📚 Clinical Reference Guides

Pregnancy lasts, on average, 280 days (40 weeks) from the first day of the LMP — 9 calendar months or 10 lunar months. Always expressed in completed weeks.

Rules to estimate EDD: Wahl (LMP+10 days, -3 months) · Naegele (LMP+7 days, -3 months).

Ultrasound correction: if it differs beyond the accepted margin, GA by ultrasound takes priority — the earlier the scan, the more reliable (maximum precision in the 1st trimester).

Systematic evaluation by parameter (normal/mild/moderate/severe) to detect clinical deterioration in time:

Low risk: no identifiable factors, standard follow-up.

Moderate: maternal age 35-39, overweight/obesity, adverse history, mild anemia, treated STI.

High risk: <15 or >35-40 years, multiple gestation, prior fetal death, prior preeclampsia, chronic hypertension, diabetes, heart disease, chronic renal/pulmonary disease, autoimmune disease, moderate/severe anemia, STI/HIV/hepatitis, active TB, uterine malformation, placenta previa, abruption, FGR, oligo/polyhydramnios, sexual violence, substance use.

Reassess at every visit.

Tdap: international 27-36 wk, national (EPI) 16-20 wk. COVID-19: international any trimester, national from 20 wk. Maternal RSV: 28-36 wk (not part of the national schedule). Flu: any trimester.

Contraindicated (live attenuated): MMR, varicella, yellow fever (except high risk), zoster, BCG, oral rotavirus.

• Folic acid: 400–800 µg/day standard from preconception. 4 mg/day (ACOG) or 5 mg/day (NICE) up to wk 12 with a previous neural tube defect, epilepsy, obesity or diabetes. With MTHFR: standard folic acid (CDC, the only form proven to prevent NTDs); methylfolate 400–800 µg/day as an optional alternative
• Iron: 30–60 mg/day prophylaxis (WHO). Anaemia: 120 mg/day elemental iron until Hb normalises, then prophylaxis. Hb <7 g/dL: IV iron from the 2nd trimester and consider transfusion according to the clinical picture
• Calcium: requirement 1000 mg/day (1300 under 19 years), the same as outside pregnancy (IOM 2011). WHO: 1.5–2 g/day in low-intake populations to prevent pre-eclampsia. Cochrane 2025 (Cluver, 10 trials, 37,504 women): no difference in pre-eclampsia in the large trials. Physician's decision; separate from iron
• Vitamin D: 20–29 ng/mL: supplement at the physician's discretion (1000–2000 IU/day); deficiency <20: 2000–4000 IU/day. Without testing: Endocrine Society 2024 suggests empirical supplementation; WHO 2020, no routine supplementation
• Omega-3 (DHA): 200–300 mg/day in the general population. With risk of preterm birth: 500–1000 mg/day DHA+EPA before 20 wk (Cochrane 2018: 42% fewer births <34 wk)
• Iodine: 150 µg/day supplement (potassium iodide) from preconception; total intake target 250 µg/day (ATA). Avoid supplements >500 µg/day

1st trimester: CBC, blood group/Rh/indirect Coombs, VDRL/RPR+confirmatory, HIV, HBsAg, glucose, urea/creatinine/uric acid, liver panel, TSH per risk, urinalysis/urine culture.

2nd trimester (24-28 wk): CBC, 75g OGTT, HbA1c if at risk, repeat VDRL/HIV, toxoplasmosis, urinalysis.

3rd trimester (35-37 wk): CBC, coagulation panel, glucose, renal/liver function, GBS swab.

1st trimester (5-14 wk): early scan + dedicated 11-14 wk scan (NT, nasal bone, ductus venosus, uterine artery Doppler).

2nd trimester (18-24 wk): complete morphology scan, placenta, amniotic fluid, cervical length per risk.

3rd trimester (32 wk+): growth, amniotic fluid, presentation, Doppler/biophysical profile as indicated.

• Vital signs: every visit
• Fundal height: from month 4
• FHR: Doppler from month 4, Pinard from month 6
• Leopold maneuvers: from month 6-7
• Genital exam: 1st visit and at month 8

Detection of heartbeat: real-time ultrasound 6-8 wk, Doppler from 12 wk, stethoscope from 20 wk.

Fetal movements: perceived from 18-20 wk (nulliparous).

Self-monitoring: 4 movements in the 1st hour = normal, or up to 10 in 12h · or 30min post each meal, totaling 10+.

If 10 movements are not reached in 12h, or fluid loss/contractions occur: seek care.

Warning signs: bleeding, foul-smelling discharge, decreased movements, severe abdominal pain, contractions before term, fever, severe headache/blurred vision, sudden edema, difficulty breathing, fluid loss.

Restrictions: tobacco, alcohol, drugs, unnecessary radiation, medication without indication.

The theoretical risk of a method is always lower than that of an unwanted pregnancy. Right to choose freely, without coercion.

Options: condom, ring, injectable, pills, copper/hormonal IUD, implant, sterilization, patch.

Estrogen-containing methods are contraindicated in the first 6 months of breastfeeding.

Safe and recommended: ≥150 min/week moderate aerobic activity (walking, swimming, stationary bike, prenatal yoga/pilates).

Avoid: contact sports/fall-risk activities.

Contraindications: TPL, placenta previa after week 26, PROM, FGR, severe heart disease, severe anemia.

WHO: minimum 8 contacts (before 12, then 20/26/30/34/36/38/40 wk). National (MSPyBS): minimum 4 (before 12, 22-26, 27-32, 36-38 wk).

Low risk: monthly up to 28 wk, every 2-3 wk up to 35-36, weekly in the last month.

Total energy cost ~80,000 kcal, ~300 kcal/day extra.

Gain by BMI: underweight 12.5-18.0kg · normal 11.5-16.0kg · overweight 7.5-11.5kg · obesity 6.0kg.

Distribution: 500g/month (T1) · 1000g/month (T2) · 1500g/month (T3). Macros: 55% carbs, 15% protein, 30% fat.

MAP = (SBP + 2×DBP) / 3

• MAP ≥105: warning for gestational hypertension/preeclampsia, assess proteinuria/hepatorenal function
• MAP >90 in 1st trimester (≤14 wk): higher risk, consider prophylactic aspirin
• MAP >90 outside 1st trimester: routine surveillance

By percentile (EFW): severe SGA/FGR <P3 · FGR P3-P10+abnormal Doppler · SGA P3-P10+normal Doppler · AGA P10-P90 · borderline LGA P90-P97 · significant LGA ≥P97.

By birth weight (WHO): extremely low <1000g · very low 1000-1499g · low <2500g · normal 2500-3999g · macrosomia ≥4000g · severe ≥4500g.

Classification:

• Chronic: BP ≥140/90 before pregnancy or diagnosed before week 20
• Gestational: BP ≥140/90 after wk 20, without proteinuria or organ dysfunction
• Preeclampsia: BP ≥140/90 after wk 20 + proteinuria (≥0.3g/24h) or ≥1 severity criterion, even without proteinuria
• Chronic with superimposed preeclampsia: worsening + new proteinuria/organ dysfunction
• Eclampsia: tonic-clonic seizures in preeclampsia, with no other neurological cause

Severity criteria (≥1 confirms severe preeclampsia): BP ≥160/110 on 2 readings 15min apart, thrombocytopenia <100,000, doubled transaminases, creatinine >1.1 or doubled, pulmonary edema, new neuro-visual symptoms.

Prophylaxis (high risk): ASA 100-150mg/day PO at night, from wk 12-16 to wk 36. Elemental calcium 1.5-2.0g/day if low intake.

Chronic treatment (BP >140/90): Labetalol 100-400mg PO q8-12h (max 2,400mg/day) · Alpha-methyldopa 250-500mg PO q6-8h · Extended-release nifedipine 20-60mg PO q12-24h.

⚠️ Contraindicated: ACE inhibitors, ARBs, renin inhibitors.

Hypertensive crisis (≥160/110): IV labetalol bolus 20mg → 40mg → 80mg q10min (max 300mg) · IV hydralazine bolus 5-10mg q20min (max 20mg) · Oral nifedipine 10-20mg (not sublingual).

Indication: preeclampsia with severity criteria, and eclampsia.

Dose: 4-6g IV loading dose in 100mL 0.9% NS over 15-20 min → continuous maintenance 1-2g/hour IV for 24h postpartum or post-last seizure.

Monitoring: patellar reflex present, RR >12-14/min, urine output >30mL/h.

⚠️ Signs of toxicity: RR<12rpm, absent patellar reflex, oliguria <30mL/h, AV block.

⚠️ Antidote — 10% Calcium Gluconate, two current standards (equivalent in available elemental calcium, not contradictory):

• National standard (MSPyBS Paraguay, Code Red 2nd ed. 2021): 10% Calcium Gluconate — 1g (10mL) IV slow push over 3 min.
• Advanced international resuscitation standard (AHA · Universidad de Antioquia · PAHO): 10% Calcium Gluconate — 3g (30mL) IV, or alternatively 10% Calcium Chloride — 1g (10mL) IV.

This is not a dosing error: 1g of calcium gluconate provides ~93mg of elemental calcium, while 1g of calcium chloride provides ~272mg — which is why the international advanced-resuscitation regimen uses a larger volume of gluconate (3g/30mL) to match the elemental calcium delivered by 1g of chloride. Which to use? The national standard for an isolated toxicity sign (RR<12, areflexia, oliguria); the international regimen for frank cardiorespiratory arrest from hypermagnesemia.

CPR specifics in pregnancy: continuous manual left uterine displacement (or 15-30° left lateral tilt) from the start, to relieve aortocaval compression; chest compressions slightly higher on the sternum; defibrillation at the same energies as outside pregnancy (not contraindicated).

Fundal height threshold (fundus at or above the umbilicus, ≈20 weeks): from this point on, the gravid uterus causes enough aortocaval compression to invalidate the effectiveness of chest compressions — this is the action threshold, defined by maternal benefit, not fetal viability.

≥22-24 weeks is a separate, later threshold: fetal viability — a secondary consideration about the expected neonatal outcome, not about whether to perform the hysterotomy.

4-5 minute rule: if there is no return of spontaneous circulation (ROSC) by 4 minutes of high-quality CPR, begin the cesarean/perimortem hysterotomy incision in situ (do not transfer to the operating room) to achieve delivery by minute 5. The primary goal is maternal: evacuating the uterus improves venous return and compression effectiveness.

Lipid elevation is physiological in pregnancy — no routine screening. Targeted in: family history of early CVD, pre-pregnancy obesity, prior diabetes/preeclampsia, severe hypertriglyceridemia.

Treatment: 1st line diet/exercise. Statins: FDA (2021) withdrew the absolute contraindication, individualized use in very high risk. Bile acid sequestrants (the only ones approved in pregnancy): Cholestyramine, Colestipol, Colesevelam. Omega-3: reduces preterm birth risk (Cochrane 2018).

Diagnosis: nocturnal palmoplantar pruritus, without primary skin lesion. Labs: bilirubin, AST/ALT, ALP, GGT.

National criterion (MSPBS 2018): Low risk — bile acids 10–19 μmol/L with normal enzymes → outpatient, weekly control, elective delivery at 36–37 wk. Moderate risk — bile acids 20–39 and/or AST/ALT up to 2× → ≥28 wk admission and control every 72 h; if no response, manage as high; delivery at 36–37 wk (CaVeSal® suggestion: the manual sets no week for this group). High risk — bile acids ≥40 and/or enzymes >2× (>80 IU/L) and/or no response → always admit; <34 wk: UDCA up to maximum dose and, if no improvement, lung maturation and delivery; ≥36 wk: deliver.

Regional reference (MINSAL Chile 2015): anicteric → 38 wk · icteric (bilirubin >1.2 + enzymes) → 36 wk. International reference (RCOG 2022): diagnosis ≥19 μmol/L · 40–99 → 38–39 wk · ≥100 → 35–36 wk (consider earlier).

Treatment: ursodeoxycholic acid 10–16 mg/kg/day in 2 doses (start 900 mg/day, maximum 1200 mg/day) + vitamin K if cholestasis is prolonged. Follow-up: liver profile, bile acids and PT every 1–2 wk; CTG every 3–7 days.

⚠️ Deliver at any sign of fetal compromise, regardless of pathway or GA.

Diagnosis: regular uterine dynamics (≥4/20min) + cervical changes, 22-36+6 wk.

TVUS: CL >30mm rules out TPL · CL <25mm high risk · 20-30mm → biomarkers (fetal fibronectin/PAMG-1).

Tocolysis (22/24-33+6 wk): Nifedipine (1st line) loading dose 10-20mg q20min → maintenance q6-8h · Atosiban (NICE/RCOG) · Indomethacin (before wk 32, do not combine with MgSO4 or nifedipine).

Cutoffs by guideline: ACOG wk 24-33+6 (late 34-36+6) · FIGO/WHO 24-34+6 · NICE offer 24-33+6, consider 34-35+6.

Regimens: Betamethasone 12mg IM q24h (2 doses) · Dexamethasone 6mg IM q12h (4 doses).

Rescue course: if >14 days have passed, GA <34 wk, imminent risk within 7 days.

Cutoffs by guideline: ACOG before wk 32 · NICE before wk 30 (consider 30-33+6) · FIGO/WHO before wk 32 (some extend to <34 if imminent).

Regimen: 4g IV loading dose over 20-30 min → maintenance 1g/hour until delivery or 24h.

⚠️ Antidote (see full detail in "Magnesium sulfate — Seizure prevention and management"): national standard 10% Calcium Gluconate 1g (10mL) IV slow push over 3 min · advanced international resuscitation standard 3g (30mL), or 10% Calcium Chloride 1g (10mL) — same concentration, larger gluconate volume to match the elemental calcium delivered by the chloride.

Clinical: clear fluid leakage (>90% reliability if visualized through the cervical os).

Tests: Fern test, Nitrazine (pH>6.5), PAMG-1/IGFBP-1, vaginal urea/creatinine (>90-95% sensitivity).

Amniocentesis (doubtful cases): Indigo Carmine + tampon, check staining at 20-30min. ⚠️ Methylene Blue contraindicated.

• Previable (<22-24 wk): expectant, counseling. No routine antibiotics/corticosteroids.
• Far from term preterm (24-33+6): expectant, inpatient, complete lung maturation course, neuroprotective MgSO4 if <32 wk, mandatory latency antibiotics, tocolysis restricted to 48h.
• Late preterm (34-36+6): delivery/induction at diagnosis. Exception: expectant until wk 37 if no infection.
• Term (≥37): induction within 12-24h.

Standard (7 days, 24-34 wk): Days 1-2 IV: Ampicillin 2g q6h + Erythromycin 250mg q6h. Days 3-7 oral: Amoxicillin 500mg q8h + Erythromycin 333mg q8h.

Alternative: Ampicillin 2g IV q6h x48h → Amoxicillin 500mg PO q8h x5d + Azithromycin 1g PO single dose.

⚠️ Avoid Amoxicillin+Clavulanate (neonatal NEC).

Immediate delivery: chorioamnionitis, abruption, fetal distress, established labor, stillbirth.

NVP: physiological, up to 80%, wk 4-9 to 16-20. HG: severe, 0.3-2%. Triad: intractable vomiting + >5% weight loss + ketonuria/electrolyte disturbance.

PUQE score (24h, 3 questions, 1-5pts): ≤6 mild · 7-12 moderate · ≥13 severe HG (inpatient).

1st line: Pyridoxine B6 10-25mg q6-8h · Doxylamine+Pyridoxine 2 tabs/night.

2nd line: Dimenhydrinate, Metoclopramide (<5 days), Promethazine.

3rd line: Ondansetron (from wk 10) · Methylprednisolone (last resort, >10 wk).

⚠️ Golden rule: Thiamine B1 100mg IV before/with the first dextrose infusion — prevents Wernicke's encephalopathy.

Methods: SDP/DVP (preferred) · AFI (4 quadrants).

Classic: Oligohydramnios AFI<5/SDP<2 · Normal 5.1-24.9/2.1-7.9 · Polyhydramnios AFI≥25/SDP≥8.

ACOG/SMFM ranges: Anhydramnios=0 · Severe <1/<3 · Lower borderline 5.1-8.0 (follow-up) · Physiological normal 8.1-18.0 · Upper borderline 18.1-24.9.

• Mild: AFI 25.0-29.9 (80% of cases)
• Moderate: 30.0-34.9
• Severe: ≥35 (>50% association with malformations)

Oligohydramnios: maternal (placental insufficiency, hypertension, APS, dehydration, drugs) · fetal (urinary anomalies, FGR, post-term) · membrane-related (PROM, TTTS donor).

Polyhydramnios: maternal (diabetes) · fetal (GI, CNS, neuromuscular, cardiac, chromosomal) · membrane-related (TTTS recipient) · idiopathic 50-60%.

Structured system-by-system checklist, 18-24 weeks, immediately after the 2nd-trimester FMF screening.

CNS: cavum septum pellucidum (absent ⚠️), symmetric thalami, cranial shape ("lemon"/"strawberry" sign ⚠️), lateral ventricular atrium (normal <10mm · mild 10-15mm · severe >15mm, measured at the level of the choroid plexus glomus), cisterna magna (normal 3.0-10.0mm; <2-3mm obliterated, >10mm mega cisterna magna), 2T nuchal fold (valid 15.0-20.6 wk, normal <6.0mm), banana sign, and cerebellar vermis agenesis. An obliterated cisterna magna plus a banana sign point toward open spina bifida — correlate with the spine.

Face: orbits, nose, maxilla, palate (retronasal coronal view), and upper lip. Orbital diameters: IOD/OOD ratio >0.40 hypertelorism, <0.25 hypotelorism (rule of thirds).

Spine: bony continuity on longitudinal + axial views, and intact overlying skin.

Chest and heart (+ CDH): situs, 4-chamber view, ventricular/atrial symmetry, interventricular septum (VSD), outflow tracts, 3-vessel and trachea view, aortic arch. Cardiothoracic area ratio: normal 0.25-0.33, cardiomegaly >0.35. Congenital diaphragmatic hernia: intrathoracic gastric bubble, side (left Bochdalek ~85%), O/E LHR <25% severe · 25-44.9% moderate · ≥45% favorable.

Abdomen: stomach (rule out "double bubble" — duodenal atresia, ~30% association with T21), abdominal wall/cord (omphalocele vs. gastroschisis), renal pelvic dilation (<33 wk obstructive >10.0mm; ≥33 wk obstructive >10.0mm with a distinct normal cutoff of <7.0mm), kidneys (uni/bilateral agenesis, multicystic dysplasia), single umbilical artery, 2T/3T megacystis (≥16 wk, pathological if longitudinal diameter > [GA in weeks + 12]mm), and "keyhole sign" (PUV).

Limbs: 3 segments per limb (humerus/radius-ulna/hand; femur/tibia-fibula/foot) to avoid missing reduction defects, polydactyly (soft marker for T13/Meckel-Gruber/Bardet-Biedl if isolated), and clubfoot.

Placenta, cord, amniotic fluid, cervix: placental location (low-lying <20mm from the internal os) and cord insertion site (marginal "racquet" vs. velamentous — vasa previa risk, confirm with color Doppler).

Placenta accreta spectrum (PAS: accreta/increta/percreta). Main risk factor: prior cesarean plus anterior placenta previa/low-lying placenta.

⚠️ Golden rule: whenever signs of accreta are present, never attempt manual placental removal — leave the placenta in situ and proceed to en bloc hysterectomy, at a Level III-IV center, with a planned cesarean at 34+0-35+6 weeks.

Risk factors: number of prior cesareans, prior uterine curettage, prior uterine surgery (myomectomy), history of Asherman syndrome — in addition to placenta previa/low-lying placenta and maternal age >35 or IVF, already recorded under Morphology and History.

2D ultrasound signs: loss of the clear zone, myometrial thinning (<1mm), irregular placental lacunae ("Swiss cheese" appearance), interruption of the bladder-uterine interface, placental bulging toward the bladder, focal exophytic mass.

Color Doppler signs: uterovesical and subplacental hypervascularity, bridging vessels, lacunar feeder vessels, parametrial involvement.

FIGO Classification (surgical/histopathological confirmation): Grade 1 (Accreta) · Grade 2 (Increta) · Grade 3a (Percreta limited to the uterine serosa) · Grade 3b (Percreta with urinary bladder invasion) · Grade 3c (Percreta with invasion of other pelvic tissues/organs: broad ligament, vaginal wall, pelvic sidewall or any other pelvic organ, with or without bladder invasion). Jauniaux E, et al. FIGO, Int J Gynecol Obstet 2019;146:20-24.

⚠️ Probability and Extent are calculated using the "CaVeSal Classification" — a proprietary scoring scheme developed by the team (not a published FIGO/ISUOG/ACOG score) that combines risk factors + 2D signs + Doppler signs. The FIGO Classification is a separate data point, based on surgical/histopathological confirmation — it does not replace, and should not be confused with, the CaVeSal Classification.

Antenatal diagnosis (WAPM/PMF 2026): cesarean scar pregnancy is a potential precursor of PAS — after a previous cesarean, early transvaginal ultrasound to establish the implantation site. In the 2nd-3rd trimester, combined transabdominal and transvaginal ultrasound (placental location, myometrial thickness and contour, uterovesical interface); markers: lacunae, placental bulge, uterovesical hypervascularity and bridging vessels, alone or combined. 2D ultrasound with color Doppler is the mainstay; MRI is complementary (inconclusive ultrasound, non-anterior or non-previa placenta, technical limits). If cesarean scar pregnancy or PAS is suspected: refer to a perinatal center with a multidisciplinary team, blood products, adult and neonatal ICU and complex pelvic surgery; delivery timing is individualized.

Modalities: Complete (Manning, 5 variables, 10 points + NST) · Ultrasound-only (8 points, no NST) · Abbreviated (Clark: NST + amniotic fluid) · Vintzileos (graded 0/1/2 plus Grannum placental grade, up to 12 points).

Variables: fetal breathing movements, body/limb movements, fetal tone, NST reactivity, amniotic fluid volume (plus placental grade in Vintzileos).

Management depends on the combination of score × amniotic fluid status × GA, not on the total score alone:

• 10/10 or 8/10 with normal fluid: expectant management.
• 8/10 with oligohydramnios: deliver at ≥36-37 wk; if preterm, daily Doppler.
• 6/10 with normal fluid: reassess in 12-24h (or 2h per MSPyBS), or deliver if at term.
• 6/10 with oligohydramnios: deliver if viability is assured.
• 4/10 with normal fluid: if <32 wk, repeat in 2h plus corticosteroids plus MgSO4 plus ductus venosus Doppler; cesarean only if it persists or the Doppler decompensates.
• 4/10 with decreased fluid: immediate emergency cesarean, regardless of GA.
• ≤2/10 (any fluid status): immediate emergency cesarean, regardless of GA or fluid.

All markers are acute, except placenta and amniotic fluid, which are chronic markers — key to interpreting a low score in the correct context. If the score indicates delivery and GA is preterm, add lung maturation with corticosteroids.

Baseline FHR: tachycardia >160 bpm · bradycardia <110 bpm (same criterion as the heart rate assessed on the 2T morphology scan — Chest and heart).

Variability: absent, minimal, moderate, or saltatory.

Reactivity: 15×15 rule (≥32 weeks) or 10×10 (<32 weeks).

Decelerations: Dips I/II/III (Caldeyro-Barcia).

Shoulders vs. overshoot — NOT synonyms: shoulders are a reassuring finding (brief acceleration before/after a deceleration, intact autonomic baroreflex); overshoot is a non-reassuring finding (exaggerated/rigid acceleration after a deceleration, associated with evolving hypoxia/acidosis).

⚠️ Special morphological patterns — lambda waves, omega pattern: these are informal visual analogies, frequently used for teaching/clinical purposes, that describe the shape of the tracing, but are not official nomenclature of FIGO, ACOG, or NICHD. The W sign (Welt 1984) is different: it does correspond to a published pattern with its own verified source (biphasic variable deceleration).

Constitutional SGA: EFW/AC P3-P10, strictly normal Doppler, low risk.

Early FGR (<32 wk): isolated EFW/AC<P3 or UA with absent/reversed flow · or combined (≥2 of: EFW/AC<P10, UA-PI>P95, UtA-PI>P95).

Late FGR (≥32 wk, 70-80% of cases): isolated EFW/AC<P3 · or combined (≥2 of: EFW/AC<P10, drop >2 quartiles, CPR<P5, MCA-PI<P5, UtA-PI>P95).

Stage I (mild): EFW<P3, or CPR<P5, or UtA-PI>P95, or UA-PI>P95 with present diastolic flow. Doppler every 7 days. Delivery at wk 37.

Stage II (severe): persistent absent end-diastolic flow in UA (AEDF) >50% of cycles. Inpatient monitoring, Doppler every 48-72h. Elective cesarean at wk 34 (after lung maturation course).

Stage III: persistent reversed flow in UA, or DV-PI>P95. Strict hospitalization, Doppler every 24-48h. Cesarean at wk 30 (lung maturation + MgSO4 neuroprotection).

Stage IV: reversed/absent A-wave in DV, umbilical vein pulsations, or STV<3ms. Continuous emergency. Immediate cesarean from wk 26 (or limit of viability).

Summary of cutoffs: wk 37-38 (SGA/Stage I) · wk 34 (Stage II) · wk 30-32 (Stage III) · wk 26-28 immediate (Stage IV).

Confirmed HIV: immediate ART regardless of GA/CD4/viral load. Regimen: TDF+FTC/3TC+Dolutegravir.

Mode of delivery: vaginal if viral load undetectable · elective cesarean if VL>1000 at wk 36.

Neonatal prophylaxis: zidovudine 4mg/kg q12h x4 weeks.

Treatment: Benzathine penicillin G IM (the only option valid in pregnancy). Primary/secondary/early latent: 2.4M IU single dose. Late latent: 2.4M IU weekly x3 weeks.

Allergy: desensitization mandatory. Jarisch-Herxheimer reaction: 24h fetal monitoring.

HBsAg+: neonatal immunoprophylaxis within 12h (vaccine+HBIG). If HBV-DNA>200,000 IU/mL or HBeAg+: Tenofovir 300mg/day from wk 28.

Confirm Anti-HCV+ with HCV-RNA. Vertical transmission ~5-7% (up to 11% with HIV). No neonatal prophylaxis or antiviral treatment during pregnancy (contraindicated).

Confirmed (2 reactive techniques): vertical transmission ~5-10%. Benznidazole/nifurtimox contraindicated in pregnancy. Newborn: cord blood PCR + at 30 days; if positive, Benznidazole 5-7mg/kg/day x60d.

High avidity: indicates infection >16 wk before the test, not before conception — calculate GA at testing − 16wk to determine if it could have been in the 1st trimester.

3 levels of prevention: 1️⃣ primary (hygiene) · 2️⃣ secondary (infected mother: Spiramycin 1g q8h, does not cross the placenta) · 3️⃣ tertiary (fetal infection confirmed by amniotic fluid PCR: switch to Pyrimethamine+Sulfadiazine+Folinic acid, which does cross the placenta).

⚠️ Pyrimethamine-Sulfadiazine contraindicated in T1 (teratogenic) and the last month (kernicterus).

Duration: no single consensus — most continue until delivery; variants use alternating 3-week cycles, or others stop 2 weeks before delivery.

IgG(-): MMR vaccine contraindicated in pregnancy, vaccinate postpartum. IgM(+): Congenital Rubella Syndrome, risk>85% in T1 (cataracts, heart disease, deafness). No specific treatment. Mandatory reporting.

IgM(+) low avidity: vertical transmission 30-40%. Amniocentesis PCR if GA>21wk. Consider maternal Valacyclovir 8g/day. Newborn: urine/saliva PCR at 3 weeks.

Rh(-): indirect Coombs at T1 and at wk 28. Negative: anti-D prophylaxis at wk 28 and postpartum. Positive (sensitized): active surveillance for fetal anemia, no prophylaxis.

MCA-PSV in MoM: <1.29 normal · 1.29-1.49 mild anemia (surveillance) · ≥1.50 moderate-severe (cordocentesis+urgent transfusion).

ΔOD450 spectrophotometry, valid from wk 27. Zone 1 mild · Zone 2 moderate · Zone 3 severe (transfusion/delivery). Before wk 27: Queenan chart or MCA Doppler.

MoM≥1.50 before wk 35: cordocentesis+intrauterine transfusion (repeat every 2-4 wk). After wk 35: consider delivery instead of transfusion. Procedure-related fetal loss risk ~1-3%.

TSH in pregnancy (ATA 2017): use the laboratory pregnancy range. If not reported, upper limit 4.0 µIU/mL; the trimester no longer changes the cutoff. Check anti-TPO if TSH is >2.5 in 1T (ATA 2017, rec. 28) or >3.0 in 2T–3T (CaVeSal® suggestion).

Grey zone (CaVeSal® suggestion): TSH >2.5 in T1 or >3.0 in T2–T3 and ≤4.0: check anti-TPO; if positive, consider levothyroxine. The 2.5 / 3.0 / 3.0 trimester cutoffs came from ATA 2011 and Endocrine Society 2012 (ETA 2014: 2.5 / 3.0 / 3.5); ATA 2017 replaced them.

Trials: CATS (Lazarus 2012; 21,846 women, treatment at ~13 weeks, IQ at 3 years 99.2 vs 100.0) and Casey (2017; TSH ≥4.0, treatment at ~17 weeks, IQ at 5 years 97 vs 94) showed no neurodevelopmental benefit. The link between high TSH and cognitive deficit is observational.

Treated hypothyroidism: TSH in the lower half of the range; <2.5 is a reasonable goal. Isolated hypothyroxinemia (low free T4 with normal TSH): not routinely treated.

Hyperthyroidism: PTU in T1, methimazole in T2–T3. Never radioactive iodine. In T1 a low TSH may be physiological due to hCG.

Anti-TPO+ (>34 IU/mL) + TSH above range: Hashimoto's, start levothyroxine. Anti-TPO+ with TSH 2.5–4.0: consider levothyroxine (ATA 2017). Anti-TPO+ with normal TSH: recheck every 4–6 wk (2–5x risk of gestational hypothyroidism). The TABLET trial (2019) showed no benefit of levothyroxine in euthyroid anti-TPO+ women.

Preconception (ATA 2017): treated hypothyroid women, adjust to TSH between the lower limit and 2.5. IVF/ICSI with subclinical hypothyroidism: levothyroxine with a TSH goal <2.5 (rec. 20). Confirmed pregnancy on prior treatment: +25–30% starting dose.

Neurodevelopment: CATS (2012) and Casey (2017) showed no benefit of treating subclinical hypothyroidism on child IQ.

Cervical length <25mm: vaginal progesterone 200mg/night, follow-up every 2wk. <15mm: urgent cerclage if <23+6wk. History of cervical insufficiency: prophylactic cerclage wk 12-14 + progesterone from the start.

Preterm birth/short cervix: solid evidence (see cervical insufficiency guide).

Threatened miscarriage: generally controversial (ACOG). Clearer benefit only with ≥1 prior miscarriage+bleeding (RR 1.08). Regimen: 400mg q12h until wk 16.

Luteal support in IVF/ICSI: established standard, routine practice. 400mg q12h vaginal.

Advanced maternal age alone: no solid independent evidence.

Risk x10 in pregnancy, x5 postpartum (peak 1st week), x4 with cesarean. ↑fibrinogen/FVII-VIII-X/vWF/PAI. ↓Protein S. Left lower limb predilection (May-Thurner + uterine compression).

DVT: lower-limb venous Doppler ultrasound. PE: 3-item triage (signs of DVT, hemoptysis, PE most likely) → D-dimer and/or CT angiography per result.

Criteria: ≥1 thrombosis or ≥1 obstetric morbidity + confirmed labs on 2 occasions (12 wk apart). Treatment: ASA 100mg/night + prophylactic LMWH from FHR confirmation until 42 days postpartum.

Point scale (1-4 per factor). Score 0: none · 1-4: pneumatic compression · 5-6: LMWH · ≥7: LMWH+compression.

Weight-adjusted prophylactic enoxaparin (20-80mg/day by kg). Therapeutic: 1mg/kg q12h, minimum 3-6 months + 6 wk postpartum. DOACs contraindicated. Avoid warfarin in T1 and peripartum.

Hold prophylactic LMWH 12h before puncture/surgery, therapeutic 24h before. Resume 12h post-vaginal / 24h post-cesarean.

Active bleeding, platelets<50,000, CrCl<15, PT<40%, persistent severe hypertension ≥4h.

Latch: mouth >130°, everted lip, chin touching breast, rounded cheeks. On-demand 8-12 feeds/day. Crack prevention: correct latch, avoid soaps, own milk after feeding.

Clinical picture: localized pain/erythema/warmth + fever ± flu-like symptoms. S. aureus predominant. Do not stop breastfeeding — frequent emptying of the affected breast (hand/nursing/pump), continue nursing on that side.

Antibiotic therapy (if systemic/persistent >12-24h despite emptying):

• Cephalexin 500mg PO q6h for 7-10 days (first line)
• Amoxicillin/clavulanate 875/125mg PO q12h (or 500/125mg q8h) for 7-10 days
• Penicillin allergy or suspected MRSA: Clindamycin 300-450mg PO q8h for 7-10 days

First visit (before 15 weeks): guidelines disagree on the 92–125 mg/dL band. The Calculator shows both readings.

TOBOGM (Simmons 2023): treatment before 20 weeks reduced the composite outcome (24.9 vs 30.5%; RR 0.82). The benefit was concentrated in the higher band; in the lower band a possible excess of SGA newborns was seen. Between 92 and 109, management is at the physician's discretion.

Weeks 24–28 — 75 g OGTT:

MSPBS (Paraguay): 2 h between 140 and 152 = high risk of developing diabetes (not GDM by IADPSG): nutrition plan, physical activity and follow-up.

ADA — two-step: non-fasting 50 g ≥130, 135 or 140 → 100 g OGTT (Carpenter-Coustan 95 / 180 / 155 / 140), with ≥2 values. ACOG accepts 1 abnormal value and also the NDDG thresholds.

Postpartum: 75 g OGTT with non-pregnancy criteria at 4–12 weeks (ADA 2026, rec. 2.33).

Prevention: metformin does not prevent GDM (ADA 2026, meta-analysis of 11 RCTs).

Targets: fasting 70-95, 1h<140, 2h<120. Split diet into 6 meals. Insulin if ≥20% of readings out of target after 1-2 wk of diet/exercise.

15-15 rule for hypoglycemia. Scheduled basal-bolus regimen preferred over reactive sliding scale. Ultra-rapid analogs preferred over Regular insulin.

TDD: 0.7-1.0 IU/kg/day by trimester. 50% basal + 50% bolus. ISF = 1800/TDD (ultra-rapid). Titrate per persistent fasting/postprandial values.

Viral etiology (70-80%): Norovirus and Rotavirus (community outbreaks), enteric Adenovirus, Astrovirus. Self-limiting (24-72h): profuse watery diarrhea, nausea, vomiting, low-grade fever.

Bacterial: Campylobacter jejuni (most common bacterial cause), non-typhoidal Salmonella enterica / S. typhi (risk of bacteremia/transplacental spread), Shigella spp. (dysentery, tenesmus, mucus/blood), E. coli (ETEC/EPEC/STEC-EHEC O157:H7), Clostridioides difficile (post-antimicrobial).

Listeria monocytogenes: flu-like illness with fever, myalgias and preceding watery diarrhea. ⚠️ Critical risk: maternal bacteremia with transplacental spread → chorioamnionitis, septic abortion, intrauterine fetal death or severe neonatal sepsis.

Parasitic: Giardia lamblia, Entamoeba histolytica, Cryptosporidium parvum.

General management: hydration and electrolyte rebalancing as the cornerstone. Mild-moderate: ORS in frequent sips. Severe/oral intolerance: admission + 0.9% NS or Lactated Ringer's 2,000-3,000mL/24h, adjusted by electrolyte panel (potassium monitoring).

Safe symptomatic treatment: antiemetics (Doxylamine+Pyridoxine, Metoclopramide 10mg PO/IV q8h, Dimenhydrinate 50mg PO/IV q6-8h) · Acetaminophen 500-1000mg PO q6-8h (max 4g/day). Loperamide restricted use (avoid in inflammatory/dysenteric diarrhea with fever or suspected invasive pathogen, due to risk of toxic megacolon); Racecadotril has limited data in pregnancy.

By trimester:

• 1st trimester: mandatory differential diagnosis with Hyperemesis Gravidarum (AGE presents with watery diarrhea and sudden onset, unlike HG). Avoid NSAIDs entirely. If antibiotics are required: beta-lactams (Amoxicillin, Ampicillin) or macrolides (Azithromycin), safe during organogenesis.
• 2nd trimester: dehydration and prostaglandins from the intestinal inflammatory process can irritate the myometrium and trigger uterine activity/threatened late miscarriage. Differential: acute appendicitis (the cecum and appendix rise with the gravid uterus). Monitor FHR and cervical length if regular contractions are present.
• 3rd trimester: severe bacterial diarrhea and hypovolemia are frequent triggers of preterm labor (PTL) and placental abruption. Electronic fetal monitoring/NST with maternal fever. In the peripartum period, if active bacterial AGE is present (Salmonella, Campylobacter, Listeria): maximize enteric isolation and precautions during delivery (vertical transmission).

Antibiotic therapy — indications: dysenteric diarrhea (blood/mucus + fever ≥38.5°C), suspected/confirmed gestational Listeriosis, suspected invasive Shigella/Campylobacter/Salmonella, immunocompromised pregnant patients, severe dehydration or bacteremia/sepsis.

ILI (Influenza-Like Illness): sudden-onset fever (≥37.8-38.0°C) + cough or sore throat, with no other diagnosis. Virologic diagnosis: nasopharyngeal swab for multiplex RT-PCR (Influenza A/B, SARS-CoV-2, RSV), or rapid antigen test (high specificity, lower sensitivity — confirm with PCR if clinical suspicion is high and the result is negative).

1st trimester: Acetaminophen 500-1000mg PO q6-8h (max 3-4g/day). Early temperature control is mandatory — sustained hyperthermia >38.5°C during organogenesis is associated with neural tube defects and congenital heart disease. Influenza: Oseltamivir 75mg PO q12h x5d, within the first 48h (safe in all trimesters). Mild COVID-19: hydration and rest, avoid NSAIDs; risk of progression: consider Nirmatrelvir/Ritonavir based on risk-benefit balance.

2nd trimester: continue Acetaminophen and Oseltamivir at standard dosing. Fetal monitoring: FHR and uterine activity (paroxysmal cough and fever can induce myometrial irritability). Moderate/severe COVID-19 requiring O2: Dexamethasone 6mg/day IV/PO x10 days (or until discharge). Hospitalize if SpO2 <94% or tachypnea.

3rd trimester: greater vulnerability — diaphragm elevation reduces functional residual capacity, with risk of rapid hypoxemia and ARDS. Continuous electronic fetal monitoring (NST/CTG). Thromboprophylaxis in hospitalized COVID-19: Enoxaparin 40mg SC/day during admission, extend based on postpartum risk factors. If pregnancy must be ended for maternal respiratory deterioration between wk 24-34: Dexamethasone 6mg q12h (4 doses) — dual purpose (maternal treatment + fetal lung maturation).

Preferred antiviral regimens:

• Influenza A and B: Oseltamivir 75mg PO q12h x5 days (double to 10 days in immunosuppressed patients or severe ICU cases).
• High-risk mild-moderate COVID-19: Nirmatrelvir + Ritonavir (Paxlovid) 300/100mg PO q12h x5 days (start within the first 5 days of symptoms).
• Severe/hospitalized COVID-19 with hypoxemia (SpO2 <94%): Dexamethasone 6mg IV/PO once daily for up to 10 days + Remdesivir 200mg IV day 1, then 100mg IV/day x4 additional days (safe in pregnancy under hepatic/renal monitoring) + weight-adjusted prophylactic Enoxaparin.

The physiologic hypervolemia and baseline tachycardia of pregnancy mask the early signs of shock. The period of greatest risk is the defervescence phase (fever drop, days 3-7), with massive plasma leakage and hemoconcentration.

Obstetric risk: threatened miscarriage, preterm birth, placental abruption, postpartum hemorrhage and vertical transmission (if the illness occurs in the immediate peripartum period).

Group A — no warning signs (supervised outpatient management): acute fever + ≥2 of: myalgias, arthralgias, headache, retro-orbital pain, rash, leukopenia; no decompensated comorbidities and adequate oral tolerance. Abundant oral hydration 2-3L/day. Acetaminophen 500-750mg PO q6h (max 3g/day). ⚠️ Absolute prohibition: NSAIDs, Dipyrone (hypotension/dyscrasias) and Aspirin (hemorrhage/Reye syndrome). Daily clinical review with CBC (Hct/platelets) until 48h post-defervescence.

Group B — every pregnant patient is classified here due to her physiologic vulnerability → requires hospital observation:

• B1 (no warning signs, with a risk condition): hospitalization for close monitoring and maintenance oral or IV fluid/electrolyte replacement.
• B2 (with warning signs — incipient leakage): intense/continuous abdominal pain, persistent vomiting (≥3/h or ≥4/6h), fluid accumulation (ascites, pleural effusion, thickened gallbladder wall), mucosal bleeding, lethargy/drowsiness, postural hypotension, hepatomegaly >2cm, rising Hct with rapidly falling platelets. 0.9% NS or Lactated Ringer's 10mL/kg/h x1-2h → if improving: stepwise taper (5-7 → 3-5 → 2-3mL/kg/h) to complete 24-48h; if not improving or Hct rises: manage as Group C.

Group C — severe dengue (hemorrhagic/shock/organ failure, ICU management): dengue shock (weak/undetectable pulse, cold extremities, capillary refill >2sec, pulse pressure ≤20mmHg) or respiratory distress from fluid accumulation; severe hemorrhage (hematemesis, melena, massive genital bleeding/PPH, intra-abdominal bleeding); severe organ involvement (AST/ALT ≥1,000 IU/L, altered consciousness, cardiomyopathy, renal failure).

Resuscitation: crystalloids (Lactated Ringer's or 0.9% NS) 20mL/kg IV bolus over 15-30min. If shock reverses: reduce to 10mL/kg/h x1-2h and taper gradually. If it does NOT reverse after 2-3 boluses: elevated Hct → colloids (Albumin 0.5-1g/kg or synthetic colloids 10-20mL/kg over 30-60min); sharply falling Hct → suspect occult/GI/uterine hemorrhage → immediate packed red blood cell transfusion (10mL/kg).

Platelet transfusion: not recommended prophylactically based on count alone (<20,000-50,000/µL). Indicated for active severe hemorrhage or need for emergency surgery/cesarean with platelets <50,000/µL.

4-5-3 mnemonic rule for the first hour of management of obstetric septic shock (postpartum/endometritis/septic abortion source):

Fluid resuscitation: crystalloids 20-30mL/kg IV bolus within the first hour for hypoperfusion or elevated lactate.

Vasopressor (if MAP<65 despite volume load): Norepinephrine 0.05-0.5mcg/kg/min IV, titrated to MAP≥65.

Empiric antibiotic therapy within the first hour (postpartum/endometritis/septic abortion source): Ampicillin/Sulbactam 3g IV q6h + Gentamicin 5mg/kg/day IV — alternative: Piperacillin/Tazobactam 4.5g IV q6-8h ± Clindamycin (anaerobic/pelvic source coverage).

Obtain blood cultures and achieve source control (uterine evacuation if septic abortion/retained products) without delaying antibiotic initiation.

Candidiasis: C. albicans (85-90%). Intense itching + clumpy white discharge. pH<4.5, hyphae. Tx: Fluconazole 150mg PO single dose. Recurrent: days 1-4-7 → weekly maintenance x6mo.

Bacterial vaginosis: dysbiosis. Fishy-smelling discharge. Amsel ≥3/4. Tx: Metronidazole 500mg q12h x7d.

Trichomoniasis: STI. Frothy yellow-green discharge. "Strawberry" cervix. Tx: Metronidazole 2g single dose + treat partner.

Polymicrobial ascending infection. Stages (Monif): I salpingitis without peritonitis · II with pelvic peritonitis · III TOA · IV rupture/septic shock.

Dx: pelvic pain + cervical/uterine/adnexal motion tenderness.

Outpatient Tx: Ceftriaxone 500mg IM + Doxycycline 100mg q12h x14d + Metronidazole 500mg q12h x14d.

Inpatient: Ceftriaxone 1g IV q24h + same regimen. Surgery: TOA ≥8-10cm or failure at 48-72h; rupture = emergency.

In May 2026, an international consensus of 56 organizations (The Lancet, endorsed by WHO) renamed the condition from "Polycystic Ovary Syndrome (PCOS)" to "Polyendocrine Metabolic Ovarian Syndrome (PMOS)" — it does not change the diagnostic criteria (Rotterdam/Monash), it better reflects the systemic, metabolic and multi-hormonal nature of the condition.

≥2 of 3: (1) oligo/anovulation · (2) clinical/biochemical hyperandrogenism · (3) PCOM (ultrasound ≥20 follicles or elevated AMH).

Phenotypes: A complete · B anovulatory (normal ultrasound) · C ovulatory (PCOM, regular cycles) · D non-androgenic.

Endometrial gland/stroma within the myometrium. Criteria: asymmetric uterus, myometrial cysts 1-5mm, echogenic islands, fan-shaped shadowing, transition zone ≥12mm, translesional vascularity on Doppler. Classification: Focal or Diffuse.

rASRM: I minimal 1-5pts · II mild 6-15 · III moderate 16-40 · IV severe >40.

Enzian (deep): A vagina/rectovaginal septum · B uterosacrals/parametria · C rectum/sigmoid · FA extraperitoneal. Severity 1(<1cm)/2(1-3cm)/3(>3cm).

Infertility with ultrasound-diagnosed ovarian or deep endometriosis: a small trial (Benaglia 2026; 55 randomized and 75 preference-cohort women, stopped early) favored IVF over surgery: live births 57% vs. 26% in the randomized cohort (RR 2.20). Preliminary evidence.

Type 0 pedunculated intracavitary · 1 sessile <50% intramural · 2 sessile ≥50% · 3 100% intramural (contacts endometrium) · 4 100% intramural (no contact) · 5 subserosal ≥50% · 6 subserosal <50% · 7 subserosal pedunculated · 8 other locations.

Distance relative to the hymen (0cm). Stage 0 no prolapse (-3cm) · I >1cm above the hymen · II between -1 and +1cm · III >+1cm without exceeding TVL-2 · IV total eversion.

SUI: urethral hypermobility, triggered by effort, small volume, no urinary frequency. UUI: detrusor overactivity, sudden urge, large volume, with frequency/nocturia.

SUI Tx: Kegel → pessaries → sling (TVT/TOT). UUI Tx: bladder retraining → antimuscarinics/Mirabegron → botulinum toxin/neuromodulation.

MRS (11 items): somatic, psychological, urogenital. NAMS/Heinemann scheme (total score only): 0-4 none or little · 5-8 mild · 9-15 moderate · ≥16 severe (consider HRT). SOCHEG scheme (broken down by domain, each with its own severe-alteration cutoff): Somatic (items 1-4) ≥8 · Psychological (items 5-8) ≥6 · Urogenital (items 9-11) ≥3 · Total (items 1-11) ≥15.

HRT by uterine status: no uterus → estrogen alone. Uterus present, perimenopause → sequential/cyclic. Postmenopause → continuous combined.

Transdermal HRT (preferred, especially with hypertension, obesity BMI>30, hypertriglyceridemia, VTE risk): 17β-Estradiol gel 0.75-1.25g/day, or patches 25-50mcg/day.

Endometrial protection (intact uterus): Micronized natural progesterone 200mg/day for 10-14 days/month (sequential regimen) or 100mg/day continuous · or Dydrogesterone 10-20mg/day.

Tibolone (STEAR): 2.5mg/day PO (or 1.25mg/day in lower body weight or advanced perimenopause) — covers vasomotor symptoms, urogenital atrophy and bone loss prevention (estrogen doses to prevent bone loss and what to do when MHT is stopped: see Osteoporosis and bone densitometry); does not require an added progestogen.

Tissue-selective estrogen complex (alternative when avoiding a progestogen is preferred): Conjugated equine estrogens 0.45mg/day + Bazedoxifene 20mg/day — bazedoxifene (a SERM) replaces the progestogen for endometrial protection, without the bleeding or breast tenderness associated with it. Evidence from the SMART-1/SMART-2 trials (12 weeks): significant reduction in hot flush frequency/severity vs. placebo, with a 50% reduction by day 8-10 and a sustained ~90% reduction by day 83 of use; no increased risk of breast cancer, endometrial cancer, VTE, stroke or coronary disease in pooled analyses (follow-up up to 2 years — confidence limited by low event incidence and lack of longer-term data). ⚠️ Availability in Paraguay not confirmed — verify locally before prescribing.

Alternative endometrial protection — 52mg LNG-IUD: off-label use alongside systemic estrogen to provide endometrial protection (plus contraception if applicable) — replace at 5 years when used for this purpose (the approved contraceptive lifespan is 8 years, but the evidence supporting endometrial protection in HRT covers up to 5 years).

Local availability (Paraguay, confirm against the current pharmacy/distributor): transdermal 17β-estradiol gel/spray (e.g., Ginoderm) — available. 17β-estradiol vaginal ring — not available. Conjugated equine estrogens + bazedoxifene — availability unconfirmed. This information is contextual, to anticipate the availability conversation with the patient — it should not be used to exclude an option from the clinical list.

Interaction with GLP-1/GIP agonists: the gastric emptying delay induced by semaglutide/tirzepatide (more pronounced with the latter) may reduce absorption of oral HRT — in patients on GLP-1/GIP therapy, prefer the transdermal route for estrogen therapy (same pharmacokinetic principle as in the Contraception during tirzepatide guide).

Order of pharmacologic treatment for vasomotor symptoms (ACP 2026): 1st line — estrogen + progestogen with a uterus, or estrogen alone without a uterus (strong recommendation, high certainty). 2nd line, if contraindicated or not tolerated — SNRI: desvenlafaxine or venlafaxine. 3rd line — SSRI (escitalopram or paroxetine), gabapentin or NK antagonists (fezolinetant or elinzanetant): see Fezolinetant and elinzanetant. Shared decision: benefits, harms, comorbidities, preferences, cost and availability.

Window of opportunity: systemic MHT started within 10 years of the FMP or before age 60 keeps the most favorable cardiovascular risk-benefit profile (↓ all-cause mortality, ↓ composite outcome of CV death and non-fatal MI in RCT meta-analyses). Starting it beyond that window should not be considered for a cardioprotective purpose — see also MRS scale and Hormone Replacement Therapy.

CV risk stratification before prescribing MHT (symptomatic woman, within 10 years of the FMP): assess family and personal CVD history. Low risk: no restrictions on MHT type, dose or route. High risk: low-dose transdermal estrogen, combined with micronized progesterone or dydrogesterone if the uterus is intact. Intermediate risk (e.g., an estimated 10-year CV event risk of 5-7% on standard calculators such as SCORE2): when feasible, coronary artery calcium score by CT (CAC-CT) — CAC = 0 suggests very low CV risk; CAC ≤10 reclassifies the patient as low risk (no MHT restrictions); CAC >10 confirms high-risk management (transdermal + a safer progestogen). In any category, treat hypertension and other modifiable risk factors before or alongside starting MHT.

Established ischemic heart disease: differentiate the subtype before deciding on management. INOCA (ischemia with nonobstructive CAD) and MINOCA (myocardial infarction with nonobstructive CAD): if MHT had already been started within 10 years of the FMP, discontinuing it may be unnecessary. Obstructive coronary disease and SCAD (spontaneous coronary artery dissection): insufficient evidence on MHT use — individualized management, with particular caution in SCAD. Across all 4 categories, if MHT is continued or started: low-dose transdermal estrogen + micronized progesterone or dydrogesterone (intact uterus), concurrent primary and secondary prevention (statins, antihypertensives, antiplatelet therapy as appropriate) and multidisciplinary management (cardiology + gynecology).

Progestogen and differentiated thrombotic/cerebrovascular risk: micronized progesterone and dydrogesterone — no significant increase in VTE risk, oral or transdermal (the safer option). ⚠️ Higher VTE risk: oral estrogen of any type, and transdermal estradiol combined with norpregnane/pregnane or nortestosterone derivatives (e.g., medroxyprogesterone acetate, nomegestrol acetate) — the risk increases from the start of treatment. Norethisterone acetate (NETA): uncertain risk, insufficient evidence. ⚠️ Tibolone: not associated with higher VTE risk, but is associated with higher ischemic and hemorrhagic stroke risk — consider especially with a history of stroke or high cerebrovascular risk.

Route and dose across scenarios: in any high CV risk scenario, intermediate risk reclassified as high, or established ischemic heart disease, the preferred combination is low-dose transdermal estrogen + micronized progesterone or dydrogesterone (if uterus intact) — consistent with the route/dose already recommended in MRS scale and Hormone Replacement Therapy for hypertension, obesity and VTE risk.

Key messages (FIGO/WHF summary): menopause is a critical window for cardiovascular assessment and prevention. Early MHT initiation relieves climacteric symptoms and may be associated with reduced all-cause mortality and reduced composite cardiovascular outcome. Risk stratification is mandatory before prescribing: type, dose and route must be individualized. In high risk, the transdermal + micronized progesterone/dydrogesterone combination is the preferred option. In established ischemic heart disease, MHT may be considered for symptomatic relief after counseling and shared decision-making. Always maintain concurrent primary and secondary prevention (statins, blood pressure control) and use multidisciplinary management for complex cases.

Mechanism: neurokinin receptor antagonists that act on hypothalamic KNDy neurons involved in thermoregulation, with no hormonal action. Fezolinetant: selective NK3 antagonist. Elinzanetant: dual NK1/NK3 antagonist.

Fezolinetant: 45mg PO once daily, with or without food. FDA-approved for vasomotor symptoms (VMS). ⚠️ FDA boxed warning: requires baseline liver function testing, repeated monthly during the first 3 months of use, and again at 6 and 9 months.

Elinzanetant: 120mg PO once daily. FDA-approved for VMS and also for menopause-related sleep disturbance (a sleep benefit not included in fezolinetant's specific approval). Requires liver function testing before starting and again at 3 months of treatment — a less intensive monitoring cadence than fezolinetant.

Indication (both): moderate-to-severe VMS of the climacteric, a non-hormonal alternative when HRT is contraindicated or not the patient's preference (hormone-dependent cancer history, VTE, personal preference).

In indirect network comparisons (ACOG CPG13), both drugs show similar efficacy on VMS frequency and severity; elinzanetant showed a greater effect on sleep disturbance (PROMIS sleep disturbance score) in indirect comparison with fezolinetant. Most common adverse effects vs. placebo in the OASIS trials with elinzanetant: headache and fatigue.

Place in treatment (ACP 2026): 3rd line (moderate certainty), after HRT and SNRIs (desvenlafaxine or venlafaxine), alongside SSRIs and gabapentin. See MRS Scale and Hormone Replacement Therapy.

Interventions with supporting evidence for vasomotor symptoms (VMS), sleep disturbance and mood symptoms of the climacteric — all recommended as adjuncts to hormonal or non-hormonal pharmacologic therapy, not as first-line substitutes when pharmacologic treatment is indicated:

Cognitive behavioral therapy (CBT): improves VMS, sleep and mood (conditional recommendation, low-to-moderate-quality evidence). Can be delivered in person, by phone, or online.

Mindfulness-based interventions (meditation, body scanning, breathing exercises, yoga): improve sleep and mood (conditional recommendation, low-to-moderate-quality evidence); usual duration 8 weeks in the trials.

Physical exercise: improves sleep and mood (conditional recommendation, low-to-moderate-quality evidence); greatest sleep benefit with 70-90 minute sessions.

Clinical hypnosis: reduces VMS and improves sleep and anxiety symptoms (conditional recommendation, low-quality evidence); weekly 45-minute sessions or self-hypnosis programs with a daily 20-minute recording.

Acupuncture: reduces VMS and improves sleep and mood (conditional recommendation, low-quality evidence); high heterogeneity across protocols, most trials conducted in China.

⚠️ Natural products and supplements — NOT recommended: the available evidence does not support the efficacy or safety of phytoestrogens (e.g., soy isoflavones) or herbal supplements for the treatment of vasomotor or menopausal symptoms — limited by small sample sizes and heterogeneity of formulations/doses/durations across trials. Since they are not FDA-regulated or evaluated for safety/purity as nutritional supplements, no leading international guideline (ACOG, NAMS/The Menopause Society, IMS) includes them among recommended treatment options.

T-Score: normal ≥-1.0 · osteopenia -1.0 to -2.5 · osteoporosis ≤-2.5 · severe +fracture. Z-Score (premenopausal): ≤-2.0 abnormal.

FRAX (osteopenia, established postmenopause): treat if major fracture risk ≥20% or hip ≥3%. FRAX and OST are not useful to identify perimenopausal women who will develop osteoporosis.

Basic support (all patients): Elemental calcium 1,000-1,500mg/day + Vitamin D3 800-2,000 IU/day (target ≥30ng/mL).

Antiresorptives: Alendronate 70mg PO weekly · Risedronate 35mg weekly or 150mg monthly · Zoledronic acid 5mg IV annually · Denosumab 60mg SC every 6 months (do not stop abruptly without transitioning to another antiresorptive, due to rebound vertebral fracture risk).

Anabolics (severe osteoporosis/high fracture risk): Teriparatide 20mcg/day SC, maximum 24 months of use.

Treatment by risk category (SVGO 2026, Swiss guideline): imminent or very high risk → anabolic first, then antiresorptive consolidation; romosozumab or abaloparatide when the fastest BMD gain is needed, especially at the hip. High risk → bisphosphonates or denosumab first line. Moderate risk → lifestyle + raloxifene or oral bisphosphonate; in selected osteopenia or early osteoporosis, infrequent zoledronate as prevention. Treat-to-target by hip BMD, reassess at 2 years. Check local availability of romosozumab and abaloparatide.

Prevention of bone loss in perimenopause and menopause

Prevention ≠ treatment: treatment is given to women at high current fracture risk; prevention aims to maintain bone density so that osteoporosis does not develop later. Bone loss is fastest in the year before and the first years after the final menstrual period (≈10% at the spine and ≈9% at the hip at 5 years, almost 1 T-score unit); abrupt estrogen withdrawal (oophorectomy, stopping MHT) accelerates it.

Higher risk: the best predictor is bone density on entering perimenopause — with a T-score <−1.0 most women reach osteoporosis (≤−2.5) before age 65. Risk factors for low BMD: weight <57 kg, prolonged amenorrhea after puberty or delayed puberty (Turner syndrome, exercise-related amenorrhea), previous fracture, family history of osteoporosis, illnesses or drugs that harm the skeleton.

Densitometry (DXA): in every perimenopausal woman with any of these factors, to identify those with a T-score <−1.0 who benefit most from prevention.

Nutrition, supplements and exercise: advisable for all women, but they do not prevent menopause-related bone loss (calcium, vitamin D, vitamin K2, collagen, phytoestrogens and the various exercise regimens at best slow it modestly).

Estrogen: oral, transdermal or systemic-dose vaginal MHT prevents bone loss for as long as it is used (also combined with a progestogen or bazedoxifene) and reduces spine and hip fractures by 30–40%. Consider it in women reaching menopause with a T-score <−1.0. Best response in early postmenopause with oral estradiol 2mg or a 0.1mg/day patch; in perimenopause, contraceptives with 20µg ethinyl estradiol are effective. Lower doses protect a smaller proportion of women (the 0.014mg patch was only studied in late postmenopause, ages 60–80). No serum estradiol target has been validated; with transdermal products it can be measured to check absorption. No fixed duration limit; individualize.

When estrogen is stopped: the bone benefit is lost within 12 months. Give a bisphosphonate for 2–3 years (alendronate, or one zoledronic acid infusion), then raloxifene or intermittent bisphosphonate to maintain density.

If estrogen is contraindicated: approved for prevention are raloxifene (weak effect, does not fully prevent loss) and the bisphosphonates alendronate, ibandronate, risedronate and zoledronate. For prevention, alendronate and zoledronate are used at half the treatment dose: alendronate 35mg PO weekly for 3–5 years, or zoledronic acid 2 doses 2 years apart; then intermittent bisphosphonate.

MHT without vasomotor symptoms: The Menopause Society considers it reasonable to prevent bone loss in women at high risk of osteoporosis; the USPSTF (2022) recommends against MHT for the primary prevention of chronic conditions. Use shared decision-making.

CaVeSal® own algorithm · Based on: McClung MR, Clark AL. Menopause 2026;33(11):1209-1211 (The Menopause Society) · Bolland MJ, et al. NEJM 2025 · USPSTF 2022.

Mechanism: vitamin K2 is a cofactor for the carboxylation of vitamin K-dependent proteins — it activates osteocalcin (calcium binding to bone) and matrix Gla protein/MGP (an inhibitor of soft-tissue calcification, including the arterial wall). Distinct from vitamin K1 (dietary, predominantly hepatic/coagulation-related).

Bone (Knapen et al. 2013, RCT, n=244 healthy postmenopausal women, 3 years): MK-7 180mcg/day decreased age-related loss of bone mineral content (BMC) and bone mineral density (BMD) at the lumbar spine and femoral neck (not at total hip), improved femoral neck bone strength indices, and reduced loss of vertebral height in the lower thoracic region. The source consulted does not publish the exact percentage BMD change figures or p-values — refer to the original article for those numbers before citing them with decimal precision.

Vascular (Vossen et al., VitaK-CAC, JAMA Cardiology 2026, RCT, n=167 with symptomatic coronary artery disease and coronary calcium 50-400 AU, 2 years): MK-7 360mcg/day modestly slowed progression of coronary calcification (Agatston score) vs. placebo (between-group difference p=0.02), with plasma MK-7 levels in the active arm rising from 0.50 to 6.56mcg/L (p<0.001). ⚠️ The authors and the accompanying editorial describe the effect as "modest" and of still-uncertain clinical significance — they call for larger, longer-follow-up trials before considering it an intervention with impact on hard cardiovascular events. No relevant adverse events were reported.

Practical doses (per the evidence cited, two distinct contexts — not interchangeable): bone loss prevention in the climacteric: MK-7 180mcg/day (as an adjunct: supplements slow bone loss modestly but do not prevent menopause-related bone loss — see Prevention in the Osteoporosis guide). Cardiovascular context (established coronary disease): the dose studied was 360mcg/day, in a population with already-diagnosed heart disease — there is no equivalent evidence in general primary prevention.

Combination with vitamin D3: both vitamins act on complementary axes of bone metabolism (D3 increases calcium absorption and osteocalcin synthesis; K2 activates/carboxylates it) — see the vitamin D3 dose in the Osteoporosis and bone densitometry guide (above).

Categories: 1 no restriction · 2 advantages generally outweigh risks · 3 risks generally outweigh advantages (only if no other method is available or acceptable, with follow-up) · 4 unacceptable risk, do not use. With several conditions, the highest category applies. Some conditions have one category for initiation and another for continuation.

Cat 4 for combined methods (US MEC 2024): breastfeeding or postpartum under 21 days; smoker aged 35 or older with 15 or more cigarettes per day; BP 160/100 or higher or vascular disease; prior VTE with high recurrence risk (no anticoagulation or prophylactic dose); known thrombophilia; major surgery with prolonged immobilization; ischemic heart disease; stroke; complicated valvular disease; peripartum cardiomyopathy (under 6 months or moderately or severely impaired function); SLE with antiphospholipid antibodies; migraine with aura; current breast cancer; decompensated cirrhosis; hepatocellular adenoma or carcinoma; chronic kidney disease (nephrotic syndrome or dialysis); sickle cell disease; transplant with graft failure. Cat 3 to 4 by severity: multiple cardiovascular risk factors, diabetes with end-organ damage or over 20 years' duration.

Progestin-only: cat 4 with current breast cancer; cat 3 with past cancer and no disease for 5 years. The 3-monthly injectable (DMPA) is cat 3 with BP 160/100 or higher, vascular disease, ischemic heart disease, stroke, high-risk VTE, thrombophilia and diabetes with end-organ damage.

IUD (copper and LNG), cat 4 for initiation: pregnancy, puerperal sepsis, immediately after septic abortion, current PID or purulent cervicitis, chlamydia or gonorrhea, distorted uterine cavity, unexplained bleeding before evaluation, cervical or endometrial cancer awaiting treatment, trophoblastic disease with intrauterine disease, pelvic tuberculosis.

Differences with WHO 2025 (6th ed.): progestin injectables while breastfeeding under 6 weeks moved from cat 3 to 2 and can be offered immediately after delivery; nevirapine and ritonavir-boosted protease inhibitors moved to cat 1 with all hormonal methods (US MEC 2024 keeps cat 2 or 3 for some); with PrEP all methods are cat 1; repeated emergency contraception in the same cycle is cat 1; inflammatory bowel disease was added.

Over 40 (SIC consensus 2025): cardiovascular safety is the main factor. Estrogen-free methods do not increase venous or arterial risk. Among combined methods, EE/levonorgestrel, EE/norgestimate and natural estradiol increase VTE the least; EE 20 µg with drospirenone and natural estradiol do not increase arterial risk. Heavy bleeding, from most to least effective: LNG-IUD 52 mg, estradiol valerate/dienogest, ring, COC with EE 30-35 µg, progestin-only. COCs protect bone; the implant, progestin-only pill and LNG-IUD are neutral.

When to stop contraception (FSRH): generally at 55. Non-hormonal method: 2 years of amenorrhea under 50 and 1 year at 50 or older. Combined and DMPA: until 50, then switch method. Implant, progestin-only pill or LNG-IUD with amenorrhea from age 50: if FSH is above 30 IU/L, stop after 1 more year. FSH is not useful on combined methods or MHT. MHT can be added to a non-combined method.

Other data: tirzepatide may reduce the efficacy of oral contraceptives; use a non-oral method or add a barrier for 4 weeks after starting and after each dose increase (FDA label). The etonogestrel implant is approved for 5 years (ANMAT 2025).

By family: hormonal (combined estrogen+progestin vs. progestin-only) · barrier (condom, diaphragm, spermicides) · IUD (non-hormonal copper vs. hormonal LNG-IUS) · LARC (implant, IUD/IUS) · permanent (tubal ligation/vasectomy) · fertility awareness-based methods (FABM).

Combined mechanisms (estrogen+progestin): suppression of the hypothalamic-pituitary axis (inhibit the GnRH/FSH-LH surge → anovulation) + thickening of cervical mucus + endometrial thinning.

Progestin-only mechanisms: the dominant and constant effect is thickening of cervical mucus (barrier to sperm migration); suppression of ovulation is dose- and route-dependent — high with the injectable/implant, variable with the minipill.

Copper IUD: local spermicidal/inflammatory effect, non-hormonal (foreign-body reaction + copper cytotoxicity on sperm and the ovum).

LNG-IUS: dominant local endometrial effect (atrophy, mucus thickening) + partial, dose-dependent suppression of ovulation, greater with higher released doses.

Group of non-hormonal methods that identify the fertile window to avoid intercourse (or use a barrier) on those days. Effectiveness is highly dependent on instruction and discipline of use — the gap between perfect use and typical use is the widest of all contraceptive methods (see comparative table).

Calendar/Ogino-Knaus: estimates the fertile window from the history of previous cycles — unreliable with irregular cycles.

Basal body temperature (BBT): detects the post-ovulatory rise (~0.3-0.5°C), retrospectively confirming that ovulation has already occurred — see also the biphasic pattern described in the ovarian cycle physiology guide.

Cervical mucus (Billings method): identifies the elastic/clear mucus around ovulation.

Symptothermal (Sensiplan protocol): combines basal temperature + cervical mucus in a standardized protocol — has shown high effectiveness in studies with intensive training and adherence; those results should not be automatically extrapolated to the whole user population without that same level of instruction.

Standardized mucus methods (Creighton Model FertilityCare System): conceptually derived from Billings, with structured observation and charting; requires formal instruction and follow-up by a certified instructor.

Standard Days Method / CycleBeads: a simplified calendar-based method, included in WHO/CDC recommendations — identifies a fixed fertile window based on cycle day, most useful with regular cycles.

Fertility monitors/apps (e.g. Marquette): algorithms that combine urinary biomarkers (LH, estrogen metabolites) with cervical mucus and/or temperature via a dedicated monitor; evidence of population-level effectiveness is heterogeneous by protocol and device — consider as a support tool, not a substitute for method education.

For FABM effectiveness figures, use the Peragallo Urrutia et al. 2018 systematic review (above) as the main reference — not a single figure for all methods: real-world effectiveness varies a great deal depending on which of these protocols is used and with what level of instruction/adherence, not merely by "being a FABM".

Failure rate per year (pregnancies per 100 users), approximate Pearl Index:

LARCs (implant, IUD/IUS) are the only methods where perfect use and typical use practically coincide — they do not depend on the user's daily/per-act adherence, which explains their superior real-world effectiveness.

Etonogestrel subdermal implant (Implanon/Nexplanon, 1 rod): approved duration of 5 years — already approved by the US FDA (January 2026), UK MHRA (May 2026), ANMAT Argentina (2025 — also covering already-placed implants), and ANVISA Brazil (October 2026 — which also authorized immediate postpartum and post-abortion insertion, 1st and 2nd trimester). Based on trial MK-8415-060 (NCT04626596, Merck/Organon): 0 pregnancies in years 4 and 5, Pearl Index 0.0 (95% CI 0-0.69), no difference by BMI (the trial included BMI 17.2-64.3, 38.1% with BMI ≥30 — the updated label no longer warns of reduced efficacy at high BMI). It does not "run out" at 3 years: etonogestrel release declines slowly (label: ~60-70 mcg/day at weeks 5-6, ~35-45 mcg/day at the end of year 1, ~25-30 mcg/day at the end of year 3), and median serum levels stay above 90 pg/mL — the anovulation threshold — across all BMI categories through year 5 (McNicholas 2017). Independent extended-use studies agree: McNicholas 2015 (CHOICE: 123 users completed year 4 and 34 year 5, 0 pregnancies), McNicholas 2017 (291 users, 444 woman-years, 0 pregnancies; year-4 failure: 0 [97.5% CI 0-1.48], year-5: 0 [0-2.65]) and Ali et al. 2016 (390 women with extended use, 0 pregnancies in years 4 and 5). Dominant mechanism: suppression of ovulation (anovulation) + thickening of cervical mucus. Immediate reversibility upon removal. ⚠️ Paraguay: the current national MSPBS guideline (Manual Nacional de Normas de Planificación Familiar, 3rd ed. 2021) still states 3 years, with earlier replacement if BMI ≥30 — it has not incorporated this update. Until MSPBS updates its guideline, in Paraguay's public sector record the insertion date and explain both criteria to the patient (international regulatory agencies vs. the current national guideline).

CaVeSal® own algorithm · Based on: FDA 2026, MHRA 2026, ANMAT 2025, ANVISA 2026, McNicholas 2015 and 2017, Ali 2016, MSPBS 2021.

2-rod levonorgestrel implant (Jadelle/Norplant-2/Sino-Implant): 5 years. Mechanism somewhat different from etonogestrel: endometrial atrophy and the cervical mucus plug predominate over suppression of ovulation (which is more variable with this implant).

LNG-IUS (levonorgestrel-releasing intrauterine system) — 3 distinct doses/durations, not a single one:

• LNG 52mg (Mirena/Liletta/Levosert/Asertia): 8 years.
• LNG 19.5mg (Kyleena): 5 years.
• LNG 13.5mg (Jaydess/Skyla — sometimes marketed as a hormonal "Mini IUD", not to be confused with the copper mini-IUD in the following row): 3 years, with lower serum LNG levels and greater preservation of ovulatory cycles than the higher doses.

Copper IUD — duration depends on copper load/frame size, not a single value:

• High-load (TCu380A and equivalents, e.g. Multiload 375, Nova T, Flexi, T Cu 380A): 10-12 years per WHO (the range depends on the specific product).
• Reduced-frame/"mini" copper IUD (smaller copper surface area, usually reserved for nulliparous patients or small uterine cavities): shorter duration, typically on the order of 5 years — confirm against the specific model/brand's insert, since a lower copper load corresponds to a shorter approved duration.

Silver-core IUD (Cu-Ag, e.g. Andalan Silverflex): the silver core slows fragmentation/oxidation of the copper wire inside the uterus — a mechanism that in theory extends the device's useful life relative to a pure copper IUD. However, at least one regional manufacturer labels its "Silver T" presentation with a duration of 5 years, shorter than that of high-load copper IUDs — ⚠️ there is real variability between brands/markets; confirm the duration against the specific brand's insert used in your practice before treating it as a single figure for this guide. Regarding silver's "bactericidal" effect: ionic silver does have well-documented general antibacterial activity in the microbiology/materials literature — but the source educational material (AC Hormonal 2025) specifically describes silver's role in the IUD as slowing copper fragmentation, not as a local anti-infective mechanism aimed at reducing PID; ⚠️ I did not find a gynecology-specific source documenting a clinically relevant bactericidal effect of the silver core on pelvic infection risk — if you have a specific reference for that, happy to add it.

All IUDs/IUSs are also useful as post-coital emergency contraception (see following guide).

Non-contraceptive benefits of the LNG-IUS: significantly reduces menstrual bleeding (therapeutic use in AUB, see corresponding guide), and offers some relative protection against symptomatic PID compared with the copper IUD.

Contraindications (MEC Cat 4): see the WHO Medical Eligibility Criteria guide — distortion of the uterine cavity, active pelvic infection, untreated cervical/endometrial cancer (IUDs in general); active breast cancer (LNG-IUS, due to the hormonal component).

LNG, Ulipristal, and Yuzpe share a mechanism: they inhibit or delay ovulation — they are not abortifacients, they do not interrupt an already-implanted pregnancy. Mifepristone (added to this group by WHO in 2026) is the exception on this list: its mechanism is dose/timing-dependent (see detail in its own bullet).

• Levonorgestrel 1.5mg single dose: effective up to 72-96h, with decreasing effectiveness the more time has passed since intercourse — the sooner, the better.
• Ulipristal acetate 30mg single dose: effective up to 120h (5 days), and holds its effectiveness better near the day of ovulation than LNG. ⚠️ Reduces the effectiveness of regular hormonal contraception started afterward — use a barrier method or postpone restarting the usual hormonal method by ~5 days.
• Yuzpe regimen (combined high-dose ethinylestradiol+levonorgestrel, given as 2 doses 12h apart): historical alternative when LNG/Ulipristal are not available — less effective and with more adverse effects (nausea/vomiting) than current dedicated methods.
• Mifepristone 10-50mg single dose (added by WHO, expanded contraceptive options guideline, Sept. 2026): effective as soon as possible and within 5 days post-coitus. Dose/timing-dependent mechanism: given before the LH surge, it delays/inhibits ovulation just like the other methods in this group; given already in the luteal phase (post-ovulation), its antiprogestogenic effect does demonstrably delay endometrial maturation — unlike LNG (no demonstrated endometrial alteration) and Ulipristal (theoretical antiprogestogen, with no demonstrated anti-implantation effect at the EC dose). Availability and the regulatory framework vary by country — confirm before prescribing. ⚠️ Medico-legal note (relevant given CaVeSal®'s international reach): this mechanistic distinction matters depending on each jurisdiction's legal framework on the onset of life. Where life is considered to begin at fertilization/conception (e.g. Paraguay), a method with no demonstrated anti-implantation effect is not classified as abortifacient; where it is considered to begin at implantation, the distinction loses legal relevance. This guide describes both frameworks without taking a position.
• Post-coital copper IUD: the most effective method of emergency contraception (failure rate <0.1%), insertable up to 5 days post-coitus — with the added advantage of remaining in place as long-term ongoing contraception.

What it is: a natural estrogen of fetal origin (synthesized by the fetal liver from estriol), with tissue-selective activity — agonist in the CNS, bone and genital tissue, antagonist in breast tissue, and little estrogenic effect in liver and vascular tissue. Hepatic metabolism by glucuronidation only (no CYP450 pathway), which reduces the risk of drug interactions.

Combined formulation: Estetrol 15mg + Drospirenone 3mg, 1 tablet/day.

Efficacy: Pearl Index 1.52 (95% CI 1.04-2.16) in the pivotal phase 3 trials (31 pregnancies / 2,837 women / 26,455 cycles). Regular cycles in 82-94%; spotting ~15% at cycle 12; amenorrhea ~10%.

Coagulation/VTE profile: ⚠️ the available literature does not provide a relative risk or odds ratio for VTE versus other combined hormonal contraceptives — this figure is pending verification against the primary articles before being cited as a number. What is documented: a smaller rise in sex hormone-binding globulin (SHBG +54% vs. +74% with ethinylestradiol) and smaller changes in lipid profile, with no change in thrombin generation (Douxfils 2020) — surrogate markers suggesting a smaller hepatic/procoagulant impact than ethinylestradiol, but which do not equate to a confirmed clinical VTE risk figure: the pivotal studies recorded 1 case of DVT in 30,289 cycles, too small a number to estimate a comparative rate. The authors themselves note that these advantages remain mostly theoretical and require post-marketing surveillance.

Why it may be worth raising in consultation: it is an additional option within the combined contraceptive group, useful for an informed conversation with patients who ask about it specifically — the evidence does not yet support positioning it ahead of established combined methods in terms of thrombotic safety.

LAM (>98%): amenorrhea + exclusive breastfeeding + <6 months postpartum, all three together.

Progestin-only: Cat 1-2 from the start. Combined: Cat 4 if <6 wk breastfeeding; improves over time. Copper IUD: Cat 1 immediate (<48h) or delayed (≥4wk); Cat 3 in between.

What drives the choice: cardiovascular safety (venous and arterial risk) is the first criterion after 40. In perimenopause, menstrual irregularity and heavy bleeding, changes in sexuality and bone loss also weigh in. Fertility declines, but unplanned pregnancy is still possible. Eligibility of each method is always defined with the WHO Medical Eligibility Criteria (MEC).

Venous risk (VTE): oestrogen-free methods — etonogestrel implant, LNG-IUS, progestogen-only pill (desogestrel) and drospirenone-only pill — do not increase VTE risk. Among combined methods, those that increase it least are EE/levonorgestrel, EE/norgestimate and those with natural oestrogen (oestradiol, oestradiol valerate). Vaginal ring and patch: conflicting data versus EE/levonorgestrel (Nordic registries suggest higher risk). Estetrol: insufficient data — see Estetrol (E4).

Arterial risk (MI and ischaemic stroke): progestogen-only methods, short- or long-acting, do not increase it. ⚠️ EE 30–40 µg with an androgenic progestogen (especially levonorgestrel) increases the risk of MI and ischaemic stroke, in a dose-dependent way. EE 20 µg with drospirenone does not increase it. Combined methods with natural oestrogen did not increase it in post-marketing studies (with few events).

Cycle control: with menstrual irregularity, the vaginal ring (EE/etonogestrel) and EE/norgestimate give the best regularity and the least unscheduled bleeding. EE doses ≥30 µg control the cycle better than EE 20 µg or natural oestrogens.

Heavy menstrual bleeding, from most to least effective: LNG-IUS 52 mg → oestradiol valerate/dienogest → vaginal ring → combined oral with EE 30–35 µg → progestogen-only or drospirenone-only pill. LNG-IUS and progestogen-only methods can be used with increased cardiovascular risk. Rule out a structural cause first — see AUB — PALM-COEIN.

Sexuality: it is multifactorial (biological, psychological, relational and sociocultural), and contraception itself improves it by removing the fear of pregnancy. Prefer natural oestrogens (lower effect on SHBG) or EE 20 µg with an androgenic progestogen. Vaginal ring: possible positive effect (local action). Implant: limited uncontrolled studies suggest a positive effect. Progestogen-only pills: undetermined effect. LNG-IUS: neutral. See also Sexual health in climacteric and postmenopause.

Bone: in perimenopause, combined oral contraceptives protect against bone loss. Progestogen-only pills, drospirenone-only pill and implant: neutral effect. LNG-IUS: neutral (one retrospective study suggests fewer fractures).

About the consensus: Italian Society of Contraception, systematic review up to October 2024 and vote at a national congress (95–99% agreement on the 7 statements). It does not include medroxyprogesterone acetate or norethisterone, which are not used as contraceptives in Italy.

PALM (structural): Polyp · Adenomyosis · Leiomyoma · Malignancy/hyperplasia.

COEIN (non-structural): Coagulopathy · Ovulatory dysfunction · Endometrial · Iatrogenic · Not otherwise classified.

Primary/secondary by definition. Secondary algorithm: β-hCG+TSH+PRL → progesterone challenge test (bleeds=anovulation/PCOS) → combined E+P test (bleeds=estrogen deficiency, measure FSH/LH) → hyper/hypogonadotropic.

No menarche by 13 without secondary sexual characteristics, or by 15 with characteristics. Breasts absent→FSH/LH (Turner vs. Kallmann). Breasts present→anatomy (MRKH vs. AIS vs. obstruction).

PCOS: ovulation induction or OCPs. Asherman's: hysteroscopy + estrogen. POI: HRT until 50-51 years.

💡 For hyperprolactinemia (anovulation/infertility), see the full guide in the "Preconception and Fertility" chapter.

Reproductive age: Mediterranean diet, 500-750kcal deficit, aerobic 150-300min/week + strength training.

Climacteric: protein 1.2-1.6g/kg/day, Calcium+Vitamin D, strength training 3x/week, impact/balance exercises.

Semaglutide 0.25→2.4mg/wk. Tirzepatide 2.5→10-15mg/wk. Indication: BMI≥30, or ≥27+comorbidity.

⚠️ "Ozempic babies" (restores ovulation), reduces OCP efficacy, stop ≥2 months preconception, risk of sarcopenia.

Non-response rates (<5% weight loss) by pivotal trial: STEP-1 (semaglutide 2.4mg, non-diabetic adults) 13.6% · STEP-TEENS (semaglutide 2.4mg, adolescents with excess-weight comorbidity) 27% · SURMOUNT-1 (tirzepatide 15mg, non-diabetic adults) 9% · STEP-2 (semaglutide 2.4mg, diabetic adults) 31.2% — response is consistently lower in patients with concomitant type 2 diabetes, a point to anticipate when counseling on expectations.

Maintaining weight loss requires continuing the medication (STEP 4 with semaglutide and SURMOUNT-4 with tirzepatide): in both trials, patients who, on reaching a weight-loss plateau, were randomized to continue the drug maintained or further deepened their weight loss, while those switched to placebo progressively regained weight over the remaining follow-up — obesity behaves here as a chronic condition requiring sustained treatment, not as a short course with a permanent outcome.

GLP-1/GIP + hormone therapy in the climacteric (retrospective cohort, Mayo Clinic): Castaneda et al. (The Lancet Obstetrics, Gynaecology, & Women's Health. 2026;2(2):e118-e128), in 120 postmenopausal women with overweight/obesity on tirzepatide (40 on HRT vs. 80 without, propensity-matched), reported that at 15 months HRT users had 35% greater total body weight loss than non-users, along with additional cardiometabolic improvements in both groups. ⚠️ This is retrospective matched-cohort evidence, not a randomized trial — it suggests a possible synergy but does not establish causality, nor does it by itself change the indication for HRT, which should be decided on its own criteria (see the MRS Scale and HRT guide). Note: the preliminary figure presented at the ENDO 2025 congress (~17% vs. 14%) differs from the final Lancet publication — this guide uses the final published figure (35% relative difference), not the preliminary congress figure.

An EASO decision framework that separates two treatment goals depending on whether obesity-associated complications are present — not a single "weight loss" algorithm, but one that guides drug choice by the outcome being targeted:

No complications (mechanical adiposity) — goal: total body weight loss (TBWL): available options (evidence published through Nov 21, 2025, ranked from highest to lowest relative efficacy vs. placebo): tirzepatide, semaglutide, phentermine-topiramate, liraglutide, naltrexone-bupropion, orlistat.

Complications present (metabolic adiposity — deranged endocrine-immune responses) — goal: reverse the affected organ's dysfunction, not just lower weight:

• OSAS (remission): tirzepatide.
• Knee osteoarthritis/KOA (pain remission): semaglutide, liraglutide.
• Prediabetes (normoglycemia restoration): semaglutide, tirzepatide, liraglutide.
• Type 2 diabetes (remission): tirzepatide, semaglutide, liraglutide, naltrexone-bupropion.
• Cardiovascular disease (MACE reduction): semaglutide, naltrexone-bupropion.
• Heart failure (reduced hospitalization): tirzepatide, semaglutide.
• MASLD/MASH (MASH remission): tirzepatide, semaglutide — new in 2026: liver fibrosis improvement with semaglutide.

The original framework also lists, for each endpoint, the drugs in the same class without available evidence for that specific indication (e.g., orlistat has no MASH remission data) — a drug's absence for a given endpoint does not imply demonstrated inefficacy, only a lack of published evidence as of the framework's cutoff date. Consult the original source for the full drug-by-endpoint detail.

Quick-reference map of incretin agonists beyond the 3 already approved (semaglutide, tirzepatide, liraglutide — see GLP-1/GIP analogs guide). None of the following yet has approval for general clinical use; they are listed for context and to anticipate patient questions, not as a use recommendation.

Closest to approval (per the source's timeline, subject to change):

• Oral semaglutide: GLP-1, oral daily, Novo Nordisk.
• CagriSema (semaglutide + cagrilintide): GLP-1 + amylin receptor co-agonist, SC weekly, Novo Nordisk.
• Encoglutide (XW003): GLP-1, SC weekly, Sciwind (in development in China).
• Orforglipron (LY3502970): GLP-1 and glucagon receptor agonist, oral daily, Eli Lilly.
• Mazdutide: GLP-1/glucagon receptor co-agonist, SC weekly, Eli Lilly/Innovent (in development in China).
• Survodutide (BI 456906): GLP-1/glucagon receptor co-agonist, SC weekly, Boehringer Ingelheim.
• Retatrutide (LY343794): GLP-1/GIP/glucagon triple agonist, SC, Eli Lilly — this is the molecule mentioned in the Preconception washout guide as "under investigation."
• Pemvidutide: GLP-1/glucagon receptor co-agonist, SC weekly, Altimmune.

Earlier-stage development / distinct mechanisms:

• Cagrilintide (AM833): GLP-1/amylin co-agonist, SC weekly, Novo Nordisk.
• Amycretin: amylin receptor and GLP-1 co-agonist, SC and oral under investigation, Novo Nordisk.
• Maridebart cafraglutide (AMG-133): GLP-1/GIP co-agonist, SC weekly, Amgen.
• Bimagrumab: monoclonal antibody blocking activin signaling (not an incretin agonist), IV infusion every 4 weeks, Versanis/Eli Lilly.
• Danuglipron: GLP-1 agonist, oral, Pfizer — discontinued development: after completing Phase 2, Phase 3 planning was cancelled due to hepatic adverse effects; kept in this list only as historical reference, not as an active candidate.
• APH-012 / SYNTH-101: oral capsule that simulates the effect of gastric bypass (duodenal lining, stimulates the small intestine), Phase 2 in development, APHAIA FARMA/SYNTIS BIO.
• ARD-101: oral agonist targeting taste receptors (denatonium), activates endogenous GLP-1/GLP-2/cholecystokinin, finishing Phase 2, Aardvark Therapeutics.
• CT-388: GLP-1/GIP co-agonist, SC weekly, Structure Therapeutics.
• VK2735: GLP-1/GIP co-agonist, SC weekly, Viking Pharmaceuticals.
• HU6: "controlled metabolic accelerator" (distinct mechanism, not an incretin), oral daily, Rivus Pharmaceuticals.
• INV-202: CB1 blocker, oral daily, Novo Nordisk.
• EC5004: GLP-1 agonist, oral daily, AstraZeneca/Eccogene.
• GSBR-1290: GLP-1 agonist, oral daily, Structure Therapeutics.

⚠️ None of these investigational molecules has, as of this guide, reproductive safety studies or a validated preconception washout recommendation — for any patient in a clinical trial with one of these, strictly follow the study's own contraception protocol; do not extrapolate the semaglutide/tirzepatide windows.

Timeline and availability taken from the original source (clinicaltrials.gov and company websites, at the time of the presentation) — these can change; verify current regulatory status before discussing with a patient.

Insulin resistance is a central pathophysiological axis in most patients with PMOS — including many without obesity, according to the Teede et al. 2026 consensus itself that renamed PCOS to PMOS —, not merely an associated comorbidity. Within this, the prevalence of insulin resistance is higher in phenotypes A and B (see the PCOS/PMOS phenotypes guide) than in C/D, per the general PCOS/PMOS phenotype literature (a consistent finding across several case-control studies and meta-analyses, not specific to the Teede paper). This underlies the growing interest in GLP-1/GIP agonists as a metabolic approach in PMOS with an obesity/insulin-resistance component, and in classic insulin sensitizers (metformin, myo-inositol — see next guide) as non-hormonal first-line treatment for ovulatory dysfunction.

Recent supporting evidence: Carmina & Longo (J Clin Med, July 2026) treated 96 women with PMOS and overweight/obesity with semaglutide for 6 months — 52.5% of those previously anovulatory achieved ovulatory cycles, with a response strongly dependent on the degree of obesity (~95% menstrual normalization in overweight vs. ~25% in moderate-severe obesity). The authors propose considering GLP-1 before other fertility interventions in obese patients with PMOS — this is prospective cohort evidence, not a trial that has changed society guidelines.

⚠️ Off-label / evolving use: GLP-1/GIP agonists improve ovulation indirectly (weight loss + improved insulin sensitivity), not through a direct reproductive mechanism. Their formal indication remains the management of obesity/type 2 diabetes — despite the cohort evidence cited above, use specifically directed at PMOS does not yet have endorsement from reproductive society guidelines (ASRM, ESHRE, FLASOG) as a primary indication; approach it as a reasoned extension of its approved metabolic indication, case by case.

Mechanism: myo-inositol and D-chiro-inositol are second messengers in the insulin signaling pathway — supplementation improves ovarian insulin sensitivity, reduces compensatory hyperinsulinemia, and thereby favors resumption of ovulatory cycles in PMOS. It is not a drug in the strict sense but a dietary nutrient/supplement, which shapes its reproductive safety profile (see the inadvertent exposure note below).

Indication: ovulatory dysfunction in PMOS/metabolic phenotype, as an adjunct or alternative to metformin in patients with digestive intolerance to the latter; also used as an adjuvant in ovulation induction/IVF protocols to improve oocyte quality.

Usual dose: Myo-inositol 2-4g/day PO, frequently combined with D-chiro-inositol in the physiological 40:1 ratio (the physiological serum ratio described in healthy ovarian tissue), divided into 1-2 daily doses. Clinical response (resumption of cycles) is expected within 3-6 months of continuous use.

Evidence: the Cochrane review (2023 update) on inositol for PMOS-associated subfertility finds low-to-moderate certainty evidence favoring a possible improvement in clinical pregnancy and ovulation rates versus placebo, with meta-analyses by Unfer et al. and Facchinetti et al. also showing benefit on metabolic parameters (HOMA-IR, androgen profile) — overall evidence quality remains limited by study size and heterogeneity.

Inadvertent exposure during fertility recovery (relevant in women coming off tirzepatide/semaglutide who are improving their metabolic profile): as a physiological nutrient normally present in the diet rather than a synthetic molecule with dedicated teratogenicity studies, myo-inositol is not subject to the same preconception washout restrictions as GLP-1/GIP analogues — no teratogenic warning signal has been described with continued use during an unrecognized pregnancy, and it has in fact also been studied as a supplement for gestational diabetes prevention in at-risk populations. This does not exempt confirming the pregnancy and reassessing the overall therapeutic plan as soon as it is detected.

Specific meta-analysis on myo-inositol and gestational diabetes prevention (Poyatos-León R, et al. Am J Obstet Gynecol. 2026;235(5):1024-1036. DOI 10.1016/j.ajog.2026.05.020): 12 randomized controlled trials, 4,765 women without preexisting diabetes (pregnant or planning conception within 6 months), search through April 2025. Myo-inositol supplementation substantially reduced the risk of gestational diabetes versus control (44% relative risk reduction), with no significant differences in hypertensive disorders, cesarean delivery, macrosomia, preterm birth, or neonatal hypoglycemia.

Phenomenon colloquially described as "Ozempic babies": weight loss and improved insulin sensitivity under GLP-1/GIP treatment can restore spontaneous ovulation in anovulatory women with obesity — sometimes unexpectedly, when the patient assumed she did not need contraception or that the effectiveness of her oral hormonal method was not compromised. ("Ozempic babies" is a descriptive/colloquial term, spread through case reports and medical coverage — it does not correspond to a single formal reference; the underlying clinical basis is the mechanism of ovulatory recovery via weight loss/improved insulin resistance, documented in the international PMOS guideline and in the Carmina & Longo cohort cited in the previous guide.)

Direct clinical implication: every patient on GLP-1/GIP treatment who is not seeking pregnancy should receive active counseling on effective contraception, even if she previously had anovulation due to PMOS — recovery of ovulatory cycles can occur before the patient notices the change (recovery of menstrual regularity), which is why it is important to proactively address both contraception and preconception planning from the start of GLP-1/GIP treatment, not only when it is stopped (see the Contraception during tirzepatide and Preconception washout guides).

Tirzepatide's dual GIP/GLP-1 agonism slows gastric emptying more markedly than pure GLP-1 agonists (semaglutide) — this can reduce the absorption of oral drugs, including oral hormonal contraceptives.

Recommendation: use a non-oral contraceptive method, or add a barrier method, for 4 weeks after starting tirzepatide and after each dose escalation — not only once at treatment start.

⚠️ Do not confuse with preconception washout (next guide): this 4-week window is due to a pharmacokinetic interaction with the oral contraceptive, while preconception washout is the recommended time to stop the drug before trying to conceive — two distinct concepts, with different durations, and both may apply to the same patient at different times.

Practical approach for a patient on tirzepatide who is losing weight and recovering fertility, and who is not seeking pregnancy: prefer non-oral methods whenever possible — LARC (subdermal implant, IUD/IUS — see LARC guide), injectable (DMPA), patch, or vaginal ring — since these do not depend on gastrointestinal absorption and sidestep the underlying problem; if the patient already uses or prefers an oral contraceptive, add a barrier method (condom) for the 4 weeks after starting and after each dose escalation, without needing to stop the oral agent. Discuss contraception from the start of GLP-1/GIP treatment in every woman of reproductive age, not only when she presents seeking pregnancy (see the GLP-1 and fertility recovery guide).

Imbroane et al. (AJOG 2025, observational preconception cohort of 8,534 women) document the underlying clinical context — women recovering ovulatory cycles and fertility during GLP-1/GIP use — that supports the need for this proactive contraceptive conversation, although the study does not directly evaluate contraceptive failure rates.

Semaglutide: the 2026 FDA Wegovy label recommends stopping ≥2 months before trying to conceive, due to its prolonged half-life (~1 week, ~5 half-lives for near-complete elimination).

Tirzepatide: here the regulatory agencies differ, and CaVeSal presents both positions without resolving them, so you can decide according to the patient's context: the European label (EMA/Lilly Mounjaro SmPC) recommends stopping ≥1 month before trying to conceive; the U.S. prescribing information (FDA, Zepbound) does not set a mandatory preconception window and instead instructs discontinuing upon recognizing pregnancy — reflecting a genuine difference in regulatory stance, not an error in either source.

Liraglutide (daily dosing, shorter half-life): common practice uses a shorter washout window (on the order of 1 week), although it is less standardized in the guidelines than semaglutide/tirzepatide.

Dulaglutide, exenatide, lixisenatide: the labels of these older molecules do not set a specific preconception washout window the way semaglutide/tirzepatide do — the usual instruction is to discontinue upon confirming pregnancy, with no preconception interval validated by dedicated studies. ⚠️ Absence of a validated interval does not mean "no need to stop before trying to conceive" — in the absence of specific data, a prudent approach is to apply a criterion similar to semaglutide (weekly-order half-lives) for weekly-depot dulaglutide and exenatide, and one closer to liraglutide for short-acting exenatide/lixisenatide (daily dosing).

Retatrutide: a triple GLP-1/GIP/glucagon agonist still under investigation — not approved for general clinical use as of this guide (see the Incretin development pipeline guide). It therefore has no indication or label for use in a population seeking pregnancy; any exposure would occur in the context of a clinical trial, with its own study-specific contraception/washout protocol — do not extrapolate the windows above to this molecule.

Imbroane et al. (AJOG 2025;233(2):116.e1-e7; n=4,267 per cohort after matching, 8,534 total) found, in their retrospective preconception cohort (TriNetX), an association with lower incidence of gestational diabetes (18.2% vs. 15.2%; OR 0.81; 95% CI 0.72-0.91), hypertensive disorders of pregnancy (22.8% vs. 19.9%; OR 0.84; 95% CI 0.76-0.94), preterm delivery (4.4% vs. 3.0%; OR 0.68; 95% CI 0.54-0.85), and cesarean delivery (19.7% vs. 17.6%; OR 0.89; 95% CI 0.87-0.97) in the group with prior GLP-1/GIP prescription versus the unexposed group. ⚠️ Before matching, the exposed group had a much higher prevalence of overweight/obesity (76.8% vs. 10.7%), type 2 diabetes (37.6% vs. 1.5%), hypertension (32.5% vs. 3.7%), and prior GDM (25.3% vs. 10.0%) — matching adjusted only for age/race/ethnicity/comorbidity categories, not finely for these factors, so much of this apparent protection may reflect residual confounding by indication (who receives GLP-1/GIP) rather than a true protective drug effect. This does not change this guide's preconception washout recommendation — see also the Inadvertent pregnancy during GLP-1/tirzepatide guide for a contrasting read on maternal metabolic/hypertensive outcomes.

Immediate management of an inadvertent pregnancy in a patient using GLP-1/GIP:

• Stop the drug as soon as pregnancy is confirmed — current evidence does not support continuing it during gestation, regardless of the duration of periconceptional exposure that has already occurred.
• Reassess the patient's overall metabolic management plan (glycemia, weight, possible metformin indication — see corresponding guide) now in the context of pregnancy, not of weight loss.
• There is no indication for pregnancy termination based solely on periconceptional GLP-1/GIP exposure — the conversation with the patient should be grounded in the available evidence (summarized below), which so far shows no consistent signal of harm.

What the evidence shows (quick-reference summary, not a substitute for each study's methodological detail):

Brown et al. (Ann Intern Med 2026, target trial emulation, n=3,572) found no significant increase in major congenital malformations associated with periconceptional exposure to GLP-1 agonists, using a design that emulates a randomized trial from observational data to reduce confounding by indication.

D'Antonio et al. (Med 2026, large-scale meta-analysis, n=2,118,215) likewise found no consistent signal of increased risk of adverse obstetric/neonatal outcomes associated with periconceptional or early-pregnancy exposure to GLP-1/GIP agonists — this being the largest sample-size analysis available to date on the topic.

The AJOG 2024 review (PII S0002-9378(24)00864-0) synthesizes the body of evidence available at that time in the same reassuring direction, although — like the rest of this literature — it is based predominantly on observational studies rather than randomized trials specifically designed to assess reproductive safety.

⚠️ All of this evidence is observational (cohorts, target trial emulation, cohort meta-analyses) — absence of a harm signal is not equivalent to definitive evidence of safety, and it does not change the recommendation to stop the drug as soon as pregnancy is recognized, nor the recommendation to respect the preconception washout by molecule when pregnancy is planned (see the Preconception washout by molecule guide).

Malformations — additional meta-analysis (Uysal et al., Sci Rep 2026;16:31416): across 7 cohort studies with over 40,000 exposed pregnancies, there was no significant signal for congenital malformations overall (OR 1.11; 95% CI 0.82-1.51) nor for major malformations with first-trimester exposure (OR 1.39; 95% CI 0.73-2.65). An isolated significant signal was found for urinary malformations (OR 1.24; 95% CI 1.05-1.47), based on unadjusted data from only 2 studies — the authors themselves attribute it most likely to residual confounding (underlying maternal diabetes/obesity), not a direct teratogenic effect. No increased signal was found for stillbirth, spontaneous abortion, small for gestational age, or preterm birth.

Major congenital malformations — largest sample-size meta-analysis available to date (Liu X, et al. Endocrine Connections 2026;15(7). DOI 10.1530/EC-26-0280): across 6 studies (1 prospective + 5 retrospective) with 286,599 women, of whom 43,577 had periconceptional GLP-1RA exposure, there was no significant difference in the risk of major congenital malformations between exposed and unexposed women (RR 1.02; 95% CI 0.96-1.08). No significant signal was found either for preterm birth (RR 1.09; 95% CI 0.80-1.49), large for gestational age (RR 2.31; 95% CI 0.56-9.44), small for gestational age (RR 0.71; 95% CI 0.39-1.27), or stillbirth (RR 1.16; 95% CI 0.24-5.69) — these last three have very wide confidence intervals due to low event numbers, and should be read as "insufficient statistical power to detect a risk if one existed," not as "no risk." The authors themselves note that, given the observational design and limited number of exposed pregnancies, these findings should not be interpreted as proof of safety.

Gestational weight gain and complications after stopping the drug (Maya J, et al. JAMA 2025;334(24):2186-2196 — retrospective cohort, Mass General Brigham, n=448 exposed vs. 1,344 unexposed, matched by propensity score 1:3, 84% with obesity): exposure to GLP-1/GIP between 3 years before and 90 days after conception was associated with greater gestational weight gain (mean 13.7kg vs. 10.5kg; difference +3.3kg; 95% CI 2.3-4.2; p<0.001), a higher risk of excess gestational weight gain (65% vs. 49%; RR 1.32; 95% CI 1.19-1.47), of preterm delivery (17% vs. 13%; RR 1.34; 95% CI 1.06-1.69), of gestational diabetes (20% vs. 15%; RR 1.30; 95% CI 1.01-1.68), and of hypertensive disorders of pregnancy (46% vs. 36%; RR 1.29; 95% CI 1.12-1.49) — with no difference in birth length, large/small for gestational age, or cesarean delivery. ⚠️ Unlike Liu et al. (above), which looks for a malformation signal, this cohort looks at the pregnant patient's own metabolic/hypertensive outcomes after periconceptional exposure — a different, and to some extent contrasting, perspective to the reassurance conveyed by Imbroane et al. 2025 (see the Preconception washout by molecule guide): "no malformation signal" does not equal "no maternal risk at all." Cohort composed mostly of women with obesity — limits generalization to a non-obese population.

Gestational weight gain and hypertensive disorders — independent cohort (Pondugula N, et al. Obstet Gynecol. 2026;147(3):293-302. DOI 10.1097/AOG.0000000000005995): a retrospective cohort distinct from Maya et al. (Yale, n=243 exposed up to 1 year before pregnancy — 103 for pregestational diabetes, 140 for weight management — vs. 175 and 200 unexposed, respectively). Found no association between GLP-1RA exposure and hypertensive disorders of pregnancy in either cohort (pregestational diabetes: adjusted OR 0.72; 95% CI 0.42-1.25 · weight management: adjusted OR 0.83; 95% CI 0.45-1.52). There was also no association with gestational weight gain in the pregestational diabetes cohort; in the weight-management cohort, exposure was associated with a lower likelihood of gestational weight gain below recommendations (adjusted OR 0.37; 95% CI 0.18-0.78) — the authors interpret this as a possible rebound weight gain after stopping the drug, not as excess weight gain. ⚠️ Important attribution note: the figures of 65% vs. 49% excess weight gain, 20% vs. 15% gestational diabetes, and 46% vs. 36% hypertensive disorders (above) belong to Maya et al., not to this study — these are two independent cohorts with different findings (Pondugula et al. reports no hypertensive-disorder signal; Maya et al. does).

Branch 1 — Patient on GLP-1/GIP treatment who is NOT seeking pregnancy (or has not yet decided):

• Active contraceptive counseling from the start of treatment, even if she previously had anovulation due to PMOS (see the GLP-1 and fertility recovery guide) — fertility can recover before the patient notices.
• Prefer non-oral methods (LARC, injectable, patch, ring), especially with tirzepatide; if she uses an oral method, add a barrier method for 4 weeks after starting and after each dose escalation (see the Contraception during tirzepatide guide).

Branch 2 — Patient who IS seeking pregnancy (preconception planning):

• Washout by molecule before attempting to conceive (see the Preconception washout by molecule guide) — different windows for semaglutide, tirzepatide, liraglutide; no validated interval for dulaglutide/exenatide/lixisenatide; retatrutide does not apply, as it is not approved.
• Reassess baseline metabolic management (metformin, myo-inositol) in a preconception context, not a weight-loss one (see the Metformin in pregnancy and Myo-inositol guides).
• Preconception folic acid according to risk level (see the Preconception screening and folic acid guide).

Branch 3 — Inadvertent pregnancy already confirmed during GLP-1/GIP use:

• Stop the drug immediately.
• Reassess the metabolic plan in a pregnancy context, not a weight-loss one (see the Inadvertent pregnancy during GLP-1/tirzepatide guide).
• Discuss the available evidence with the patient — reassuring regarding malformations, more mixed regarding gestational weight gain/gestational diabetes/hypertension (see the same guide) — without creating unwarranted alarm or false reassurance.

5 key messages for counseling:

1. GLP-1/GIP-slowed gastric emptying can reduce absorption of oral contraceptives — discuss it proactively, not reactively.
2. Fertility recovery from weight loss can occur before the patient notices the menstrual change.
3. Preconception washout varies by molecule — there is no single rule for "the GLP-1s."
4. Facing an inadvertent pregnancy, stopping the drug is the immediate step — evidence on malformations is reassuring so far, but evidence on maternal metabolic/hypertensive outcomes is more mixed and warrants active pregnancy follow-up, not just reassurance.
5. The real teratogen in diabetes is uncontrolled hyperglycemia, not the drug itself — do not stop an antidiabetic agent without an already-defined replacement plan.

The approach to metformin once pregnancy is confirmed depends on why it was prescribed — it is not a single rule:

• PMOS with ovulation induction/insulin resistance: depending on the clinical context it is continued in early pregnancy or stopped on confirming pregnancy — an individualized, not automatic, decision. Many of these patients reach pregnancy already on metformin and/or myo-inositol as part of their baseline metabolic management (see the PMOS and Myo-inositol guides) — there is no teratogenicity signal for metformin requiring its immediate discontinuation upon confirming pregnancy, unlike GLP-1/GIP analogues (see the Inadvertent pregnancy guide).
• Prediabetes: individualize according to glycemic control and risk factors. ADA (2026 Standards of Care) does not position metformin as routine in isolated gestational prediabetes — its use follows the same individualization logic as in non-pregnant high-risk patients (elevated BMI, prior GDM, PMOS). NICE (NG3) is somewhat more permissive when risk factors for frank gestational diabetes coexist, where metformin may be anticipated as part of early management if glycemia warrants it — neither guideline indicates it routinely in isolated prediabetes without another risk factor. ADA 2026: metformin does not prevent gestational diabetes (meta-analysis of 11 RCTs).
• Pregestational diabetes: ADA prioritizes insulin as first-choice treatment (type 1 and, in most cases, type 2) due to metformin's transplacental passage and a preference for more predictable control; it reserves metformin as an adjunct in type 2 diabetes with high insulin resistance/high requirements, not as monotherapy. NICE (NG3) accepts metformin as first-line or adjunctive therapy in pregestational type 2 diabetes, adding insulin if the glycemic target is not reached — a stance more favorable to oral therapy than ADA's.
• Gestational diabetes: metformin as a second-line agent versus insulin per ADA (insulin as the preferred first line, metformin as an acceptable alternative after discussing transplacental passage with the patient); NICE (NG3) accepts metformin as a reasonable first line before insulin, barring contraindication or lack of response — see also the algorithm already described in the Gestational Diabetes guide.

Summary of the ADA vs. NICE divergence: both agree that uncontrolled hyperglycemia, not metformin, is the real teratogen, but they differ in how much weight they give oral metformin versus insulin: ADA tends to favor insulin as first-line therapy in overt diabetes (pregestational and gestational), reserving metformin as an adjunct or an alternative discussed case by case; NICE accepts metformin more broadly as a reasonable first line in several scenarios. Neither guideline diverges on PMOS, where the decision is individualized for reasons unrelated to fetal safety.

Key counseling point: the demonstrated teratogen in this context is uncontrolled hyperglycemia — not metformin itself. This should guide the decision not to abruptly stop an antidiabetic agent without an already-defined replacement plan (insulin or another scheme).

Offspring follow-up (MiG TOFU): follow-up of the MiG trial children at 2 years (Diabetes Care 2011) and 7-9 years (BMJ Open Diabetes Res Care 2018) assessed body composition and metabolic outcomes after in-utero metformin exposure — with no signal of harm that would contraindicate its use in gestational diabetes; this is the longest-term support available for this specific indication.

Metformin: compatible with breastfeeding — infant exposure via milk is generally <0.5% of the weight-adjusted maternal dose, with no adverse effects reported (LactMed, updated 15 August 2026; greater caution in newborns, preterm infants, and infants with renal impairment). LactMed also lists a postpartum restart schedule of 500 mg every 12 hours from day one — useful if an immediate postpartum restart is chosen.

Semaglutide: in the only dedicated study to date (Diab et al., Nutrients 2024; 8 women, SC doses 0.25-1 mg/week), semaglutide was not detectable in any of the milk samples analyzed after subcutaneous administration. The authors themselves note the data remain limited — long-term follow-up and data on maternal nutrition/milk composition are lacking. Do not automatically extrapolate this data (subcutaneous semaglutide) to oral formulations.

Tirzepatide: per the Zepbound label (DailyMed, section 8.2), in 11 breastfeeding women after a single 5 mg SC dose, tirzepatide was undetectable in 164 of 171 milk samples; the cumulative amount in the remaining 7 samples represented <0.02% of the administered maternal dose — a reassuring figure, though it comes from a single dose, not continuous use over time.

With this data it is no longer accurate to say "dedicated studies are lacking" for semaglutide/tirzepatide in lactation — they do exist, although small and short-term. Still distinguish the real risk of infant exposure (low, per this preliminary data) from the mere convenience of restarting maternal treatment as soon as possible — two distinct considerations that should not be blended when counseling the patient.

The vitamin D receptor (VDR) is present in multiple tissues of the reproductive tract and neighboring tissues, underlying the clinical associations described in Table 1 of the FLASOG document:

Table 1 — Tissue distribution of the VDR and impact on gyn-obstetric conditions:

• Ovary and endometrium → PMOS (formerly PCOS), infertility, endometriosis → proposed mechanism: endometrial receptivity, implantation, insulin sensitivity, inflammatory modulation.
• Placenta → gestational complications (preeclampsia, gestational diabetes, preterm birth) → placental angiogenesis and maternal-fetal immune tolerance.
• Vagina, bladder, and urethra → genitourinary syndrome of menopause, recurrent urinary tract infections → vaginal epithelial integrity, collagen synthesis, pH regulation, mucosal immunity.
• Bone and skeletal muscle → osteosarcopenia, osteoporosis, bone fragility, risk of falls/fractures → bone mineralization, preservation of muscle mass (type II fibers), muscle fat clearance.
• Pelvic floor musculature → pelvic floor dysfunction, urinary incontinence, pelvic sarcopenia → type II striated muscle fibers, muscle strength.
• Mammary gland → proliferative conditions → regulation of cell proliferation, local tissue homeostasis.

Table 2 — Guiding supplementation schemes (cholecalciferol, unless calcifediol is indicated):

• Prevention: 1,000-2,000 IU/day — standard maintenance dose.
• Insufficiency: 2,000 IU/day or 50,000 IU/month — gradual correction.
• Moderate deficiency: 50,000 IU every 2 weeks × 6-8 weeks — prioritizes comfort and adherence.
• Severe deficiency (<10 ng/mL): 50,000 IU/week × 6-8 weeks — rapid correction; avoid massive annual/spaced-out doses.
• Obesity or malabsorption: doses 2-3 times the usual amount, due to lower bioavailability.

Clarification — GLP-1/GIP is not the same as malabsorption: use of GLP-1/GIP analogues (semaglutide, tirzepatide — see corresponding guide) is not by itself an indication to raise the Vitamin D dose under the "obesity or malabsorption" scheme above. These drugs slow gastric emptying and reduce intake, but do not create a state of fat/fat-soluble vitamin malabsorption comparable to bariatric surgery (gastric bypass, sleeve with a malabsorptive component), which does justify it. Adjust the Vitamin D dose in a patient on GLP-1/GIP according to her actual nutritional status/serum levels, not automatically because she is on the drug.

Cholecalciferol vs. calcifediol: the FLASOG document positions cholecalciferol as the usual first line, reserving calcifediol for scenarios of obesity/malabsorption, liver disease, need for faster correction, or insufficient response to cholecalciferol.

Pregnancy: 1,000-2,000 IU/day as the usual scheme; for deficiency requiring more intensive correction, individualize under supervision, not exceeding 4,000 IU/day.

Note: the FLASOG document frames the therapeutic goal as reaching "adequate serum 25(OH)D concentrations," without setting a single numeric target range in ng/mL in its text — which is why this guide does not reproduce a single "target" figure (an earlier version used 40-80 ng/mL; it was removed as it was not sourced in this document). The deficiency/insufficiency thresholds are explicit and underlie Table 2 above.

⚠️ Caution note: some educational sources mention experimental very-high-dose protocols (e.g. "Coimbra," 40,000-100,000 IU/day) for autoimmune disease — these protocols are experimental, carry real risk of hypercalcemia/hypercalciuria/kidney stones, and are not endorsed by any formal FLASOG, ACOG, NICE, or USPSTF guideline; they must not be confused with the standard supplementation schemes in this guide.

See the next guide for the current controversy over whether population-wide screening (routine 25-OH-D testing) is warranted before prescribing this supplementation.

There is a real, current divergence between organizations over whether population-wide screening (routine 25-OH-D testing) and active supplementation are warranted in healthy women — CaVeSal presents both positions explicitly, without taking sides, so the clinical decision remains in your hands case by case:

FLASOG 2026 position (interventionist): recommends active assessment and supplementation to reach "adequate serum 25(OH)D concentrations" (the document does not set a single numeric target range in its text — see the deficiency/insufficiency thresholds in Table 2 of the previous guide), based on the tissue associations described in the previous guide (preeclampsia, gestational diabetes, preterm birth, PMOS).

Neuquén Bulletin 2026 position (restrictive, citing USPSTF/NICE/CONETEC/Endocrine Society): recommends against routine 25-OH-D testing in the healthy population — available evidence does not consistently demonstrate that screening followed by supplementation improves clinically relevant maternal or fetal outcomes beyond standard population-wide supplementation without prior testing (already in the Supplementation in Pregnancy guide in this same index); reserves targeted testing for specific risk groups.

Both positions come from current literature from different bodies — there is, as of this guide, no single consensus reconciling them. The choice between actively screening or supplementing without prior testing remains at your clinical discretion, case by case.

There is no single 25(OH)D threshold. Laboratories usually report the Endocrine Society 2011 criterion; IOM 2011 uses lower cutoffs aimed at bone health (comparison in Bouillon 2017).

20–29 ng/mL: grey zone; supplement at the physician's discretion.

WHO 2020: no routine supplementation in pregnancy; supplement if deficiency is documented or suspected.

Endocrine Society 2024: empirical supplementation in pregnancy without testing (trials used 600–5000 IU/day, mean ~2500). It advises against routine 25(OH)D testing, including for obesity or dark skin, and no longer endorses sufficiency cutoffs.

FLASOG 2026: pregnancy 1000–2000 IU/day, maximum 4000 IU/day.

The choice between not supplementing, supplementing without testing, or testing in selected cases is at the physician's discretion.

Basson model. Pelvic floor/Kegel. Lubricants. Dual protection + post-coital voiding.

GSM: hyaluronic acid, local topical estrogen, Prasterone, Ospemifene. HSDD: off-label transdermal testosterone + CBT.

Definition: onset of secondary sexual characteristics before age 8 (thelarche or adrenarche) or menarche before age 9.

Central precocious puberty (CPP/true, GnRH-dependent): premature activation of the hypothalamic-pituitary-gonadal axis, with a complete and accelerated isosexual sequence (thelarche → pubarche → menarche). Idiopathic in >80-90% of girls; rule out CNS lesions (hamartomas, gliomas, hydrocephalus), especially if <6 years.

Peripheral precocious puberty (PPP/pseudopuberty, GnRH-independent): autonomous secretion of sex steroids, with basal or suppressed FSH/LH from negative feedback. May be isosexual or contrasexual (virilization).

Non-progressive variants: isolated premature thelarche (no bone-age advance or uterine estrogenization) and idiopathic premature adrenarche (pubic/axillary hair and apocrine odor, with DHEA-S consistent with Tanner II-III and normal basal 17-OHP).

Pelvic ultrasound (transabdominal, with bladder filling) — quantitative criteria:

A pubertal uterus (2:1 ratio, visible endometrium) reflects sustained estrogen exposure — central or ovarian in origin. Strictly prepubertal uterus and ovaries with isolated adrenarche rule out a gonadal origin and point to the adrenal gland.

Anteroposterior and transverse uterine diameters are recorded together with length to calculate volume by the ellipsoid formula (L×AP×T×0.523); they do not carry an independently validated cutoff of their own.

Interpretation and limitations of ultrasound (Calcaterra et al. 2021 · Kim et al., Korean CPP Guideline 2023 · Nguyen et al., meta-analysis 2021 · Chen et al. 2015 · Eugster 2015): pelvic ultrasound is an ancillary/complementary tool, not diagnostic on its own — it is interpreted together with clinical findings, Tanner stage, and hormonal profile. Published cutoffs vary considerably between studies (uterine length ≈32-40mm, ovarian volume ≈1-3mL depending on the series); a meta-analysis of 13 studies found that a uterine length of 3.2cm had a pooled sensitivity of 81.8% and specificity of 82.0% for differentiating precocious puberty from premature thelarche (Nguyen et al. 2021) — useful as a reference point, not as an absolute boundary. After age 8, overlap between prepubertal and early-pubertal values increases considerably (Eugster 2015): in girls aged 8-9, avoid concluding "axis not activated" from ultrasound alone — report in terms of presence or absence of ultrasound signs of estrogenization, and always correlate with Tanner stage and gonadotropins. Follicular distribution (peripheral/diffuse) is documented descriptively: the isolated presence of small follicles does not equal pubertal activation and can be seen normally in prepubertal girls (Eugster 2015).

Algorithm: bone age by left hand-wrist X-ray (Greulich & Pyle) — an advance >1.5-2 years confirms biological impact. Basal LH ≥0.3mIU/mL + elevated estradiol + pubertal uterus → CPP (confirm with GnRH test, LH peak >5mIU/mL, and mandatory brain MRI). Basal LH <0.3mIU/mL (quiescent axis) → evaluate peripheral causes: elevated 17-OHP and DHEA-S → adrenal origin; elevated estradiol with normal 17-OHP → ovarian origin (autonomous follicular cyst, granulosa cell tumor, McCune-Albright).

Doppler (optional): not essential; ovarian vascularization can be described and, if color Doppler is available, uterine vascularization as well.

Additional findings to rule out: ovarian cysts, tumors, müllerian malformations, free pelvic fluid, adnexal abnormalities.

Structured ultrasound report template:

Transabdominal pelvic ultrasound
Uterus: anteverted, ___ × ___ × ___ mm (length × AP × transverse), volume ___ mL. Tubular/pear-shaped morphology. Body/cervix ratio ___. Homogeneous myometrium.
Endometrium: not visible / visible, thickness ___ mm.
Right ovary: ___ × ___ × ___ mm, volume ___ mL. ___ follicles present, largest ___ mm, peripheral/diffuse distribution.
Left ovary: ___ × ___ × ___ mm, volume ___ mL. ___ follicles present, largest ___ mm, peripheral/diffuse distribution.
Cul-de-sac: no free fluid.
Conclusion: uterus and ovaries with morphological and biometric features showing no clear ultrasound signs of significant pubertal estrogenization / with ultrasound signs of estrogenization and onset of pubertal development / with pubertal development appropriate for age. Correlate with Tanner stage and hormonal evaluation (LH, FSH, estradiol) according to clinical context, especially in girls aged 8-9 given the overlap between prepubertal and early-pubertal patterns.

Basal 17-OHP (points to adrenal origin): <1.0ng/mL rules out a major 21-hydroxylase deficiency. 1.0-2.0ng/mL gray zone — stimulation test needed. >2.0ng/mL high suspicion of non-classic congenital adrenal hyperplasia (NC-CAH). >10-20ng/mL virtually unequivocal diagnosis of CAH, or suspicion of an adrenal neoplasm (add adrenal ultrasound/CT/MRI).

ACTH stimulation test (250µg IV/IM, 17-OHP at 60 min): post-stimulation >10ng/mL (>1000ng/dL) is the gold standard confirming NC-CAH from 21-hydroxylase deficiency.

CPP — axis suppression with depot GnRH agonists: Leuprolide 3.75-7.5mg IM/SC every 28 days (monthly) or 11.25mg every 84 days (quarterly). Triptorelin 3.75mg IM every 28 days or 11.25mg every 12 weeks. Goal: growth velocity <4-5cm/year, stabilizing Tanner stage and preserving adult height. Discontinuation: once bone age reaches 11.0-11.5 years.

NC-CAH — adrenal suppression: hydrocortisone 8-12mg/m²/day in 2-3 oral doses, with the larger dose at night (suppresses the morning ACTH peak). Indicated for symptomatic accelerated adrenarche, bone age advanced >1.5-2 years, virilization, or compromised predicted height. Follow-up: growth velocity, annual bone age, and periodic 17-OHP/androstenedione/DHEA-S — avoid iatrogenic hypercortisolism.

Primary medical emergency. Do not require a prior police report. Non-judgmental history: time elapsed, type of contact, LMP, subsequent hygiene.

Exam with consent explained step by step. Forensic and clinical samples if <72h (HIV, VDRL, HBsAg, NAAT).

Levonorgestrel 1.5mg single dose (ideally <72h). Ceftriaxone+Azithromycin+Metronidazole. Hep B + Tetanus vaccination.

HIV PEP: TDF/FTC + Dolutegravir, start <72h, 28 days. Mandatory reporting. Immediate mental health referral.

Breast development (girls): M1 prepubertal (nipple only) · M2 breast bud/thelarche · M3 further enlargement without contour separation · M4 areola forms a secondary mound · M5 mature.

Genital development (boys): G1 infantile (<4mL) · G2 volume 4-8mL, scrotal reddening · G3 penile lengthening, 10-12mL · G4 increased girth+glans, 15-20mL, darkened scrotum · G5 adult, >20mL.

Pubic hair (both sexes): I no hair · II sparse/fine · III darker/curlier · IV adult type, reduced area · V adult type, complete.

Thelarche precedes menarche by ~2.5 years (average 12.5 years). Assess breast/genital development and hair separately.

Technique: AP X-ray of the left hand and wrist.

Greulich and Pyle Atlas: visual comparison by age/sex. Key milestone: sesamoid bone of the adductor pollicis marks the onset of the growth spurt (≈11 girls, 13 boys).

TW3 Method: quantitative, 20 bones, greater precision for predicting adult height.

Interpretation: normal ±1-1.5 years · delayed >1.5-2 years (constitutional delay, hypothyroidism, GH deficiency, malnutrition) · advanced >1.5-2 years (precocious puberty, obesity, CAH).

Embryology: Müllerian ducts → tubes/uterus/cervix/upper 2-3 of vagina. Urogenital sinus → lower 1/3 of vagina/hymen/bladder/urethra.

⚠️ 30-50% of Müllerian anomalies are associated with renal malformations — renal ultrasound mandatory.

Class I (MRKH): absent uterus/vagina, functional ovaries, primary amenorrhea with developed breasts.

Class II (unicornuate): failure of one duct. Risk of ectopic pregnancy in the rudimentary horn + preterm birth.

Class III (didelphys): 2 uteri/cervices, vaginal septum. OHVIRA syndrome: +obstructive septum+ipsilateral renal agenesis → hematocolpos.

Class IV (bicornuate): 1 cervix, external fundal notch >1cm.

Class V (septate, most common): normal serosa, internal septum. Leading cause of recurrent miscarriage. Tx: hysteroscopic metroplasty.

Class VI (arcuate): normal variant. Class VII (DES): T-shaped uterus.

Imperforate hymen: cryptomenorrhea + violaceous bulging → hematocolpos.

Transverse vaginal septum: perforated or complete. Congenital cloaca: vagina-urethra-rectum confluence (common in CAH).

Algorithm: 3D ultrasound → pelvic MRI → mandatory renal ultrasound → HSG/hysteroscopy.

Bettocchi/"no-touch" technique: no speculum or tenaculum.

Media: saline/Ringer's (bipolar) · Glycine/Sorbitol (monopolar only).

Fluid deficit limits: saline stop at 2,500mL (1,500 in cardiac/renal disease) · Glycine stop at 1,000mL (risk of severe hyponatremia).

Type 1 physiological (straight, smooth entry) · Type 2 tortuous (S/Z-shaped, requires scope rotation) · Type 3 stenotic/atrophic (prepare with estrogen ± Misoprostol) · Type 4 obstructed (adhesions/polyps, millimetric dissection).

Indications: AUB (1st choice for focal PALM-COEIN), polyps, FIGO 0/1/2 submucosal fibroids, hyperplasia/carcinoma, infertility/recurrent miscarriage, retained IUD.

Techniques: polypectomy (bipolar loop) · myomectomy (FIGO 0/1 ≤3-4cm, slicing) · metroplasty (septum incision) · adhesiolysis (centrifugal).

False tract/perforation: blunt+stable instrument→observation+antibiotics. Activated electrode→mandatory exploratory laparoscopy.

Vasovagal reflex: Trendelenburg+fluids+Atropine 0.5-1.0mg IV if persistent.

Gas embolism: do not purge with air, intrauterine pressure 70-100mmHg.

Hammock theory (DeLancey): fibroconnective/muscular support that compresses the urethra.

Q-Tip test: hypermobility if deflection ≥30°.

VLPP: >90 pure hypermobility · 60-90 mixed · <60 intrinsic sphincter deficiency (ISD).

Blaivas-Olsson: 0 not demonstrated · I <1.5cm without cystocele · IIa >1.5cm with cystocele · IIb already descended at rest · III open at rest (=ISD).

1st line: PFMT/Kegel ≥3 sets/day x3 months + biofeedback. Pessaries.

2nd line (office-based): Luksenburg system (suburethral PDO/PCL thread mesh, outpatient) — most recent technique, less consolidated evidence than the rest of this guide. Vaginal laser/radiofrequency. Bulking agents (Bulkamid).

Luksenburg system (suburethral spider web): PDO/PCL thread mesh, outpatient under local anesthesia — hammock-type support + directed neocollagenesis (12-24 months). Note: most recent technique, less consolidated evidence than the rest of this guide.

Other options: vaginal laser/fractional radiofrequency (collagen remodeling) · urethral bulking agents (Bulkamid) in elderly/high surgical risk patients.

Hypermobility (VLPP>60-90): Retropubic TVT (>85-90% efficacy, mandatory cystoscopy) · Transobturator TOT (lower bladder risk) · Burch colposuspension (if mesh contraindicated).

ISD (Blaivas III, VLPP<60): Retropubic TVT (superior to TOT) · Autologous fascial sling (rescue) · Artificial urinary sphincter (refractory).

Monthly, day 5-10 of the cycle. Inspection (3 positions) + palpation (3 fingers, circular motions, clavicle-inframammary fold, sternum-axilla).

NAAT/PCR: Chlamydia, gonorrhea, Mycoplasma genitalium, Trichomonas, high-risk HPV. Serology: syphilis, HIV, Hep B/C. Wet mount: Candida, clue cells, trophozoites.

Ceftriaxone 500mg IM single dose (1g if ≥150kg). Disseminated: 1g IV/IM q24h x7d. Azithromycin monotherapy no longer prioritized due to resistance.

Under study, not approved: oral ciprofloxacin guided by a molecular resistance test (gyrA codon 91 mutation), only for susceptible strains. It is an expert-group proposal (Trainor 2026) pending FDA-cleared tests; it is not a guideline recommendation. Current treatment remains ceftriaxone.

With Chlamydia not ruled out: +Doxycycline 100mg q12h x7d. With Trichomonas: Metronidazole 500mg q12h x7d. Empiric PID: Ceftriaxone+Doxycycline+Metronidazole x14d.

Chlamydia: Doxycycline 100mg q12h x7d. M. genitalium: sequential therapy Doxycycline→Azithromycin (or Moxifloxacin if resistant). Ureaplasma: usual commensal, treat only if symptomatic.

Non-hormonal: Tranexamic acid 1.3g PO 3x/day x5 days/cycle. NSAIDs.

Hormonal: combined OCPs, progestins, 52mg LNG-IUD, GnRH agonists/antagonists with add-back therapy.

Criteria: stability, severity, failed medical treatment, fertility desire. Fibroid: myomectomy/RFA/embolization/hysterectomy. Adenomyosis: hysterectomy if fertility not desired. Polyps: polypectomy. Severe acute: D&C. Endometrial ablation: alternative, ends fertility.

Ablation + LNG-IUS (MIRA2, Lancet 2026): in 715 women under 60 with heavy menstrual bleeding, inserting a 52mg LNG-IUS immediately after ablation reduced hysterectomy at 2 years (4% vs. 10%; RR 0.43), with no more serious adverse events (8% vs. 8%).

28 days: Early follicular (1-5, menstruation) · Late follicular (6-13, E2>200) · Ovulatory (14±2, LH peak) · Mid luteal (15-24, P4>10) · Late luteal (25-28, luteolysis).

LH peak 24-36h pre-ovulation. Implantation window days 20-24. Day 21 P4 >3-5 confirms ovulation.

Basal body temperature (BBT) patterns: monophasic (no clear rise — suggests an anovulatory cycle, no functional corpus luteum) · biphasic (typical ovulatory pattern — rises ~0.3-0.5°C after ovulation, sustained through the luteal phase) · triphasic (second rise 6-12 days post-ovulation — may be associated with implantation/early pregnancy in ~12% of confirmed cases, not diagnostic on its own, ~88% of pregnancies do not show this pattern).

Early follicular (2-4): FSH <8-10 optimal, >15 low reserve. LH/FSH>2-3 suggests PCOS. AMH: optimal 1.2-3.5.

Mid luteal (day 21): P4 ≥10 optimal. Thyroid: TSH target <2.5. Normal PRL <20-25.

3 pillars: (1) Ovarian — hormonal profile + AMH + AFC. (2) Tubal — HSG/HyFoSy. (3) Uterine — 3D ultrasound/sonohysterography.

HyFoSy (echogenic foam instillation under transvaginal ultrasound, no radiation or iodinated contrast) and HSG show comparable sensitivity/specificity for tubal patency (2024 meta-analysis, 2025 agreement study) — HyFoSy with better tolerability (less pain) and no radiation exposure.

Foam vs. saline (Piccioni 2017): saline medium (classic sonohysterography/SIS) disperses quickly and is limited for assessing the tubal course; foam, more viscous and echogenic, allows visualization of tubal passage and peritoneal spill — this is why it replaced saline when the goal is tubal assessment, while saline remains preferable when the goal is only the endometrial cavity (polyps, submucosal fibroids).

Hysteroscopy does not assess tubal patency (uterine cavity only) — reserved for confirming/treating already-suspected intracavitary findings, not as a first-line tubal-factor study.

Algorithm: HyFoSy = first line (tubal screening + cavity, no radiation) · HSG = valid alternative depending on resources · laparoscopy with chromopertubation = reserved for suspected associated pelvic pathology or an inconclusive result.

WHO 6th ed. minimum values: volume≥1.4mL, concentration≥16M/mL, progressive motility≥30%, morphology≥4%.

TMSC: >3-5M → IUI · 1-3M → IVF · <1M → direct ICSI.

Basic labs + serologies + Pap/mammogram as appropriate.

Folic acid: standard 400mcg/day · high risk 4 mg/day (ACOG/CDC) or 5 mg/day (NICE/RCOG) up to wk 12 (prior NTD in the woman or partner, diabetes, obesity, epilepsy or anticonvulsants).

MTHFR: standard folic acid (CDC); methylfolate 400–800 µg/day as an optional alternative.

Paraguay context (MSPyBS): the official public health communication from Paraguay's Ministry of Public Health and Welfare (MSPyBS) recommends 0.5mg (500mcg)/day as the standard preconception/gestational folic acid dose — slightly higher than the international 400mcg standard cited above, without changing the high-risk dose (4-5mg/day) in the risk scenarios already described. The MSPyBS Manual de Cuidados Perinatales (Resolución S.G. N.º 1078/2022, already cited elsewhere in this guide section for the PBF re-evaluation window) structures the preconception visit as "traffic-light" (semáforo), i.e. tiered by risk level — confirmed that this scheme exists in the official document.

Careful history/exam to choose studies. Essential female evaluation in parallel. Counseling on tobacco+STIs. Document outcomes. Psychosocial support.

Unexplained infertility: a complete work-up with normal female and male factors (ovulation, ovarian reserve, tubal patency, uterine cavity, semen analysis) with no identifiable cause, after ≥12 months of trying (or 6 months if ≥35 years).

Stress and unexplained infertility: recent evidence shows an association (not proven causation) between psychological distress measured by validated scales and unexplained infertility — but not with single-time endocrine stress markers (e.g., isolated cortisol), suggesting a phenomenon more complex than a simply hyperactivated HPA axis measurable in one sample.

Clinical implication: psychological support can be offered as an adjunct (well-being/treatment adherence), but it does not replace or delay the standard diagnostic-therapeutic algorithm (ovulation induction, IUI, IVF as appropriate).

Letrozole (aromatase inhibitor) — first-line in PCOS/WHO Type II anovulation, especially with overweight/obesity (BMI≥25-30). Higher cumulative ovulation, clinical pregnancy and live-birth rates than clomiphene (PPCOS II trial). Does not block endometrial or cervical estrogen receptors (preserves endometrial thickness and cervical mucus quality). Short half-life (~48h): favors monofollicular development, lower multiple-pregnancy rate.

Clomiphene citrate (SERM): first-line alternative when letrozole is unavailable/not tolerated, or in unexplained infertility (timed intercourse/IUI). Drawback: prolonged peripheral antiestrogenic effect (half-life >2 weeks) — refractory thin endometrium (<7mm) and hostile mucus; higher multifollicular/multiple-pregnancy rate (5-10%, mostly twins) than letrozole.

Exogenous gonadotropins (recombinant FSH / hMG): failure or resistance to oral agents (after 3-6 ovulatory cycles without conception); or Hypogonadotropic Hypogonadism (WHO Type I — hypothalamic-pituitary axis not intact, clomiphene/letrozole do NOT work, requires hMG or FSH+hCG/LH microdose); or as an adjunct in low-complexity/IUI cycles.

Letrozole: 2.5mg/day PO x5 days, starting cycle day 2-5. If no ovulation, escalate to 5.0mg/day the next cycle; maximum dose 7.5mg/day x5 days.

Clomiphene citrate: 50mg/day PO x5 days, day 2-5. If no response, increase to 100mg/day; usual maximum 150mg/day x5 days (higher doses do not improve pregnancy rates and worsen the endometrial antiestrogenic effect). Limit: 6 ovulatory cycles.

Gonadotropins — "Low-Dose Step-Up" protocol: strict goal of monofollicular development and OHSS prevention. Starting dose 37.5-50-75 IU/day SC/IM from cycle day 2-3, holding the fixed dose for 7-14 days. If after 14 days there is no follicular selection (no follicle ≥10mm), increase 50% weekly (e.g. 37.5→75 IU/day) until a response is seen, then maintain that dose through the trigger.

Baseline transvaginal ultrasound + Antral Follicle Count (AFC), cycle days 2-4 — mandatory before starting any inducing agent: thin, shed endometrium (<5mm); rule out functional cysts/persistent follicles from the previous cycle (start if no follicles/cysts >10mm; postpone/cancel if a residual cyst or growing follicle ≥10-15mm is found, usually with baseline E2 >50-60pg/mL).

AFC (bilateral 2-9mm follicles): <5-7 suggests low ovarian reserve · 8-15 normal reserve · ≥20 (or ovarian volume ≥10mL) polycystic ovarian morphology — maximum alert for hyperresponse and OHSS risk.

Serial follow-up: first post-stimulation scan on cycle day 8-10, then every 48-72h depending on follicular growth rate (expected physiologic growth 1.5-2mm/day). Record the mean diameter in 2 perpendicular planes per ovary, and endometrial thickness/pattern (optimal: periovulatory trilaminar "triple line" ≥7-8mm).

The hCG trigger mimics the endogenous LH surge: it resumes oocyte meiosis, luteinizes the granulosa cells, and times follicular rupture (36-40h after administration).

Trigger agents: Recombinant hCG (r-hCG) 250mcg SC · urinary hCG (u-hCG) 5,000-10,000 IU IM.

Follicular size by inducing agent:

• Clomiphene citrate: trigger with the leading follicle at a mean diameter of 20-28mm; ASRM notes higher pregnancy rates at 23-28mm (follicles under clomiphene mature at larger diameters: in conception cycles the leading follicle measured 20.4 ± 1.2mm). Monitor endometrial thickness because of the antiestrogenic effect.
• Letrozole: trigger with the leading follicle at 19-23mm (optimal 19.1-21mm in the first IUI cycle); tolerated up to 28mm.
• Gonadotropins (FSH/hMG): trigger with the leading follicle at 16-18mm (oocyte maturity is reached at slightly smaller sizes under direct gonadotropins; triggering above 19-20mm increases oocyte senescence).

Note: ESHRE (2025) considers that the association between follicle size and outcome has not been sufficiently studied; the trigger size is individualized.

Concurrent endometrial status: ideally ≥7mm with a trilaminar pattern before ordering the trigger.

Timing of intercourse/insemination: timed intercourse — the night of the trigger and again 36h later (or on alternating days: trigger day and the next). IUI — sperm preparation and insemination at 36h (range 34-38h) post-hCG.

In low-complexity techniques (timed intercourse/IUI), the safety threshold requires strictly avoiding high-order multiple pregnancy and Ovarian Hyperstimulation Syndrome (OHSS).

Immediate cancellation criteria — do NOT give hCG:

• ≥3 mature follicles (≥15-16mm) in women <35 years, or >3-4 mature follicles in any low-complexity patient.
• More than 4-6 intermediate follicles (11-14mm) that could respond to the trigger.
• Serum estradiol >1,000-1,500pg/mL (if measured).

Management on cancellation: cancel and withhold the hCG trigger (it is the direct trigger for the VEGF cascade and capillary hyperpermeability of OHSS). Advise strict coital abstinence or mandatory condom use for ≥7-10 days. Do not give hCG for luteal support. Rescue option at a high-complexity center: convert the cycle to IVF with follicular aspiration, GnRH-agonist trigger, and total embryo cryopreservation ("freeze-all").

Drug resistance: persistent absence of recruitment, or no follicles ≥15mm despite maximum doses. Clomiphene resistance: anovulation after 150mg/day x5 days. Letrozole resistance: anovulation after 7.5mg/day x5 days. Management: switch therapeutic line (CC→Letrozole, add Metformin in PCOS with insulin resistance, or move to low-dose gonadotropins).

Failed induction (treatment failure): confirmed regular ovulatory cycles (optimal follicular development, follicular rupture and adequate luteal phase with progesterone ≥10ng/mL) without pregnancy after 4-6 consecutive ovulatory cycles. Management: full couple re-evaluation (tubal patency by HSG if not yet done, repeat semen analysis with TMSC) and escalation to high-complexity ART (IVF/ICSI).

Endometrial failure (antiestrogenic effect): adequate follicular growth but persistently thin endometrium (<6-7mm) in the preovulatory window (common with clomiphene). Management: switch to letrozole or add exogenous estrogen support.

Calendar: ovulation≈N-14, window N-18 to N-11.

LH test: start 3-4 days before, ovulation 24-36h post-positive.

Billings method: elastic/clear mucus near ovulation, peak day ≈13-14.

Normal PRL <20-25. Micro <10mm (50-150) · Macro ≥10mm (>200-250).

Dx: morning serum level, rule out macroprolactin/hook effect, MRI if PRL>100.

Tx: Cabergoline (1st line) 0.25-1.0mg/week · Bromocriptine (if seeking pregnancy) 2.5-7.5mg/day.

Ravel classification: CST I (L. crispatus, optimal) · CST II (L. gasseri, protective) · CST III (L. iners, transitional/vulnerable) · CST IV (polymicrobial dysbiosis/vaginosis, pH>4.5) · CST V (L. jensenii, protective).

Mechanism: dysbiosis degrades mucin → TLR-4 inflammation (IL-1β/6/8, TNF-α) → MMP-2/9 → facilitates HPV entry and delays clearance → accelerates LSIL→HSIL→cancer.

Biomarkers: ↑Sneathia/Fusobacterium, ↓D-lactic/L-lactic acid ratio.

Dysbiosis alters cervical mucus and causes chronic endometritis (αvβ3 integrins). Implantation failure/recurrent miscarriage via Th1/Th17. Favorable marker: L. crispatus >90%.

Management: Metronidazole/Clindamycin (CST IV) · topical lactic acid · probiotics (L. crispatus/gasseri) · pre-fertility work-up with culture/hysteroscopy+CD138.

Gut bacteria with Beta-Glucuronidase/Glucosidase that deconjugate estrogens inactivated in the liver → reabsorption → circulation → ERα/ERβ receptors.

Hyperactivity (Bacteroides, Clostridium, E.coli) → hyperestrogenism → endometriosis, fibroids, endometrial hyperplasia/cancer, breast cancer risk, PCOS.

Hypoactivity (antibiotics, ultra-processed diet) → hypoestrogenism → worse climacteric symptoms, bone mineral density loss, infertility from implantation failure.

Nutrition: fiber 25-30g/day, cruciferous vegetables (DIM), ↓alcohol/saturated fat.

Supplementation: Calcium D-Glucarate 500-1,500mg/day (hyperestrogenism) · probiotics (L. acidophilus/rhamnosus, Bifidobacterium) · prebiotics (inulin, FOS, GOS).

Healthy woman, BMI 18.5-24.9, BP<120/80, normal history, normal labs/serologies/Pap, complete vaccination.

Folic acid 0.4-0.5mg/day from ≥3 months preconception. Education (diet, exercise, cessation of toxic exposures). Fit to attempt pregnancy.

Underweight/overweight/class I obesity, treatable infections, mild-moderate anemia, rubella/Hep B seronegativity, interpregnancy interval<18-24mo.

Temporary contraception + correction of the cause + immunization (⚠️ live vaccine → delay ≥4 weeks). Reassess in 3-6 months.

Pregestational DM with HbA1c>7%, severe chronic hypertension, heart disease, CKD, active SLE, uncontrolled epilepsy, HIV with detectable viral load, history of NTD/severe preeclampsia/recurrent loss, active teratogenic drugs.

Immediate LARC contraception + mandatory referral + replacement of teratogenic drugs. Clearance only after ≥6 months of stability.

Pap at 1st/2nd prenatal visit. <30: Pap only. ≥30: co-testing/primary HPV. Colposcopy only if high-risk HPV+ or abnormal Pap.

Not during pregnancy, yes during preconception. Average risk: from age 40. Family history: 30-35. BRCA+: 25-30.

Age: <21 no screening · 21-29 Pap/3years · 30-65 high-risk HPV/5years (preferred) · >65 stop if adequate prior screening.

Pap: ASC-US→HPV triage · LSIL→colposcopy · ASC-H→mandatory colposcopy · HSIL→colposcopy+biopsy · AGC→+endocervical curettage.

I confined to the cervix (IA<5mm, IB visible) · II upper vagina/parametria · III lower vagina/pelvic wall/nodes · IV bladder/rectal/metastasis.

Group 1 — Girls and boys aged 9 to 14 (routine schedule): 1 dose, administered at first contact.

Group 2 — Women aged 15 to 24 with no vaccination history (catch-up schedule): ages 15-20 → 1 dose at first contact. Ages 21-24 → 2 doses (at contact and at 6 months, minimum interval of 6 months).

Group 3 — People aged 15 to 45 with risk criteria (includes men and women except item 5):

• HIV: 3 doses — at contact, at 1 month and at 6 months after the first dose.
• Solid-organ or hematopoietic-component transplant recipients: 3 doses — same schedule (0-1-6 months).
• Immunosuppressive treatment: 3 doses — at 6 months after the first dose, per the PAI schedule.
• Survivors of sexual abuse: 2 doses — at contact and at 6 months after the first dose.
• Women with cervical pathology (carriers of high-risk oncogenic HPV by HPV testing, or diagnosed with CIN 1/CIN 2 by Pap smear or biopsy): 3 doses (at contact, 1 month and 6 months) — preferably before conization/LEEP; if not possible, up to 1 year after excisional treatment.

The vaccine is free and available at health services (USF) under the Paraguay PAI schedule. Recording the dose in the vaccination card is recommended.

WHO/SAGE corroboration (December 2022): the SAGE position endorses 1-dose schedules for the general population aged 9-20 (non-inferior efficacy vs. 2 doses in compared immunogenicity trials), and maintains a 2-3 dose schedule for immunocompromised individuals (including HIV) — consistent with the 3-dose reinforcement that the Paraguayan schedule maintains for the Group 3 risk categories. There is no contradiction between the two sources; the PAI schedule is, if anything, more conservative (2 doses at ages 21-24) than the minimum SAGE allows.

IOTA: B rules (benign) vs. M rules (malignant) — only B=benign, only M=malignant, both/neither=indeterminate.

O-RADS: 1 physiological (0%) · 2 almost certainly benign (<1%) · 3 low risk (1-<10%) · 4 intermediate (10-<50%) · 5 high (≥50%, mandatory referral).

Markers: CA-125, HE4 (more specific), ROMA index.

Categories: NILM (negative) · Squamous: ASC-US, ASC-H, LSIL (CIN1), HSIL (CIN2/3), invasive carcinoma · Glandular: AGC, AGC favor neoplasia, AIS, invasive adenocarcinoma.

TZ: Type 1 fully visible ectocervical · Type 2 visible endocervical component · Type 3 not fully visible.

Abnormal: Grade 1 (thin acetowhite, fine mosaic/punctation) · Grade 2 (dense acetowhite, rag sign/inner border/ridge sign) · Suspect invasion (atypical vessels, mass, necrosis).

Triad: Pap (cytological) → Colposcopy (topographic) → Biopsy (histopathological).

HSIL/CIN3 risk: <0.55% routine · 0.55-4% co-test in 1 year · 4-24% colposcopy · 25-59% colposcopy or immediate treatment · ≥60% direct immediate treatment.

By result: NILM+HPV16/18→colposcopy · ASC-US+HPV(+)→colposcopy · LSIL≥25yo→colposcopy · ASC-H→colposcopy always · HSIL≥25yo→excision/biopsy · AGC→colposcopy+mandatory endocervical curettage.

CIN 1: observation, co-test at 12 months. No routine LEEP unless persistent >2 years.

CIN 2/3: excision (LEEP/conization) or destructive (TZ1 only). Conservative exception: selected young patients, p16-negative CIN2, follow-up every 6mo up to 24mo.

Test of cure (HPV/co-test) at 6 months. Negative → annual x3 years, then every 3 years, minimum age 25 (even >65 years). Positive → immediate colposcopic re-evaluation.

Complementary ultrasound: dense breasts (ACR c/d), <30-35 years with a palpable mass, differentiate cyst/solid.

Density (ACR): a (fatty) · b (scattered) · c (heterogeneously dense, consider ultrasound) · d (extremely dense, ultrasound indicated).

BI-RADS: 0 incomplete · 1 negative (0%, routine) · 2 benign (0%, routine) · 3 probably benign (>0-≤2%, 6/12/24mo follow-up).

BI-RADS 4 (>2-<95%, biopsy mandatory): 4a (>2-≤10%) · 4b (>10-≤50%) · 4c (>50-<95%).

BI-RADS 5 (≥95%): spiculated mass, branching pleomorphic microcalcifications → immediate biopsy + oncology.

BI-RADS 6: previously proven malignancy → definitive treatment.

Values by phase: proliferative 4-8mm, periovulatory 8-12mm, secretory up to 14-16mm. AUB ≥45yo: biopsy mandatory. <45yo without risk factors: progestins/OCPs. With risk factors or failure: biopsy.

With PMB: ≤4mm expectant · >4mm biopsy mandatory. Asymptomatic: ≤11mm no routine biopsy · >11mm individualize. Continuous HRT target ≤4-5mm.

Almost always functional (anovulation). Transabdominal ultrasound. Biopsy/curettage contraindicated as 1st line. Progestins in the 2nd half of the cycle. Rule out coagulopathies if bleeding since menarche.

Measurement: sagittal plane, double layer. Echogenicity: uniform (trilaminar/hyperechogenic) vs. non-uniform (suggestive of pathology). Endometrial-myometrial interface regular vs. irregular (suspicious for invasion).

Color Score 1-4. Single dominant vessel → polyp. Multiple disorganized vessels → malignancy. Scattered vessels without a dominant one → hyperplasia.