key: cord-0835386-l9wtz73z
authors: Domar, Alice D.; Shah, Jaimin S.; Gompers, Annika; Meyers, Alison J.; Khodakhah, Darya R.; Hacker, Michele R.; Penzias, Alan S.; Sakkas, Denny; Toth, Thomas L.; Vaughan, Denis A.
title: The Psychological Impact of the COVID-19 Pandemic on Women Pregnant Following Infertility Treatment: A Longitudinal Study
date: 2022-01-25
journal: F S Rep
DOI: 10.1016/j.xfre.2022.01.004
sha: ee64ebfcb68f1349c4f4057db48a628a09e757e0
doc_id: 835386
cord_uid: l9wtz73z

Objective To compare the impact of the COVID-19 pandemic on the psychological health of infertility patients who have become pregnant to women who have not. Design Prospective cohort study from April to June 2020. Participants completed three questionnaires over this period. Setting A single large, university-affiliated infertility practice. Patient(s) 443 pregnant women and 1476 women still experiencing infertility who completed all three questionnaires. Intervention(s) None. Main Outcome Measure(s) Patient-reported primary stressor over three months of the first major COVID-19 surge. Further data on self-reported sadness, anxiety, loneliness and the use of personal use of coping strategies. Results Pregnant participants were significantly less likely to report taking an antidepressant (p<0.01) or anxiolytic medication (p<0.001), to have a prior diagnosis of depression (p<0.01), were more likely to cite COVID-19 as a top stressor (p<0.001) and overall were less likely to practice stress-relieving activities during the first surge. Conclusion Women pregnant following infertility treatment cited the pandemic as their top stressor and were more distressed about the pandemic than their non-pregnant counterparts but were less likely to be engaging in stress-relieving activities. Given the ongoing impact of the pandemic, infertility patients pregnant after treatment should be counseled and encouraged to practice specific stress-reduction strategies.

The inability to achieve and sustain a clinical pregnancy is concomitant with substantial psychological distress and mental health challenges in both female and male patients. Infertilityrelated distress can be attributed to a wide range of factors including the diagnosis itself, familial and societal pressures, physical burdens of treatment interventions, financial strains due to the cost of fertility treatment, and the uncertainty of treatment outcomes (1-4). Individuals and couples experiencing infertility report relationship strain, heightened levels of anxiety and depression, and decreased self-esteem (5-7). In addition, 13% report taking antidepressant medication (8) and unsuccessful ART is associated with negative impacts on mental health and self-esteem (9) .

Infertility patients frequently characterize infertility as their most stressful life experience, with psychological distress being one of the primary reasons they discontinue treatment (10) (11) (12) . In an evaluation of the psychological wellbeing of women with infertility, chronic pain, heart disease, cancer, hypertension, or human immunodeficiency virus (HIV), the researchers found that the overall scores of women with infertility were comparable to patients with cancer, cardiac rehabilitation, and hypertension (13) . Additionally, the anxiety and depression scores of women with infertility were comparable to all other groups excluding the chronic pain patients (13) . The results of this study emphasize that infertility is equally as distressing as other serious medical conditions, including cancer.

In response to the global COVID-19 pandemic declared on March 11 th , 2020 by the World Health Organization (WHO), professional organizations governing reproductive medicine in the United States (American Society for Reproductive Medicine, ASRM) and Europe (European Society of Human Reproduction and Embryology, ESHRE) advocated for halting infertility treatments so that resources may be directed to patients with coronavirus (14, 15) . Our center terminated treatment for nearly nine weeks during the peak of the pandemic in New England from April 9 to June 15, 2020. Previously, our group indicated that infertility remained the most frequently reported top stressor among over 2,200 patients, even amid a devastating global pandemic (16) .

The previous longitudinal study (16) was extended and identified how the top stressors of the respondents changed over the first several months of the pandemic (17) . By analyzing the responses from three distributed questionnaires, we found that COVID-19 was the number one J o u r n a l P r e -p r o o f stressor at the initial peak of the pandemic, but was replaced by infertility just three weeks later.

Furthermore, 29% of respondents thought that infertility treatments should be offered early in the pandemic, however, this sentiment drastically changed by June 2020 with 77% of individuals reporting that treatments should be provided. This longitudinal study demonstrates that despite the immense and ubiquitous impact of COVID-19, women with infertility still ranked infertility as their greatest stressor, underscoring the significant psychological impact infertility has on our patient population and the need for the provision of mental health resources.

When each of the questionnaires were distributed, there was minimal data on the effects of COVID-19 on fetal and perinatal outcomes with no proven cases of vertical transmission from the mother to the fetus (18, 19) . Nevertheless, pregnancy is a high-risk state due to affiliated physiological and immunological changes. Recent infectious illnesses, including the Zika virus and the 2009 H1N1 influenza virus pandemic, revealed the susceptibility pregnancy presents and potentially devastating impacts that viral diseases can have on pregnancy outcomes (20) (21) (22) . As our previous study was being conducted, multiple case series of COVID-19 in pregnancy were published (23, 24) . Still, little was known about the effects of COVID-19 on pregnancy outcomes, creating uncertainty and fear for this patient population although at the time, there was no data on the psychological impact of the pandemic on pregnant women.

There are new studies being published on the mental health of pregnant women during the pandemic, however, women who become pregnant following infertility treatments during COVID-19 is an understudied population. Our first analysis assessing reported stressors during the COVID-19 pandemic focused on infertility patients who did not achieve pregnancy following treatments. The objective of this follow-up study is to assess reported stressors for women who became pregnant during the pandemic following infertility treatments. Specifically, we wanted to identify differences in reported stressors between infertile non-pregnant women and pregnant patients. We hypothesized that pregnant women would be more concerned about the potential adverse impact of COVID-19 on pregnancy outcomes, and that they would be more likely to practice stress-reducing in an attempt to decrease their anxiety levels compared to non-pregnant infertility patients.

J o u r n a l P r e -p r o o f

In the previous study (16) , a 45-item questionnaire with questions on demographics and mental health history was developed, including history of anxiety and depression, and use of anxiolytic or antidepressant medications. Respondents' anxiety and sadness levels at the time of the questionnaire were assessed using a 7-point Likert scale (where 1 was not at all sad/anxious and 7 was extremely sad/anxious). Additionally, participants were asked to list their current top three stressors from a provided list. Further, participants were asked to note whether they believed that infertility treatment should be offered during the pandemic, and whether their work hours or compensation had been reduced because of the pandemic. The first questionnaire was disseminated to eligible patients from April 9 to 16, 2020.

Subsequently, we modified the questionnaire and distributed the second and third iterations from April 30 to May 7, 2020 and June 11 to 17, 2020, respectively (17). Questionnaires 2 and 3 included 19 and 29 items, respectively, with similar questions to the initial questionnaire; demographic questions were not asked again but the second and third questionnaires included additional questions regarding coping strategies employed by patients to relieve stress. A 7-point Likert scale was also added to questionnaire 3 to evaluate respondents' loneliness (1 being not at all lonely, to 7 being extremely lonely; see supplemental data).

The surveys used in this study were disseminated using REDCap™ (a secure HIPAA compliant data storage platform) to female patients who had been seen for a consultation at a single, large, university-affiliated infertility practice in New England, U.S. from January 1, 2019, to April 1 2020 (25) . Women who completed the first questionnaire were sent two further questionnaires. This included both non-pregnant and pregnant participants. We were able to link questionnaires from the same respondent; however, responses remained anonymous.

After the first questionnaires were distributed, all non-responders were emailed an invitation to complete the questionnaire and enter into a raffle for a $50 gift card. This incentive was implemented again during the third time point to encourage patients to fully complete all three questionnaires. There were three raffle winners at each of the two time points.

In the previous studies, participants who had become pregnant or were otherwise no longer pursing infertility treatment during the distribution of the survey were excluded from the study's final analysis (16, 17) . For this follow-up study, data from pregnant respondents were analyzed and compared to non-pregnant participants still pursuing infertility treatments. Descriptive statistics are reported as mean (standard deviation) or frequency (percent). To compare pregnant and non-pregnant respondents, we used Chi-square or Fisher's exact test for categorical variables and a two-sample t-test for continuous variables. P < 0.05 was considered statistically significant.

This protocol was determined to be exempt from review (IRB protocol number: 2020P000322) by the Institutional Review Board of the Beth Israel Deaconess Medical Center.

The first survey in April 2020 was sent to 10,481 infertility patients at our institution. The response rate on the first survey was 34%, with 3,604 patients fully completing the survey. The second survey was sent in May 2020 to 3,617 patients (including patients who conceived between survey 1 and 2), with a completion rate of 73% (2,644 total respondents). The third survey was sent in June 2020 to the same 3,617 patients (although two patients were removed upon request; resulting in 3,615 recipients, including patients who conceived between surveys 2 and 3) with a completion rate of 54% (1,943 patients). Patients who completed all three surveys were included in this analysis, resulting in a study sample of 1,919 respondents.

Thirty-one percent of pregnant infertility participants and 34% of non-pregnant infertility patients reported a prior diagnosis of anxiety, although this difference was not significant (p=0.18). However, there was a significant difference between the number of participants who reported currently taking anxiolytics, with about 5% of pregnant participants versus 12% of nonpregnant participants (p<0.001) ( Table 2) . Twenty-two percent of pregnant patients and 28% of non-pregnant patients reported a prior diagnosis of depression (p=0.01). There was also a significant difference between the percent of patients who reported current use of antidepressant J o u r n a l P r e -p r o o f medication; 8% of pregnant respondents compared to 12% for non-pregnant respondents (p=0.01).

In survey 1, pregnant infertility patients reported significantly less sadness (p<0.001) than non-pregnant infertility patients, with mean sadness scores of 2.6 (±1.5) versus 3.0 (±1.7) ( Table   2 ). There was no significant difference between the mean anxiety levels of pregnant infertility patients (4.0 ±1.5) and their non-pregnant counterparts (3.8 ±1.5) (p=0.12). On survey 2, the sadness levels of pregnant patients and non-pregnant patients remained constant and significantly different (p<0.001) at 2.6 (±1.5) and 3.0 (±1.6), respectively (Table 3) There was no significant difference in patient-reported loneliness between pregnant and non-pregnant respondents at the time of questionnaire three (p=0.48), with both groups reporting a mean loneliness score of 2.4 (±1.6) ( Table 4 ). Furthermore, on survey three, about 40% of pregnant patients and 44% of non-pregnant patients reported their sleep quality changed since the start of the pandemic (p=0.09), with 90% of pregnant patients versus 86.8% of non-pregnant patients reporting that change was for the worse (p=0.66). Finally, for surveys 2 and 3, there were consistent and significant differences between the two groups on the majority of stressreducing activities, with the pregnant patients employing fewer at both time points (Table 3 and   4 ).

The top three stressors for the two groups on survey 1 are listed in Table 2 . These stressors stayed largely consistent for pregnant women in survey 2, in which pregnant patients' top stressors were COVID-19 (40%), their job (15%), and their health (14%) ( Table 3 ).

However, the top stressors of non-pregnant patients changed on survey 2 to be infertility (29%), then COVID-19 (25%), and finally their job (20%) ( Table 3) . On the third survey, pregnant patients reported their top stressors to be their job (23%), COVID-19 (20%), and their health (16%), whereas non-pregnant patients still reported infertility (35%) to be their top stressor, followed by their job (23%), and lastly their family (12%) ( Table 4 ).

Finally, survey 3 asked participants how concerned they were or would be about being pregnant during the COVID-19 pandemic. Results revealed that pregnant patients were overall more concerned about becoming infected with COVID-19 while pregnant than non-pregnant patients, as well as being more concerned about a COVID-19 infection causing a poor pregnancy outcome than non-pregnant patients (p<0.001) ( Table 4 ).

The data presented in this paper brings to light the psychological impact the COVID-19 pandemic has on pregnant infertility patients relative to their non-pregnant infertile counterparts.

Infertility remained a top stressor for non-pregnant patients despite the hardships of the pandemic while COVID-19 was ranked as the top stressor by pregnant patients. This is not surprising as other research has documented the extreme adverse impact the pandemic has had on pregnant women, leading to huge increases globally in depressive symptoms (26) . Women who were pregnant during the COVID-19 pandemic reported being significantly more depressed and anxious than women pregnant prior to the pandemic (27) . In another study of 100 pregnant women assessed during the first surge in 2020, the majority reported that the pandemic had a severe impact on their psychological health and half were highly anxious about the risk of vertical transmission of disease; these symptoms were the highest in women during their first trimester (28) . However, given the severe impact that the pandemic has had on infertility patients, especially those whose cycles were cancelled or postponed in the spring of 2020, it is somewhat surprising that they didn't rank the pandemic higher (29) . (30) . An international review reported that the pooled global rates of depression, anxiety, and overall stress increased significantly as compared to global rates before the pandemic (31).

The COVID-19 pandemic was extremely distressing because of its impact on almost all aspects of one's life; isolation required for disease containment, constant media reports of bad news, economic shutdowns and unemployment, as well as fear of contamination, all caused extreme emotional, social, economic, and mental strain (32) . Several risk factors emerged that were found to increase the likelihood and severity of negative mental health impacts due to COVID-19 including age (≤ 40 years), sex (female), socioeconomic status (lower status being most vulnerable), and medical condition (having a mental, physical or chronic illness) (19, (33) (34) (35) . It is important to recognize that the female infertility cohort is thus considered high risk by being female, mostly ≤ 40 years old, and having a chronic disease (34, 35) .

Infertility is a stressful and sometimes traumatic condition that causes social, emotional and economic strain (36) . In fact, female infertility patients have depression levels comparable to cancer patients (37) . Thus, infertility patients had levels of anxiety and depression higher than the general public before the onset of the COVID-19 pandemic (16) . Of the cohort of pregnant infertility patients in this study, 31% reported a prior diagnosis of anxiety and 22% of patients Recent research has documented the emotional vulnerability of pregnant women during this pandemic. In a study of 63 pregnant women who were assessed both prior to and during the pandemic, anxiety and depression scores rose significantly (41) . The authors recommended that healthcare teams need to develop strategies to prevent "mental trauma" to lessen the risk of adverse birth outcomes. In another study on 283 pregnant women during the first surge of the pandemic, pregnancy complications, which are common in post-ART pregnancies, were significantly associated with anxiety, and the presence of COVID-19 symptoms were predictive of PTSD symptoms (42) . High risk pregnancy patients are especially vulnerable; in a study of 446 pregnant women, those identified as being high risk were significantly more anxious, leading the authors to recommend routine psychological screening and increased emotional support (43) . Lastly, the pandemic has led to increased anxiety amongst pregnant patients with regards to hospital presentation and admission, with fears of access to care and further risks of viral transmission (44) Although both pregnant and non-pregnant patients continued to practice stress-reducing activities or developed new ones to help cope during the pandemic, pregnant patients used significantly fewer during both of the surveyed time points. This needs to be addressed as many of the suggested activities are well known to decrease anxiety and depression. Given the most recent research on the 22-fold increased risk of death and 2.2 increased risk of perinatal mortality in pregnant women who contract COVID-19 (45) , it is obvious why all of our patients should be encouraged to address their distress in as many ways as they are able. Since infertility patients are at increased risk for pregnancy complications, which in turn increases their risk for negative psychological symptoms including PTSD, this represents even more urgency to the need to increase the support offered.

One main strength of this study is the large sample size of pregnant infertility patients and the inclusion of a "control" sample of non-pregnant infertility patients with similar characteristics. Furthermore, this study investigated the novel subject of the psychological responses of patients pregnant after infertility versus non-pregnant infertility patients during the first surge of the COVID-19 pandemic. The longitudinal nature of the study of surveying patients at three time points also allows for a perspective on how the psychological state of the cohort changed relative to the surge of the pandemic in New England.

A limitation of this study, however, is the lack of generalizability of the sample. The sample was homogenous in characteristics like socioeconomic status, race, and education level, and was only distributed to patients in one infertility practice in one geographic region.

Despite the COVID-19 pandemic, infertility remains a top stressor for non-pregnant infertility patients. This may be related to the distress caused when all infertility treatments were stopped due to pandemic guidelines from the ASRM and ESHRE (14, 15, 37) . On the other hand, patients pregnant after infertility reported COVID-19 as their top stressor, perhaps relating to the stress involved in achieving that pregnancy and then unknown safety of pregnancy outcomes during COVID-19 (37) . Despite the heightened anxiety expressed by pregnant patients during the first surge, they did not employ nearly as many stress-reducing activities as the infertility cohort, any of which could have theoretically have led to lower distress levels. Due to the innate stress of conceiving and sustaining a pregnancy as an infertility patient, it is important that support systems focused on reducing stress be implemented for current and coming global challenges. Patients who conceive following infertility treatment should be provided with multiple sources of written and online resources designed to support them in reducing their level of distress, and encouraged by staff to practice and incorporate these coping skills on a day-today basis; especially in light of the alarming spread of the COVID-19 variants, and the resultant anxiety-inducing media reports. This is especially crucial for the time period after the patient is discharged from the REI clinic after a scan confirming a normal intrauterine pregnancy, before J o u r n a l P r e -p r o o f they are able to be seen and connect with an obstetrician or midwife, a time period of up to five weeks.

This work was conducted with support from Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR001102) and financial contributions from Harvard University and its affiliated academic health care centers.

The funding sources had no involvement in the study design, collection, analysis or interpretation of data, the writing of the report or the decision to submit the article for publication. 

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