Sage Journals: Discover world-class research

Abstract

Background:

Previous research has focused on the immediate psychological experiences of women and couples with infertility, yet little is known about the associations of infertility with anxiety and depressive symptoms years later during midlife, when anxiety and depressive symptoms are common.

Materials and Methods:

Women enrolled in the Project Viva cohort 1999–2002 during early pregnancy completed the Patient Health Questionnaire (PHQ-9) and Generalized Anxiety Disorder (GAD-7) “Midlife Visit” questionnaire during 2017–2021, each of which we categorized into symptom scores of 0, 1–3, and ≥4. We performed adjusted multinomial logistic regression models to examine associations of lifetime history of infertility with anxiety and depressive symptoms among a parous sample in midlife.

Results:

Among the 746 participants who completed midlife PHQ-9 or GAD-7, 259 (35%) ever experienced infertility and mean (standard deviation) age at midlife visit was 50.9 ± 5.1. There was a slightly higher frequency of scores in the highest categories for both PHQ-9 (28% vs. 21%) and GAD-7 (21% vs. 20%) among those who had ever experienced infertility compared to those without a history of infertility. In a model adjusting for age at enrollment and race and ethnicity, a history of infertility was associated with a higher relative risk ratio (RRR) of a PHQ-9 score ≥4, versus the reference group of score 0 (RRR = 1.58, 95% confidence interval [CI] = 1.03, 2.43). A lifetime history of infertility was not associated with anxiety in midlife across models (e.g., when adjusted for age at enrollment and race and ethnicity, GAD-7 score ≥4 vs. score 0: RRR = 1.19, 95% CI = 0.78, 1.82).

Conclusions:

Our findings suggest that based on the PHQ-9 categories defined according to the distribution of scores among our sample that the experience of infertility may be associated with greater depressive symptoms in midlife.

Introduction

The experience of infertility, defined as the inability to achieve a pregnancy after 12 months of regular unprotected sexual intercourse, can be psychologically stressful. Reactions to infertility include shock, sadness, depression, anger and frustration, loss of self-esteem and self-confidence, and a general loss of sense of control.^1,2 A recent report from the World Health Organization estimates that 18% of the adult population worldwide—an overwhelming one in six people globally—is affected by infertility at some point in their lifetime.³ Women with infertility have higher depression prevalence compared with other women of reproductive age, with rates ranging from 20% to 40%.⁴ Existing research has focused on the immediate psychological experiences of women and couples with infertility, yet little is known about the effects of infertility on long-term mental health outcomes. This study addresses the limitations of prior studies by using a prospective longitudinal cohort that has followed women across the reproductive years into midlife.

Symptoms of depression and anxiety are common during midlife,^2,4 likely related to the observation that women are most vulnerable to developing mental health disorders during reproductive life stages of high hormonal fluctuation, such as perimenopause. Perimenopause is described as the time around a woman’s final menstrual period, which begins with the onset of irregular periods and ends after one full year of amenorrhea.^5,6 The effect of the hormonal fluctuations during this time period (increased follicle-stimulating hormone and luteinizing hormone with highly variable estradiol and progesterone levels) is associated with an increased prevalence of anxiety and depressive symptoms.⁷ Additionally, negative life events, when combined with estradiol variability, have been shown to predict depressive symptoms during perimenopause.^7–11 As infertility is a negative life event, women with a history of infertility may be at greater risk of experiencing depressive and anxiety symptoms during the menopausal transition.^10–12

There is not extensive literature on the association of infertility with mental health symptoms in midlife. In prior work in the Project Viva cohort, we explored an association of history of infertility with menopausal symptoms.¹³ We found that women with a history of infertility were more likely to experience greater total menopausal symptoms in midlife, primarily attributable to more sleep problems and depressive mood during midlife.¹³ In that analysis, symptoms of depression were measured using one question on the Menopause Rating Scale. In this scale, participants were asked to report the presence and severity of 11 menopausal symptoms over the past year, including depressive mood (feeling down, sad, on the verge of tears, lack of drive, mood swings).¹³ That study prompted our investigation of the question whether women with a history of infertility have more depressive and anxiety symptoms in midlife using the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) instruments.

The aim of this study was to examine symptoms of depression and anxiety among women in midlife who had ever experienced infertility at some point in their lifetime compared to women without a history of infertility. We hypothesized that women with a history of infertility would report more severe symptoms of depression and anxiety at midlife.

Materials and Methods

Project Viva is a longitudinal prospective observational cohort of 2100 women who delivered singleton infants between 1999 and 2002. Women were recruited during their first trimester of pregnancy from eight obstetric offices of Atrius Harvard Vanguard Medical Associates. Exclusion criteria during enrollment included multiple gestation, inability to answer questions in English, gestational age of ≥22 weeks at the initial prenatal care appointment, or plans to move away from the area before delivery. Additional details on recruitment and eligibility have been described elsewhere.¹⁴ The research team conducted follow-up in-person research visits throughout the woman’s pregnancy and postpartum course, as well as when her offspring was in early childhood, mid-childhood, early teen, and mid-teen. The midlife visit, which was conducted at the same time as the mid-teen visit with offspring, occurred between 2017 and 2021. For this analysis, we included 746 women who completed the midlife visit and completed all questions of either the PHQ-9¹⁵ to assess depressive symptoms (N = 711) or the GAD-7 Questionnaire¹⁶ (N = 720) to assess anxiety symptoms (Supplementary Figure S1). All participants provided written informed consent at enrollment and at each follow-up visit. The study was approved by the institutional review board at Harvard Pilgrim Health Care.

Exposure: Lifetime history infertility

At enrollment, participants were asked if they had been trying to get pregnant when they conceived, and if so, to report how many menstrual cycles it took to become pregnant. Similarly, at the midlife visit, participants completed a reproductive history questionnaire in which they recorded the number of cycles it took to conceive each pregnancy that they had ever had in their lifetime, as well as any history of infertility diagnosis or treatment. We defined infertility if at any point in a woman’s lifetime ≥6 cycles were required to achieve pregnancy if ≥35 years of age or ≥12 cycles to achieve pregnancy if ≤35 years of age, reported history of infertility diagnosis or treatment, or claims for infertility treatments/prescriptions abstracted from medical records.¹⁷

Outcomes: Depressive and anxiety symptoms in midlife

Symptoms of depression were measured using the PHQ-9 and symptoms of anxiety were measured using the GAD-7 applied at the midlife visit. The PHQ-9 is a reliable and valid measure of depression severity that scores each of the nine Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria for depression as “0” (not at all), “1” (several days), “2” (more than half of the days) to “3” (nearly every day).¹⁴ PHQ-9 total scores of 5, 10, 15, and 20 represent clinical cutoff points for mild, moderate, moderately severe, and severe depression, respectively. The GAD-7 is a reliable and valid measure of anxiety severity which scores each of the seven DSM criteria for generalized anxiety as “0” (not at all), “1” (several days), “2” (more than half of the days) to “3” (nearly every day).¹⁶ A GAD-7 score of 0–4 indicates “minimal symptoms,” 5–9 indicates mild symptoms, 10–14 points indicates moderate symptoms, and 15–21 points indicates severe symptoms. We classified depression and anxiety scores on the PHQ-9 and the GAD-7 in categories of 0, 1–3, and ≥4 based on the distribution of participant responses. Supplementary Table S1 provides rationale for the way categories were derived, and Supplementary Figure S2 provides a histogram showing the distribution of PHQ-9 scores in our sample. The PHQ-9 scores in our sample, like that of the general population, are right-skewed.¹⁸ Supplementary Table S1 shows that the association gets stronger as it approaches scores of ≥4, providing a signal that an association is not meaningless at this cutoff.

Covariates

We assessed participant demographics from Project Viva questionnaires and interviews. For our analyses, the timepoint for assessment of covariates was at enrollment, although we also reported the re-assessment of those covariates at the midlife visit. Participants reported employment and we dichotomized responses as either employed/student or not employed. Participants reported annual household income and we dichotomized responses as $\leq$ $70,000 per year or greater. Partner status was dichotomized as married or cohabiting or not. Participants reported the highest level of education completed at enrollment and we dichotomized responses as college degree or not. Participants were asked about their cigarette smoking habits before and during pregnancy and we categorized smoking as never, former, and smoked during pregnancy. We calculated body mass index (BMI, kg/m²) during both enrollment and midlife using self-reported weight and height. We classified maternal history of polycystic ovarian syndrome (PCOS) as yes if there was an International Classification of Diseases code from medical record for PCOS around the index pregnancy or through self-report of PCOS diagnosis on the midlife visit questionnaire. Participants self-reported a history of thyroid disease enrollment and self-reported a history of ectopic or tubal pregnancy before index pregnancy on the midlife visit questionnaire. Participants self-reported ever having a history of depression on the midlife questionnaire. Participants were asked about their perceived body weight at age 10, and responses were categorized into underweight, average, and overweight.

Statistical analyses

We calculated means and standard deviations or frequencies and percentages as appropriate to describe the characteristics of the sample. We reported characteristics of the sample overall and separately for women with and without a lifetime history of infertility. We performed unadjusted and adjusted multinomial logistic regression models, adjusting for sociodemographic characteristics, to examine associations of a lifetime history of infertility with categories of depression and anxiety symptoms in midlife (categorized as 0 [reference], 1–3, and ≥4). The first model (Model 1) was adjusted for age at enrollment as a continuous variable, and for race and ethnicity (categorized as Black, White, and all other races and ethnicities). We adjusted for age and race and ethnicity because we considered them to be confounding factors. Increasing age is known to affect both fertility and depression.^9,19,21,22 and research has found discrepancies in the presentation of depression among minorities when compared to Caucasians as well as factors that serve as boundaries for successful treatment.²³ The grouping of “all other races and ethnicities” is not intended to undermine the distinct experiences of these individuals, and was done for sample size purposes only. The variable “all other races and ethnicities” is comprised of participants who identify as Asian, Hispanic, more than one race, and other. We consider race a social construct that reflects neither biological nor cultural differences between groups.^22–24 Model 2, our fully adjusted model, included additional confounders such as BMI at enrollment, and demographic characteristics measured at enrollment (partner status, household income, and employment status). In the fully adjusted model, we included only those covariates that were of a priori interest. Model 3 was adjusted for age, race and ethnicity, and perceived body weight at age 10, because perceived body weight is a factor that could potentially mediate the relationship of the outcomes. Model 4 was adjusted for age, race and ethnicity, and BMI in midlife because these are factors that may be potentially related to our outcomes of depression and anxiety and represent a possible mediator of the relationship. To reduce bias due to missing values for covariates, we performed multiple imputations by chained equation for all 2100 women of Project Viva and limited our analyses to participants with nonmissing exposure and outcome data. We imputed 50 values for each missing observation and combined multivariable modeling estimates using MI ESTIMATE in Stata 17. We included all exposures, outcomes, and covariates in our multiple imputation model, as well as additional variables to help predict missing values. All analyses were conducted using Stata 17.²⁵

In sensitivity analyses for depressive symptoms. First, we repeated our analyses using the clinical cutoffs of 0–4 (none/minimal), 5–9 (mild), ≥10 (moderate) on the PHQ-9, as well as the PHQ-9 values continuously. Because only 38 participants in our total sample had PHQ-9 scores ≥10 (moderate), we collapsed the top 3 categories of 10–14 (moderate), 15–19 (moderately severe), and >20 (severe), to create ≥10 as our top category. The distribution of these cutoffs and absolute risks are presented in Table 1. We also repeated our analyses excluding women with a history of self-reported depression. History of depression was self-reported, and we did not explore the use of medications, if any, were used in the treatment of depression.

Table 1.

Characteristics of the Study Participants According to Lifetime History of Infertility

	Overall sample		Ever infertility in lifetime		Never infertility
	N	%	N	%	N	%
	n = 746		n = 259		n = 487
Demographics
Age at enrollment	32.5 ± 5.0		34.4 ± 4.6		31.5 ± 5.0
Age during midlife visit, years	50.9 ± 5.1		52.7 ± 4.7		49.9 ± 5.0
Race and ethnicity
Black	105	14.1	21	8.1	84	17.3
White	512	68.8	194	74.9	318	65.6
All other races and ethnicities	127	17.1	44	17.0	83	17.1
Partner status during enrollment
Married or cohabiting	691	93.0	249	96.1	442	91.3
Not married or cohabiting	52	7.0	10	3.9	42	8.7
Education at enrollment
College degree	558	75.0	212	81.9	346	71.3
No college degree	186	25.0	47	18.2	139	28.7
Household income during enrollment
per year	442	64.8	170	71.1	272	61.4
≤$70,000 per year	240	35.2	69	28.9	171	38.6
Employment during enrollment
Employed or student	613	89.2	219	89.8	394	88.9
Not employed	74	10.8	25	10.3	49	11.1
Physical characteristics
BMI, kg/m² during enrollment
<25 kg/m²	473	63.5	157	60.6	316	65.0
25–<30 kg/m²	172	23.1	63	24.3	109	22.4
≥30 kg/m²	100	13.4	39	15.1	61	12.6
BMI, kg/m² during midlife visit
<25 kg/m²	248	38.3	79	35.4	169	39.9
25–<30 kg/m²	189	29.2	64	28.7	125	29.5
≥30 kg/m²	210	32.5	80	35.9	130	30.7
Perceived body weight at age 10
Underweight	115	16.6	40	16.5	75	16.7
Average	502	72.4	175	72.0	327	72.7
Overweight	76	11.0	28	11.5	48	10.7
Smoking (during enrollment)
Never	537	72.2	188	72.6	349	72.0
Former	141	19.0	47	18.2	94	19.4
Smoked during pregnancy	66	8.9	24	9.3	42	8.7
Polycystic ovarian syndrome	38	5.1	21	8.1	17	3.5
Thyroid disease	36	4.9	15	5.8	21	4.4
Ectopic pregnancy history	11	1.5	6	2.3	5	1.0
History of depression	74	11.3	35	15.4	39	9.1
Outcomes
PHQ-9
Score 0	242	34.0	80	32.5	162	34.8
Score 1–3	303	42.6	98	39.8	205	44.1
Score ≥4	166	23.4	68	27.6	98	21.1
GAD-7
Score 0	325	45.1	114	46.2	211	44.6
Score 1–3	246	34.2	80	32.4	166	35.1
Score ≥4	149	20.7	53	21.5	96	20.3
PHQ-9 scores by clinical categories
None/Minimal: 0–4	589	82.8	201	81.7	388	83.4
Mild: 5–9	84	11.8	31	12.6	53	11.4
Moderate: 10–14	32	4.5	13	5.3	19	4.1
Moderately severe: 15–19	4	0.6	0	0.0	4	0.9
Severe: $\geq$ 20	2	0.3	1	0.4	1	0.2

Ns for some characteristics do not add up to the column N because of missing values.

BMI, body mass index; GAD-7, Generalized Anxiety Disorder-7; kg/m², kilogram per square meter; PHQ-9, Patient Health Questionnaire-9.

Results

Participants

There were 746 participants eligible for our analysis: 259 (35%) who had experienced infertility at some point in their lifetime and 487 (65%) without a lifetime history of infertility. Characteristics of these two groups of women are summarized in Table 1. Women in the study sample were primarily White (69%) and had a mean (standard deviation) age of 50.9 ± 5.1 years at the midlife visit. At enrollment, most were employed (89%), college educated (75%), reported annual household income >$70,000 (65%), and were married or in a partnership (93%). Women with a lifetime history of infertility were slightly older at the midlife visit than women without a lifetime history of infertility (52.7 ± 4.7 vs. 49.9 ± 5.0) and more likely to have PCOS (8.1% vs. 3.5%). At midlife, there was a slightly higher absolute risk of depressive symptoms (28% vs. 21%) and anxiety (21% vs. 20%) in the highest categories among those who had ever experienced infertility compared to those without a lifetime history of infertility. No other major differences were observed between these two groups of women (Table 1).

Association of lifetime history of infertility with depressive symptoms

In Model 1, which was adjusted for age at enrollment and race and ethnicity, a lifetime history of infertility was associated with a higher relative risk ratio (RRR) of a PHQ-9 score in the top category (score ≥4 vs. score 0: RRR 1.58, 95% confidence interval [CI] 1.03, 2.43) (Table 2). Women with a lifetime history of infertility were 58% more likely than women without a lifetime history of infertility to experience depressive symptoms in midlife. Although a category of ≥4 may not be suggestive of a clinical diagnosis of depression, it does suggest that a lifetime history of infertility is associated with more depressive symptoms. Lifetime history of infertility was not associated with a PHQ-9 score 1–3 versus score 0 in Model 1. The results in Models 2–4 were very similar to those in Model 1 for scores 1–3 and ≥4. However, for the latter, further adjustment for covariates did not improve the precision of the estimates, and the confidence intervals became wider (Table 2). We did not find any associations between lifetime history of infertility and depressive symptoms when we repeated our analyses using the clinical categorical cutoffs for the PHQ-9 (Table 3), when we used the PHQ-9 scores continuously (Table 4), and when we excluded women with a lifetime history of depression (Table 5).

Table 2.

Associations of Lifetime History of Infertility with Depressive and Anxiety Symptoms in Midlife

	PHQ-9 N = 711 RRR (95% CI)			GAD-7 N = 720 RRR (95% CI)
History of infertility in lifetime	Score 0	Score 1–3	Score ≥4	Score 0	Score 1–3	Score ≥4
Model 1	Reference	0.92 (0.63, 1.34)	1.58 (1.03, 2.43)	Reference	0.93 (0.65, 1.34)	1.19 (0.78, 1.82)
Model 2	Reference	0.90 (0.60, 1.35)	1.58 (0.98, 2.56)	Reference	0.96 (0.65, 1.42)	1.18 (0.74, 1.87)
Model 3	Reference	0.93 (0.63, 1.37)	1.55 (0.99, 2.43)	Reference	0.98 (0.67, 1.43)	1.19 (0.77, 1.86)
Model 4	Reference	0.91 (0.62, 1.35)	1.50 (0.95, 2.37)	Reference	0.97 (0.66, 1.42)	1.17 (0.75, 1.83)

Note. Lifetime history of infertility is dichotomized as 0 = no history of infertility within lifetime, 1 = infertility within lifetime.

Model 1: Adjusted for age at enrollment and race and ethnicity.

Model 2: Model 1 + body mass index categories at enrollment, demographic characteristics at enrollment (income, employment, partner) (potential confounders).

Model 3: Model 1 + perceived body weight at age 10 (potential confounder).

Model 4: Model 3 + body mass index categories at midlife (potential mediator).

Bold value represents statistical significance.

CI, confidence intervals; RRR, relative risk ratio.

Table 3.

Associations of Lifetime History of Infertility with Depressive Symptoms Using PHQ-9 Clinical Cutoff Categories

History of infertility in lifetime	Score 0–4 None/Minimal N = 589	Score 5–9 Mild N = 84	Score ≥10 Moderate N = 38
History of infertility in lifetime	RRR (95% CI)	RRR (95% CI)	RRR (95% CI)
Model 1	Reference	1.29 (0.79, 2.13)	1.35 (0.66, 2.76)
Model 2	Reference	1.18 (0.68, 2.05)	1.24 (0.55, 2.82)
Model 3	Reference	1.17 (0.69, 1.70)	1.39 (0.65, 2.96)
Model 4	Reference	1.12 (0.66, 1.91)	1.34 (0.62, 2.90)

Note. Lifetime history of infertility is dichotomized as 0 = No history of infertility within lifetime, 1 = Infertility within lifetime.

Model 1: Adjusted for age at enrollment and race and ethnicity.

Model 2: Model 1 + body mass index categories at enrollment, demographic characteristics at enrollment (income, employment, partner) (potential confounders).

Model 3: Model 1 + perceived body weight at age 10 (potential confounder).

Model 4: Model 3 + body mass index categories at midlife (potential mediator).

AIC, Akaike information criterion.

Table 4.

Associations of Lifetime History of Infertility with Depressive Symptoms Using PHQ-9 Continuous Values in Midlife

History of infertility in lifetime	PHQ-9 N = 711 β (95% CI)
Model 1	0.40 (−0.13, 0.93)
Model 2	0.33 (−0.22, 0.88)
Model 3	0.39 (−0.15, 0.94)
Model 4	0.31 (−0.22, 0.85)

Note. Lifetime history of infertility is dichotomized as 0 = no history of infertility within lifetime, 1 = infertility within lifetime.

Model 1: Adjusted for age at enrollment and race and ethnicity.

Model 2: Model 1 + body mass index categories at enrollment, demographic characteristics at enrollment (income, employment, partner) (potential confounders).

Model 3: Model 1 + perceived body weight at age 10 (potential confounder).

Model 4: Model 3 + body mass index categories at midlife (potential mediator).

Table 5.

Associations of Lifetime History of Infertility with Depressive Symptoms Excluding Women with History of Depression

History of infertility in lifetime	PHQ-9 N = 581 RRR (95% CI)
History of infertility in lifetime	Score 0	Score 1–3	Score ≥4
Model 1	Reference	1.01 (0.66, 1.52)	1.48 (0.89, 2.46)
Model 2	Reference	0.99 (0.64, 1.54)	1.61 (0.93, 2.81)
Model 3	Reference	1.01 (0.66, 1.54)	1.51 (0.90, 2.53)
Model 4	Reference	0.99 (0.65, 1.52)	1.47 (0.87, 2.49)

Note. Lifetime history of infertility is dichotomized as 0 = no history of infertility within lifetime, 1 = infertility within lifetime.

Model 1: Adjusted for age at enrollment and race and ethnicity.

Model 2: Model 1 + body mass index categories at enrollment, demographic characteristics at enrollment (income, employment, partner) (potential confounders).

Model 3: Model 1 + perceived body weight at age 10 (potential confounder).

Model 4: Model 3 + body mass index categories at midlife (potential mediator).

Association of lifetime history of infertility with symptoms of anxiety

In all adjusted models (Models 1–4), a lifetime history of infertility was not associated with symptoms of anxiety in midlife (e.g., Model 1, score ≥4 vs. score 0: RRR = 1.19, 95% CI = 0.78, 1.82) (Table 2).

Discussion

Results from this study highlight that parous women with a lifetime history of infertility may have more depressive symptoms during midlife and the menopausal transition. Clinicians should consider women with a history of infertility within the lifetime at increased risk and consider providing additional support, as depressive symptoms significantly impact quality of life and well-being. Although Models 2–4 contain the null, our results are based on Model 1, as Model 1 is exclusive of the potential confounding and mediating variables identified, specifically those related to BMI and perceived body weight.

Results in the context of what is known

Although there is extensive literature on women’s mental health during periods of high hormonal fluctuation, including infertility, pregnancy, postpartum, and the menopause transition, little exists regarding mental health in midlife among women with experiences of infertility during their lifetime, especially women who were not involuntary childless. Fitz et al. found that a history of infertility is associated with depressive symptoms at midlife, with risk greatest in the premenopausal stage (RRR = 1.25, 95% CI = 1.06, 1.79) among participants in the Study of Women’s Health Across the Nation (SWAN) cohort.¹² Results are similar to our study, which is also a longitudinal study, although the SWAN analysis classified elevated depressive symptoms as a score ≥16 on the Center for Epidemiological Studies-D scale, whereas our study used the PHQ-9 instrument and selected a cutoff based on the distribution of scores in our sample. In contrast, Fitz et al. found that involuntary childlessness is associated with anxiety in postmenopause compared to noninfertile participants as classified by a score ≥5 using the GAD-7, whereas our study did not find an association between infertility and anxiety symptoms in midlife. A potential explanation for this difference is that all of our participants had at least one child and we did not track our participants across the menopausal transition stages.¹⁴ It is important to note that in existing literature depressive symptoms appear to increase during menopause, yet the prevalence of diagnosable depressive disorders may not be higher during this period. Any positive response on the scales may still negatively impact women’s lives despite the fact that it does not meet clinical categorical criteria for depression or anxiety, as in our study.

Limitations and strengths

The findings of our study need to be interpreted within the context of several limitations. The Project Viva cohort, which was drawn from a multispecialty group practice setting within Massachusetts, contains a relatively high proportion of participants who were college graduates, employed, White, and from higher income households. The results may not be generalizable to women of different demographic, geographic, ethnic, or socioeconomic backgrounds. In addition, all participants were parous, so women with the most severe forms of infertility may not have been included. Future studies would benefit from exploring the extent to which the association of infertility with depressive symptoms in midlife is observed in different populations. Infertility is more common as women age; therefore, it is not surprising that those with a history of infertility were older at enrollment and at the midlife visit. Women with infertility may have been more advanced in the menopausal transition and experienced more depressive symptoms that were unrelated to prior experiences of infertility; this may have influenced the PHQ-9 scores. Although we accounted for age in our statistical models, we were unable to account for the stage of the menopausal transition. Because depressive and anxiety symptoms in our study were assessed by self-report rather than a clinical diagnoses, there may be potential bias due to self-report for the outcome variables, although we would not expect it to be differential with respect to infertility history, given that it may have occurred years prior. The PHQ-9 and GAD-7 do not include items that quantify the duration or frequency of depressive and anxiety symptoms or whether the participant is engaged in treatment. The categories for the PHQ-9 and GAD-7 that we derived in our study based on the distribution of participant responses differs from the clinical categorical cutoffs used in practice to help aid in the diagnosis of depression and anxiety. However, they are validated and reliable instruments that are widely used in clinical practice, and depressive symptoms may have a negative impact on women’s lives despite the fact that the PHQ-9 score does not meet the standard criteria for a depression diagnosis. The distribution of our sample’s PHQ-9 responses is more similar to that of the general population¹⁸, and we did find a strength in the association as scores approached 4. Therefore, clinicians should not rely solely on the clinical categorical cutoffs for such screens, as the complexity of the menopausal transition can overlap with depressive symptoms.²⁶

Strengths of this study were the use of data obtained from a relatively large sample of women (N = 746), and the longitudinal cohort design. In contrast to many studies focusing on women solely during either the time of infertility or the time of menopause, our study captures women who experienced infertility during their reproductive years and are now in midlife. The findings provide new knowledge about the mental health outcomes during midlife in a group of women who had experienced infertility in their lifetime. Strengths also include the adjustment for potential demographic and early life hardship confounders and mediators, the use of validated instruments (PHQ-9 and GAD-7), the ascertainment of infertility exposure from medical records as well as self-report, and the use of multiple imputation, which limits the bias due to missing covariate data.

Conclusion

Our findings present a call for additional research between a lifetime history of ever experiencing infertility and depressive symptoms at midlife. Our findings suggest that based on the PHQ-9 categories defined according to the distribution of scores among our sample that the experience of infertility may be associated with greater depressive symptoms in midlife, and there is a need for more work in this area. Further studies are needed to examine the causal mechanisms for such an association if it exists as it has important implications for health care providers caring for women with this history as they approach the menopausal transition. Enhanced support from health care providers at midlife may be helpful to women at increased risk of depressive symptoms due to their history of infertility.

Footnotes

Acknowledgment

The authors thank the participants and staff of Project Viva. The abstract was previously published with the “Associations of Infertility with Symptoms of Anxiety and Depression During Midlife in Project Viva” on pages E82–E83 in Nursing Research 2024 Volume 73 Issue 3. URL: DOI: 10.1097/NNR.0000000000000726.

Authors’ Contributions

The author’s responsibilities were as follows: M.P.C.: Conceptualization, formal analysis, methodology, visualization, and writing—original draft and review and editing. D.C.S.C.: Software, validation, and writing—review and editing. A.W.B.: Supervision, writing—review & editing. S.R.S.: Data curation, formal analysis, project administration, validation, software, and writing—review and editing. V.F.: Writing—review & editing. J.S.: Writing—review and editing. J.E.C.: Conceptualization, formal analysis, funding acquisition, methodology, supervision, visualization, and writing—review and editing. E.O.: Conceptualization, funding acquisition, methodology, project administration, supervision, and writing—review and editing.

Data Sharing Statement

The datasets used and/or analyzed in this study are available from the corresponding author upon reasonable request.

Author Disclosure Statement

The authors report no conflicts of interest.

Funding Information

Project Viva is supported by grants from the US National Institutes of Health (R01 HD034568, R24ES030894, R01HD096032, UH3OD023286, and U54AG062322-01 funded by The National Institute on Aging (NIA) and the Office of Research on Women’s Health (ORWH). M.P.C. was also supported by a diversity supplement grant (R01HD096032-04S1). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Supplementary Material

Abbreviations Used

References

Simionescu

, Doroftei

, Maftei

, et al. The complex relationship between infertility and psychological distress (Review). Exp Ther Med, 2021; 21(4):306; doi: 10.3892/etm.2021.9737

Greil

, McQuillan

, Lowry

, et al. Infertility treatment and fertility-specific distress: A longitudinal analysis of a population-based sample of U.S. women. Soc Sci Med, 2011; 73(1):87–94; doi: 10.1016/j.socscimed.2011.04.023

1 in 6 people globally affected by infertility: WHO. Available from: https://www.who.int/news/item/04-04-2023-1-in-6-people-globally-affected-by-infertility [Last accessed: May 23, 2023].

Timur

, Sahin

. The prevalence of depression symptoms and influencing factors among perimenopausal and postmenopausal women. Menopause N Menopause, 2010; 17(3):545–551; doi: 10.1097/gme.0b013e3181cf8997

Bromberger

, Kravitz

, Chang

, et al. Does risk for anxiety increase during the menopausal transition? Study of women’s health across the nation (SWAN). Menopause N Menopause, 2013 May;20(5):488–495; doi: 10.1097/GME.0b013e3182730599

Tangen

, Mykletun

. Depression and anxiety through the climacteric period: An epidemiological study (HUNT-II). J Psychosom Obstet Gynaecol, 2008; 29(2):125–131; doi: 10.1080/01674820701733945

Santoro

. Perimenopause: From research to practice. J Womens Health (Larchmt), 2016; 25(4):332–339; doi: 10.1089/jwh.2015.5556

Harlow

, Gass

, Hall

, et al. STRAW 10 Collaborative Group.. Executive summary of the Stages of reproductive aging workshop + 10: Addressing the unfinished agenda of staging reproductive aging. Menopause N Menopause, 2012; 19(4):387–395; doi: 10.1210/jc.2011-3362

Raglan

, Schulkin

, Micks

. Depression during perimenopause: The role of the obstetrician-gynecologist. Arch Womens Ment Health, 2020; 23(1):1–10; doi: 10.1007/s00737-019-0950-6

10.

Gordon

, Girdler

, Meltzer-Brody

, et al. Ovarian hormone fluctuation, neurosteroids, and HPA axis dysregulation in perimenopausal depression: A novel heuristic model. Am J Psychiatry, 2015; 172(3):227–236; doi: 10.1176/appi.ajp.2014.14070918

11.

Gordon

, Rubinow

, Eisenlohr-Moul

, et al. Estradiol variability, stressful life events, and the emergence of depressive symptomatology during the menopausal transition. Menopause N Menopause, 2016; 23(3):257–266; doi: 10.1097/GME.0000000000000528

12.

Fitz

, Grau

, Mierau

, et al. Infertility and involuntary childlessness are associated with depressive and anxiety symptoms in menopause: SWAN analyses. Fertil Steril, 2022; 118(4):e63–4–e64; doi: 10.1016/j.fertnstert.2022.08.198

13.

Fitz

, Soria-Contreras

, Rifas-Shiman

, et al. Exploring the relationship between history of infertility and the experience of menopausal symptoms. Menopause, 2023; 30(9):913–919; doi: 10.1097/GME.0000000000002229p

14.

Oken

, Baccarelli

, Gold

, et al. Cohort profile: Project viva. Int J Epidemiol, 2015; 44(1):37–48; doi: 10.1093/ije/dyu008

15.

Kroenke

, Spitzer

, Williams

JBW

. The PHQ-9. J Gen Intern Med, 2001; 16(9):606–613; doi: 10.1046/j.1525-1497.2001.016009606.x

16.

Spitzer

, Kroenke

, Williams

JBW

, et al. A brief measure for assessing generalized anxiety disorder: The GAD-7. Arch Intern Med, 2006; 166(10):1092–1097; doi: 10.1001/archinte.166.10.1092

17.

Infertility workup for the women’s health specialist: ACOG committee opinion, number 781. Obstet Gynecol, 2019; 133(6):e377–84; doi: 10.1097/AOG.0000000000003271

18.

Tomitaka

, Kawasaki

, Ide

, et al. Stability of the distribution of patient health questionnaire-9 scores against age in the general population: Data from the national health and nutrition examination survey. Front Psychiatry, 2018; 9:390; doi: 10.3389/fpsyt.2018.00390

19.

Guo

, Robakis

, Miller

, et al. Prevalence of depression among women of reproductive age in the United States. Obstet Gynecol, 2018; 131(4):671–679; doi: 10.1097/AOG.0000000000002535

20.

Raglan

, Schulkin

, Juliano

, et al. Obstetrician-gynecologists’ screening and management of depression during perimenopause. Menopause, 2020; 27(4):393–397; doi: 10.1097/GME.0000000000001488

21.

Faleschini

, Tiemeier

, Rifas-Shiman

, et al. Longitudinal associations of psychosocial stressors with menopausal symptoms and well-being among women in midlife. Menopause, 2022; 29(11):1247–1253; doi: 10.1097/GME.0000000000002056

22.

Smedley

, Smedley

. Race as biology is fiction, racism as a social problem is real: Anthropological and historical perspectives on the social construction of race. Am Psychol, 2005; 60(1):16–26; doi: 10.1037/0003-066X.60.1.16

23.

Adkins-Jackson

, Chantarat

, Bailey

, et al. Measuring structural racism: A guide for epidemiologists and other health researchers. Am J Epidemiol, 2022; 191(4):539–547; doi: 10.1093/aje/kwab239

24.

StataCorp.. 2023. Stata Statistical Software: Release 17. StataCorp LLC: College Station, TX.

25.

Banger

. Affective syndrome during perimenopause. Maturitas, 2002; 41(Suppl 1):S13–S18; doi: 10.1016/s0378-5122(02)00011-7

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.04 MB

0.02 MB

0.01 MB

0.00 MB

Associations of History of Infertility with Symptoms of Anxiety and Depression Among Parous Women During Midlife in Project Viva

Abstract

Background:

Materials and Methods:

Results:

Conclusions:

Introduction

Materials and Methods

Exposure: Lifetime history infertility

Outcomes: Depressive and anxiety symptoms in midlife

Covariates

Statistical analyses

Results

Participants

Association of lifetime history of infertility with depressive symptoms

Association of lifetime history of infertility with symptoms of anxiety

Discussion

Results in the context of what is known

Limitations and strengths

Conclusion

Footnotes

Acknowledgment

Authors’ Contributions

Data Sharing Statement

Author Disclosure Statement

Funding Information

Supplementary Material

Abbreviations Used

References

Supplementary Material