Keywords
3D printing - Mayer-Rokitansky-Küster-Hauser syndrome - vaginal agenesis - vaginal
dilation
Palavras-chave
impressão 3D - síndrome de Mayer-Rokitansky-Küster-Hauser - agenesia vaginal - dilatação
vaginal
Introduction
Vaginal agenesis (VA) is a congenital malformation and 90% of cases are associated
with Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS). The MRKHS has an incidence ranging
from one case for every 4,000 to 5,000 female births, and is characterized by the
congenital absence of the uterus and the upper ⅔ of the vagina.[1] Such patients have a female karyotype (46XX), function ovarian and normal sexual
characters. Differential diagnosis should be made for patients with a transverse vaginal
septum and an imperforate hymen.[1]
[2]
According to the American College of Obstetricians and Gynecologists (ACOG), the treatment
for VA can be conservative or surgical, and has the objective of restoring the vagina's
anatomy and function. Vaginal dilation is the method used in the conservative treatment
of VA.[3]
[4]
[5] This method was developed by Frank in 1938 and modified by Ingram in 1981, reaching
an effectiveness of approximately 90%.[3]
[4]
[5] It is performed using progressively larger sized rigid vaginal molds until the proper
vaginal length is achieved.
While there is no consensus on the best therapeutic strategy, the ACOG and most of
the scientific community recommend that the least invasive and effective treatment
should be adopted, with vaginal dilation being the first line of treatment for VA.[3]
[4]
[5] Additionally, conservative treatment through vaginal dilation is the first choice
due to the good results and low rate of complications.[5]
Three-dimensional (3D) printing is gaining wide use in the health care field. Especially
in gynecology, it is possible to manufacture various devices, such as pessaries and
vaginal molds, using a wide variety of materials.[6] Using this technology, devices that are fit for purpose and cost-effective are created.
The objective of this study was to evaluate the use of personalized vaginal molds
made with 3D printing for conservative treatment through vaginal dilation in patients
with VA.[1]
Methods
The study was performed at the Federal University of São Paulo (UNIFESP), between
June 2017 and October 2019, after approval by the Human Research Ethics Committee
of the same institution, under the Certificate of Presentation of Ethical Appreciation
number (CAAE): 91233917–9 and opinion number 2970405. The interventions were only
made after approval, with the aim of offering an individualized and conservative treatment
for each patient who voluntarily proposed to participate in the study. The patients
who were willing to participate in the study signed an informed consent form.
The present study protocol was purely observational, which obviated the need for registration
on clinical trial platforms. Additionally, it was not a randomized study or clinical
trial, due to the rarity of the pathology, requiring patients to make a clear choice
for conservative treatment before the beginning of the study.
The patients were selected from the Female Genital Malformations Sector at UNIFESP
according to the following inclusion criteria: confirmed diagnosis of VA due to SMRKH,
androgen insensitivity syndrome (AIS), or cervicovaginal agenesis, and desire to undergo
conservative treatment.
The exclusion criterion was not wanting conservative treatment or not having free
will or availability to participate in the research. All patients underwent evaluation
by a multidisciplinary team: physician, physiotherapist, and psychologist. All patients
were properly advised about the anatomy of the external genitalia before treatment.
The study's protocol had three phases: prototype development, patient selection, and
mold application. Characteristics, dimensions, and initial parameters were defined
through research of devices already available on the market and adjusted for each
patient.
The initial geometric parameters were defined (cylindrical mold with the tip tapering
progressively). For modeling the prototypes, the AutoCAD (Autodesk Inc., Mill Valley,
California, USA) and FreeCAD 3D parametric modeling software were used based on the
requirements defined above; computer aided design (CAD) system is the generic name
for software used by engineering, geology, geography, health systems, and architecture
and design to facilitate technical design and drawing.[6]
The production of the devices was performed using the 3D cube printer, developed by
the company 3D Systems (Rock Hill, SC, USA), using the polymeric filament of lactic
polyacid (PLA) as raw material. The devices were evaluated by the medical staff for
adjustments before application in the study. Three standard molds were created ([Fig. 1]) with the following sizes (from right to left): Dilator A (1.5 × 8 cm); Dilator
B (2 × 9 cm); and Dilator C (2.5 × 12 cm).[6]
Fig. 1 Vaginal dilators created with 3D printing. Source: Marta Maria Kemp.
The individual molds were reused only by the patient herself. The molds were not sterile,
but the patients were instructed to clean them with soap and water and use them with
condom protection. During the test period, the authors realized that the sizes described
above were the most used. These 3 sizes were used because there was no need to use
larger or smaller sizes at any time. Despite the biological plausibility of having
no contraindication for use in the supine position, as long as the patient is well
oriented, the present study prioritized the systematic methodology of the same position
of introduction of the casts in the gynecological position.
The applicability of the molds and the success of the vaginal dilation treatment were
evaluated considering variables such as final total vaginal length (TVL), patient
satisfaction, complication rate, and cost of mold production.
The patients were instructed to perform light pressure exercises from the vaginal
introitus, positioning as shown in [Fig. 2]. The first return was within 15 days, and after that there was a monthly follow-up
during the first year of the study. Patients who reached 6 cm or more in TVL were
considered treated. After 6 cm of TVL, the patients were allowed to attempt sexual
intercourse.
Fig. 2 Positioning the dilator into vaginal introitus (purple). Source: Marta Maria Kemp.
The orientation of the direction and strength of the perineal massage vectors was
standardized as introduction movements into the vagina and circular movements, toward
the sides of the vagina and posterior wall or toward the perineal region, to preserve
possible urethral trauma in the anterior region, according to [Fig. 3], for 20 minutes during the study. The strength guidance was individualized, being
gradual and progressive according to the sensitivity to pain or discomfort of each
patient.
Fig. 3 Orientation of perineal massage with the dilator. Source: Marta Maria Kemp.
All patients were followed up every month from the beginning of the treatment, during
the 1st year, and every 2 months in the 2nd year of the study, with free return as needed. During follow-up, the newly created
vaginal canal was analyzed using a speculum and by digital vaginal exam. The aspect,
amplitude, and length were observed. All patients were allowed to have sexual intercourse
when vaginal length was greater than 6 cm. The clinical aspects of the vagina were
subjectively analyzed by the first two independent authors, with no difference regarding
the appearance of the neovagina, such as presence or absence of active bleeding, the
color of the vaginal mucosa, and granulation tissue in all patients, in the period
of 3, 6, 12 and 24 months, and after treatment. The patients remain under follow-up
at the same service with possible long-term results in future studies.
To compare the means of the initial and final TVL variable, the Student t-test for related samples was used. The D'Agostino normality test was performed for
the assumptions of the analysis. To assess the magnitude of the difference, the effect
size (d) with a 95% confidence interval (95% CI) was used. According to Cohen,[7] it was agreed that the values of d are considered small if (20 ≤ d < 50); medium
if (50 ≤ d < 80); and large if (d ≥ 80).
Results
A total of 16 patients were treated with the 3D printing dilators between October
2017 and October 2019. The patients in the present study had no exposure to previous
treatments. The mean age was 19 years (standard deviation, SD: 2.84), mean initial
vaginal length of 1.8 cm, and 60% of the patients had an associated malformation.
Furthermore, 14 patients (87,5%) achieved a TVL greater than 6 cm at the end of the
evaluation ([Table 1]). The median time taken to reach treatment TVL was 5.6 months. The 2 patients who
did not achieve TVL (patient number 15 and 16–Table 1) had used the molds for only
2 and 3 months, respectively.
Table 1
Initial and final TVL
|
Patient
|
Initial TVL (cm)
|
Final TVL (cm)
|
|
1
|
2
|
7
|
|
2
|
4
|
6.5
|
|
3
|
1.5
|
7
|
|
4
|
1
|
7
|
|
5
|
2
|
7
|
|
6
|
4
|
8
|
|
7
|
1.5
|
6
|
|
8
|
2
|
6
|
|
9
|
1
|
6
|
|
10
|
0.5
|
6.5
|
|
11
|
1
|
6
|
|
12
|
1
|
6
|
|
13
|
1.5
|
7
|
|
14
|
1
|
7
|
|
15
|
2
|
4
|
|
16
|
3
|
5
|
Abbreviation: TLV, total vaginal length.
As shown in [Table 2], there was a significant difference (p < 0.05) between the initial and final TVL measurements. The effect size was 4.58,
reinforcing the great magnitude of this difference.
Table 2
Statistical Analysis: Initial and Final TVL
|
Initial TVL
mean (SD)
|
Final TVL
mean (SD)
|
Difference (95% CI)
|
Effect size (95% CI)
|
p-value*
|
|
1.81 (1.05)
|
6.37 (0.94)
|
4.56 (5.27–3.84)
|
4.58 (2.88–6.28)
|
0.0001
|
Abbreviations: CI, confidence interval; SD, standard deviation; TLV, total vaginal length. Note: * p-values < 0.05 were considered statistically significant.
The patients did not report any adverse effects, such as pain, discomfort, or bleeding,
as they were instructed to perform dilation according to their ability, respecting
their limitations of pain or discomfort. The authors believe that the absence of complications
may be related to the previous educational guidelines and follow-up. Only 2 patients
had inadvertent dilation of the urethra at the beginning of the treatment. Both had
a smaller vaginal introitus (shorter distance between the urethral meatus and the
vaginal furcula). They were reoriented in relation to anatomy and perineal massage
exercises. After that, both were able to reach the treatment TVL. The patients were
not operated on later because they were satisfied with the conservative treatment's
results. They remain under follow-up at the specialized outpatient clinic of the same
service for future follow-ups. [Fig. 4] shows the evolution analysis of the time of prothesis use by each patient. According
to these results, there was no statistically significant difference between the time
of use of the 14 patients that patients who adhered and were successful during the
evolution of the treatment (p = 0.189).
Fig. 4 Time of use of the prosthesis and the evolution of total vaginal length of each patient.
Discussion
In 1938, Frank[4] described the first conservative treatment for vaginal dilation using Pyrex (Corning
Inc., Corning, NY, USA) tubes of gradually increasing sizes (0.8, 1.5, and 2.0 cm
in diameter). This was used to force the mucous membrane into the vaginal introitus
region. No incisions were required for this procedure.[4] The main criticism of this therapeutic modality is that it requires a special dedication
from the patients, as the exercises with the dilators make it possible to create a
vaginal canal that enables sexual intercourse. Maintaining a vaginal prosthesis is
sometimes necessary to keep the vaginal canal patent, as well as performing exercises
in the absence of regular sexual practice.
Decades after Frank's first description, several studies reported favorable results
using his method.[8]
[9]
[10]
[11] In 1981, Ingram[12] suggested that the failures in the technique used by Frank were due to tiredness
of the hands and fingers during the procedure, the need to use the embarrassing position,
and the inability to perform other productive activities during the procedure.[10] In an attempt to overcome these limitations, Ingram[12] proposed a modification of the original Frank method. In the Ingram method, the
patient's weight is used to replace manual and digital effort. The specially designed
bicycle seat bench was used to facilitate perineal mold pressure.[12]
Additionally, corroborating the results of the successful experiment by Ingram,[12] Roberts et al.[13] reported a 91% success rate using the Ingram method in their study of 51 patients
with MRKHS. When well advised and emotionally prepared, almost all patients (90–96%)
will achieve a satisfactory anatomical and functional result with vaginal dilation.[5] A recent study performed at the same reference center of the present project compared,
in terms of anatomical, functional, and sexual aspects, two types of treatment for
women with VA: progressive dilation (using the Frank method) or surgical neovaginoplasty
(using the modified Abbé-McIndoe technique with oxidized cellulose). According to
that study, both treatments had satisfactory efficacy and positive outcomes regarding
the analyzed aspects. These data reinforce the reliability of the results from the
present study, which indicate that dilation treatment can remain the first-line therapy
for VA.[14]
The literature lacks more consistent and robust studies comparing the different surgical
techniques with each other and with vaginal dilation. However, so far, no surgical
technique has surpassed the success rate of nonsurgical treatment; a fact that, together
with the benefit of being a safer technique, places vaginal dilation as the first
line in the treatment of VA.[5]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22] In this context, the present study suggests the development of a personalized conservative
treatment for each patient through vaginal dilation with 3D molds.
In 1984, Charles Hull[23] founded the world's first 3D printing company, with the use of production technologies
such as Additive Manufacturing (AM) and Rapid Prototyping. The AM is used in the synthesis
of a given physical object by adding layers to form a part based on data generated
by CAD. These technologies are widely used to quickly prototype products and tools
for commercial purposes. Over time, it has also been integrated into other areas,
such as the health area, since these tools have enabled the assistance of health professionals
in diagnosis, surgical planning, and synthesis of orthotics and prostheses for the
rehabilitation of patients.[23]
The use of 3D printing is gaining considerable acceptance in many medical fields,
including surgery. The resulting tactile feedbacks significantly help the comprehension
of anatomical details, especially the spatial relations between structures. Currently,
an increasing number of applications have been successfully tested in many surgical
disciplines, extending the range of possible uses to preoperative planning, counselling
with patients, education of students and residents, surgical training, intraoperative
navigation, and others.[23]
[24]
In a recent systematic review, Barbosa et al. assess previous publications within
3D printing in human reproduction and gynecology. Based on the included studies, it
was possible to design 3D models (uterus, ovaries, uterine cervix, and uterus with
fibroids) that provided enriched information to improve presurgical planning, medical
training, fertility-sparing surgery, patient comprehension of surgical procedures,
and assisted reproduction applications.[25]
Future expectations for 3D printing concern the reduction of manufacturing costs and
time to further increase accessibility, as well as the development of novel techniques
and suitable materials for biological structures, making it possible to recreate the
architecture and functionality of real human organs and tissues.[23]
[24]
The choice of devices made using a 3D printer was based on the possibility of offering
an individualized treatment for each patient at a low cost and with a low rate of
complications, in line with the plausibility of mold development already demonstrated
in other areas, such as in Gynecology. The devices can be made with the most diverse
formats and materials, which allows them to be adapted to the needs of each patient.
Of the 16 patients treated, 14 reached the vaginal length considered for treatment,
representing an 86% success rate. The only 2 patients who did not achieve a TVL of
6 cm or greater were still starting treatment (only 2 and 3 months ago).
According to the results of this present study, as well as in the literature,[5]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22] conservative treatment for VA remains an excellent choice, with good efficacy and
few complications, through personalized vaginal molds made with 3D printing. These
results highlight the good applicability of the devices, bringing a cost-effective
and easily reproducible option for the treatment of VA, making this a promising and
accessible tool. Therefore, it would be a fruitful option to facilitate its use over
the country, train professionals to apply the treatment, and shorten the distances
so that more patients could benefit from it, thus eliminating the bias of distance
and regularity in performing the exercises.
The main relevance of this research is the possibility of offering an individualized
treatment option that is recommended in the scientific community with ethics, efficacy,
and safety for a patient in an international reference center for the treatment of
VA. Additionally, this is the first study to analyze reproductible 3D molds with conservative
treatment and improve sexual function in women with VA. The homogeneous patient sample,
standardized procedures, and prospective model are also strong points.
Another positive impact of this project was the effective response to the guidance
of perineal massage exercises with the cast in patients with smaller vaginal introitus.
This strategy can be used before the beginning of the dilation itself, aiming to reduce
the chance of inadvertent dilation of the urethra.
The present study was not a randomized trial because of ethical issues. The main limitation
of this trial was the small sample size. However, VA is a rare disease, with an incidence
of 1:4.000 female births. The seriousness and scientific effort of this study are
not diminished because of the difficulty to include more patients.
The main difficulties encountered in this study were the lack of motivation, lack
of privacy in the patients' home, and distance from the city of origin to the hospital.
Another obstacle was the attendance to outpatient follow-ups, since many patients
lived in different cities and some even in other districts, as well as the regularity
in the performance of the exercises, which depended on the personal motivation of
each patient, home privacy, and emotional situation during treatment.
Considering the statements above, the authors believe that the study's strengths overcome
its limitations. As VA is a rare disease that affects young women and involves the
sensitive issues of sexuality and self-esteem, disclosure of well-structured trials
can contribute to gaining knowledge so that an increasing number of women can benefit
from the results of the studies.
Conclusion
Based on the present findings, a 3D model device can be offered in a personalized
and individualized way as the first-line conservative treatment for VA in nonspecialized
health centers in developed and developing countries. Furthermore, the use of 3D printing
for making the molds proved to be a promising, effective and reproductible strategy,
especially to be applied in health care centers with limited financial resources or
a shortage of professionals specialized in the surgical treatment of VA, with low
rate of complications. Considering the encouraging outcomes of this project and the
rarity of the evaluated clinical condition affecting young women, the authors suggest
more well-structured trials should be performed to better treat and benefit this population.
