyridoxine (B6) to prevent neuropathy
Chloramphenicol	Avoid at term	Grey baby syndrome
Aminoglycosides	Caution	Fetal ototoxicity (prolonged/high doses)

Key Immunological Differences in Pregnancy

Parameter	Normal Pregnancy	Pathological (Pre-eclampsia/Miscarriage)
Th1/Th2 balance	Th2 dominant	Th1 dominant
Treg	↑ Increased	↓ Decreased
NK cells	CD56^bright CD16^- (decidual, angiogenic)	More cytotoxic profile
Th17	Balanced	↑ Increased
Complement	Well-regulated	Excessive activation
Cytokines	IL-10, TGF-β high	TNF-α, IFN-γ, IL-17 high

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SAMPLE MRCOG PART 1 STYLE QUESTIONS

Q1. A 28-year-old primigravida at 39 weeks presents in spontaneous labour. She has a history of genital herpes. She has no visible lesions today. What is the most appropriate management?

A. Intravenous aciclovir in labour B. Elective caesarean section C. Vaginal delivery with scalp electrode monitoring D. Vaginal delivery without intervention E. Oral aciclovir suppression from 36 weeks

Answer: D. If no active lesions or prodrome at delivery, vaginal delivery is safe. Suppressive aciclovir from 36 weeks reduces the chance of recurrent outbreak. In the absence of lesions, C-section is not indicated.

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Q2. Which of the following is the most common cause of non-immune hydrops fetalis?

A. Parvovirus B19 B. Cytomegalovirus C. Toxoplasmosis D. Rubella E. Syphilis

Answer: A. Parvovirus B19 targets erythroid progenitor cells → severe fetal anaemia → high-output cardiac failure → hydrops fetalis.

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Q3. A woman with anti-Ro antibodies delivers a term infant. Which neonatal complication is most specific to this condition?

A. Haemolytic disease of the newborn B. Transient tachypnoea of the newborn C. Congenital heart block D. Neonatal herpes E. Meconium aspiration syndrome

Answer: C. Anti-Ro/SSA antibodies cross the placenta and bind to fetal cardiac conducting tissue, causing inflammation and fibrosis of the AV node → congenital heart block (usually 18–24 weeks gestation).

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Q4. Which of the following vaccines is contraindicated in pregnancy?

A. Inactivated influenza vaccine B. Tdap (pertussis) C. MMR (measles, mumps, rubella) D. Recombinant hepatitis B vaccine E. COVID-19 mRNA vaccine

Answer: C. MMR is a live attenuated vaccine and is contraindicated in pregnancy. The others are inactivated/recombinant and safe.

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Q5. A woman presents at 34 weeks with a new diagnosis of primary genital HSV. What is the most appropriate management?

A. Oral aciclovir, plan for vaginal delivery at term B. Oral aciclovir, plan for elective caesarean delivery at 39 weeks C. No treatment needed; plan vaginal delivery D. IV aciclovir, plan for C-section at 38 weeks E. Oral valaciclovir, plan for C-section if active lesions at delivery

Answer: B. Primary HSV in the third trimester carries a high risk (30–50%) of neonatal transmission because protective maternal IgG has not crossed the placenta. Women should receive suppressive aciclovir (400 mg TDS from 36 weeks) and be offered elective C-section at 38–39 weeks (or as soon as membranes rupture).

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Q6. Which immunoglobulin class is transferred across the placenta?

A. IgA B. IgD C. IgE D. IgG E. IgM

Answer: D. Only IgG crosses the placenta via the neonatal Fc receptor (FcRn). Transfer increases in the third trimester.

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Q7. What is the mechanism by which the trophoblast evades recognition by maternal NK cells?

A. Expression of HLA-A and HLA-B B. Expression of HLA-G C. Downregulation of MHC class II D. Secretion of IL-2 E. Expression of CD4

Answer: B. Trophoblast expresses HLA-G (non-classical MHC-I), HLA-C, and HLA-E. HLA-G binds to inhibitory receptors (LILRB1, KIR2DL4) on maternal NK cells, preventing NK-mediated killing.

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Q8. Which of the following best describes the role of regulatory T cells (Treg) in pregnancy?

A. Promote Th1 responses B. Activate NK cells C. Suppress alloreactive T cells and maintain maternal-fetal tolerance D. Enhance complement activation E. Produce perforin and granzymes

Answer: C. Treg are essential for maternal-fetal tolerance. They suppress alloreactive T cells that recognise paternal antigens, via IL-10, TGF-β, and CTLA-4. Treg deficiency is associated with miscarriage.

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Q9. A woman with antiphospholipid syndrome (APS) and a history of three consecutive first-trimester miscarriages is now pregnant. What is the most appropriate management?

A. Low-dose aspirin alone B. LMWH alone C. Low-dose aspirin + LMWH D. Prednisolone + aspirin E. IVIG + aspirin

Answer: C. The standard of care for obstetric APS is low-dose aspirin (75–150 mg daily) + prophylactic LMWH (e.g., enoxaparin 40 mg daily) throughout pregnancy and for 6 weeks postpartum.

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Q10. Which of the following antibodies is responsible for neonatal lupus and congenital heart block?

A. Anti-dsDNA B. Anti-Smith C. Anti-Ro/SSA D. Anti-CCP E. Anti-cardiolipin

Answer: C. Anti-Ro/SSA antibodies cross the placenta and react with fetal cardiac tissue, causing congenital heart block and neonatal lupus rash.

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KEY REFERENCES & FURTHER READING

1. RCOG Green-top Guidelines:
2. Group B Streptococcus (GBS) in Pregnancy and Newborn (No. 36)
3. Chickenpox in Pregnancy (No. 13)
4. Cytomegalovirus in Pregnancy (No. 88)
5. HIV in Pregnancy (No. 39)
6. Antiphospholipid Syndrome (No. 17a, 17b)
7. Sepsis in Pregnancy (No. 64a, 64b)
8. Bacterial Sepsis in Pregnancy (No. 64a)

9. Urinary Tract Infections in Pregnancy (No. 66)

10. BASHH UK Guidelines: STI management.

11. Immunisation Against Infectious Disease (The Green Book): Pregnancy vaccination.

12. BHIVA Guidelines: HIV in pregnancy.

13. MBRRACE-UK Reports: Maternal deaths — sepsis lessons.

14. Textbooks:

15. Obstetrics by Ten Teachers — infection and immunology chapters.
16. Gynaecology by Ten Teachers — STI, pelvic infection chapters.
17. Kumar & Clark's Clinical Medicine — immunology and infection.
18. Abbas: Cellular and Molecular Immunology — core immunology.

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MNEMONICS FOR REVISION

"TORCH" infections in pregnancy: - Toxoplasmosis - Other (Syphilis, Varicella, Parvovirus B19, Zika, HIV, TB) - Rubella - Cytomegalovirus - Herpes simplex

Bacteria in puerperal sepsis — "the Sixes": - Group A Streptococcus (S. pyogenes) - Group B Streptococcus (S. agalactiae) - E. coli - Clostridium perfringens - Staphylococcus aureus - Bacteroides fragilis

Congenital rubella syndrome: - Cataract - Deafness - PDA (Patent Ductus Arteriosus)

Congenital toxoplasmosis (Sabin's triad): - Chorioretinitis - Hydrocephalus - Calcifications (intracranial)

Amsel criteria for BV: - Discharge (thin, homogeneous) - Odour (fishy — amine test) - PH >4.5 - Clue cells (>20%)

Sepsis Six (1-hour bundle): 1. Oxygen 2. Blood cultures 3. Antibiotics IV 4. Lactate 5. Urine output 6. Fluids IV

Immunoglobulin placental transfer: - Only Goes across — IgG

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End of document. This study guide covers the full MRCOG Part 1 syllabus for Microbiology & Immunology. Use it alongside past papers, RCOG guidelines, and question banks for comprehensive preparation.

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