a b s t r a c t

Background: ovarian hyperstimulation syndrome (OHSS) is a rare, but serious, risk of assisted reproductive tech- nologies. In severe cases, patients may present to the emergency department (ED) for assessment, treatment of related complications, and even in-patient admission. Significant effort has been made to reduce the incidence and complications of OHSS; however, it is unknown if these strategies have decreased patient presentation for treatment in the ED. Purpose: To assess ED utilization for OHSS over time and to examine admission rates, patient demographics, and charges.

Methods: Retrospective longitudinal study utilizing data from the Nationwide Emergency Department Sample Database and the National ART Surveillance System. All ED visits between 2006 and 2016 with an ICD-9 or -10 diagnosis of OHSS were included. Demographics including age, geographic location, and income quartile and Alternative diagnoses, admission rates, overall charges, and number of stimulation cycles annually were assessed.

Results: The number of ovarian stimulation cycles steadily increased from 2006 (n = 110,183) to 2016 (n = 157,721), while the number of OHSS-related ED visits remained relatively stable (APC 2.08, p = 0.14). Admission rates for OHSS decreased from 52.7% in 2006 to 33.1% in 2016 (APC -4.43%, p < 0.01). The average charge for OHSS-related ED visits almost doubled from 2006 to 2016 (APC 8.53, p < 0.01) and was significantly higher than charges for non-OHSS-related visits for age-matched controls (p < 0.01).

Conclusion: Despite an increase in total stimulation cycles, there was no significant change in the estimated num- ber of patients presenting to the ED; however, admission rates significantly declined. These observations suggest a possible shift in the severity and/or management of OHSS during the study period.

(C) 2022

1. Introduction

Ovarian hyperstimulation syndrome (OHSS) is a serious risk of assisted reproductive technologies (ART) such as In vitro fertilization (IVF). This syndrome can involve a spectrum of clinical signs and symp- toms including ovarian enlargement, ascites, hemoconcentration, elec- trolyte imbalances, oliguria, Pleural effusions, and Liver dysfunction [1,2]. OHSS is typically classified as mild, moderate, severe, or critical with estimates of moderate to Severe OHSS occurring in 1-5% of IVF

* Corresponding author at: L4000 University Hospital South, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA.

E-mail addresses: [email protected] (S.B. Schon), [email protected] (A.S. Kelley), [email protected] (C. Jiang), [email protected] (M. Xu), [email protected] (M. Menke), [email protected] (E.E. Marsh).

¹ Aspire Fertility, 911W. 38th St., Suite 402, Austin, TX 78705 USA.

cycles [1-3]. Mild OHSS is characterized by abdominal discomfort and ovarian enlargement with normal laboratory values. Moderate OHSS is similar in clinical presentation, however, is distinguished by evidence of hemoconcentration and the presence of ascites on US. Severe OHSS may involve hydrothorax, severe dyspnea, oliguria/anuria, VTE and lab- oratory evidence of severe hemoconcentration, sodium and potassium abnormalities and Renal impairment [3,4]. Critical OHSS is very rare and may include renal failure, pericardial effusions, arterial thrombosis, acute respiratory distress syndrome and sepsis [3,4].

The management of mild to moderate OHSS usually involves sup- portive outpatient management with close follow-up. In patients with moderate to severe OHSS, procedural interventions such as paracentesis or culdocentesis may be performed in the office or in the emergency de- partment (ED) or hospital to alleviate symptoms. In some cases of se- vere OHSS, hospitalization is needed for aggressive management of fluids and electrolytes and treatment of resulting complications such

https://doi.org/10.1016/j.ajem.2022.08.014

0735-6757/(C) 2022

as Thromboembolic events, pleural effusions, and renal failure [3,5]. Significant effort has been made to reduce the risk of this syndrome including selection of particular IVF stimulation protocols, use of gonadotropin-releasing hormone (GnRH) agonist triggers, incorpora- tion of adjuvant medications such as metformin and cabergoline, and an increased trend toward freeze-all cycles [3]. In freeze-all cycles where all embryos are cryopreserved (and the patient does not have an opportunity for pregnancy), the risk of late-onset OHSS can be signif- icantly reduced as this phenomenon is propagated by HCG production from an early pregnancy [6]. A frozen embryo is then transferred in a subsequent programmed cycle when the patient is not at risk of OHSS since the ovaries are suppressed.

Despite these efforts, OHSS still remains a major complication of ART [7-9] and little is known about OHSS and ED utilization. To investigate this, as well as the incidence, trend, and national burden of OHSS- related complications, we utilized the Nationwide Emergency Depart- ment Sample (NEDS) database to examine national ED utilization over time. The overall objective of this study was to assess ED utilization and subsequent admissions and discharges for an OHSS-related diagno- sis between 2006 and 2016 and to examine patient demographics, pre- senting diagnoses, and the overall healthcare burden.

1. Materials and methods

This was a retrospective longitudinal study utilizing the NEDS data- base (Healthcare Cost and Utilization Project, Agency for Healthcare Re- search and Quality, Rockville, MD), which is the largest all-payer publicly available database of ED visits in the United States [10]. This da- tabase contains information from 33.5 million ED visits at 984 hospitals to create a 20% stratified sample of U.S. hospital-based ED visits. Weighted, the database describes >100 million ED visits annually. Hos- pital and patient characteristics, as well as information on the nature of the visits, are included in the database.

The number of IVF cycles per year was obtained from the Centers for Disease Control and Prevention (CDC) annual report by the National ART Surveillance System (NASS) [11]. All fresh autologous IVF, fresh donor oocyte, and oocyte/embryo cryopreservation cycles were in- cluded in the annual number of IVF cycles. Frozen embryo cycles were excluded since these patients are not at risk of OHSS. Due to changes in the reporting of cycle outcomes (exclusion of separate reporting of oocyte/embryo cryopreservation cycles) beginning in 2017, the analysis was limited to 2006-2016.

For each year during 2006-2016, we selected all ED visits among fe- male patients between the ages of 18 and 49 inclusive, with an ICD-9 code of 256.1 (“Other ovarian hyperfunction“) or ICD-10 code of N98.1 (“Hyperstimulation of ovaries“) listed in any of the diagnostic fields. Prior to the change to ICD-10 on October 1, 2015, ICD-9256.1 (“Other ovarian hyperfunction“) was the only available code to capture a diagno- sis of OHSS. When 256.1 or N98.1 were not listed as the primary ICD code, the alternative primary diagnosis was captured for analysis. ED characteristics explored include number of ED visits, number of admis- sions from the ED, age, hospital region, zip code-based income quartile, hospital teaching status, and principal presenting diagnosis. ED charges were also obtained from the database and adjusted for inflation using the Consumer Price Index [12] related to the 2016 U.S. dollar. If ED charges were excessively low or high, the value was set to missing by NEDS. Subsequently, missing charge values were treated as missing at random and imputed for the calculation of Total charges. The average annual percentage of changes (APC) was estimated by fitting trend data to a log-linear model using Joinpoint 4.7.0.0 (National Cancer Insti- tute, Washington, D.C.).

The study institution’s Institutional Review Board reviewed this study before it began, determined that it was exempt, and waived informed consent, as the data are both de-identified and publicly available.

Descriptive statistics were calculated as counts and percentages for categorical variables and means for continuous variables. Chi Square, t-test, and F-test were used as appropriate and p < 0.05 was considered statistically significant. Initially, a separate analysis was performed for ED visits with a principal diagnosis of OHSS compared with ED visits with a diagnosis of OHSS listed in any of the diagnostic fields. As the trend in both groups was similar, we continued with ED visits that in- cluded any diagnosis of OHSS. All analyses were performed with SAS

9.4 (SAS Institute, Cary, NC).

1. Results

During the study period, there were a total of 11,068 ED visits for OHSS among women between the ages of 18 and 49. There were a total of 388,851,387 ED visits for all diagnoses among women in the same age group during the 11-year study period. total ED visits per year and their descriptive characteristics are outlined in Table 1. The number of ED visits per year ranged from a low of 867 (95% CI 592-1142) in 2008 to 1303 (95% CI 1044-1562) in 2015. When adjusted for total number of IVF cycles per year, ED visits per 1000 fresh IVF cy- cles ranged from a low of 6.1 (95% CI 4.7-7.5) in 2016 to 9.9 (95% CI 7.4-12.4) in 2006. The percent of visits resulting in admission ranged from 31.3% (n = 407) in 2015 to 52.7% (n = 574) in 2006. The mean age of patients per year remained fairly consistent and ranged from

30.3 (95% CI 29.6-31.0)-31.5 (95% CI 30.6-32.4) years. The percent of

visits by geographic location varied by year, with a predominance of visits in the Northeast in 2006 (n = 467, 42.9%) and a more equal distri- bution in 2016 (Northeast, n = 276, 28.6%; Midwest, n = 232, 24.1%; South, n = 152, 15.8%; and West, n = 303, 31.5%). Similarly, the distri- bution of income quartile also varied by year, although most years there were a higher percentage of women from the highest quartile. Indeed, between 39% (n = 332) and 48.7% (n = 428) of patients each year were from the highest income quartile. Admission rates by income quartile were similar to visit distribution by income quartile. The major- ity of women with OHSS presented to teaching hospitals (397 [45.5%]- 775 [76.8%]).

OHSS was billed as the primary diagnosis in 46.3% of cases (n = 989). For those with an alternative primary diagnosis, the most com- mon were complications of pregnancy (n = 322, 15.1%) and abdominal pain (n = 155, 7.3%). All primary diagnoses of patients presenting to the ED are presented in Fig. 1.

The number of IVF stimulation cycles steadily increased from 110,183 in 2006 to 157,721 in 2016 (annual percent change (APC) 3.63, p < 0.01) (Table 1 and Fig. 2A). In contrast, the number of ED visits for OHSS remained relatively stable during the study period (APC 2.0, p = 0.13) (Table 1 and Fig. 2A). To determine whether there was a pro- portional change in ED visits, the number of ED visits per 1000 cycles of IVF were compared during this time (Fig. 2B). While the overall number of visits declined from 9.9/1000 cycles in 2006 to 6.1/1000 cycles in 2016, the annual percent change (APC -1.57, p = 0.25) was not statis- tically significant. Despite there not being a change in ED visits, admis- sion rates for OHSS significantly decreased during the study period from 52.7% in 2006 to 33.1% in 2016 (APC -4.43%, p < 0.01) (Fig. 2B).

The average adjusted charge for ED visits for OHSS almost doubled during the study period, from $2896 in 2006 to $5601 in 2016 (APC 8.53, p < 0.01) (Fig. 3). Furthermore, the average charge for ED visits for OHSS was significantly higher than charges for non-OHSS-related visits (p < 0.01). Not surprisingly, total adjusted ED charges associated with OHSS also steadily increased from $2.9 million in 2006 to $4.9 mil- lion in 2016 (APC 9.26, p < 0.01.

1. Discussion

In this study utilizing two large national databases (NEDS and NASS), we found that the proportion of patients undergoing IVF who presented to the ED for OHSS between 2006 and 2016 remained

Table 1

General demographic and descriptive data for patients presenting with a diagnosis of OHSS, 2006-2016.

Characteristic 2006	2007	2008	2009	2010	2011	2012	2013	2014	2015	2016
Total number of visits to the ED 1089	871	867	896	880	1054	1102	1034	1009	1303	963
with Any Dx of (814-1365) OHSS	(633-1108)	(592-1142)	(711-1081)	(684-1076)	(829-1278)	(902-1302)	(803-1264)	(804-1214)	(1044-1562)	(746-18,181)
Number of
admissions to 574 (52.7)	423 (48.6)	442 (51.0)	425 (47.4)	370 (42.1)	494 (46.9)	495 (44.9)	409 (39.5)	381 (37.7)	407 (31.3)	319 (33.1)
hospital
Total number of 110,183	113,172	116,450	113,516	111,673	112,010	129,204	131,069	136,775	144,205	157,721

the same

IVF Cycles^a ED visits per

1000 Fresh IVF Cycles

9.9	7.7	7.4	7.9	7.9	9.4	8.5	7.9	7.4
(7.4-12.4)	(5.6-9.8)	(5.1-9.8)	(6.3-9.5)	(6.1-9.6)	(7.4-11.4)	(7-10.1)	(6.1-9.6)	(5.9-8.9)

9 (7.2-10.8) 6.1 (4.7-7.5)

Mean age of patients presenting

31.1

(30.4-31.9)

30.8

(30-31.7)

30.5

(29.6-31.4)

31.1

(30.3-31.9)

30.9

(30.2-31.7)

31.3

(30.6-31.9)

30.9

(30.1-31.7)

30.3

(29.6-31.0)

31.5

(30.6-32.4)

31.0

(30.3-31.7)

31.2

(30.4-32.0)

Hospital region
Northeast	467 (42.9)	317 (36.4)	276 (31.9)	301 (33.6)	298 (33.9)	253 (24.0)	391 (35.5)	299 (28.9)	250 (24.8)	256 (19.6)	276 (28.6)
Midwest	175 (16.1)	209 (24.0)	185 (21.3)	176 (19.6)	240 (27.3)	266 (25.3)	201 (18.3)	269 (26.1)	328 (32.5)	320 (24.6)	232 (24.1)
South	270 (24.8)	165 (19.0)	176 (20.3)	171 (19.1)	150 (17.1)	317 (30)	267 (24.2)	194 (18.7)	175 (17.4)	342 (26.2)	152 (15.8)
West	177 (16.2)	180 (20.6)	230 (26.6)	248 (27.6)	192 (21.8)	218 (20.7)	242 (22)	272 (26.3)	255 (25.3)	385 (29.6)	303 (31.5)
Income Quartile Lowest	110 (10.2)	113 (13.4)	114 (13.4)	133 (15.1)	123 (14.2)	121 (11.7)	127 (11.7)	111 (10.9)	142 (14.4)	170 (13.2)	95 (10.1)
Second	174 (16.1)	173 (20.5)	179 (21.1)	119 (13.5)	143 (16.5)	160 (15.4)	210 (19.3)	146 (14.3)	214 (21.8)	272 (21.1)	175 (18.7)
Third	276 (25.6)	213 (25.2)	225 (26.5)	199 (22.7)	193 (22.3)	324 (31.2)	282 (25.9)	361 (35.3)	243 (24.7)	312 (24.2)	276 (29.5)
Highest	517 (48.0)	346 (40.9)	332 (39.0)	428 (48.7)	408 (47.0)	434 (41.7)	470 (43.1)	404 (39.5)	384 (39.1)	534 (41.4)	391 (41.7)
Teaching
Hospital,	650 (59.7)	397 (45.5)	470 (54.2)	446 (49.8)	506 (57.5)	707 (67.1)	677 (61.4)	655 (63.3)	775 (76.8)	927 (71.1)	698 (72.4)
weight count

Data presented as n (%) or mean (95% CI). Count (n) estimates are unweighted; percentage estimates are weighted using Healthcare Cost and Utilization Project discharge weights, which are representative of the reported total of ED visits in the United States. The percentages within each covariate are column percentages. Some counts do not sum totals because of missing data for the factor; percentages calculated from all nonmissing data. Fewer than 0.5% of the data were missing.

ED = emergency department; Dx = diagnosis; OHSS = ovarian hyperstimulation syndrome; IVF = in vitro fertilization.

^a Per CDC ART National Summary Report.

Fig. 1. Primary diagnosis by clinical classification for those with OHSS listed in any field.

Clinical classification and frequency of primary diagnosis for those presenting to the ED during the study period with any listed diagnosis of OHSS.

*Includes those with a frequency >= 0.06%.

OHSS = ovarian hyperstimulation syndrome; ED = emergency department.

Fig. 2. ED visits and admission rates for OHSS from 2006 to 2016.

1. Number of IVF cycles per year based on CDC national summary report and ED visits for OHSS from 2006 to 2016.
2. ED visits for OHSS per 1000 cycles of IVF from 2006 to 2016.
3. Percent of ED visits for OHSS resulting in admission from 2006 to 2016. Values represent national estimate with 95% CI.

ED = emergency department; OHSS = ovarian hyperstimulation syndrome; IVF = in vitro fertilization; APC = annual percent change.

Fig. 3. Average ED charge per year for OHSS.

Average estimated ED charge per year for a diagnosis of OHSS from 2006 to 2016, adjusted for inflation.

ED = emergency department; OHSS = ovarian hyperstimulation syndrome; APC = annual percent change.

relatively stable. Given increasing efforts to reduce OHSS, this finding is surprising. However, despite the consistent number of patients present- ing to the ED, the percentage of patients subsequently admitted to the hospital drastically decreased. This suggests that while patients are still developing OHSS at a similar rate, the severity of the disease may be reduced. A recent study by Rotshenker-Olshinka et al. that utilized the HCUP National Inpatient Sample (NIS) database similarly found a decrease in admission rates between 2004 and 2008; however, they noted a plateau in admissions between 2008 and 2014 [13]. In contrast, our study noted a continuous decline in admission rates throughout the study period. The NEDS database utilized in our study only captures admissions that occurred through the ED to the same hospital; thus, it is possible that there were additional admissions directly to the hospital that were not captured in this study. It is also possible that a sharper decline in admissions between 2014 and 2016 contributed to the significant overall difference found in our study.

Among patients presenting to the ED with a complication of OHSS, over 46% included a primary diagnosis of OHSS. Other presenting diagnoses were often non-specific, such as “other complications of preg- nancy” or “other female genital disorders.” Given that human chorionic gonadotropin is a key mediator of OHSS, and the syndrome is exacer- bated by pregnancy, it is not surprising that a diagnosis related to pregnancy would frequently be noted [14,15]. Other primary diagnoses are similarly related to OHSS such as liver disease, pleurisy, fluid and Electrolyte disorders, and nausea and vomiting. Additionally, when the analysis was restricted to those who only had a primary diagnosis of OHSS, the results were similar. By including those with any diagnosis of OHSS, an increasing number of ED visits was captured.

We found that the average charge per ED visit for OHSS was signifi- cantly higher than the average ED charge for any other diagnosis among women in the same age group presenting to the ED and that this charge also increased with time. Thus, despite a relatively small proportion of overall ED visits for OHSS, these visits are costly. Furthermore, the num- ber of visits to the ED for OHSS over time remained stable, despite de- creasing admission rates. This suggests that perhaps the ED is being inappropriately utilized for treatment of OHSS. Formalized or expanded guidelines on the management of patients with OHSS on an outpatient

basis vs in the ED could help practitioners manage symptoms safely in a more cost-effective manner-thus saving resources and reducing un- necessary utilization of the ED. Patients may often be adequately treated and monitored on an outpatient basis. Indeed, it has been suggested that even those with severe OHSS can frequently and safely be managed as outpatients [16]. Strategies for outpatient management have in- cluded early paracentesis/culdocentesis as an outpatient, use of GnRH antagonist in the luteal phase, and hydration and thromboprophylaxis when appropriate [16-21]. The American Society for Reproductive Med- icine (ASRM) acknowledges that there is overall fair evidence to recom- mend paracentesis/culdocentesis for the management of OHSS in an outpatient setting [3]. There are, however, definite indications for pre- sentation and management of OHSS in the ED and hospital settings. A recent paper utilizing the NIS from 2002 to 2011 demonstrated that 1 in 25 patients admitted for OHSS are at risk of life-threatening complica- tions. Examples of such complications included acute respiratory dis- tress syndrome, deep vein thrombosis/pulmonary embolism, need for intubation, and acute renal failure. The authors noted that underlying comorbidities were associated with prolonged hospital stays and higher hospital costs [22]. Thus, while overall improvements in admission rates have occurred, there is still much work to be done.

Importantly, in this study we also found that 39-48.7% of patients presenting to the ED were from the highest income quartile. Previous research has consistently demonstrated that women with lower house- hold income are less likely to access infertility care, despite an equal prevalence of infertility [23-25]. Our results support this finding, as the majority of women seen in the ED were from the highest two income quartiles, while only 10-15% were from the lowest income quartile. Furthermore, this breakdown in utilization of care persisted throughout the 11-year study period. Increased awareness and advo- cacy to improve these disparities is critical, as highlighted by the recent ASRM Ethics Committee Opinion [26].

Limitations of this study include the inability to collect detailed clin- ical information or associated outcomes. As ICD-9 and -10 codes were used to capture OHSS, misdiagnosis is always a possibility. However, by including any associated diagnosis of OHSS, it is likely that we captured most patients presenting to the ED with an OHSS-related

complication. Importantly, our study period included the transition from ICD-9 to ICD-10; thus, it is possible this may also have led to a dif- ference in observations. Additionally, our study period concluded in 2016, which is the year the ASRM guidelines recommending strategies to reduce OHSS was published [3]. It would be very informative to cap- ture information regarding OHSS trends following this publication to determine its impact.

Despite these limitations, our study also has a number of strengths. First, the NEDS database is a powerful resource that provides a nation- ally representative weighted sample, thus allowing for generalizability throughout the United States. Second, by assessing ED visits and subse- quent admissions over time, a comprehensive picture of temporal changes in OHSS care can be obtained. Finally, to our knowledge, it is also the first study utilizing ED data to assess care for OHSS.

1. Conclusions

In summary, we show that the frequency of ED utilization for com- plications of OHSS remained unchanged from 2006 to 2016, while ad- mission rates significantly declined and ED charges increased. It is important to continue efforts to decrease the incidence of OHSS and consider outpatient treatment management when safely possible. Fu- ture studies should continue to assess the impact of additional guide- lines on the incidence and severity of OHSS, as well as increased utilization of lower-cost outpatient management when appropriate.

Funding

This research did not receive any specific grant from funding agen- cies in the public, commercial, or not-for-profit sectors.

Credit authorship contribution statement

Samantha B. Schon: Writing - review & editing, Writing - original draft, Supervision, Methodology, Investigation, Data curation, Concep- tualization. Angela S. Kelley: Writing - review & editing, Methodology. Charley Jiang: Writing - review & editing, Formal analysis. Min Xu: Writing - review & editing, Methodology. Marie Menke: Writing - review & editing, Methodology. Erica E. Marsh: Writing - review & editing, Supervision, Methodology, Conceptualization.

Declaration of Competing Interest

EM is a consultant for Myovant Sciences and Pfizer and receives grant funding from Allergan. The remaining authors report no conflicts of interest.

Acknowledgments

None.

References

1. Navot D, Bergh PA, Laufer N. Ovarian hyperstimulation syndrome in novel reproduc- tive technologies: prevention and treatment. Fertil Steril. 1992;58(2):249-61. https://doi.org/10.1016/s0015-0282(16)55188-7.
2. Golan A, Ron-el R, Herman A, Soffer Y, Weinraub Z, Caspi E. Ovarian hyperstimula- tion syndrome: an update review. Obstet Gynecol Surv. 1989;44(6):430-40. https://doi.org/10.1097/00006254-198906000-00004.
3. Practice Committee of the American Society for reproductive medicine. Electronic address Aao, practice Committee of the American Society for reproductive M. pre- vention and treatment of moderate and severe ovarian hyperstimulation syndrome: a guideline. Fertil Steril. 2016;106(7):1634-47. https://doi.org/10.1016/j.fertnstert. 2016.08.048.
4. Navot D, Bergh PA, Laufer N. Reprint of: ovarian hyperstimulation syndrome in novel reproductive technologies: prevention and treatment. Fertil Steril. 2019;112(4 Suppl 1):e209-21. https://doi.org/10.1016/j.fertnstert.2019.08.094.
5. Shmorgun D, Claman P. Joint Sogc-Cfas clinical practice guidelines C. The diagnosis and management of ovarian hyperstimulation syndrome. J Obstet Gynaecol Can. 2011;33(11):1156-62. https://doi.org/10.1016/S1701-2163(16)35085-X.
6. Mathur RS, Akande AV, Keay SD, Hunt LP, Jenkins JM. Distinction between early and late ovarian hyperstimulation syndrome. Fertil Steril. 2000;73(5):901-7. https://doi. org/10.1016/s0015-0282(00)00492-1.
7. Fatemi HM, Popovic-Todorovic B, Humaidan P, Kol S, Banker M, Devroey P, et al. Se- vere ovarian hyperstimulation syndrome after gonadotropin-releasing hormone (GnRH) agonist trigger and “freeze-all” approach in GnRH antagonist protocol. Fertil Steril. 2014;101(4):1008-11. https://doi.org/10.1016/j.fertnstert.2014.01.019.
8. Ling LP, Phoon JW, Lau MS, Chan JK, Viardot-Foucault V, Tan TY, et al. GnRH agonist trigger and ovarian hyperstimulation syndrome: relook at ‘freeze-all strategy’. Reprod Biomed Online. 2014;29(3):392-4. https://doi.org/10.1016/j.rbmo.2014.05. 012.
9. Santos-Ribeiro S, Polyzos NP, Stouffs K, De Vos M, Seneca S, Tournaye H, et al. Ovar- ian hyperstimulation syndrome after gonadotropin-releasing hormone agonist trig- gering and “freeze-all”: in-depth analysis of genetic predisposition. J Assist Reprod Genet. 2015;32(7):1063-8. https://doi.org/10.1007/s10815-015-0498-y.
10. Agency for Healthcare Research and Quality. Overview of the Nationwide Emer- gency Department Sample (NEDS). https://www.hcup-us.ahrq.gov/nedsoverview. jsp; 2022. [accessed March 3, 2022].
11. CDC. National assisted reproductive technology surveillance system annual report. https://www.cdc.gov/art/nass/index.html; 2022. [2006-2016].
12. Statistics USBoL. Consumer price index for all urban consumers. https://www.bls. gov/cpi/. [accessed December 1 2020].
13. Rotshenker-Olshinka K, Badeghiesh A, Volodarsky-Perel A, Steiner N, Suarthana E, Dahan MH. Trends in ovarian hyperstimulation syndrome hospitalization rates in the USA: an ongoing concern. Reprod Biomed Online. 2020;41(3):357-60. https:// doi.org/10.1016/j.rbmo.2020.06.004.
14. Neulen J, Yan Z, Raczek S, Weindel K, Keck C, Weich HA, et al. Human chorionic gonadotropin-dependent expression of vascular endothelial growth factor/vascular permeability factor in human granulosa cells: importance in ovarian hyperstimula- tion syndrome. J Clin Endocrinol Metab. 1995;80(6):1967-71. https://doi.org/10. 1210/jcem.80.6.7775647.
15. Johnson MD, Williams SL, Seager CK, Liu JH, Barker NM, Hurd WW. Relationship be- tween human chorionic gonadotropin serum levels and the risk of ovarian hyper- stimulation syndrome. Gynecol Endocrinol. 2014;30(4):294-7. https://doi.org/10. 3109/09513590.2013.875998.
16. Gebril A, Hamoda H, Mathur R. Outpatient management of severe ovarian hyper- stimulation syndrome: a systematic review and a review of existing guidelines. Hum Fertil (Camb). 2018;21(2):98-105. https://doi.org/10.1080/14647273.2017. 1331048.
17. Shrivastav P, Nadkarni P, Craft I. Day care management of severe ovarian hyperstim- ulation syndrome avoids hospitalization and morbidity. Hum Reprod. 1994;9(5): 812-4. https://doi.org/10.1093/oxfordjournals.humrep.a138601.
18. Smith LP, Hacker MR, Alper MM. Patients with severe ovarian hyperstimulation syn- drome can be managed safely with aggressive outpatient transvaginal paracentesis. Fertil Steril. 2009;92(6):1953-9. https://doi.org/10.1016/j.fertnstert.2008.09.011.
19. Lainas GT, Kolibianakis EM, Sfontouris IA, Zorzovilis IZ, Petsas GK, Tarlatzi TB, et al. Outpatient management of severe early OHSS by administration of GnRH antagonist in the luteal phase: an observational cohort study. Reprod Biol Endocrinol. 2012;10:

69. https://doi.org/10.1186/1477-7827-10-69.

1. Lainas TG, Sfontouris IA, Zorzovilis IZ, Petsas GK, Lainas GT, Kolibianakis EM. Man- agement of severe early ovarian hyperstimulation syndrome by re-initiation of GnRH antagonist. Reprod Biomed Online. 2007;15(4):408-12. https://doi.org/10. 1016/s1472-6483(10)60366-5.
2. Rova K, Passmark H, Lindqvist PG. Venous thromboembolism in relation to in vitro fertilization: an approach to determining the incidence and increase in risk in suc- cessful cycles. Fertil Steril. 2012;97(1):95-100. https://doi.org/10.1016/j.fertnstert. 2011.10.038.
3. Selter J, Wen T, Palmerola KL, Friedman AM, Williams Z, Forman EJ. Life-threatening complications among women with severe ovarian hyperstimulation syndrome. Am J Obstet Gynecol. 2019;220(6):e1-11. https://doi.org/10.1016/j.ajog.2019.02.009. 575.
4. Galic I, Negris O, Warren C, Brown D, Bozen A, Jain T. Disparities in access to fertility care: who’s in and who’s out. F&S Rep. 2021;2(1):109-17. https://doi.org/10.1016/j. xfre.2020.11.001.
5. Jain T, Hornstein MD. Disparities in access to infertility services in a state with man- dated insurance coverage. Fertil Steril. 2005;84(1):221-3. https://doi.org/10.1016/j. fertnstert.2005.01.118.
6. Kelley AS, Qin Y, Marsh EE, Dupree JM. Disparities in accessing infertility care in the United States: results from the National Health and nutrition examination survey, 2013-16. Fertil Steril. 2019;112(3):562-8. https://doi.org/10.1016/j.fertnstert.2019.

04.044.

1. Disparities in access to effective treatment for infertility in the United States: an ethics committee opinion. Fertil Steril. 2021;116(1):54-63. https://doi.org/10. 1016/j.fertnstert.2021.02.019.