Keywords gestational trophoblastic disease - geographical health district - distance traveled
- clinical status - referral center
Palavras-chave doença trofoblástica gestacional - distrito de saúde - distância viajada - estado
clínico - centro de referência
Introduction
Gestational trophoblastic disease (GTD) is the term given to a group of rare tumors
that arise during pregnancy, which are associated with abnormal proliferation of trophoblastic
cells and increased secretion of human chorionic gonadotropin (hCG). Hydatidiform
mole (HM), also known as pre-malignant GTD, can be either complete (no embryonic/fetal
tissue is present) or partial (some embryonic/fetal tissue develops). Gestational
trophoblastic neoplasia (GTN), is the malignant form of GTD that encompasses different
histopathological types (invasive mole, choriocarcinoma, placental-site trophoblastic
tumor, and epithelioid trophoblastic tumor).
The clinical characteristics of GTD patients at presentation at a specialized center
are considerably influenced by social and economic factors, as well as barriers to
healthcare access, which lead to patient presentation at later stage disease.[1 ]
[2 ]
[3 ] A potential cause for a less favorable outcome may be the distance required to travel
to a specialized center.[3 ]
[4 ] Given the rarity of GTD, centralizing care for this condition has been internationally
promoted as a means to improve care. However, disadvantages such as longer travel
times are not usually taken into account.
To ensure universal health coverage and equity in the country, Brazil has implemented
the regionalization of health services.[5 ] The Botucatu Trophoblastic Disease Center (BTDC) of the São Paulo State University
(UNESP), provides tertiary care primarily to residents in the state Health District-VI,
which encompasses 68 municipalities and covers an area of 26.790,1 km2 , with an estimated population of 1.8 million inhabitants. Nonetheless, women with
GTD from other localities are also treated at BTDC, regardless of their home residence.
Regionalizing health care, however, has not guaranteed equity in the treatment of
GTD in Brazil because the disease cases of a region must be treated within the patient's
own region of residence, and not all regions have a center specialized in GTD. Consequently,
women with GTD are often referred to centers very far from where they live. Additionally,
the efficiency of the referral system relies on the first physician seeing the patient
being able to identify GTD.[1 ] Since this is not always the case, the patient may be subjected to a pilgrimage
from service to service before being referred to a specialized center. This is a very
bureaucratic and time-consuming process that has economic implications to the patient
who cannot always pay the costs of transportation and lodging.
Within this framework, the objective of this study was 3-fold:
to determine the residence of the GTD patients referred to BTDC;
to compare the health districts referring GTD patients to our center regarding patient
demographic characteristics, clinical status at admission, and distance traveled;
to assess the potential association between clinical status at admission and distance
traveled among patients with HM or GTN (gestational trophoblastic neoplasia) referred
to BTDC.
Methods
This cross-sectional study included women with GTD referred for initial treatment
to the Botucatu Trophoblastic Disease Center (BTDC) from health districts in the state
of São Paulo, Brazil, between 1990 and 2018. Although women from all over the country
can be referred to our center, those from other Brazilian states were not included.
The BTDC is affiliated with a public state university, and as such, provides multimodality
treatment, and follow-up with multidisciplinary management, as well as chemotherapy
drugs, all free of charge to women with GTD. This study was approved by the Research
Ethics Committee of the Botucatu Medical School, UNESP (CAAE: 96348318.5.0000.5411).
The clinical diagnosis of HM was based on ultrasound findings suggestive of complete
hydatidiform mole (CHM) or partial hydatidiform mole (PHM), and pre-uterine evacuation
hCG level. The clinical diagnosis of CHM was based on ultrasound images showing a
heterogeneous uterine mass with cystic spaces, vesicles, or hydropic villi,[6 ] while PHM was diagnosed when ultrasound findings indicated the presence of a thick
placenta with several anechoic cystic lesions and, in some cases, ovular membrane
and fetal growth restriction, and multiple malformations inherent to triploidy.[7 ] After evacuation, the sonographic diagnosis was confirmed by histopathological analysis[8 ]
[9 ] and immunohistochemical staining with p57 (KIP2).[10 ]
The diagnosis of GTN was established according to the International Federation of
Gynecology and Obstetrics (FIGO) criteria:[11 ] hCG plateau ± 10% for 4 measurements over 3 consecutive weeks (days 1,7,14, and
21); hCG level rise > 10% for 3 consecutive weekly measurements over at least 2 weeks
(days 1, 7, and 14); hCG elevated for ≥ 6 months after evacuation or histologic diagnosis
of choriocarcinoma.
Demographics, data on clinical status at admission, and health district of the patients'
residence were collected from paper-based and electronic medical records.
The distance (km) traveled to reach the BTDC was estimated using Google Maps (Google
LLC., Mountain View, CA, USA), considering the documented residential address of the
patient and the address of the Botucatu Medical School Hospital, where the center
is located.
According to the National Council of Health Secretaries,[5 ] the state of São Paulo is subdivided into 17 health districts. Thus, the health
district of residence of all GTD patients was identified at admission based on each
patient's municipality of residence.
The clinical status of patients with HM and GTN upon admission were considered as
outcome variables. The HM level was assessed according to the molar pregnancy risk
score system proposed by Berkowitz et al.,[12 ] which is based on clinical, laboratory and radiologic findings (S1). The risk score
for molar pregnancy included the following parameters: ultrasound diagnosis, uterine
size for gestational age, pre-evacuation hCG, longitudinal (larger) diameter of the
ovary, patient age, and presence of clinical complications. Based on the score assigned
to each of these parameters, the clinical status of the patient with HM at admission
was quantified using a point system ranging from 0 to 15. Patients with HM were classified
as low-risk HM (score < 4) or high-risk HM (score ≥ 4) for developing GTN.
The clinical status at admission of patients referred for GTN treatment was assessed
using the FIGO/WHO staging classification system and risk score (S2). The FIGO staging
is performed according to the anatomical distribution of the neoplasm (stages I, II,
III, and IV), and the risk scoring system uses prognostic factors for resistance to
single-agent chemotherapy. A value of 0, 1, 2, or 4 is given for each risk factor,
resulting in scores ranging from 0 to 25 points. Depending on the score obtained,
the condition of the patient with GTN was categorized into low-risk (≤ 6 points) or
high-risk GTN (≥ 7 points).
The following variables were considered as potential confounders: age (years), race
(white/non-white), parity (total number of viable pregnancies), education level (elementary,
high school, college/university, postgraduate), marital status (partner/no partner),
employment (yes/no), and prior knowledge of GTD (yes/no).
The geographical distribution of the participants according to residence (health district)
and clinical status at admission were plotted on a map of the state of São Paulo subdivided
into its 17 health districts (shapefile obtained through the package geobr). Using
the latitude and longitude coordinates of the study participants' home addresses provided
by Google Maps, each one was scored on the map of the state of São Paulo. The thematic
map according to clinical status at admission was built using the ggplot2 package.
Both geobr and ggplot2 packages were used through the R software (R Foundation for
Statistical Computing, Vienna, Austria) version 3.4.3.
The Chi-square, Fisher exact, or Kruskall-Wallis tests were used to compare demographic
data, clinical status at admission, and traveled distance among patients from health
districts VI, IX, and XVI, followed by the Dunn test for multiple comparisons. Associations
of clinical status at admission of patients with HM and GTN by health district (VI,
IX, and XVI) were made using multiple regression models, adjusted for confounding
factors. The significance level was set at p < 0.05. Analyses were performed using the Statistical Package Social Sciences (SPSS,
IBM Corp. Armonk, NY, USA) version 21.0, and the R software 3.4.3.
Results
During the study period, 470 patients were registered at BTDC. Of these, 366 met this
study's inclusion criteria, and 104 were considered ineligible due to history of nonmolar
pregnancy (n = 13), residence outside the state of São Paulo (n = 4), or missing data (n = 87). Thus, the final study population consisted of 366 women: 335 with HM and 31
with GTN ([Fig. 1 ]).
Fig. 1 Patient flow chart.
Of the 17 health districts in São Paulo State, 8 referred patients to BTDC. Approximately
30% of the patients referred resided in health districts outside the area covered
by this center (HD VI). Furthermore, HD VI (73.5%), HD XVI (19.1%), and HD IX (4.1%)
accounted for the largest number of referrals. Among GTD cases, 8.5% were referred
for GTN treatment and 91.5% for molar evacuation. Notably, of the 335 patients with
HM, 197 (58.8%) had the high-risk form (score ≥ 4). Among GTN patients, 22.6% were
scored as high risk (≥ 7) (S3). [Fig. 2 ] shows that the majority of the patients referred to the BTDC resided in the areas
covered by health districts VI, XVI, and IX, and that the number of women with high-risk
HM was greater in health district IX.
Fig. 2 Thematic map showing the residence of the patients reffered to BTDC and their GTN
status.
Given that only a small number of patients were from health districts I, VII, X, XII,
and XIII, all the analyses presented from this point on are based on data from health
districts VI, IX, and XVI, where 96% (354/366) of the study population resided.
[Table 1 ] indicates that, overall, women from the health districts accounting for the largest
number of referrals (VI, IX, and XVI) were young (median age = 23 years, min–max,
13–52), white (n = 263; 74.5%), nulliparous (n = 180; 50.8%), had a low education level (primary education; n = 179; 51.0%), and lived with a partner (n = 275; 77.9%). About 30% (107) of these women were adolescents, as per the definition
of the World Health Organization.[13 ] Among nonadolescents (n = 247), less than half (49.6%) had a job. In general, prior knowledge of GTD (as
assessed per the BTDC's protocol) was poor (3/354; 0.8%).
Table 1
Demographics, clinical status at admission and distance traveled according to health
district
Variable
Overall (n = 354)
HD
p -value
HD VI
(n = 269)
HD XVI
(n = 70)
HD IX
(n = 15)
Age (years)
23 (13–52)
22 (13–47)
25 (15–52)
19 (13–45)
0.017
10–19
107 (30.2%)
86 (32%)
12 (17.1%)
9 (60%)
20–39
225 (63.6%)
169 (62.8%)
51 (72.9%)
5 (33.3%)
0.005
≥ 40
22 (6.2%)
14 (5.2%)
7 (10.0%)
1 (6.7%)
Race
White
263 (74.5%)
203 (75.7%)
48 (68.6%)
12 (80%)
0.452
Non-white
90 (25.5%)
65 (24.3%)
22 (31.4%)
3 (20%)
Parity
0 (0–8)
0 (0–8)
0.5 (0–5)
1 (0–2)
0.551
Nulliparous
180 (50.8%)
139 (51.7%)
35 (50%)
6 (40%)
Primiparous
103 (29.1%)
81 (30.1%)
17 (24.3%)
5 (33.3%)
0.505
Multiparous
71 (20.1%)
49 (18.2%)
18 (25.7%)
4 (26.7%)
Education
Elementary school
179 (51%)
144 (53.9%)
27 (39.1%)
8 (53.3%)
Highschool
147 (41.9%)
108 (40.4%)
33 (47.8%)
6 (40%)
0.103
College / Post-graduation a
25 (7.1%)
15 (5.6%)
9 (13%)
1 (6.7%)
Had a partner
275 (77.9%)
203 (75.7%)
60 (85.7%)
12 (80.0%)
0.187
Employed (age > 19 years)
122 (49.6%)
89 (48.6%)
29 (50.9%)
4 (66.7%)
0.434
Knowledge of GTD
3 (0.8%)
2 (0.7%)
0 (0.0%)
1 (6.7%)
0.130
HM Score (n = 329)
4 (0–11)
4 (0–11)
5 (0–11)
7 (2–10)
0.048
HM classification (n = 329)
Low risk
137 (41.6%)
115 (44.9%)
19 (31.7%)
3 (23.1%)
0.07
High risk
192 (58.4%)
141 (55.1%)
41 (68.3%)
10 (76.9%)
FIGO score
3 (1–14)
3 (1–7)
4 (2–14)
1.0 (1–2)
0.085
FIGO classification (n = 25)
Low risk
19 (76%)
11 (84.6%)
6 (60%)
2 (100%)
0.373
High risk
6 (24%)
2 (15.4%)
4 (40%)
0 (0%)
Distance traveled (km)
92 (2–325)
76.1 (2–244)
203.5 (70.9–325)
200 (159–315)
0.001
Distance traveled > 80 km
209 (59%)
125 (46.5%)
69 (98.6%)
15 (100%)
0.001
Abbreviations: FIGO, International Federation of Gynecology and Obstetrics; GTD, gestational trophoblastic
disease; GTN, gestational trophoblastic neoplasia; HD, health district; HM, hydatidiform
mole. Notes: Data are expressed as median (min–max) or n (%). a Only 4 patients were post-graduated; Fisher exact test, Chi-square and Kruskal-Wallis;
HD XVI > HD VI > HD IX regarding age (p < 0.05); HD IX > HD XVI > HD VI regarding HM risk score (p < 0.05).
Regarding clinical status at admission, the median HM risk score was 4 (min–max, 0–11)
and the median GTN risk score was 3 (min–max, 1–14). The median distance traveled
to reach the BTDC was 92 km. More than 50% of the patients (209/354; 59%) lived at
a distance > 80 km from the BTDC. No significant differences in demographic data were
observed, except for age (p = 0.017). Nonetheless, clinical status at admission and distance traveled significantly
differed between women from the area covered by the BTDC (health district VI) and
those residing outside this area. The median HM risk score was significantly higher
in health district IX than in the others (p = 0.048). The median distance traveled by patients from health districts IX and XVI
was significantly longer compared with patients from health district VI (p < 0.001). Furthermore, the percentage of long-distance travelers (> 80 km) was higher
in health districts IX and XVI than in health district VI (p < 0.001) ([Table 1 ]).
[Table 2 ] shows the multiple linear regression analysis of the association of HM clinical
status at admission with health district (VI, IX, and XVI), adjusted for confounders.
Patients referred from health districts IX (β = 2.38 [0.87–3.88], p = 0.002) and XVI (β = 0.78 [0.02–1.55], p = 0.045) had higher HM scores than those from health district VI.
Table 2
Adjusted multivariate analysis of the association between HM clinical status at admission
and health district of residence (VI, IX and XVI)
Variable
β
95%CI
p -value
Health district (Ref: HD VI)
XVI
0.78
0.02
1.55
0.045
IX
2.38
0.87
3.88
0.002
Age (years)
-0.03
-0.08
0.02
0.244
Parity
0.1
-0.21
0.41
0.516
Non-white
0.2
-0.48
0.87
0.569
Education (Ref: Elementary school)
Secondary school
-0.65
-1.28
0.01
0.045
College/Postgraduation
-0.12
-1.43
1.19
0.86
Had a partner
-0.36
-1.09
0.33
0.326
Employed
0.2
-0.47
0.9
0.544
Knowledge of GTD
-1.68
-4.78
1.41
0.287
Abbreviations: CI, confidence interval; GTD, gestational trophoblastic disease; HD, health district;
HM, hydatidiform mole.
Notably, the rate of high-risk HM was nonsignificantly 33% higher among women from
health district VI who resided more than 80 km far from BTDC (long-distance travelers)
(RR = 1.33; 95% confidence interval [CI] = 0.96–1.86, p = 0.088; Poisson regression) (S4). The association between long distance and high-risk
HM was not calculated for health districts IX and XVI because nearly all patients
from those districts lived farther than 80 km from BTDC.
[Table 3 ] shows the multiple linear regression analysis adjusted for confounders of the association
of the GTN patients' clinical status at admission with health district of residence
(VI, IX, and XVI).
The GTN patients referred from health district XVI showed a 3.32 increase in FIGO
risk scores when compared with those from district VI (β = 3.32, 95% CI = 0.78–5.87,
p = 0.010). No woman with GTN had any previous knowledge about the disease, so it was
not possible to estimate its effect on the risk score.
Table 3
Adjusted multivariate analysis of the association between GTN clinical status at admission
and health district of residence (VI, IX and XVI)
Variable
β
95% CI
p -value
Health district (Ref: HD VI)
XVI
3.32
0.78
5.87
0.01
IX
-1.51
-5.72
2.7
0.481
Age (years)
0.16
0
0.33
0.048
Parity
-1.56
-2.87
-0.03
0.046
Nonwhite
-0.37
-3.03
2.31
0.783
Education (Ref: Elementary school)
Secondary school
0.83
-1.78
3.43
0.534
College/Postgraduation
-3.24
-6.97
0.5
0.089
Had a partner
-2.37
-6.5
1.76
0.26
Employed
0.16
-2.14
2.45
0.892
Knowledge of GTD
–
–
–
–
Abbreviations: CI, confidence interval; IFGO, International Federation of Gynecology and Obstetrics;
GTN, gestational trophoblastic neoplasia. Notes: No GTN patient had any previous knowledge of the disease.
Discussion
This study indicates that geographical residence influenced the clinical status of
the GTD patients referred to BTDC. Considering the demographic characteristics associated
with worse outcome, we observed that GTD patients referred from health districts outside
the area covered by our specialized center were mostly long-distance travelers (>
80 km) and had a higher risk score compared with those residing in the BTDC (health
district VI) coverage area.
Irrespectively of the health district of residence, there was no difference in demographic
characteristics in the population studied. Most women were young, had no or only 1
child, had a low educational level, and were unemployed. Such unfavorable sociodemographic
status has also been reported by other centers in developing countries.[2 ]
[14 ]
[15 ]
[16 ]
[17 ]
Among the patients with HM referred to our center, 58.8% were at high-risk of molar
pregnancy (score ≥ 4). Compared with women residing in the specialized center district,
women from other districts had a significantly higher molar pregnancy score. This
might have resulted from the fact that despite advances in the early diagnosis of
HM worldwide,[18 ]
[19 ]
[20 ]
[21 ] ultrasound exams and hCG assays are not always readily available in developing countries.
As a result, women may be diagnosed with HM by the end of the first trimester or during
the second trimester of pregnancy, when many have already developed medical complications.[2 ]
[17 ]
A substantial number of GTN patients referred to our center (22.6%) had a high-risk
score (≥ 7) (high-risk GTN), particularly patients from health district XVI, which
is not in the area covered by our center (VI). In the patients from health district
XVI, risk scores were significantly higher (mean of 3.32 points) than in those from
district VI. Notably, this 3.32 increase in the risk score is enough to change the
categorization of GTN from low to high risk.
Whereas the rate of high-risk GTN among our patients was 22.6%, Maestá et al.[22 ] found that in South American (Brazil and Argentina) trophoblastic disease centers,
15% of the women with GTN had the high-risk form of the disease. Both of these rates
are high compared with those reported by trophoblastic centers in developed countries
(2.7–6.3%).[23 ]
[24 ]
Regarding residence, approximately ⅓ of the patients referred to the BTDC were from
health districts outside the area covered by our center. The visualization of the
thematic map shows that districts IX and XVI were the ones who most referred GTD patients,
and both border district VI, where BTDC is located. The greater influx of patients
from these districts could be easily explained as the result of a shorter distance
to be traveled by the patients. However, these districts are quite large, and the
median distance covered by patients to obtain care at the specialized center is 200 km,
which makes them long-distance travelers. Virtually all patients residing outside
the coverage area of the specialized center and about half (HD VI: 46.5%) of those
residing in the coverage area of the specialized center were long-distance travelers
(> 80km).
Several studies have shown that long distance travel constitutes a barrier to treatment
among cancer patients.[25 ]
[26 ]
[27 ] Travel time to health care services has also been shown to influence access, utilization
and outcomes among patients with various malignancies.[28 ]
[29 ]
[30 ] In women with GTN, a single study evaluating the effect of distance traveled showed
that long-distance travelers were significantly more likely to present with high-risk
disease (relative risk [RR] = 2.4; 95% CI = 1.1–5.2).[3 ] Feltmate et al.[4 ] also noted that a distance greater than 20 miles from the patient's home to the
trophoblastic disease center was associated with failure to complete hCG follow-up
(p = 0.001). Furthermore, the impact of distance traveled is stronger for patients of
lower socioeconomic status.[25 ]
[26 ]
Among South American women with GTN, long distances, social and economic disparities,
inefficiency of the referral system, and limited GTD training may lead to late referral
to a specialized center.[22 ] Very often, patients are not referred to an hCG follow-up program upon hospital
discharge after molar evacuation, and when they are referred to the primary healthcare
system, the results of postmolar serum hCG level are very frequently delayed, and
misinterpretation of hCG regression curves may delay referral to a specialized center.
Furthermore, patients living far away from a specialized center may cause them to
postpone seeking care because of transportation issues and reluctance to miss days
of work.[3 ]
It is worth noting that the high growth fraction of the placental trophoblast causes
GTD to rapidly develop. Therefore, the timely management of patients with GTD in a
specialized center can reduce morbidity and mortality. Moreover, the inefficiency
of the referral system, as well as the gaps in GTD training, can lead to late referral
to a specialized center. However, Brazilian regulations still do not consider it an
urgent/emergency condition, which leads to delays in referral. Efforts should be made
to change these referral/counter-referral regulations, as well as to allow the remote
management of these patients through consultation with specialists when referral to
a specialized center is not possible.
The limitations of this study were those inherent to its retrospective design and
possible referral bias. As our study was conducted in a tertiary center for the treatment
and follow-up of women with GTD, the data collected may overrepresent the incidence
of high-risk HM and GTN at presentation. Additionally, the small number of patients
from each health district might have limited statistical analysis of the effects of
demographic characteristics and distance traveled on clinical status at admission.
In summary, this study showed that 1) a considerable proportion of patients with GTD
(∼ 30%) referred to BTDC came from health districts outside the center's geographical
area of coverage; 2) women attending this center were characterized by low socioeconomic
and education level, as well as unemployment status regardless of region of residence;
3) patients from health districts outside the area covered by the specialized center
had higher risk scores for both HM and GTN at admission; 4) long distances (> 80 km)
seemed to adversely influence the clinical status of GTD patients at admission, indicating
barriers to accessing specialized centers.
Conclusion
Patients from health districts outside the specialized center area had higher risk
scores for both HM and GTN at admission. Long distances (>80 km) seemed to adversely
influence GTD clinical status at admission, indicating barriers to accessing specialized
centers. Further studies are warranted to determine the potential impact of geographic
location and travel distance on obtaining care in a specialized center among women
with GTD.
