Appendix 1. Analysis of Sensitivity to Unmeasured Confounders

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Nitecki R, Clapp MA, Fu S, Lamiman K, Melamed A, Brady PC, et al. Safety of the first pregnancy after fertility- sparing surgery for early-stage ovarian cancer. Obstet Gynecol 2021;137.

The authors provided this information as a supplement to their article.

Appendix 1. Analysis of Sensitivity to Unmeasured Confounders

The E-value is the minimum strength of association, on the risk ratio scale, that an unmeasured confounder would need to have with both the treatment and out- come, conditional on the measured covariates, to explain away a treatment– outcome association

¹

. In our study we use it to assess how much confounding would be required to move a near- null association to clinically meaningful levels, and how much confounding would be required to exclude the null from the confidence intervals in treatment-outcome associations.

We calculated E-values to examine the confounder associations that would be needed to move an estimate to a clinically meaningful estimate, using the following formula described by

VanderWeele and Ding

¹

:

E-value=

^{𝑂𝑂𝑂𝑂1}

𝑂𝑂𝑂𝑂2

+ √([(

^{𝑂𝑂𝑂𝑂1}_{𝑂𝑂𝑂𝑂2}

𝑥𝑥 (

^{𝑂𝑂𝑂𝑂1}_{𝑂𝑂𝑂𝑂2}

− 1)])

Where OR1= The estimate derived from the study and OR2= the chosen clinically meaningful estimate the E-value would shift OR1 to, in our case, 2.0.

To calculate the E-value required to exclude 1.0, the null, from the confidence interval we used the following formula

¹

:

E-value=

¹

𝐿𝐿𝐿𝐿𝐿𝐿

+ √([(

_{𝐿𝐿𝐿𝐿𝐿𝐿}¹

𝑥𝑥 (

_{𝐿𝐿𝐿𝐿𝐿𝐿}¹

− 1)])

Where LCL= the lower confidence level derived from the study divided by 1.01.

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Appendix 2. Characteristics of Women With Stage IA and IC Ovarian Cancer With and Without Pregnancy 3 Months After Surgery

Characteristic

Ovarian Cancer Patients who Conceived at Least 3 Months after Surgery

(n=153)

Ovarian Cancer Patients

Excluded from Cohort (n=1464) P-Value^†

Age Group <.001

18-25 70 (45.8%) 186 (12.7%)

26-35 74 (48.4%) 417 (28.5%)

36-45 9 (5.9%) 861 (58.8%)

Race/Ethnicity 0.02

White 51 (33.3%) 684 (46.7%)

Black 9 (5.9%) 75 (5.1%)

Hispanic 55 (35.9%) 409 (27.9%)

Asian/Pacific Islander 38 (24.8%) 284 (19.4%)

Other^‡ 0 (0.0%) 12 (0.8%)

Insurance Type 0.9

Any Medicaid 19 (12.4%) 172 (11.7%)

Insured 122 (79.8%) 1294 (82.3%)

Uninsured 7 (4.6%) 51 (3.5%)

Unknown 5 (3.3%) 37 (2.5%)

Year of Diagnosis <.001

2000-2003 84 (54.9%) 491 (33.5%)

2004-2007 42 (27.5%) 361 (24.7%)

2008-2012 27 (17.6%) 612 (41.8%)

Marital Status 0.8

Single 68 (44.4%) 612 (41.8%)

Married 73 (47.7%) 706 (48.2%)

Separated/divorced/widowed 9 (5.9%) 108 (7.4%)

Unknown 3 (2.0%) 38 (2.6%)

Histology <.001

Epithelial 84 (54.9%) 1147 (78.3%)

Germ-cell 57 (37.3%) 233 (15.9%)

Sarcoma 0 (0.0%) 10 (0.7%)

Sex cord stromal 11 (7.2%) 73 (5.0%)

Other 1 (0.7%) 1 (0.1%)

Grade <.001

I 30 (19.6%) 349 (23.8%)

II 18 (11.8%) 277 (18.9%)

III 20 (13.1%) 268 (18.3%)

Unknown 85 (55.6%) 570 (38.9%)

Chemotherapy 0.005

Yes 40 (26.1%) 540 (36.9%)

No 113 (73.9%) 898 (61.3%)

Unknown 0 (0.0%) 26 (1.8%)

Radiotherapy 0.7

Yes 0 (0.0%) 5 (0.3%)

No 153 (100.0%) 1458 (99.6%)

Unknown 0 (0.0%) 1 (0.1%)

Surgery <.001

Fertility-sparing 153 (100.0%) 1108 (75.7%)

Non fertility-sparing 0 (0.0%) 330 (22.5%)

No surgery 0 (0.0%) 11 (0.8%)

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Unknown 0 (0.0%) 15 (1.0%)

Charlson Comorbidity Score 0.3

0 142 (92.8%) 1298 (88.7%)

1 10 (6.5%) 145 (9.9%)

≥2 1 (0.7%) 21 (1.4%)

Socio-Economic Status* 0.3

Lowest 27 (17.6%) 207 (14.1%)

Lower-Middle 37 (24.2%) 287 (19.6%)

Middle 28 (18.3%) 335 (22.9%)

Upper-Middle 31 (20.3%) 333 (22.7%)

Highest SES 30 (19.6%) 302 (20.6%)

Data are no. (%) unless otherwise specified.

* 2000-2005 based on Yost score², and 2006-2012 based on Yang score³

†P-values derived by Pearson chi-square test or Wilcoxon rank-sum test.

‡ Pre-specified formal category in the database

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Appendix 3. Obstetric Outcomes in Ovarian Cancer Cases Stratified by Time to Conception

Time from Surgery to Conception (mo)

Outcome 3-12

(n=29)

>12-24 (n=43)

>24 (n=81)

P-Value^* PTB < 37 weeks 13.8% (1.2-26.3) 11.6% (2.1-21.2) 14.8% (7.1-22.5) 0.9 PTB < 32 weeks 3.4% (0.0-10.1) 2.3% (0.0-6.8) 2.5% (0.0-5.8) 0.9 SGA < 5%ile 3.4% (0.0-10.1) 2.3% (0.0-6.8) 7.4% (1.7-13.1) 0.5 SGA < 10%ile 13.8% (1.2-26.3 11.6% (2.1-21.2) 11.1% (4.3-18.0) 0.9

Fetal demise 3.4% (0.0-10.1) 0.0% 1.2% (0.0-3.6) 0.4

Cesarean Delivery 37.9% (20.3-55.6) 39.5% (24.9-54.1) 45.7% (34.8-56.5) 0.7

SMM 0.0% 2.3% (0.0-6.8) 3.0% (0.0-7.8) 0.9

Neonatal Morbidity 10.3% (0.0-21.4) 2.3% (0.0-6.8) 6.2% (1.0-11.4) 0.4

Data are % (95% CI)

*P-values derived by Fisher’s Exact test

Abbreviations: Abbreviations: PTB, preterm birth; SGA, small for gestational age based on curves by Oken and colleagues⁴¹; SMM, severe maternal morbidity based on the CDC algorithm.⁴²

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Appendix 4. Obstetric Outcomes in Ovarian Cancer Cases Stratified by Histology and Receipt of Chemotherapy

Histology Chemotherapy

Outcome Epithelial

(n=84)

Non-epithelial (n=69)

P- Value^*

Yes (n= 40)

No (n=113)

P- Value^* PTB < 37 weeks 17.9% (9.7-26.0) 8.7% (2.0-15.3) 0.1 12.5% (2.2-22.7) 14.2% (7.7-20.6) 0.9

PTB < 32 weeks 2.4% (0.0-5.6) 2.9% (0.0-6.9) 0.9 0.00% 3.5% (0.1-6.9) 0.6

SGA < 5%ile 5.9% (0.9-11.0) 4.3% (0.0-9.2) 0.7 5.0% (0.0-11.7) 5.3% (1.2-9.4) 0.9 SGA < 10%ile 13.1% (5.9-20.3) 10.1% (3.0-17.3) 0.6 15.0% (3.9-26.1) 10.6% (4.9-16.3) 0.6

Fetal demise 0.0% 2.9% (0.0-6.9) 0.2 0.0% 1.7% (0.0-4.2) 0.9

Cesarean Delivery 44.0% (33.4-54.7) 40.6% (29.0-52.2) 0.7 45.0% (29.6-60.4) 41.6% (32.5-50.7) 0.7

SMM 1.2% (0.0-3.5) 4.3% (0.0-9.2) 0.3 2.5% (0.0-7.3) 2.6% (0.0-5.6) 0.9

Neonatal Morbidity 5.9% (0.9-11.0) 5.8% (0.3-11.3) 0.9 2.5% (0.0-7.3) 7.1% (2.3-11.8) 0.9

Data are % (95% CI)

*P-values derived by Fisher’s Exact test

Abbreviations: Abbreviations: PTB, preterm birth; SGA, small for gestational age based on curves by Oken and colleagues⁴¹; SMM, severe maternal morbidity based on the CDC algorithm.⁴²

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Appendix 5. Results of Sensitivity Analyses for Unmeasured Confounders

Associations of Unmeasured Confounding with Ovarian Cancer and Selected Outcome

Outcome To shift OR to 2.0 To exclude null from CI

PTB < 37 weeks 2.63 2.32

PTB < 32 weeks 1.79 4.13

SGA < 5th percentile 5.9 6.95

SGA < 10th percentile 3.82 3.45

Cesarean Section

^*

1.99 1.99

Neonatal Morbidity 3.41 4.02

*Used formula for common outcome (>15% at the end of follow-up), by replacing the risk ratio with the square root of the OR, i.e., OR1 ≈ √ (OR), in the E-value formula

Abbreviations: OR, odds ratio; CI, confidence interval; PTB, preterm birth; SGA, small for gestational age based on curves by Oken and colleagues⁴

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Appendix 6. Value of the joint minimum strength of association on the risk ratio scale that an unmeasured confounder must have with both ovarian cancer and preterm birth to shift the observed OR= 1.23 to OR=2.0. The orange E-value demonstrates that an unmeasured confounder that was associated with both ovarian cancer and preterm birth < 37 weeks of gestation by an odds ratio of 2.6-fold each, could move the odds ratio for the association between ovarian cancer and preterm birth to 2.0, but weaker confounding could not.

Because, 2.0 is included in the confidence interval for the OR (1.23, 95% CI 0.69-2.20),

there is no E-value for the lower confidence interval depicted.

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Appendix 7. Value of the joint minimum strength of association on the risk ratio scale that

an unmeasured confounder must have with both ovarian cancer and preterm birth to shift

the observed OR= 1.23 to OR=2.5. The orange E-value demonstrates that an unmeasured

confounder that was associated with both ovarian cancer and preterm birth < 37 weeks of

gestation by an odds ratio of 3.5-fold each, could move the odds ratio for the association

between ovarian cancer and preterm birth to 2.5, but weaker confounding could not. The

green E-value demonstrates the lower confidence interval this confounder would result in,

and the maroon line demonstrates the upper confidence interval.

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References

1. VanderWeele TJ, Ding P. Sensitivity Analysis in Observational Research: Introducing the E-Value. Ann Intern Med. 2017;167(4):268. doi:10.7326/M16-2607

2. Yost K, Perkins C, Cohen R, Morris C, Wright W. Socioeconomic status and breast cancer incidence in California for different race/ethnic groups. Cancer Causes Control.

2001;12(8):703-711. doi:10.1023/a:1011240019516

3. Yang J, Schupp CW, Harrati A, Clarke C, Keegan THM GS. Developing an area-based socioeconomic measure from American Community Survey data. Cancer Prevention Institute of California, Fremont, California.

4. Aris IM, Kleinman KP, Belfort MB, Kaimal A, Oken E. A 2017 US Reference for Singleton Birth Weight Percentiles Using Obstetric Estimates of Gestation. Pediatrics.

Appendix 1. Analysis of Sensitivity to Unmeasured Confounders