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• Response to the comments
  Kamilla Karlsen, Ulrik Kesmodel and Pernille Ravn
  Published on: 4 May 2020
• Fibroids and Obstetrical Outcomes
  William H. Parker
  Published on: 16 April 2020
• Dear Dr. Karlsen and Colleauges,
  Elizabeth A Pritts, David L Olive
  Published on: 14 April 2020

• Published on: 4 May 2020

  Response to the comments

  • Kamilla Karlsen, MD, PhD University of Southern Denmark
  • Other Contributors:
    • Ulrik Kesmodel, Professor
    • Pernille Ravn, professor

  We thank Dr. Elizabeth A Pritts, Dr. David L Olive, and Dr. William H. Parker for their great interest in our study and for the very qualified comments. To investigate the influence of uterine fibroids on obstetrical outcomes is complex and can be viewed from different angles. - We aimed to investigate symptomatic uterine fibroids. Well conducted cohort studies are the best available substitutes when experiments are not possible. Methodological limitations need to be taken into consideration, and associations can be explored. We are fully aware that limitations must be relevantly discussed. David A Grimes 1 pointed out some important issues regarding cohort studies:
  1) The exposure should be clear: we argue to have a clearly defined exposure.
  2) The importance of potential confounders: we have been able to include important confounders using the directed acyclic graph, DAG.
  3) Awareness that the risk of a weak association (HR 0.5-2) is likely to be due to bias and not causation: We have clearly stated that we have found associations and further that the association could be interesting for further research, but we do not recommend changes in clinical recommendations.
  The risks of misclassification of exposure were related to the uterine fibroid diagnoses codes. The daily clinical coding may be incorrect or lacking due to various work-related distractions or variable individual interpretation of clinical cases. The low prevalence of uterine fibroids...

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  We thank Dr. Elizabeth A Pritts, Dr. David L Olive, and Dr. William H. Parker for their great interest in our study and for the very qualified comments. To investigate the influence of uterine fibroids on obstetrical outcomes is complex and can be viewed from different angles. - We aimed to investigate symptomatic uterine fibroids. Well conducted cohort studies are the best available substitutes when experiments are not possible. Methodological limitations need to be taken into consideration, and associations can be explored. We are fully aware that limitations must be relevantly discussed. David A Grimes 1 pointed out some important issues regarding cohort studies:
  1) The exposure should be clear: we argue to have a clearly defined exposure.
  2) The importance of potential confounders: we have been able to include important confounders using the directed acyclic graph, DAG.
  3) Awareness that the risk of a weak association (HR 0.5-2) is likely to be due to bias and not causation: We have clearly stated that we have found associations and further that the association could be interesting for further research, but we do not recommend changes in clinical recommendations.
  The risks of misclassification of exposure were related to the uterine fibroid diagnoses codes. The daily clinical coding may be incorrect or lacking due to various work-related distractions or variable individual interpretation of clinical cases. The low prevalence of uterine fibroids in our study population is likely to be a result of underreporting, or due to DNBC representing a selected group of women.
  Specific diagnosis codes within the DNPR have been validated with different results. As you correctly point out, several studies have found specific data within the DNPR invalid, but others have in contrast found other data valid and suitable for research 2-7. A detailed validation of the uterine fibroid diagnosis codes was not possible and has not previously been performed. We relied on previous studies that have shown that reproductive gynecological coding in the DNPR is generally valid and suitable for clinical quality control 8. Further, we made it clear that we investigated a specific group of women with symptomatic uterine fibroids and not uterine fibroids in general. We cannot completely eliminate the risk that some women got the diagnosis code without symptoms, but we found it unlikely, considering that women in Denmark are mainly examined by ultrasound scan due to symptoms, not a routine basis. If the uterine fibroids were symptomatic and required treatment, we found it likely that the women were given a diagnosis code linked to the treatment code. On these ground we argue that we have investigated a group of women with symptomatic uterine fibroids. Others have defined the exposure based on routine ultrasound scans made in the first trimester of pregnancy, irrespective of symptoms. Symptomatic uterine fibroids might represent another group of fibroids with other associated obstetrical risks.
  Participants in cohort studies are often a selected group due to the acceptance of participation and may not fully represent the source population. The DNBC mainly consists of white women with middle or high social status 9. We are therefore evaluated a selected group of women, which could explain the lower prevalence of uterine fibroid diagnosis codes.
  A potential bias will lead towards exposed women being categorized as unexposed. Since the potential underreporting is independent of the outcome because of the prospective nature of data collection in a cohort study, the potential misclassification could have led to non-differential information bias and hence attenuation of the association between exposure (uterine fibroids) and outcomes 10.
  Regarding the very relevant comment on our use of robust standard errors we would like to clarify our decision. Some women contributed with more than one pregnancy in the analyses. Hence, we had clustered data, since observations from two different pregnancies in the same woman would tend to be more similar to each other than to individuals in the rest of the sample. By the use of robust standard errors, we corrected the standard errors for the clustering 11, a well-known and appropriate statistical method.
  Response to the comment; "The authors state that risk of preterm birth is decreased, and cesarean section rates increased among women with untreated fibroids compared with women with surgical excision. However, this appears to be based upon raw numbers and not statistical analysis, as the two groups (fibroids in situ versus fibroids removed) were never compared"
  In the article we wrote that ‘’ In the present study, the risk of preterm birth decreased whereas the risk of CS increased after myomectomy compared with the risks among women with untreated uterine fibroids‘’ We might have added ”insignificantly” to make it clear that none of the formal comparisons between groups 2 and 4 were significant. However, this is evident from the published odds ratios and 95% CIs in table 2. For example, 1.81 (1.24 – 2.65) is clearly not significantly different from 2.27 (1.30 – 3.96).
  Future research on uterine fibroids and impact on obstetrical outcome can be approached in different ways. It could include all uterine fibroids as one big group. Uterine fibroids could be identified and number, type and size of the fibroids recorded. Another approach could be to examine women with clinical symptoms of the uterine fibroids. It is possible that these groups of fibroids are different in terms of associated obstetrical outcomes and thereof potentially different in terms of clinical recommendations.
  1.Grimes DA. Epidemiologic research with administrative databases: red herrings, false alarms and pseudo-epidemics. Hum Reprod 2015;30(8):1749-52.) 2.Hess DT Jr. The Danish National Patient Register. Surg Obes Relat Dis. 2016 Feb;12(2):304. doi: 10.1016/j.soard.2015.11.001. Epub 2015 Nov 5. 3.Adelborg K, Sundbøll J, Munch T, Frøslev T, Sørensen HT, Bøtker HE, Schmidt M. Positive predictive value of cardiac examination, procedure and surgery codes in the Danish National Patient Registry: a population-based validation study. BMJ Open. 2016 Dec 9;6(12):e012817. doi: 10.1136/bmjopen-2016-012817.
  4.Lund H, Vyberg M, Eriksen HH, Grove A, Jensen AØ, Sunde L.Hydatidiform mole: validity of the registration in the Danish National Patient Registry, the Danish Cancer Registry, and the Danish Pathology Registry 1999-2009. Clin Epidemiol. 2018 Sep 18;10:1223-1231. doi: 10.2147/CLEP.S169657. eCollection 2018. 5.Loft ND, Andersen CH, Halling-Overgaard AS, Thyssen JP, Skov L, Egeberg A.Validation of Psoriasis Diagnoses in the Danish National Patient Register. Acta Derm Venereol. 2019 Oct 1;99(11):1037-1038. doi: 10.2340/00015555-3278. 6.Guillain-Barré syndrome in Denmark: validation of diagnostic codes and a population-based nationwide study of the incidence in a 30-year period. Clin Epidemiol. 2019 Apr 18;11:275-283. doi: 10.2147/CLEP.S199839. eCollection 2019. 7.Kirkegård J, Mortensen MR, Johannsen IR, Mortensen FV, Cronin-Fenton D.Positive predictive value of acute and chronic pancreatitis diagnoses in the Danish National Patient Registry: A validation study. Scand J Public Health. 2020 Feb;48 (1):14-19. doi: 10.1177/1403494818773535. Epub 2018 May 3.
  8. Lidegaard O, Vestergaard CH, Hammerum MS. [Quality monitoring based on data from the Danish National Patient Registry]. Ugeskrift for laeger. 2009;171(6):412-415.
  9. Jacobsen TN, Nohr EA, Frydenberg M. Selection by socioeconomic factors into the Danish National Birth Cohort. European journal of epidemiology. 2010;25(5):349-355.
  10. Kesmodel US. Information bias in epidemiological studies with a special focus on obstetrics

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  Conflict of Interest:
  None declared.

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• Published on: 16 April 2020

  Fibroids and Obstetrical Outcomes

  • William H. Parker, MD, Gynecology UC San Diego

  To the Editor,

  I read with interest the article by Karlsen, et al. concluding that here was an association between clinically significant uterine fibroids and pre-term birth. (1) The study has several significant shortcomings. The likely inaccuracies of the use of a large retrospective, administrative, coded database and the low prevalence of fibroids only identified clinically and not confirmed by ultrasound or other imaging modality were mentioned by the authors in the limitations section of the article. However, the degree of these limitations makes the data uninterpretable and the conclusions unfounded.

  Administrative databases are inadequate to answer clinical questions as they are subject to clinical misdiagnosis and coding errors which are blind to the goals of the study. The only way to assure accuracy of such a data set is to adjudicate the data by chart review, which was not done by the authors.

  Reliance on clinical examination to determine the presence of uterine fibroids, especially submucous fibroids that might more significantly impact pregnancy, is inaccurate. (3) Virtually all women in the developed world currently have an ultrasound as part of their early pregnancy evaluation. Most studies using ultrasound for the diagnosis of fibroids in early pregnancy report a prevalence of 3-4%. One such study found that among 64,047 pregnant women, 2058 had fibroids diagnosed with 1st trimester US, a prevalence of 3.2%. (Stout)

  The c...

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  To the Editor,

  I read with interest the article by Karlsen, et al. concluding that here was an association between clinically significant uterine fibroids and pre-term birth. (1) The study has several significant shortcomings. The likely inaccuracies of the use of a large retrospective, administrative, coded database and the low prevalence of fibroids only identified clinically and not confirmed by ultrasound or other imaging modality were mentioned by the authors in the limitations section of the article. However, the degree of these limitations makes the data uninterpretable and the conclusions unfounded.

  Administrative databases are inadequate to answer clinical questions as they are subject to clinical misdiagnosis and coding errors which are blind to the goals of the study. The only way to assure accuracy of such a data set is to adjudicate the data by chart review, which was not done by the authors.

  Reliance on clinical examination to determine the presence of uterine fibroids, especially submucous fibroids that might more significantly impact pregnancy, is inaccurate. (3) Virtually all women in the developed world currently have an ultrasound as part of their early pregnancy evaluation. Most studies using ultrasound for the diagnosis of fibroids in early pregnancy report a prevalence of 3-4%. One such study found that among 64,047 pregnant women, 2058 had fibroids diagnosed with 1st trimester US, a prevalence of 3.2%. (Stout)

  The current study captured 124 women with fibroids coded among 92,696 pregnancies, for a prevalence of 0.13%. If we assume that the prevalence of fibroids is approximately that found in other studies, then we would expect to find 2,966 pregnancies with concurrent fibroids in the Karlsen study. Therefore, 2,842 pregnancies were likely undetected clinically or improperly coded and thus misclassified as not having fibroids. The authors suggest that mistakenly including women with fibroids in the control group would attenuate the association between fibroids and pregnancy outcomes. I disagree. If these women had adverse outcomes, the findings would be diluted by the outcomes of the other 89,730 pregnancies. However, if the women had favorable outcomes, then that data would significantly decrease the adverse outcome conclusions reported in this study. To emphasize this point, 95% of the data is missing and basing any conclusions on this degree of incomplete data is misleading and irresponsible.

  Another important question considered in this study, which remains controversial in the literature, is whether myomectomy prior to pregnancy improves outcomes. However, based on the inaccurate data, I am disappointed that no conclusions can be made for this or any other fibroid-related pregnancy outcome the authors attempted to study.

  William H. Parker, MD
  Department of Ob Gyn and Reproductive Sciences
  UC San Diego
  La Jolla, California

  Email: w1parker@health.ucsd.edu

  (1) Karlsen K, Schiøler Kesmodel U, Mogensen O, Humaidan P, Ravn P. Relationship between a uterine fibroid diagnosis and the risk of adverse obstetrical outcomes: a cohort study. BMJ Open. 2020;10:e032104
  (2) L. Flickinger, G. D’Ablaing III, D.R. Mishell Jr. Size and weight determinations of nongravid enlarged uteri Obstet Gynecol, 68 (Dec (6)) (1986), pp. 855-858
  (3) Stout MJ, Odibo AO, Graseck AS, Macones GA, Crane JP, Cahill AG. Leiomyomas at routine second-trimester ultrasound examination and adverse obstetric outcomes. Obstet Gynecol. 2010;116:1056-63.

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  Conflict of Interest:
  None declared.

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• Published on: 14 April 2020

  Dear Dr. Karlsen and Colleauges,

  • Elizabeth A Pritts, Reproductive Endocrinologist Wisconsin Fertility Institute
  • Other Contributors:
    • David L Olive, Reproductive Endocrinologist

  We read Dr. Karlsen’s paper entitled “Relationship between a uterine fibroid diagnosis and the risk of adverse obstetrical outcomes: a cohort study” with great interest. We understand the authors evaluated a large and complicated set of data and appreciate their effort. However, the authors used a database fraught with errors without validation of said database, made incorrect assumptions and conclusions about the data, and incompletely discussed some of the major queries in the discussion.

  The first issue surrounds the use of the Danish National Birth Cohort, Patient Registry and Birth Registry. Although the authors write about the limitations of a registry that uses codes “more closely connected to hospital budgets than hospital diagnosis codes”, they rely on a single study to prove the quality of their database.

  Multiple authors have shown that administrative databases are inadequate to answer clinical questions. They are are set up for billing purposes only, not epidemiological research (1,2), and elaborate statistical machinations do not overcome the impact of anomalous data (3). Several studies have shown that the very registry used in this report; the Danish National Patient Registry, is highly inaccurate from a clinical standpoint. The authors from a study in 2009 have a self-proclaimed 10% inaccuracy rate in their diagnoses addressing oral contraceptive research (4). Other authors have found higher erroneous rates for diagnoses of hypertension, rhe...

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  We read Dr. Karlsen’s paper entitled “Relationship between a uterine fibroid diagnosis and the risk of adverse obstetrical outcomes: a cohort study” with great interest. We understand the authors evaluated a large and complicated set of data and appreciate their effort. However, the authors used a database fraught with errors without validation of said database, made incorrect assumptions and conclusions about the data, and incompletely discussed some of the major queries in the discussion.

  The first issue surrounds the use of the Danish National Birth Cohort, Patient Registry and Birth Registry. Although the authors write about the limitations of a registry that uses codes “more closely connected to hospital budgets than hospital diagnosis codes”, they rely on a single study to prove the quality of their database.

  Multiple authors have shown that administrative databases are inadequate to answer clinical questions. They are are set up for billing purposes only, not epidemiological research (1,2), and elaborate statistical machinations do not overcome the impact of anomalous data (3). Several studies have shown that the very registry used in this report; the Danish National Patient Registry, is highly inaccurate from a clinical standpoint. The authors from a study in 2009 have a self-proclaimed 10% inaccuracy rate in their diagnoses addressing oral contraceptive research (4). Other authors have found higher erroneous rates for diagnoses of hypertension, rheumatoid arthritis and uterine rupture (5). Another independent review of the database revealed a 41% misclassification rate in women with alleged hormone-related thromboembolic events (6) In fact, in 2010, Shapiro et al (7) recommended ignoring data from unconfirmed data base reports, citing unreliable data from the Danish National Patient Registry.

  The attempt by the authors to compare women with symptomatic uterine fibroids is laudable, as this has not been covered in the existing literature, but unfortunately it is not clear that they were able to accomplish this. Simply having a diagnostic code for “fibroid” does not ensure that the fibroid was indeed symptomatic; in fact, an unknown number may have been given the diagnosis due to ultrasound detection in the absence of symptoms. Unfortunately, the authors did not attempt to validate this assumption.

  There are other issues with this manuscript. Hysteroscopic myomectomy was presumed if the operation codes included “resection and excision of pathological tissue”, but we do not know this to be the case, and again no attempt at validation was conducted by the authors. When a fibroid diagnosis was given, there was no concern regarding number or size of fibroids, both potential confounders that were not corrected for in the regression analysis. Finally, the authors included women with multiple separate pregnancies, stating that this was valid due to “robust standard errors”. Which standard errors were robust, how robust were they, and why did this correct for an obvious methodologic flaw of including some women multiple times?

  The conclusions reached by the authors regarding preterm delivery and caesarean section are incompletely reviewed in the discussion. To date, ten studies have addressed the effect of fibroids on the rate of preterm delivery, with six showing an increased risk with fibroids and four showing no difference. However, five of the six that adjusted the risk ratio for known confounders found an increase, similarly found this study (8). Including this information would have strengthened their findings. Regarding caesarean section, 13 of 15 published studies show an increase in the presence of fibroids, including all 11 studies that adjusted for confounders via regression analysis (as does this manuscript) (8). The authors, however, do not focus on cesarean sections that were acute in nature; these were not different between the two groups. This is an interesting and novel finding, implicating surgeon or patient choice as the driving force behind increased cesarean sections in women with fibroids.

  Whether myomectomy prior to pregnancy improves outcomes for women and their children is the crucial unanswered question in the current literature. The authors state that risk of preterm birth is decreased, and cesarean section rates increased among women with untreated fibroids compared with women with surgical excision. However, this appears to be based upon raw numbers and not statistical analysis, as the two groups (fibroids in situ versus fibroids removed) were never compared. At first glance, it appears that there is no significant difference between these groups for any outcome measure, although without appropriate statistical analysis we cannot be sure. This shortcoming diminishes the value in addressing this important issue.

  In conclusion, this paper has important methodologic flaws, and deficient conclusions. We would be interested in further publications from these authors.

  (1) Grimes DA. Epidemiologic research using administrative databases. Obstet Gynecol 2010;116(5):1018-19.
  (2) Grimes DA. Epidemiologic research with administrative databases: red herrings, false alarms and pseudo-epidemics. Hum Reprod 2015;30(8):1749-52.
  (3) Ault MR. Combating the garbage-in, gospel-out syndrome. Rad Protect Manage 2004;20:26-30.
  (4) Lidegaard O, Lokkegaard, E, Svendsen AL, Agger C. Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ 2009;339:b2890.
  (5) Pedersen M, Klarlund M, Jacobsen S, Svendsen AJ, Frisch M. Validity of rheumatoid arthritis diagnoses in the Danish National Patient Registry. Eur J Epidemiol 2004;19:1097-1103.
  (6) Severinsen MT, Kristensen SR, Overvad K, Dethlefsen C, Tjonneland A, Johnsen SP . Venous thromboembolism discharge diagnoses in the Danish National Patient Registry should be use with caution. J Clin Epidemiol 2010;63:223-8.
  (7) Shapiro S, Dinger J. Risk of venous thromboembolism among users of oral contraceptives: a review of two recently published studies. J Fam Plann Reprod Health Care 2010;36:33-8.
  (8) Pritts EA, Olive DL. Fibroids and reproduction. In Modern Management of Uterine Fibroids. Cambridge University Press, 2020.

  Sincerely and Appreciatively,

  Elizabeth A. Pritts
  David L. Olive

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  Conflict of Interest:
  None declared.

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