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Müllerian Anomalies & Vaginal Agenesis

Müllerian anomalies encompass a spectrum of congenital developmental defects of the female reproductive tract arising from abnormal formation, fusion, or resorption of the paramesonephric (Müllerian) ducts, affecting up to 5% of the general population, 8% of infertile women, and 24.5% of those with both infertility and recurrent pregnancy loss.[1] Vaginal agenesis, most commonly seen in Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, is managed first-line with nonsurgical vaginal dilation (90–96% success), with surgical neovagina creation (McIndoe, Davydov, Vecchietti, bowel vaginoplasty) reserved for dilation failures.[2]

This article is the cisgender-congenital counterpart to Feminizing Genital Reconstruction; the same operative techniques (Davydov, McIndoe, sigmoid colpoplasty) appear in both contexts but with different anatomic starting points and lifelong-care considerations. For the geometry of vaginal-septum repair, see Z-plasty; for sigmoid-segment selection in bowel vaginoplasty, see Bowel Anatomy.

Embryology of Müllerian Duct Development​

The Müllerian (paramesonephric) ducts form the fallopian tubes, uterus, cervix, and upper vagina. Normal development involves three sequential phases:[3][4]

  1. Organogenesis (~6 weeks) — Müllerian ducts form as invaginations of the coelomic epithelium lateral to the Wolffian (mesonephric) ducts, regulated by BMP/Pax2 and FGF/Lim1 signaling cascades.[5]
  2. Fusion (~8–12 weeks) — The paired ducts migrate medially and fuse in the midline to form the uterovaginal canal.
  3. Septal resorption — The fused midline septum undergoes apoptosis, creating a single uterine cavity.

Disruption at any stage produces the spectrum of Müllerian anomalies. Key genes implicated include WNT4, PAX2, LHX1, HNF1B, and HOXA gene clusters.[3][6][7] In males, anti-Müllerian hormone (AMH) from Sertoli cells causes Müllerian duct regression; mutations in AMH or AMHR2 cause persistent Müllerian duct syndrome.[8] See also the broader GU Embryology reference.[9]

Classification of Müllerian Anomalies​

The ASRM Müllerian Anomalies Classification 2021 (MAC2021) updated the 1988 AFS system, using descriptive terminology rather than numbered categories and incorporating vaginal and cervical anomalies.[10]

CategoryDescriptionKey Features
Müllerian agenesisAbsent or hypoplastic uterus / vaginaMRKH syndrome; most severe
Unicornuate uterusOne Müllerian duct fails to develop± rudimentary horn (communicating or non-communicating)
Uterus didelphysComplete non-fusionTwo separate uteri, two cervices; ± longitudinal vaginal septum
Bicornuate uterusPartial non-fusionTwo uterine horns with single cervix; fundal indentation > 1 cm
Septate uterusFailed septal resorptionMost common anomaly (~55%); indentation > 15 mm, angle < 90°
Longitudinal vaginal septumFailure of vaginal fusion / resorptionMay be obstructing or non-obstructing
Transverse vaginal septumFailure of canalizationObstructing → hematocolpos at menarche
Complex anomaliesCombined elementsCross-referenced between categories

Other classification systems include the ESHRE/ESGE system (based on uterine anatomy with cervical / vaginal subclasses) and the VCUAM system (Vagina, Cervix, Uterus, Adnexa, associated Malformations).[10] Septate-uterus resection has its own evidence base — most recently the 2025 Cochrane review.[11]

Mayer-Rokitansky-Küster-Hauser (MRKH) Syndrome​

Epidemiology and Presentation​

MRKH syndrome is the most common cause of vaginal agenesis, with a prevalence of 1 in 4,500–5,000 live female births and the second most common cause of primary amenorrhea (10–15% of cases).[2][12][13][14] Patients have a 46,XX karyotype, normally functioning ovaries, and normal secondary sexual characteristics. The diagnosis is typically made during adolescence when menstruation fails to begin.[2][13]

Classification[13][14]​

  • Type I (isolated) — uterovaginal aplasia only (~79% of cases).[12]
  • Type II (associated) — extragenital anomalies present, including:
    • Renal anomalies (15–31%) — unilateral renal agenesis, ectopic / pelvic kidney, horseshoe kidney.[12][14][15]
    • Skeletal anomalies (32%) — vertebral defects (Klippel-Feil, scoliosis).[14]
    • MURCS association (16.5%) — Müllerian duct aplasia, Renal agenesis, Cervicothoracic Somite dysplasia.[12]
    • Hearing loss, cardiac defects.[13]

Diagnostic Workup[2]​

  • Laboratory — testosterone, FSH, karyotype (to exclude androgen insensitivity syndrome).
  • Imaging — transabdominal / translabial ultrasound initially; MRI is the gold standard for characterizing Müllerian remnants, endometrial activity, and associated anomalies. Rudimentary Müllerian structures are found in 90% of patients on MRI.
  • Evaluation for associated anomalies is essential — up to 53% have concomitant congenital malformations.
  • Laparoscopy is not required for diagnosis but may be useful for pelvic pain evaluation or excision of obstructed uterine horns with active endometrium.

Genetics​

The etiology remains largely elusive, though familial clustering suggests genetic causes with autosomal-dominant inheritance, reduced penetrance, and variable expressivity.[6][16] Candidate genes include HNF1B (17q12 deletion), LHX1, WNT4, and PAX2. Loss of HNF1B function in Müllerian duct epithelium has been shown to reproduce the MRKH type II phenotype (uterine hypoplasia + renal anomalies) in mouse models.[3][6]

Management of Vaginal Agenesis​

First-Line: Nonsurgical Vaginal Dilation​

ACOG recommends primary vaginal dilation as first-line therapy, with success rates of 90–96%.[2] Two approaches exist:

  • Frank method — progressive self-dilation using graduated dilators applied to the vaginal dimple for 20–30 minutes daily. Mean vaginal depth achieved: 7.3 cm.[17][18]
  • Coital dilation — achieves the longest mean vaginal depth (8.7 cm) with the lowest complication rate (5%), but requires a willing partner.[17]

Both dilation and surgical approaches produce comparable vaginal lengths and Female Sexual Function Index (FSFI) scores (p = 0.72).[18]

Second-Line: Surgical Neovagina Creation​

Surgery is reserved for patients who fail dilation or prefer surgery after thorough informed consent. ACOG emphasizes that surgery does not eliminate the need for postoperative dilation, and failure to comply with post-surgical dilation can have deleterious effects. Referral to experienced centers is essential, as the initial procedure is more likely to succeed than revision surgery.[2]

McIndoe Vaginoplasty (Modified Abbé-McIndoe)​

Technique[2][19]​

The historically most common surgical approach:

  1. Perineal dissection — a space is created between the bladder anteriorly and rectum posteriorly using electrocautery, sharp dissection, and blunt finger dissection to the level of the peritoneal reflection.
  2. Graft harvest — a split-thickness skin graft (typically 10 × 20 cm) is harvested from the buttock or thigh.
  3. Mold placement — the graft is secured over a condom-covered rubber-sponge mold, which is inserted into the dissected space and held in place with labial stay sutures.
  4. Second stage (~14 days) — the mold is removed, graft take is assessed, and distal edges are secured. A polyethylene mold replaces the sponge mold for continued healing.
  5. Postoperative dilation — lifelong intermittent dilation or regular intercourse is required to maintain vaginal patency.

Modifications​

  • Micromucosa graft technique — vulvar mucosa is minced into particles and transplanted to the neovagina, achieving epithelialization ~20× the harvested area with invisible scars and spontaneous lubrication.[20]
  • Oxidized cellulose (instead of skin graft) — used as a scaffold in the modified Abbé-McIndoe technique with comparable outcomes.[18]

Outcomes[2][17][18]​

  • Mean vaginal depth: 7.4 cm (95% CI 6.8–8.1).
  • Overall complication rate: 65%.
  • Resurgery rate: 33%.
  • Complications include graft necrosis, hair-bearing vaginal skin, stenosis, bladder / rectal perforation, and fistulae.

Davydov Vaginoplasty​

Technique[2][21]​

Originally a three-stage open procedure, now predominantly performed laparoscopically in 8 steps:

  1. Perineal dissection — the rectovesical space is dissected from below.
  2. Laparoscopic peritoneal mobilization — the pelvic peritoneum is incised and mobilized as flaps.
  3. Peritoneal-vaginal anastomosis — the peritoneal flaps are pulled down through the dissected space and sutured to the vaginal introitus.
  4. Vault reconstruction — the peritoneal dome is closed laparoscopically to create the neovaginal apex.
  5. Mold placement — an intravaginal dilator is left in place.

The key advantage is the use of autologous pelvic peritoneum as the lining tissue, avoiding the need for skin grafts, bowel segments, or specialized equipment.[21]

Outcomes[15][22][23]​

  • Mean neovaginal length at 12 months: 8.3 cm (95% CI 8.1–8.6).[22]
  • Functional vaginal depth (long-term, 40-year series): 7.8 cm (range 1–13 cm).[15]
  • Mean FSFI score: 28.9 (95% CI 26.8–31.1) — indicating no sexual dysfunction.[22]
  • Mean operative time: 126 minutes (laparoscopic).[22][23]
  • Major complications: granulation tissue (23%) and tendency to obliterate (12%) are the primary concerns.[15]
  • Complete epithelialization: 80% at 6 months, 100% at 12 months.[23]

Vecchietti Procedure​

A traction-based technique in which an acrylic olive is placed at the vaginal dimple and connected via sutures passed through the rectovesical space to an external traction device on the abdominal wall. Continuous traction (~1 cm/day for 7–10 days) progressively invaginates the vaginal dimple to create a neovagina. Now performed laparoscopically or via single-port robotic approach.[22][28][29][30]

  • Operative time: 30–40 minutes (shortest of all techniques).[22][29]
  • Neovaginal length: 8.7 cm at 12 months.[22]
  • Requires postoperative dilation and close follow-up.[30]

Bowel (Intestinal) Vaginoplasty​

Uses a pedicled segment of sigmoid colon (most common), ileum, or right colon to line the neovaginal canal. Advantages include self-lubricating mucosa, greater canal depth (11.5–14.6 cm), and minimal dilation requirements.[26][31][32] However, it carries the risks of major abdominal surgery:[25][31]

  • Introital stenosis (~11%).
  • Mucorrhea / excessive discharge (~7%).
  • Vaginal prolapse (~6%).
  • Diversion colitis (rare but potentially serious).
  • Anastomotic leak, flap necrosis (rare).
  • Overall complication rate: 33%; reoperation rate: ~17–18%.[25]

Bowel vaginoplasty is particularly useful for cervicovaginal agenesis with a functional uterus (utero-colo-neovaginoplasty), where it can restore uterovaginal continuity and allow menstruation.[33] A 2026 retrospective review of robot-assisted sigmoid vaginoplasty in 12 trans-women confirmed the operative feasibility of the same technique in the gender-affirming context.[24]

Comparison of Surgical Techniques​

FeatureMcIndoeDavydov (laparoscopic)Vecchietti (laparoscopic)Sigmoid Colpoplasty
Lining materialSplit-thickness skin graftPelvic peritoneumNone (traction-based)Sigmoid colon segment
Mean vaginal depth7.4 cm8.3 cm8.7 cm11.5–14.6 cm
Operative timeVariable~126 min~30–40 minHours (open or robotic)
Complication rate~65%~23–35%Comparable to Davydov~33% overall
Resurgery rate~33%~12% obliterationSimilar~17–18%
FSFI scoreComparable28.9ComparableHigh satisfaction
Key advantageWell-established, widely knownNo graft harvest; minimally invasiveShortest operative timeSelf-lubricating; greatest depth; minimal dilation
Key disadvantageDonor site morbidity; hair growth; high complication rateGranulation tissue; obliteration riskRequires traction device; postop painMajor abdominal surgery; mucorrhea; prolapse risk
References[2][17][18][19][20][15][21][22][23][22][29][30][25][26][31][32]

A 2024 systematic review and meta-analysis comparing laparoscopic Davydov vs Vecchietti found no superiority of either technique in functional terms — comparable neovaginal length, sexual function, and complication rates — though the Vecchietti procedure is significantly faster (~40 vs ~126 minutes).[22] A 2025 comparative study of laparoscopic peritoneal vaginoplasty (Davydov) vs sigmoid colon vaginoplasty found that the peritoneal approach had shorter operative time, faster recovery, shorter mold duration, and higher sexual satisfaction (p < 0.05).[27]

Complications of Vaginoplasty (All Techniques)​

ACOG highlights that compared with primary dilation, vaginoplasty complications are much more common and include:[2]

  • Bladder or rectal perforation.
  • Graft necrosis.
  • Hair-bearing vaginal skin (McIndoe).
  • Fistulae (vesicovaginal, rectovaginal).
  • Neovaginal stenosis / contracture.
  • Diversion colitis (bowel vaginoplasty).
  • Inflammatory bowel disease (rare).
  • Adenocarcinoma — extremely rare, reported in bowel-lined neovaginas.

Reproductive Options​

MRKH syndrome involves absolute uterine factor infertility (AUFI). Options include:[2][14]

  • Gestational surrogacy — IVF with the patient's own oocytes and a gestational carrier. A systematic review of 140 MRKH patients reported 71 live births from 369 IVF cycles.[34]
  • Uterus transplantation (UTx) — the first live birth occurred in 2014 (Gothenburg, Sweden). The 2024 ISUTx registry reports 91 transplants worldwide (67 live donors, 24 deceased donors), with 12-month graft survival of 74–75% and 44 singleton live births (live-birth rate 30.3% per embryo transfer). MRKH accounts for 88% of recipients. Preeclampsia occurred in 23% of live-birth pregnancies. Mean gestational age at delivery was 34.5 weeks.[35][36][37]
  • Adoption.[2]

Importantly, the choice of neovagina creation method may impact suitability for subsequent UTx. Vecchietti-based approaches provide ideal conditions (sufficient length, natural axis, no prior major abdominal surgery), while bowel vaginoplasty may complicate future UTx.[28]

Psychosocial Considerations​

The psychological impact of MRKH diagnosis should not be underestimated. ACOG recommends:[2]

  • All patients should be offered counseling and encouraged to connect with peer support groups.
  • Future fertility options should be discussed early to help patients cope with the diagnosis.
  • Timing of intervention should align with the patient's emotional maturity and readiness to adhere to postoperative dilation.
  • Multidisciplinary care involving gynecology, psychology, and reproductive endocrinology is essential.

Key Takeaways​

  • Müllerian anomalies are a continuum of developmental defects classified by the ASRM MAC2021 system into descriptive categories.[10]
  • MRKH syndrome (1:5,000 females) is the most common cause of vaginal agenesis; up to 53% have associated congenital anomalies requiring systematic evaluation.[2]
  • Nonsurgical dilation remains first-line (90–96% success); surgery is reserved for failures.[2]
  • Among surgical options, no single technique has demonstrated clear superiority — the choice depends on surgeon expertise, patient anatomy, and patient preference.[2][22]
  • Uterus transplantation has emerged as a viable fertility treatment, with 44 live births reported worldwide through 2024.[37]
  • For the obstructive transverse vaginal septum, the Garcia / Plymouth double-opposing-Z-plasty approach is the contemporary standard — see Z-plasty.

References​

1. Bortoletto P, Romanski PA, Pfeifer SM. "Müllerian Anomalies: Presentation, Diagnosis, and Counseling." Obstet Gynecol. 2024;143(3):369–377. doi:10.1097/AOG.0000000000005469

2. Amies Oelschlager AM. "Committee Opinion: Müllerian Agenesis: Diagnosis, Management, and Treatment." American College of Obstetricians and Gynecologists, 2018.

3. MacLaughlin DT, Donahoe PK. "Sex Determination and Differentiation." N Engl J Med. 2004;350(4):367–378. doi:10.1056/NEJMra022784

4. Robbins JB, Broadwell C, Chow LC, Parry JP, Sadowski EA. "Müllerian Duct Anomalies: Embryological Development, Classification, and MRI Assessment." J Magn Reson Imaging. 2015;41(1):1–12. doi:10.1002/jmri.24771

5. Atsuta Y, Takahashi Y. "Early Formation of the Müllerian Duct Is Regulated by Sequential Actions of BMP/Pax2 and FGF/Lim1 Signaling." Development. 2016;143(19):3549–3559. doi:10.1242/dev.137067

6. Thomson E, Tran M, Robevska G, et al. "Functional Genomics Analysis Identifies Loss of HNF1B Function as a Cause of Mayer-Rokitansky-Küster-Hauser Syndrome." Hum Mol Genet. 2023;32(6):1032–1047. doi:10.1093/hmg/ddac262

7. Venkata VD, Jamaluddin MFB, Goad J, et al. "Development and Characterization of Human Fetal Female Reproductive Tract Organoids to Understand Müllerian Duct Anomalies." Proc Natl Acad Sci U S A. 2022;119(30):e2118054119. doi:10.1073/pnas.2118054119

8. National Library of Medicine. "Persistent Müllerian Duct Syndrome." MedlinePlus Genetics.

9. Johnston A, Eylert MF, Amer T, et al. "Embryology for the Urologist." Chapter 3.

10. Pfeifer SM, Attaran M, Goldstein J, et al. "ASRM Müllerian Anomalies Classification 2021." Fertil Steril. 2021;116(5):1238–1252. doi:10.1016/j.fertnstert.2021.09.025

11. Joosse MI, Kostova EB, Rikken JF, et al. "Septum Resection for Women of Reproductive Age With a Septate Uterus." Cochrane Database Syst Rev. 2025;11:CD008576. doi:10.1002/14651858.CD008576.pub5

12. Vency B, Kumari M, Ebenezer ED, Varghese L, Kumari P. "Prevalence, Clinical Profile, and Associated Anomalies With Women With Mayer-Rokitansky-Küster-Hauser Syndrome in a Tertiary Care Center: A Cross-Sectional Study." Int J Gynaecol Obstet. 2026. doi:10.1002/ijgo.70825

13. National Library of Medicine. "Mayer-Rokitansky-Küster-Hauser Syndrome." MedlinePlus Genetics.

14. Herlin MK, Petersen MB, Brännström M. "Mayer-Rokitansky-Küster-Hauser (MRKH) Syndrome: A Comprehensive Update." Orphanet J Rare Dis. 2020;15(1):214. doi:10.1186/s13023-020-01491-9

15. Willemsen WN, Kluivers KB. "Long-Term Results of Vaginal Construction With the Use of Frank Dilation and a Peritoneal Graft (Davydov Procedure) in Patients With Mayer-Rokitansky-Küster Syndrome." Fertil Steril. 2015;103(1):220–227.e1. doi:10.1016/j.fertnstert.2014.10.014

16. Santana González L, Artibani M, Ahmed AA. "Studying Müllerian Duct Anomalies — From Cataloguing Phenotypes to Discovering Causation." Dis Model Mech. 2021;14(6):dmm047977. doi:10.1242/dmm.047977

17. Herlin M, Bay Bjørn AM, Jørgensen LK, Trolle B, Petersen MB. "Treatment of Vaginal Agenesis in Mayer-Rokitansky-Küster-Hauser Syndrome in Denmark: A Nationwide Comparative Study of Anatomical Outcome and Complications." Fertil Steril. 2018;110(4):746–753. doi:10.1016/j.fertnstert.2018.05.015

18. Apfel VR, Takano CC, Marquini GV, et al. "Treatment for Vaginal Agenesis: A Prospective and Comparative Study Between Vaginal Dilation and Surgical Neovaginoplasty." Int J Gynaecol Obstet. 2022;157(3):574–581. doi:10.1002/ijgo.13931

19. Linder BJ, Gebhart JB. "McIndoe Neovagina Creation for the Management of Vaginal Agenesis." Int Urogynecol J. 2021;32(2):453–455. doi:10.1007/s00192-020-04425-y

20. Teng Y, Zhu L, Chong Y, et al. "The Modified McIndoe Technique: A Scar-Free Surgical Approach for Vaginoplasty With an Autologous Micromucosa Graft." Urology. 2019;131:240–244. doi:10.1016/j.urology.2019.05.020

21. Vermel M, Wehr M, Schwaab T, et al. "Surgical Video Tutorial: Treatment of Congenital Vaginal Agenesis: Laparoscopic Modified Davydov in 8 Steps." J Minim Invasive Gynecol. 2021;28(9):1564. doi:10.1016/j.jmig.2021.02.003

22. Martens L, Tannenbaum L, Van Kuijk SMJ, Notten KJB, Kluivers KB. "Laparoscopic Davydov vs Laparoscopic Vecchietti Neovaginoplasty in Women With Mayer-Rokitansky-Küster-Hauser Syndrome: A Systematic Review and Meta-Analysis." Fertil Steril. 2024;121(4):679–692. doi:10.1016/j.fertnstert.2023.12.015

23. Bianchi S, Frontino G, Ciappina N, Restelli E, Fedele L. "Creation of a Neovagina in Rokitansky Syndrome: Comparison Between Two Laparoscopic Techniques." Fertil Steril. 2011;95(3):1098–1100.e1–3. doi:10.1016/j.fertnstert.2010.11.032

24. Kim KH, Kim KH, Hwang NH, et al. "Gender-Affirming Robot-Assisted Sigmoid Vaginoplasty: Outcomes and Complications From a Retrospective Review of 12 Cases." Medicine. 2026;105(9):e47849. doi:10.1097/MD.0000000000047849

25. Robinson IS, Cripps CN, Bluebond-Langner R, Zhao LC. "Operative Management of Complications Following Intestinal Vaginoplasty: A Case Series and Systematic Review." Urology. 2023;180:105–112. doi:10.1016/j.urology.2023.07.005

26. Darai E, Toullalan O, Besse O, Potiron L, Delga P. "Anatomic and Functional Results of Laparoscopic-Perineal Neovagina Construction by Sigmoid Colpoplasty in Women With Rokitansky's Syndrome." Hum Reprod. 2003;18(11):2454–2459. doi:10.1093/humrep/deg443

27. Yinuo L, Zihan L, Xiaorui L, et al. "Comparative Study of Laparoscopic Peritoneal Vaginoplasty Versus Sigmoid Colon Vaginoplasty in the Treatment of Congenital Absence of Vagina." Surg Endosc. 2025. doi:10.1007/s00464-025-11868-1

28. Kölle A, Taran FA, Rall K, et al. "Neovagina Creation Methods and Their Potential Impact on Subsequent Uterus Transplantation: A Review." BJOG. 2019;126(11):1328–1335. doi:10.1111/1471-0528.15888

29. Yang X, Liang J, Li W, et al. "Modified Vecchietti Vaginoplasty Using Self-Made Single-Port Laparoscopy in Mayer-Rokitansky-Küster-Hauser Syndrome." Fertil Steril. 2021;116(1):266–268. doi:10.1016/j.fertnstert.2020.10.001

30. Clay J, Ferrando C, Gallant T, King CR. "Laparoscopic Vecchietti Procedure: Pearls for Success." Fertil Steril. 2024;122(6):1154–1156. doi:10.1016/j.fertnstert.2024.08.349

31. Bouman MB, van Zeijl MC, Buncamper ME, et al. "Intestinal Vaginoplasty Revisited: A Review of Surgical Techniques, Complications, and Sexual Function." J Sex Med. 2014;11(7):1835–1847. doi:10.1111/jsm.12538

32. Kwun Kim S, Hoon Park J, Cheol Lee K, et al. "Long-Term Results in Patients After Rectosigmoid Vaginoplasty." Plast Reconstr Surg. 2003;112(1):143–151. doi:10.1097/01.PRS.0000066169.78208.D4

33. Kumar V, Thotan SP, Prabhu SP, et al. "Long-Term Outcomes of the Restoration of Uterovaginal Continuity and Vaginoplasty — Utero-Colo-Neovaginoplasty — in Cervicovaginal Agenesis Using the Sigmoid Colon." Int Urogynecol J. 2024;35(9):1807–1816. doi:10.1007/s00192-024-05878-1

34. Friedler S, Grin L, Liberti G, et al. "The Reproductive Potential of Patients With Mayer-Rokitansky-Küster-Hauser Syndrome Using Gestational Surrogacy: A Systematic Review." Reprod Biomed Online. 2016;32(1):54–61. doi:10.1016/j.rbmo.2015.09.006

35. American Society for Reproductive Medicine. "Position Statement on Uterus Transplantation: A Committee Opinion." Fertil Steril. 2018;110(4):605–610. doi:10.1016/j.fertnstert.2018.06.017

36. Brännström M, Dahm Kähler P, Greite R, et al. "Uterus Transplantation: A Rapidly Expanding Field." Transplantation. 2018;102(4):569–577. doi:10.1097/TP.0000000000002035

37. Brännström M, Racowsky C, Wiik J, et al. "Second Report of Registry of the International Society of Uterus Transplantation (ISUTx): International Activities 2000–2024." Hum Reprod. 2026;41(4):541–551. doi:10.1093/humrep/deag017