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Risk of pelvic organ prolapse treatment based on extended family history

Published:January 15, 2020DOI:https://doi.org/10.1016/j.ajog.2019.12.271

      Background

      Family history of pelvic organ prolapse among first-degree relatives is an established risk factor for pelvic organ prolapse; however, consideration of the constellation of family history that extends to distant relationships allows for more accurate determination of risk and may improve pelvic organ prolapse risk prediction estimates.

      Objective

      The purpose of this study was to assess risk for pelvic organ prolapse treatment based on varying family histories of pelvic organ prolapse and included number and types of affected relatives, ages of relatives at pelvic organ prolapse treatment, and whether the family history is of maternal or paternal origin.

      Study Design

      This was a retrospective, population-based study that involved the Utah Population Database, which is a population resource that includes extensive genealogy information linked to medical records. The study population included 453,522 total women: 4628 women with a diagnosis of treated (surgical or pessary) pelvic organ prolapse and their 15,530 first-degree relatives; 33,782 second-degree relatives, and 66,469 third-degree relatives. We estimated relative risk of treated pelvic organ prolapse based on specific family history constellations.

      Results

      Relative risk estimates increased with a family history of increasing numbers of treated first-degree relatives with pelvic organ prolapse (first-degree relatives, ≥1 [relative risk, 2.36; 95% confidence interval, 2.15–2.58], first-degree relatives, ≥2 [relative risk, 3.79; 95% confidence interval, 2.65–5.24], and first-degree relatives, ≥3 [relative risk, 6.26; 95% confidence interval, 1.29–18.30]). Having a family history of ≥3 affected third-degree relatives (eg, first cousins) and no affected first- or second-degree relatives was similar in risk to having 1 affected first-degree relative. Relative risk estimates decreased with increasing age of treatment for first-degree family members. Risks in individuals with a positive maternal family history for pelvic organ prolapse were consistently higher than risks in individuals with equivalent paternal family history, but paternal inheritance still played a role. Approximately 4% of the total studied female population was found to have a >2-fold risk of being treated for pelvic organ prolapse and is considered high-risk based on their family history.

      Conclusion

      We provide estimates for treated pelvic organ prolapse based on an extensive family history of pelvic organ prolapse using a large population-based sample. Risk for treated pelvic organ prolapse increased with increasing numbers of affected close and distant female relatives, earlier age of pelvic organ prolapse treatment in relatives, and maternal inheritance. These risk estimates may be useful for genetic studies and investigation of risk reduction strategies in those at highest risk for pelvic organ prolapse.

      Key words

      Pelvic organ prolapse (POP) is a disorder that results in the abnormal descent of the uterus, bladder, colon, or rectum into the vagina. The prevalence of symptomatic POP ranges from 5–10% of adult women,
      • Milsom I.
      • Altman D.
      • Cartwright R.
      • et al.
      Epidemiology of urinary incontinence (UI) and other lower urinary tract symptoms (LUTS), pelvic organ prolapse (POP) and anal (AI) incontinence.
      and the lifetime risk of surgical treatment for POP in the United States by age 80 years is 12.6% (95% confidence interval [CI], 12.4–12.7).
      • Wu J.M.
      • Matthews C.A.
      • Conover M.M.
      • Pate V.
      • Jonsson Funk M.
      Lifetime risk of stress urinary incontinence or pelvic organ prolapse surgery.
      POP is a public health problem because it imparts a significant burden on the health, quality of life, and economic strain on those impacted.
      • Subak L.L.
      • Waetjen L.E.
      • Van Den Eeden S.
      • Thom D.H.
      • Vittinghoff E.
      • Brown J.S.
      Cost of pelvic organ prolapse surgery in the United States.
      ,
      • Jelovsek J.E.
      • Barber M.D.
      Women seeking treatment for advanced pelvic organ prolapse have decreased body image and quality of life.
      Hence, understanding the contributing risk factors for POP is of great importance because it will enable identification of those women who are at highest risk for investigation of risk reduction strategies.

      Why was this study conducted?

      The purpose of this study was to determine risk assessments for treated pelvic organ prolapse based on specific family history that would include numbers and types of affected relatives, earliest relative treatment age, and maternal vs paternal family history.

      Key findings

      Risk of prolapse treatment was associated with increasing numbers of female-affected close and distant relatives. The risk of prolapse treatment was associated with earlier age of prolapse treatment in first-degree relatives. Risk of prolapse treatment was associated with mostly maternal inheritance, but paternal inheritance still played a role.

      What does this add to what is known?

      Approximately 4% of women are at high risk for treated prolapse based on their family history. Family history in second- and third-degree female relatives also contributes to risk of prolapse.
      The cause of POP is considered multifactorial, with the number of vaginal deliveries being the most important risk factor. However, a number of studies have observed that a family history of POP is also a significant and strong predictor of POP.
      • Asresie A.
      • Admassu E.
      • Setegn T.
      Determinants of pelvic organ prolapse among gynecologic patients in Bahir Dar, North West Ethiopia: a case-control study.
      • Jelovsek J.E.
      • Chagin K.
      • Gyhagen M.
      • et al.
      Predicting risk of pelvic floor disorders 12 and 20 years after delivery.
      • Chiaffarino F.
      • Chatenoud L.
      • Dindelli M.
      • et al.
      Reproductive factors, family history, occupation and risk of urogenital prolapse.
      • Lince S.L.
      • Van Kempen L.C.
      • Vierhout M.E.
      • Kluivers K.B.
      A systematic review of clinical studies on hereditary factors in pelvic organ prolapse.
      • Rinne K.M.
      • Kirkinen P.P.
      What predisposes young women to genital prolapse?.
      • Slieker-Ten Hove M.C.
      • Pool-Goudzwaard A.L.
      • Eijkemans M.J.
      • Steegers-Theunissen R.P.
      • Burger C.W.
      • Vierhout M.E.
      Prediction model and prognostic index to estimate clinically relevant pelvic organ prolapse in a general female population.
      • Levin P.J.
      • Visco A.G.
      • Shah S.H.
      • Fulton R.G.
      • Wu J.M.
      Characterizing the phenotype of advanced pelvic organ prolapse.
      • Miedel A.
      • Tegerstedt G.
      • Maehle-Schmidt M.
      • Nyren O.
      • Hammarstrom M.
      Nonobstetric risk factors for symptomatic pelvic organ prolapse.
      Recently published risk prediction models for POP at 12 and 20 years after childbirth delivery found that a family history of POP ranked second in most models following the strongest predictor, childbirth delivery route.
      • Jelovsek J.E.
      • Chagin K.
      • Gyhagen M.
      • et al.
      Predicting risk of pelvic floor disorders 12 and 20 years after delivery.
      For those studies that assessed family history, subjects typically are asked about the existence of any symptoms or treatment for POP in either their mother or sisters.
      • Jelovsek J.E.
      • Chagin K.
      • Gyhagen M.
      • et al.
      Predicting risk of pelvic floor disorders 12 and 20 years after delivery.
      ,
      • Lince S.L.
      • Van Kempen L.C.
      • Vierhout M.E.
      • Kluivers K.B.
      A systematic review of clinical studies on hereditary factors in pelvic organ prolapse.
      ,
      • Levin P.J.
      • Visco A.G.
      • Shah S.H.
      • Fulton R.G.
      • Wu J.M.
      Characterizing the phenotype of advanced pelvic organ prolapse.
      • Miedel A.
      • Tegerstedt G.
      • Maehle-Schmidt M.
      • Nyren O.
      • Hammarstrom M.
      Nonobstetric risk factors for symptomatic pelvic organ prolapse.
      • Alcalay M.
      • Stav K.
      • Eisenberg V.H.
      Family history associated with pelvic organ prolapse in young women.
      • Hamer M.A.
      • Persson J.
      Familial predisposition to pelvic floor dysfunction: prolapse and incontinence surgery among family members and its relationship with age or parity in a Swedish population.
      However, more distant relatives (eg, aunts and cousins) and paternal inheritance may also contribute to the risk of POP.
      The primary objective of this study was to assess risk for treated POP based on extended family histories of POP that include the number and types of affected relatives, ages of relatives at POP treatment, and whether the family history is of maternal or paternal origin with the use of an extensive statewide genealogy database linked to medical records. Consideration of an extended family history allows for more accurate determination of risk and may improve risk prediction estimates for POP.

      Materials and Methods

      Utah population database (UPDB)

      The UPDB includes, among other data sources, linked data from family history records dating back to the 19th century for the pioneer founders of Utah, birth and death certificates, and inpatient and outpatient electronic medical records beginning in 1994 from the University of Utah Health Sciences Center (UUHSC), an academic medical center, and Intermountain Healthcare, a not-for-profit healthcare system. The linked electronic health records from UUHSC and Intermountain Healthcare represent healthcare use for the majority of Utahns; UUHSC and Intermountain Healthcare together serve approximately 85% of the Utah population who use health care. Genealogy data for the Utah founders and descendants to the current population was obtained from 1.6 million family history records that were provided by the Genealogical Society of Utah and were extended with relationship data that were constructed from nearly 3 million Utah birth certificates. There are almost 11 million unique individuals represented in the UPDB currently. Approximately 1.3 million of them have genealogy data for at least 12 of 14 of their immediate ancestors (parents, all 4 grandparents, and at least 6 of 8 great grandparents) that connect to the Utah founding population. Women who meet these strict genealogy requirements and with linkage to healthcare records (n=453,522) were defined as probands in this study to better understand POP risks that are associated with extended relationships.

      POP case definition

      POP cases were defined as those individuals with an International Classification of Diseases 9th revision (ICD9) diagnosis code that indicates a diagnosis of POP (ICD9 code 618) and a Current Procedural Terminology (CPT) code that indicates treatment for POP and who also met the strict genealogy requirements and linked to healthcare records at UUHSC or at Intermountain Healthcare as described earlier. We included the following CPT procedure codes for POP: colpocleisis (57120), pessary (57160), anterior colporrhaphy (57240), posterior colporrhaphy (57250), combined anterior and posterior colporrhaphy (57260), combined anterior and posterior colporrhaphy, with vaginal repair of enterocele (57265), vaginal repair of enterocele (57268), abdominal repair of enterocele (57270), abdominal repair of vaginal vault prolapse/abdominal sacrocolpopexy (57280), vaginal repair of vaginal vault prolapse/extraperitoneal approach (57282), vaginal repair of vaginal vault prolapse/intraperitoneal approach (57283), and paravaginal repair for lateral cystocele (57284). Treated POP cases were identified from electronic medical records from 1994, when electronic medical records were first available at UUHSC and at Intermountain Healthcare, up to 2014. This study was approved by the University of Utah and Intermountain Institutional Review Boards and the Utah Resource for Genetic Epidemiological Research, which oversees the usage of UPDB data. All of the data involved in this project were deidentified, and waivers of informed consent were granted by the Institutional Review Board.

      Estimation of relative risk

      Relative risks were estimated for multiple different family history constellations. First-degree relatives (FDRs) include parents, children, and siblings; second-degree relatives (SDRs) include grandparents, grandchildren, aunts/uncles, nieces/nephews and half-siblings; third-degree relatives (TDRs) include great grandparents, great grandchildren, grandnieces/nephews, grand aunts/uncles, and first cousins. From among the 453,522 probands described earlier, we identified all female probands who met specific family history constellations of POP and computed their relative risk for being treated for POP. Relative risk estimates were computed as the ratio of the observed to the expected number of treated POP cases among the probands. The expected number of POP cases was estimated based on population rates of POP for women by birth state (Utah or not) and age (5-year birth year cohort). Each proband who was involved in a specific analysis was assigned their cohort-specific rate of POP. The expected number of POP cases was determined as the sum of all the cohort specific rates for all probands in that analysis. The 95% confidence interval was calculated with the method of Agresti.
      • Agresti A.
      • Coull B.A.
      Approximate is better than “exact” for interval estimation of binomial proportions.

      Results

      A total of 4628 female subjects with a diagnosis of treated POP between 1994 and 2014 was included in this analysis. Of this number, 786 women (17%) were treated only with pessary (no surgery). These individuals had 15,530 female FDRs, 33,782 female SDRs, and 66,469 female TDRs.

      First-degree family history of treated POP

      Table 1 shows relative risk estimates of POP for probands, defined by varying numbers of FDRs that had been treated for POP. The Table includes the number of probands with the family history specified, the observed number of probands diagnosed with POP, the expected number of POP cases, the relative risk, the significance of the relative risk test of hypothesis, and the 95% CI for the relative risk. For example, there were 719 probands with ≥2 FDRs who were treated for POP; of these individuals, 36 probands had also been treated for POP, whereas only 9.51 cases were expected based on the UPDB population-based cohort rates for POP. The relative risk estimate, 3.79, was significant at P<.00001 (95% CI, 2.65–5.24), which means that individuals with ≥2 FDRs who were treated for POP were 3.79 times more likely to also be treated for POP, compared with the expected number of women who were treated for POP in Utah, based on population rates of the disease. Relative risk estimates increased with increasing numbers of FDRs who had been treated for POP.
      Table 1Estimated relative risks for treated pelvic organ prolapse for first-, second-, and third-degree family history
      Relative risk estimates for pelvic organ prolapseProbandsObservedExpectedRelative riskP value95% Confidence interval
      Based on FDR family history, SDRs and TDRs ignored
       0622,1084,1224,396.770.94<.000010.91–0.97
       ≥118,258477202.232.36<.000012.15–2.58
       ≥2719369.513.79<.000012.65–5.24
       ≥335<5<56.26.0131.29–18.30
      Based on SDR family history; FDR (n=0) and TDRs ignored
       0577,4393,8144,146.660.92<.000010.89–0.95
       ≥144,669308250.101.23.00031.10–1.38
       ≥23,8952317.861.29.230.82–1.93
       ≥3321<5<52.14.240.26–7.71
      Based on SDR family history; FDRs (n=1) and TDRs ignored
       015,404395174.22.27<.000012.05–2.50
       11,9114216.832.50<.000011.80–3.37
       ≥2250<5<52.00.140.55–5.12
      Based on TDR family history; FDR (n=0) and SDR (n=0)
       0489,4313,0873,470.420.89<.000010.86–0.92
       ≥188,008727676.251.08.0521.00–1.16
       ≥214,478121107.301.13.190.94–1.35
       ≥32,7823515.712.23<.000011.55–3.10
       ≥467452.571.94.200.63–4.54
      Based on TDR family history; FDR (n=1) and SDRs ignored
       ≥13,47210940.492.69<.000012.21–3.25
       ≥2650387.485.08<.000013.59–6.97
      Based on TDR family history; FDR (n=1) and SDR (n=1)
       ≥1549144.742.96.00041.62–4.96
       ≥213430.993.02.0790.62–8.84
       ≥345<5<55.70.0491.01–20.58
      FDR, first-degree relative; SDR, second-degree relative; TDR, third-degree relative.
      Allen-Brady et al. Family history and risk of prolapse. Am J Obstet Gynecol 2020.

      Second-degree family history of treated POP

      Table 1 shows relative risk estimates for POP based on second-degree family history under the scenario where there are no FDRs treated for POP and where there is one FDR treated for POP. Again, we observed that relative risk estimates increased with increasing numbers of treated relatives, and risk estimates were greater for those who also had 1 FDR who had been treated for POP (Table 1). For individuals with no FDRs with POP, there was still a significantly increased risk of treated POP if an individual had only a second-degree family history of POP (FDR, 0; SDR, ≥1; relative risk, 1.23; 95% CI, 1.10–1.38).

      Third-degree family history of treated POP

      Table 1 also shows the relative risk estimates for POP based on a third-degree family history. Three scenarios are considered: (1) where there are no first-degree and no SDRs treated for POP, (2) where there is exactly 1 FDR treated for POP and SDRs are ignored, and (3) where there is exactly 1 FDR and 1 SDR who had been treated for POP. A family history of ≥3 treated TDRs and no affected FDRs or SDRs had a similar relative risk estimate as having ≥1 FDRs (FDR, 0; SDR, 0; TDR, ≥3 [relative risk, 2.23; 95% CI, 1.55–3.10] vs FDR, ≥1 [relative risk, 2.36; 95% CI, 2.15–2.58]). Increasing number of affected TDRs even in the presence of 1 affected FDR and/or 1 SDR greatly increased the risk of treated POP.

      Family history based on age of treatment for FDR

      Table 2 shows estimated relative risks for family history based on the earliest POP treatment age of FDRs. The relative risk estimate was greatest for individuals with at least 1 FDR who had been treated for POP at <40 years old; risks decreased with increasing FDR treatment age.
      Table 2Relative risk estimates based on earliest pelvic organ prolapse treatment age for first-degree relative; second- and third-degree relatives are ignored
      Family history: first-degree relativeProbandsObservedExpectedRelative riskP value95% Confidence interval
      ≥1, Age <40 y1257319.273.34<.000012.27–4.75
      ≥1, Age 40–49 y28368428.982.90<.000012.31–3.59
      ≥1, Age 50–59 y433812148.642.49<.000012.06–2.97
      ≥1, Age 60–69 y431811552.072.21<.000011.82–2.65
      ≥1, Age 70–79 y39559247.261.95<.000011.57–2.39
      ≥1, Age >79 y15543416.012.12.00011.47–2.97
      Allen-Brady et al. Family history and risk of prolapse. Am J Obstet Gynecol 2020.

      Family history risk based on specific FDR treated for POP

      Table 3 shows relative risk estimates for a family history of various combinations of affected FDRs. The specific constellation of having at least 1 sister and at least 1 daughter affected (relative risk, 5.73; 95% CI, 2.62–10.87) is noted to be significantly higher than the risk for a proband having at least 2 affected FDRs (Table 1: relative risk, 3.79; 95% CI, 2.65–5.24). This may result from an overall higher age of probands who have affection status data available for their daughters.
      Table 3Relative risk estimates for specific first-degree relatives, ignoring second- and third-degree relatives
      Family historyProbandsObservedExpectedRelative riskP value95% Confidence interval
      Mother61608846.481.89<.000011.52–2.33
      ≥1 Daughter34948630.732.80<.000012.24–3.46
      1 Sister8570292123.872.36<.000012.09–2.64
      2 Sisters304244.695.11<.000013.28–7.61
      Sister and daughter10591.575.73<.000012.62–10.87
      Allen-Brady et al. Family history and risk of prolapse. Am J Obstet Gynecol 2020.

      Family history risk based on maternal or paternal transmission

      In Table 4, we show relative risk estimates for individuals with a maternal family history of POP compared with individuals with a paternal family history of POP. Risks for a maternal family history were, in general, significantly increased compared with paternal inheritance, because there was no overlap of these relative risk estimates and respective 95% CIs across all maternal and paternal relationships that were investigated; an exception is noted for grandmothers, neither of which were significant, and for which sample sizes were limited. Of note, there was still a negligible increased risk of treated POP based on paternal inheritance alone as observed with paternal first cousins.
      Table 4Relative risk estimates for maternal, compared with paternal, relationships, ignoring other relationships
      Family historyProbandsObservedExpectedRelative riskP value95% Confidence interval
      ≥1 Maternal first cousins26,823484365.801.32<.000011.21–1.45
      ≥1 Paternal first cousins27,397433376.621.15.00391.04–1.26
      ≥1 Mother’s sister(s)8,98710672.661.46.00021.19–1.76
      ≥1 Father’s sister(s)8,3896860.931.12.370.87–1.41
      Daughter of sister9,22610667.171.58<.000011.29–1.91
      Daughter of brother9,5576559.461.09.480.84–1.39
      Maternal grandmother3,94554.011.25.800.40–2.91
      Paternal grandmother3,99073.681.90.110.76–3.91
      Allen-Brady et al. Family history and risk of prolapse. Am J Obstet Gynecol 2020.

      Results summary

      Table 5 shows a summary of the various family history constellations that had a relative risk of ≥2.0, ≥3.0, and ≥5.0 for treated POP. The Table also shows the number of high-risk probands in each group and their percentage of the total female population that met the genealogy requirements that were considered for this analysis (n=453,522). Although each individual percentage is approximately ≤1%, the combined percentage of individuals considered high-risk for POP diagnosis and treatment approximates 4% of the total female population that was studied.
      Table 5Minimal family history constellation with estimated relative risks significantly >2.0, 3.0, and 5.0
      Relative risk
      ≥2.0
      Includes percentage of high-risk probands as part of the total considered female population who met genealogy requirements (n=453,522).
      ≥3.0≥5.0
      ≥ 1 Daughter (3494 probands; 0.77% population)FDRs (n≥2) (719 probands; 0.16%)2 Sisters (304 probands; 0.07%)
      1 Sister (8570 probands; 1.89% population)FDR (n≥1), <40 years old (1257 probands; 0.28%)Sister and daughter (105 probands; 0.02%)
      FDR (n=0); SDR (n=0); TDR (n≥3) (2782 probands; 0.61% population)FDRs (n≥3) (35 probands; 0.008%)
      FDR (n=1); TDRs (n≥2) (650 probands; 0.014%)
      FDR, first-degree relative; SDR, second-degree relative; TDR, third-degree relative.
      Allen-Brady et al. Family history and risk of prolapse. Am J Obstet Gynecol 2020.
      a Includes percentage of high-risk probands as part of the total considered female population who met genealogy requirements (n=453,522).

      Comment

      Principal findings

      There is strong evidence that POP has a heritable contribution.
      • Lince S.L.
      • Van Kempen L.C.
      • Vierhout M.E.
      • Kluivers K.B.
      A systematic review of clinical studies on hereditary factors in pelvic organ prolapse.
      ,
      • Altman D.
      • Forsman M.
      • Falconer C.
      • Lichtenstein P.
      Genetic influence on stress urinary incontinence and pelvic organ prolapse.
      • Buchsbaum G.M.
      • Duecy E.E.
      • Kerr L.A.
      • Huang L.S.
      • Perevich M.
      • Guzick D.S.
      Pelvic organ prolapse in nulliparous women and their parous sisters.
      • Norton P.A.
      • Allen-Brady K.
      • Cannon-Albright L.A.
      The familiality of pelvic organ prolapse in the Utah Population Database.
      Although most previous studies have focused on POP family history for FDRs,
      • Jelovsek J.E.
      • Chagin K.
      • Gyhagen M.
      • et al.
      Predicting risk of pelvic floor disorders 12 and 20 years after delivery.
      ,
      • Lince S.L.
      • Van Kempen L.C.
      • Vierhout M.E.
      • Kluivers K.B.
      A systematic review of clinical studies on hereditary factors in pelvic organ prolapse.
      ,
      • Hamer M.A.
      • Persson J.
      Familial predisposition to pelvic floor dysfunction: prolapse and incontinence surgery among family members and its relationship with age or parity in a Swedish population.
      we present relative risk estimates based on an extended constellation of family history for treated POP that extends to TDRs. We found that risks for POP increased with increasing numbers of affected close and distant female relatives, earlier age of POP treatment in relatives, and maternal inheritance. Approximately 4% of women in our population are at high-risk (relative risk, >2.0) for treated POP. Results are based on a sample size of over 450,000 women and included >4000 treated POP cases who met strict genealogy requirements and linked to available healthcare records. Because POP family history may not always be known and/or may change with time, we have presented the results with the use of general descriptions such as “greater than equal to” rather than “equal to,” which allows the results to be generalizable to more individuals.

      Results

      Although first-degree family history showed the greatest contribution to risk of treated POP, family history of POP in SDRs and TDRs also contributed to risk of treated POP. Interestingly, the presence of ≥3 TDRs (most likely first cousins) who had been treated for POP predicted similar risk to a family history of 1 FDR who had been treated for POP. These findings underlie the importance of taking a 3-generation family history of POP that includes both close and distant relatives to predict the risk of POP treatment in a patient. Although many women may not know their family history of POP, it is likely that the women who do know their family history have ≥1 case of POP in their family, which places them at higher risk of POP. This article presents the magnitude of the risk of having a specific family history constellation of POP.
      The relative risk estimates generated for this study are similar to other published results for risks to mothers and sisters of probands who underwent POP surgery. Hamer and Persson,
      • Hamer M.A.
      • Persson J.
      Familial predisposition to pelvic floor dysfunction: prolapse and incontinence surgery among family members and its relationship with age or parity in a Swedish population.
      using 61,323 women who had had a surgical procedure for POP based on the Swedish Hospital Discharge information and family relationship information for their mothers and sisters, estimated a relative risk to mothers for POP surgery of 2.56 (95% CI, 2.41–2.73) and to sisters 6.58 (95% CI, 6.32–6.86). Although the risks that we estimated in our study are based on risks to the proband based on a specific family history constellation, our results are similar. We estimated relative risk of 1.89 (95% CI, 1.52–2.33) to a proband for a mother treated for POP, and a relative risk of 2.36 (95% CI, 2.09–2.64) and a relative risk of 5.11 (95% CI, 3.28–7.61) for having a family history of 1 sister and 2 sisters treated for POP, respectively. Hamer and Persson did not differentiate risks by the number of affected sisters or number of affected FDRs. Our Utah population is of mostly northern European descent
      • Jorde L.B.
      • Skolnick M.
      Demographic and genetic applications of computerized record linkage: the Utah Mormon genealogy.
      ; hence, it is not surprising that our results are similar.
      We observed that earlier treatment age for POP of FDRs also predicted increased risk of treated POP. Probands with FDRs who were treated for POP at <40 years old had the greatest risk of treated POP; risks decreased with increasing ages of relatives who were treated for POP. A number of studies have observed that a family history of POP is more prevalent among younger women who are diagnosed with POP.
      • Rinne K.M.
      • Kirkinen P.P.
      What predisposes young women to genital prolapse?.
      ,
      • Alcalay M.
      • Stav K.
      • Eisenberg V.H.
      Family history associated with pelvic organ prolapse in young women.
      ,
      • Hamer M.A.
      • Persson J.
      Familial predisposition to pelvic floor dysfunction: prolapse and incontinence surgery among family members and its relationship with age or parity in a Swedish population.
      Hamer and Persson
      • Hamer M.A.
      • Persson J.
      Familial predisposition to pelvic floor dysfunction: prolapse and incontinence surgery among family members and its relationship with age or parity in a Swedish population.
      found that sisters and mothers were at the highest risk for pelvic floor surgery for incontinence or POP if the proband had pelvic floor surgery before their youngest considered age of 50 years. Alcalay et al
      • Alcalay M.
      • Stav K.
      • Eisenberg V.H.
      Family history associated with pelvic organ prolapse in young women.
      observed that a family history of surgically treated POP was 5 times more prevalent in young women (age, <45 years) who were surgically treated for POP, compared with older women (>55 years) who also were surgically treated for POP and matched on parity. Rinne and Kirkinen
      • Rinne K.M.
      • Kirkinen P.P.
      What predisposes young women to genital prolapse?.
      found that 30% of the 85 young women (≤45 years) surgically treated for POP in their study reported a positive family history of POP compared with women of the same age who underwent surgery for benign ovarian tumor. These treatment age results, in combination with the previously published findings, support a greater genetic contribution in those women with early onset disease, given the strong family inheritance of disease. Individuals with a first-degree family member who had been diagnosed with POP at an early age may benefit from increased surveillance.
      In this study, we observed a significant increased risk of treated POP from maternal inheritance compared with paternal inheritance, but a slight increased risk was also observed for a family history of affected paternal cousins. Jack et al
      • Jack G.S.
      • Nikolova G.
      • Vilain E.
      • Raz S.
      • Rodriguez L.V.
      Familial transmission of genitovaginal prolapse.
      previously observed both maternal and paternal transmission of POP diagnosis. Although there are no studies to date to have associated genetic variants on Chromosome X with POP, several previous publications have shown mitochondrial changes associated with POP.
      • Alujevic Jakus I.
      • Jakus D.
      • Marinovic J.
      • Cavar M.
      • Banic I.
      • Vilovic K.
      Expression of mitochondrial respiratory chain complexes in the vaginal wall in postmenopausal women with pelvic organ prolapse.
      • Kim E.J.
      • Chung N.
      • Park S.H.
      • et al.
      Involvement of oxidative stress and mitochondrial apoptosis in the pathogenesis of pelvic organ prolapse.
      • Sun M.J.
      • Cheng W.L.
      • Wei Y.H.
      • et al.
      Low copy number and high 4977 deletion of mitochondrial DNA in uterosacral ligaments are associated with pelvic organ prolapse progression.
      • Sun M.J.
      • Cheng Y.S.
      • Sun R.
      • Cheng W.L.
      • Liu C.S.
      Changes in mitochondrial DNA copy number and extracellular matrix (ECM) proteins in the uterosacral ligaments of premenopausal women with pelvic organ prolapse.
      • Yiou R.
      • Authier F.J.
      • Gherardi R.
      • Abbou C.
      Evidence of mitochondrial damage in the levator ani muscle of women with pelvic organ prolapse.
      Further study of genetic alternations from maternal sources (eg, chromosome X and mitochondria) may be informative.
      We previously published traditional relative risk estimates for POP using the UPDB and its links to the University of Utah Health Sciences Center with probands and their relatives who have at least 3 generations of genealogy information.
      • Norton P.A.
      • Allen-Brady K.
      • Cannon-Albright L.A.
      The familiality of pelvic organ prolapse in the Utah Population Database.
      In this study, we included treated POP cases from both the UUHSC and Intermountain Healthcare and required genealogy information for 12 of 14 of their immediate ancestors. Although our relative risk estimates between the previously published study and the current study are similar, the methods used were different, and the various constellations that were examined in the present study are much more comprehensive. In our previous study, we identified POP cases and looked at risk of POP in their FDRs, SDRs, and TDRs. In this current study, we identified individuals who met specific family history constellations (eg, ≥3 affected FDRs) and looked at the individual proband’s risk for being treated for POP; many different possible constellations of affected relatives are considered here.

      Clinical and research implications

      The results of this study may be useful in counseling women on their risk for treated POP, particularly for the approximately 4% of women who are at high risk for treated POP (relative risk, >2.0) based on their family history. Because there is much interest in the prediction of women who are at risk of experiencing POP,
      • Jelovsek J.E.
      • Chagin K.
      • Gyhagen M.
      • et al.
      Predicting risk of pelvic floor disorders 12 and 20 years after delivery.
      ,
      • Slieker-Ten Hove M.C.
      • Pool-Goudzwaard A.L.
      • Eijkemans M.J.
      • Steegers-Theunissen R.P.
      • Burger C.W.
      • Vierhout M.E.
      Prediction model and prognostic index to estimate clinically relevant pelvic organ prolapse in a general female population.
      the risk assessments provided by this study based on specific family history constellations could be incorporated into risk prediction models to predict more accurately women at risk for future POP treatment. Women at high risk for POP based on their family history can be targeted for increased surveillance and investigation of risk reduction strategies.

      Strengths and limitations

      Strengths of this study include the use of a population-based medical record system dating back to 1994 that captures approximately 85% of healthcare use for the state that has been linked to extended genealogy information. We were able to identify relatives who were treated for POP without recall or ascertainment bias. We were able to estimate risk for treated POP for family history constellations that include varying numbers of FDRs, SDRs, and TDRs. Most studies assess only the risk associated with FDRs because information on more distant relatives can be difficult or potentially unreliable to obtain. Because the definition of POP can vary between studies (anatomic vs symptomatic), our case definition of requiring surgical treatment for POP captures those symptomatic enough to seek treatment.
      Limitations of this study include that we relied on ICD9 and CPT procedure codes to identify women who had been treated for POP. Some coding errors are likely to exist. However, the requirement of both a diagnosis and a procedure code for POP likely decreases the number of ascertained individuals without true disease. Individuals not treated in 1 of the 3 Utah healthcare systems or treated before 1994 were censored. Limitations of the Utah genealogy data include the censoring of individuals who did not link to genealogy and the recognized lower record-linking success for women (because of name changes); in addition, genealogy data do not always represent biologic relationships. The excess maternal inheritance that was observed in this study may, in part, be due to “social heredity” factors
      • Hamer M.A.
      • Persson J.
      Familial predisposition to pelvic floor dysfunction: prolapse and incontinence surgery among family members and its relationship with age or parity in a Swedish population.
      that are shared between maternal relatives such as parity, exercise, and other familial environmental traits that were not assessed as part of this study, although effects observed in more distant relationships might argue against this. We have not included parity as a risk factor in these analyses but plan to do so in the future. Risk estimates may also have been affected by other factors that were not included in this analysis (eg, proband age). Results should not be extrapolated beyond similar populations with Northern European founders.

      Conclusions

      We provide risk assessments for treated POP based on family history and have identified approximately 4% of women in our population who are at high-risk (relative risk, >2.0) for treated POP.

      Acknowledgments

      We thank the Pedigree and Population Resource of the Huntsman Cancer Institute, University of Utah (funded in part by the Huntsman Cancer Foundation) for its role in the ongoing collection, maintenance, and support of the UPDB. We also thank the University of Utah Center for Clinical and Translational Science (CCTS) (funded by NIH Clinical and Translational Science Awards), the Pedigree and Population Resource, University of Utah Information Technology Services and Biomedical Informatics Core for establishing the Master Subject Index between the Utah Population Database, the University of Utah Health Sciences Center, and Intermountain Health Care.

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