Bridging the Gap Between Genetic Cardiomyopathies and Pregnancy

Authors, Journal, Affiliations, Type, DOI

• Authors: Karen Flores Rosario (Duke) and Merna Hussien (Duke) with Phoenix Grover and Courtlyn Witte (genetic counsellors), Richa Agarwal, Jenna Skowronski, Johanna Quist-Nelson, Michelle M. Kittleson (Cedars-Sinai), Rachel Peragallo Urrutia, Melinda B. Davis (Michigan), Joanna M. Joly (Inova), Dana Spears (Toronto), Julia Alvarenga Fagundes Couto; Jerome Jeffrey Federspiel and Melissa A. Daubert as joint senior authors
• Affiliations: Division of Cardiology and Department of Obstetrics and Gynecology, Duke University Hospital, Durham, North Carolina; UNC-Chapel Hill; Cedars-Sinai Smidt Heart Institute; University of Michigan; Inova Schar Heart and Vascular; Peter Munk Cardiac Centre, Toronto
• Journal: JACC: Advances. 2026;5(6):102784 — State-of-the-Art Review; open access (CC BY); received 20 Jan 2026, accepted 1 Apr 2026
• Type: Narrative state-of-the-art review with two illustrative cases. No systematic search, no quality appraisal, no GRADE
• DOI: https://doi.org/10.1016/j.jacadv.2026.102784

Overview

A cardio-obstetrics review written for a problem the guidelines have not solved: what to do with a woman who carries a cardiomyopathy variant and wants to become pregnant. The organising observation is that neither risk tool in current use accepts genotype as an input — CARPREG II and the modified WHO classification score the phenotype in front of them and are blind to the variant that predicts what the phenotype will become (#Contradictions / Open Questions).

The paper works through five phenotypes (ACM, HCM, DCM, PPCM, genotype-positive/phenotype-negative) and then through the reproductive timeline: preconception medication conversion, PGT-M and prenatal diagnosis, antepartum surveillance, delivery mode and anaesthesia, breastfeeding, and postpartum follow-up. It is explicit that most of its advice is extrapolated consensus rather than trial evidence, and it identifies GP/PN women — increasingly numerous as cascade testing spreads — as the least characterised group of all.

Keywords

Arrhythmogenic cardiomyopathy · genetic cardiomyopathy · peripartum cardiomyopathy · pregnancy

Key Takeaways

Inheritance patterns relevant to pregnancy counselling

• Autosomal dominant is the default for genetic cardiomyopathy: heterozygosity is sufficient, first-degree relatives carry a 50% risk, and de novo variants still occur in the proband.
• Autosomal recessive disease requires biallelic variants: recessive DCM from JPH2 and TNNI3, and Naxos disease from biallelic JUP — ARVC with palmoplantar keratoderma and woolly hair.
• X-linked disease (e.g. DMD) affects hemizygous males primarily; female carriers may show a milder phenotype but carry elevated DCM risk.
• Mitochondrial variants cause cardiomyopathy with severity modulated by heteroplasmy.
• Penetrance is gene-specific and is the number that matters in a preconception conversation: LMNA 90–95% by age 60 versus MYBPC3 roughly 55% over a lifetime.

Arrhythmogenic cardiomyopathy

• 50–60% of ACM patients carry a desmosomal variant (PKP2 commonest, then DSP, DSG2, DSC2, JUP), with age-dependent penetrance of 50–60%.
• Pregnancy is uneventful for the majority — in the NORDIC ARVC Register (199 females), the number of prior pregnancies did not increase ventricular arrhythmia risk — but outcomes remain worse than in unaffected women (sources/cmp-pregnancy-jaccadv-2026, rating: medium).
• The postpartum window carries the signal. Women who gave birth with previously diagnosed ACM had elevated postpartum ventricular arrhythmia risk: HR 13.74 (95% CI 2.9–63; P=0.001). In the combined Johns Hopkins/Dutch registry, 13% of pregnancies were complicated by ventricular arrhythmia and 5% by heart failure.
• mWHO class II–III; neither mWHO nor CARPREG II incorporates gene-specific risk.
• HRS 2023 consensus gives a Class 1 recommendation for secondary-prevention ICD in ACM with prior ventricular arrhythmia or aborted SCD, and implantation before conception is preferred because device placement during pregnancy adds procedural and fetal risk.
• Beta-blockers are first-line; flecainide, sotalol and mexiletine are alternatives when beta-blockers are contraindicated; amiodarone is a last resort for life-threatening arrhythmia only; catheter ablation carries a 2a recommendation if arrhythmia persists despite drugs.
• Surveillance: ECG, 24-hour ambulatory ECG and NT-proBNP every 3 months; monthly if LVEF is reduced, if NYHA III–IV, or if symptoms change.

Hypertrophic cardiomyopathy

• LVOTO is present in roughly 70% of HCM; MYBPC3 and MYH7 account for the majority of sarcomeric cases, with TNNI3, TNNT2, TPM1, MYL2, MYL3 and ACTC1 contributing 1–5% each.
• Pregnancy is generally well tolerated: maternal mortality 0.2%, with no difference between obstructive and nonobstructive disease. A 2025 propensity-matched analysis found no difference in 10-year all-cause mortality between parous and nulliparous women.
• Earlier data (127 women, 271 pregnancies) found symptom exacerbation in fewer than 10%. Risk concentrates in severe hypertrophy, a gradient >100 mmHg, and a personal or family history of severe arrhythmia.
• Myectomy should be done before pregnancy where indicated, and cardiac myosin inhibitors must be avoided for potential teratogenicity — a preconception surgical decision driven by a drug contraindication rather than by the cardiac indication.
• If LVOTO is uncorrected or develops in pregnancy, beta-blockers or calcium channel blockers are used where LVEF is normal. Hypotension is treated with phenylephrine preferentially plus volume; assisted second stage limits the haemodynamic cost of prolonged Valsalva.
• mWHO II–III. CARPREG II recognises LVOTO and ventricular dysfunction as adverse predictors but does not include HCM-specific variables validated in pregnancy cohorts.

Dilated cardiomyopathy

• TTN truncating variants account for 15–25% of DCM and LMNA for 4–7%, with BAG3, DES, FLNC, MYH7, PLN, RBM20, SCN5A, TNNC1, TNNT2 and DSP also established.
• ESC 2023 introduced nondilated LV cardiomyopathy as a distinct entity; with no pregnancy data, the paper extrapolates from DCM.
• DCM carries the highest maternal risk of the phenotypes reviewed: major adverse cardiovascular events in 39% of pregnancies, maternal mortality up to 7% in high-risk groups. Pre-pregnancy LVEF <50% is the strongest predictor of poor outcome — more predictive than any genetic finding.
• mWHO III (pregnancy discouraged, intensive specialist monitoring): LVEF 30–45%. mWHO IV (pregnancy contraindicated): LVEF <30% or NYHA III–IV.
• Surveillance every 3 months in low-risk patients (2025 European guideline), bimonthly at mWHO II, monthly at mWHO III.
• Management is volume control, afterload reduction, rhythm control, and anticoagulation where indicated — built around the fact that GDMT itself must be withdrawn.

Peripartum cardiomyopathy

• Defined as heart failure with LVEF ≤45% toward the end of pregnancy or in the months after delivery, with no pre-existing cardiac dysfunction. Incidence is highest in women of African, Haitian and Nigerian descent.
• ~15% share a genetic predisposition with DCM — truncating variants in TTN, FLNC, DSP, MYH6, MYH7, BAG3. In an international study of 469 women, over 10% carried TTNtvs, associated with lower ejection fraction but not with timing of presentation, preeclampsia, or recovery.
• Genetic counselling and testing are now recommended for all women with PPCM — yet only 11% were referred for genetic evaluation in a recent study.
• 2025 ESC guidance discourages subsequent pregnancy when LV dysfunction persists (LVEF <50%), but notes that risk of recurrent dysfunction, life-threatening arrhythmia and rarely death persists even when EF has recovered. Prospective European data suggest women with LVEF 40–50% may proceed under multidisciplinary monitoring.
• Outcomes after a subsequent pregnancy diverge by recovery: in a US retrospective cohort (80% African American), women with non-recovered LVEF had adverse outcomes in 53% versus 20% and 5-year all-cause mortality 13.3% versus 3.3%.

Genotype-positive, phenotype-negative

• GP/PN women are the fastest-growing group, and the least studied. Most guidance is inferred from the variant, the family history, and a baseline evaluation.
• In women with rare DCM variants, pregnancies were mostly uneventful, but 10% developed clinically significant cardiac complications during or shortly after pregnancy — approximating the rate in women whose cardiac disease predated pregnancy.
• 34% of GP/PN relatives in PKP2 families progress to definite ARVC over time, supporting a dynamic prephenotypic state that physiological stress may unmask.
• "In GP/PN, near-term clinical outcomes are driven primarily by phenotype" — genotype informs surveillance, phenotype drives the pregnancy decision.
• A VUS does not remove the need for evaluation; it shifts the question from genotype to phenotype (ECG, Holter, echo, and in selected cases exercise testing and CMR).

Reproductive genetics

• PGT-M adds the risks of IVF itself (embryo loss from sampling, false positive/negative results from mosaicism, higher maternal morbidity than spontaneous conception) on top of cost and emotional burden.

Preconception care

• Start the reproductive conversation at diagnosis, not at conception, in any woman of childbearing potential.
• Convert teratogenic therapy before pregnancy: stop ACE inhibitors, ARBs, mineralocorticoid receptor antagonists, SGLT2 inhibitors, ivabradine and vericiguat; substitute beta-blockers, hydralazine and nitrates where possible.
• Warn that conversion itself can cause reflex hypertension or heart failure decompensation — severe or symptomatic patients may need admission to do it.
• Identify any pacemaker or defibrillator before delivery, and establish pacing dependence and arrhythmia burden to plan delivery.

Delivery and postpartum

• Full-term delivery at ≥39 weeks for most women with cardiac disease; earlier only for worsening function, increasing arrhythmia burden or preeclampsia.
• Vaginal delivery preferred unless haemodynamic instability or obstetric indication; neuraxial anaesthesia recommended for most, to limit catecholamine surges.
• Low-dose aspirin from 12 weeks (81 or 162 mg in the US) for preeclampsia prevention in cardiomyopathy; its use in GP/PN women is explicitly not evidence-based.
• Cardiac output rises 50–80% during labour and takes 48 hours to 2 weeks to resolve; autotransfusion and inferior vena caval decompression make the immediate postpartum period the highest-risk window for decompensation.
• Breastfeeding: beta-blockers, ACE inhibitors, most ARBs (except candesartan) and MRAs are compatible. ARNI has no documented human harm but animal data show milk transfer. SGLT2 inhibitors are not recommended — theoretical neonatal renal toxicity, no safety data.
• Established BNP/NT-proBNP thresholds remain valid in pregnancy and early postpartum despite the dynamic haemodynamic changes; no consensus exists on monitoring frequency by subtype.

Illustrative cases

• Case 1: 36-year-old, asymptomatic, third trimester, cascade-tested after her father's transplant for nonischemic cardiomyopathy revealed FLNC c.7443del (p.Lys2481Asnfs*48). Normal NT-proBNP and biventricular function, 2% PVC burden, induction at 39 weeks, no peripartum arrhythmia. Postpartum CMR showed LVEF 47% with 7% LGE — referred to EP for ICD consideration on the basis of genotype plus new scar.
• Case 2: 33-year-old with a family history of sudden death, heart failure five months after a preeclamptic second pregnancy, LVEF 20% by echo and 33% by CMR. TNNT2 c.416G>A (p.Arg139His) on testing. Life vest for primary prevention; LVEF recovered to 45% on GDMT, so ICD deferred; counselled against further pregnancy and underwent tubal ligation.

Limitations of the document

• A narrative review with no stated search strategy, no quality appraisal and no formal evidence grading. Recommendations are consensus, and the authors say so repeatedly — "these recommendations reflect expert consensus and limited retrospective evidence."
• Genotype is the paper's subject but not its evidence. Almost every genetic statement is an inference from a penetrance figure, a family history or a variant-specific cohort; no study has prospectively compared pregnancy outcomes by genotype with adequate power.
• The risk tools are criticised without being replaced. mWHO and CARPREG II exclude genotype — correctly identified — but no genotype-inclusive alternative is offered, only the recommendation to convene a Pregnancy Heart Team and individualise.
• GP/PN guidance rests on very small studies. The 10% complication figure comes from a single DCM-variant cohort, and the 34% progression figure from PKP2 family screening — neither is a pregnancy outcome study.
• Arrhythmic drug advice is borrowed from the non-pregnant population. The beta-blocker-first, amiodarone-last hierarchy is imported from HRS 2023 without pregnancy-specific comparative data, and no safe dose or duration is given for the "single dose" of amiodarone.
• Aspirin for preeclampsia prevention in GP/PN women is recommended and simultaneously admitted to be unstudied.
• No cost, access or equity analysis of a model requiring a Pregnancy Heart Team, genetic counsellors, PGT-M and CMR — all of which are unevenly available, and the paper itself notes PPCM incidence is highest in the populations least likely to reach them.
• Two illustrative cases only, both tertiary-centre and both with good outcomes, which is a weaker illustration of risk than the complication rates quoted in the text.
• The abbreviation list defines PGT-M wrongly. It is expanded as "prenatal genetic testing for monogenic disorders," while the text uses it for preimplantation genetic testing and Table 1's footnote gives the correct expansion. The three reproductive options — PGT-M, CVS and amniocentesis — are then easily conflated, which matters because their timing and eligibility are entirely different.
• Internal typographical slips: the GP/PN aspirin passage refers to "GN/PN individuals," a term not otherwise defined; and the sentence on exercise testing before pregnancy carries reference number 77 in a reference list that ends at 66.
• CCM/imaging surveillance intervals vary between cited sources (2025 European guideline every 3 months in low-risk; the consensus document bimonthly for mWHO II and monthly for mWHO III) without a stated preferred schedule.

Key Concepts Mentioned

concepts/Pregnancy-in-Genetic-Cardiomyopathy · concepts/mWHO-Classification · concepts/Cardio-Obstetrics · concepts/Cascade-Family-Screening · concepts/Arrhythmia-in-Pregnancy · concepts/Arrhythmogenic-Cardiomyopathy · concepts/Genetic-Testing-in-Cardiomyopathy

Key Entities Mentioned

entities/Peripartum-Cardiomyopathy · entities/HCM · entities/DCM · entities/NDLVC · entities/ARVC · entities/LMNA · entities/TTN · entities/FLNC · entities/PKP2 · entities/MYBPC3 · entities/MYH7 · entities/DSP · entities/DES · entities/PLN · entities/SCN5A · entities/JUP

Named but unlinked: BAG3 · RBM20 · DSG2 · DSC2 · TNNI3 · TNNT2 · TPM1 · MYL2 · MYL3 · ACTC1 · TNNC1 · MYH6 · JPH2 · DMD · DMD-DCM · CARPREG II · PGT-M · PULSE · REBIRTH

Wiki Pages Updated

• sources/cmp-pregnancy-jaccadv-2026 — created
• concepts/Pregnancy-in-Genetic-Cardiomyopathy — created
• concepts/Cardio-Obstetrics — genotype-blind risk tools, inherited cardiomyopathy preconception pathway
• concepts/mWHO-Classification — the LVEF thresholds that actually decide the class
• concepts/Arrhythmia-in-Pregnancy — inherited cardiomyopathy section
• entities/Peripartum-Cardiomyopathy — universal genetic counselling, subsequent-pregnancy recovery thresholds
• entities/HCM — LVOTO, myosin inhibitor teratogenicity, assisted second stage
• entities/DCM — mWHO III/IV thresholds and pre-pregnancy LVEF
• entities/FLNC — the Case 1 genotype and its penetrance
• concepts/Cascade-Family-Screening — reproductive cascade and PGT-M eligibility
• wiki/wikiindex · wiki/sourceindex