Perinatal diagnosis of renal agenesis in female fetus: implication for investigation of OHVIRA syndrome in adolescence

The OHVIRA acronym describes the coexistence of obstructed hemivagina and ipsilateral renal anomaly (Figure S1), which has a prevalence of < 1/1 000 000 in the population1. The disease originates from the disturbance of Müllerian and Wolffian duct development during the early stages of embryogenesis2. Both syndrome components are systematically correlated and blind hemivagina is rarely seen as an isolated defect3, 4. OHVIRA syndrome is diagnosed consistently with defects of both the cervix and the uterine body. Treatment typically consists of vaginal septum removal, performed via the traditional vaginal approach or vaginoscopic surgery5. OHVIRA syndrome is heterogeneous in presentation, often resulting in delayed diagnosis (Figure S2). The magnitude of abdominal pain, along with the sudden onset of symptoms, often leads to misdiagnosis and improper surgical interventions6. Congenital anomalies of the kidney and urinary tract (CAKUT) constitute up to 30% of all defects identified prenatally7, with unilateral renal agenesis thought to affect 4/10 000 cases at birth8. Female fetuses with CAKUT are a target population that may suffer from OHVIRA syndrome. Ultrasound with renal evaluation remains the diagnostic standard in pregnancy; however, routine assessment of internal genitalia is not performed. Herein, we propose an algorithm for screening for OHVIRA syndrome in female fetuses and girls with unilateral renal agenesis/anomaly to prevent complications in those misdiagnosed and untreated. Double/septate cervix and one of the three uterine malformations, namely, didelphys, bicornuate and complete septate uterus, constitute typical findings in OHVIRA syndrome (Figure 1). One of the two cervical canals opens to the blind hemivagina, created by an oblique vaginal septum5. The visibility of the obstructed hemivagina and septum is dependent on the amount of mucus, blood or purulent content (Figures 2 and 3). The most popular classifications (ESHRE-ESGE9, ASRM/MAC202110, AFS11) of female tract congenital anomalies are highly confusing due to different nomenclature, and the lack of objective morphometric criteria for distinguishing between specific forms of cervical and uterine malformations characteristic for OHVIRA syndrome4, 12. Due to the obstructive nature of the disease, the principal reported complaint is persistent pain in the lower abdomen, often worsening over time3. Common ailments include nausea and vomiting correlated with menstruation and a palpable vaginal mass3, 13. The disease might also have an asymptomatic course. Delayed or improper diagnosis of OHVIRA may result in unfavorable complications, including pelvic inflammatory disease, endometriosis, intra-abdominal adhesions, infertility and persistent pain5, 13. Furthermore, patients affected by OHVIRA syndrome are often offered inadequate surgical treatment that may impair their fertility, such as total hysterectomy, hemihysterectomy, salpingectomy or oophorectomy3, 14 (Figure S3). Over 80–90% of anomalies of the renal and uterine tract diagnosed prenatally are confirmed on postnatal assessment15. Diagnosis in the spectrum of congenital solitary functioning kidney (cSFK) can be made after 20 weeks of gestation, although such a discovery requires repeated pre- and postnatal ultrasound evaluation16. Patients with cSFK need to be monitored throughout their lives16. Management of OHVIRA syndrome is relatively easy and consists of a single-step vaginoplasty with hymen-preserving consideration5. Early intervention diminishes the occurrence of complications and the need for further medical attention. The proposed screening process can accompany existing solutions, which may significantly decrease the time of assessment and diagnosis, allowing for the initiation of treatment before the appearance of symptoms. The benefits of OHVIRA screening can be described as three-fold, pertaining to time, money and overall quality of life. We propose a three-step ultrasound screening algorithm for the detection of OHVIRA syndrome in female patients with a prenatal diagnosis of renal anomaly (Figure 4), involving: (1) prenatal assessment; (2) neonatal assessment; and (3) assessment at menarche in adolescence. The algorithm consists of these three possible ultrasound evaluations based on: (i) typical use of these methods in the prenatal and newborn periods; and (ii) a well-known presence of specific morphological features (hypoechogenic mass) connected with the occurrence of menarche. Prenatal and neonatal diagnoses remain the most optimal option, although the reliability of uterine and vaginal assessment in these populations has not yet been determined. In adolescents, a triad of symptoms comprising cystic pelvic tumor, ipsilateral renal agenesis/anomaly and uterine anomaly should prompt further inspection for blind hemivagina14. We suggest that the first evaluation of the genital tract could be performed in parallel with the diagnosis of a renal anomaly. Correct diagnosis of uterine malformations can be made from the 32nd–37th week of gestation17, 18. However, the evidence for this is limited to case reports and case series. The second evaluation should be completed within the first 2 weeks of a neonate's life, considering the influence of the mother's estrogens. The third and last assessment should take place at menarche and serves as the definitive confirmation of the diagnosis, allowing for early surgery qualification. Ultrasound evaluation is a widely accessible and accepted imaging method. However, the scope and properties of tissue visualization vary depending on the sonographer's skills, experience and the machine itself. In case of any doubt, the patient should be referred to a specialist center and undergo expert assessment. The typical scanning method used in pediatric and adolescent girls with intact hymen is transabdominal ultrasound (TAUS). Three-dimensional visualization, despite not being required, is highly recommended. The transrectal route should be used secondary to TAUS, considering the greater discomfort caused and possible reluctance in adolescent patients. Magnetic resonance imaging remains the last accessible option to perform a full morphological demonstration. The main limitation of the suggested algorithm is scarce evidence on the accuracy and reliability of prenatal assessment of reproductive tract anomalies, confirmed solely on the basis of case reports and case series. In the future, the proposed algorithm should be assessed in prospective studies. The prenatal diagnosis of renal agenesis in female fetuses should be an indication for mandatory screening of OHVIRA syndrome in adolescence, especially during or immediately after menarche. Prenatal and newborn diagnosis would be a much-anticipated advancement, although the accuracy and reliability of detecting Müllerian duct anomalies in this period are yet to be determined. The data that support the findings of this study are available from the corresponding author upon reasonable request. Figure S1 Obstructed hemivagina and ipsilateral renal anomaly (OHVIRA) syndrome with triad of symptoms in adolescence: obstructed hemivagina, uterine anomaly with double uterine cavity and cervical canals, and ipsilateral renal agenesis. Schematic diagram (a) and magnetic resonance imaging (b,c) (coronal plane in (b); sagittal plane in (c)) show typical triad of symptoms. Uterine morphology (c) and blind hemivagina (d) demonstrated on ultrasound, including bicornuate uterus with two cervical canals according to ASRM/MAC202110 classification or bicorporeal uterus according to ESHRE-ESGE9 classification with septate cervix and blind hemivagina (obstructive longitudinal vaginal septum). Dotted line, renal agenesis; green asterix, uterus; red asterix, blind hemivagina. Figure S2 Schematic diagrams and images of vaginal examination of obstructive longitudinal vaginal septum (blind hemivagina) in two women of reproductive age with and without blood collection in hemivagina. Often, obstruction and blood collection in blind hemivagina is visible and palpable in reproductive age if menses has occurred (bottom row). Sometimes obstruction is not visible, especially in women with small hemivagina and retrograde menstruation, and diagnosis may be highly delayed after menarche (top row). Arrow, obstructive longitudinal vaginal septum (oblique septum). Figure S3 Misdiagnosis and mistakes in treatment are common in non-specialized centers. Three-dimensional ultrasound after unnecessary hemihysterectomy on left side (white dotted line) with persistent obstructed hemivagina and hemihematocolpos due to iatrogenic connection between cervical canals (blue dotted arrow). BV, blind hemivagina; CV, communicating hemivagina; LC, left cervix; RC, right cervix; RUC, right uterine corpus. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.