Anxiety and depression symptoms during pregnancy and postpartum among parous women with history of infertility

Capsule:

In a parous cohort, history of infertility was not associated with pregnancy anxiety (adjusted OR 1.03, 95% CI 0.69,1.53), mid-pregnancy depression (aOR 0.93, 95% CI 0.57,1.51), or postpartum depression (aOR 1.01, 95% CI 0.60,1.60).

Objective

To examine associations of infertility with pregnancy-related anxiety and depressive symptoms during pregnancy and postpartum.

Study Design

Project Viva is a longitudinal research study including 2,100 pregnant women who delivered singleton infants between 1999 and 2002. Women were recruited during their first trimester of pregnancy from 8 obstetric offices of Atrius Harvard Vanguard Medical Associates. Additional details on recruitment and eligibility have been described elsewhere.¹ For this analysis, included are those with information on time to pregnancy (if trying to become pregnant) and medical record information (infertility diagnosis code, treatment, and prescriptions), and who had also answered any of the three measures for anxiety and depressive symptoms in pregnancy and postpartum (Supplemental Figure 1). The study was approved by the institutional review board at Harvard Pilgrim Health Care.

Exposure: Infertility at index pregnancy

We used early pregnancy questionnaire data in which participants recorded the number of cycles it took to achieve pregnancy. We defined infertility before index pregnancy as ≥6 cycles to achieve pregnancy if ≥35 years of age or ≥12 cycles to achieve pregnancy if <35 years of age, or claims for infertility treatments/prescriptions abstracted from medical records. We conducted three sensitivity analyses for participants who: planned the index pregnancy, were nulliparous, and without a prior history of depression (Supplemental Tables 1– 3).

Outcomes: Anxiety and depressive symptoms in pregnancy and 6 months postpartum.

Participants completed a pregnancy-related anxiety scale² in early pregnancy (median 9.9 weeks’ gestation), the Edinburgh Postnatal Depression Scale (EPDS)³ in mid-pregnancy (median 27.9 weeks’ gestation), and the EPDS again at 6 months postpartum. We classified high pregnancy-related anxiety if participants chose “very much” to three or more questions on the 7-item pregnancy-related anxiety scale. We used an EPDS ≥13 (0–30 scale) to indicate high perinatal and postpartum depressive symptoms (Supplemental Table 4).

Covariates

Demographic, reproductive characteristics, and questions about early life hardships, such as history of physical abuse, sexual abuse, financial hardship, depression, and social support, were assessed via questionnaires and interviews.

Analysis

We performed unadjusted and multivariable adjusted logistic regression models, adjusted for baseline sociodemographic, reproductive characteristics, and early life hardships. To account for missing covariate data, we performed multiple imputation by chained equation for all 2,100 women of Project Viva, and limited our analyses to participants with non-missing exposure and outcome data. All analyses were conducted in Stata (version 17).⁴

Results

Of the 2,039 participants, 386 (18.9%) women experienced infertility at the index pregnancy. Among those with infertility, 43 (11.9%) reported high pregnancy-related anxiety, 27 (8.2%) had high mid-pregnancy depressive symptoms, and 26 (9.1%) had high postpartum depressive symptoms. Among those without infertility, 168 (10.8%) reported high pregnancy-related anxiety, 118 (9.3%) had high mid-pregnancy depressive symptoms, and 95 (8.6%) had high postpartum depressive symptoms. (Table 1) In both unadjusted and adjusted models, infertility at index pregnancy was not associated with pregnancy anxiety (adjusted odds ratio [aOR] 1.03, 95% CI 0.69,1.53), high mid-pregnancy depressive symptoms (aOR 0.93, 95% CI 0.57,1.51), or high postpartum depressive symptoms (aOR 1.01, 95% CI 0.60,1.60). (Table 2). Infertility remains unrelated to the study outcomes in sensitivity analyses (Supplemental Tables 1–3).

Table 1.

Characteristics of the study participants according to infertility at index pregnancy

	Overall Sample		Infertility		Without infertility
	N	%	N	%	N	%	p
Demographics	N=2,039		N=386		N=1,653
Age at enrollment/index pregnancy, years
Age < 35 years	1,476	72.4	203	52.6	1,273	77.0
Age ≥ 35 years	563	27.6	183	47.4	380	23.0	<0.00
Race and Ethnicity
Black	319	15.8	46	12.0	273	16.6
White	1,366	67.5	281	73.2	1,085	66.2
All other races and ethnicities	339	16.7	57	14.8	282	17.2	0.02
Partner Status
Married or Cohabiting	1,854	91.6	372	96.9	1,482	90.4
Not married or cohabiting	169	8.4	12	3.1	157	9.6	<0.00
Education
College degree	1,324	65.4	283	73.7	1,041	63.5
No college degree	700	34.6	101	26.3	599	36.5	<0.00
Household Income
> $70,000 per year	1,115	61.3	246	69.1	869	59.4
≤ $70,000 per year	704	38.7	110	30.9	594	40.6	0.00
Employment
Employed or Student	1,537	88.0	310	90.9	1,227	87.3
Not Employed/Student	209	12.0	31	9.1	178	12.7	0.07
Physical Characteristics
BMI, kg/m2
<25 kg/m2	1,271	62.6	217	56.5	1,054	64.0
25-<30 kg/m2	438	21.6	99	25.8	339	20.6
≥30 kg/m2	322	15.9	68	17.7	254	15.4	0.02
Smoking
Never	1,382	68.2	272	70.6	1,110	67.7
Former	384	19.0	78	20.3	306	18.7
Smoked during pregnancy	259	12.8	35	9.1	224	13.7	0.05
Polycystic Ovarian Syndrome	68	3.3	36	9.3	32	1.9	<0.00
Thyroid Disease	80	4.0	21	5.6	59	3.6	0.09
Nulliparous	993	48.7	219	56.7	774	46.8	<0.00
Early Life Hardships
History of Physical Abuse	573	36.3	123	39.2	450	35.6	0.24
History of Financial Hardship	201	11.6	35	10.3	166	12.0	0.40
History of Depression	185	11.3	56	16.7	129	9.9	0.00
Social Support
Partner
Low (Score 0–9)	81	4.8	9	2.7	72	5.3
High (Score 10–15)	1,615	95.2	326	97.3	1,289	94.7	0.05
Friend/Family
Low (Score 0–9)	104	6.0	23	6.8	81	5.8
High (Score 10–15)	1,625	94.0	316	93.2	1,309	94.2	0.51
Outcomes
Pregnancy-related Anxiety
High	211	11.0	317	88.1	1,390	89.2
Low	1,707	89.0	43	11.9	168	10.8	0.53
Perinatal Depressive symptoms
EPDS ≥13	145	9.1	27	8.2	118	9.3
EPDS ≤13	1,458	91.0	303	91.8	1,155	90.7	0.54
Postpartum Depressive symptoms
EPDS ≥13	121	8.7	26	9.1	95	8.6
EPDS ≤13	1,274	91.3	261	90.9	1,013	91.4	0.80

Note. BMI: body mass index, EPDS: Edinburgh Postnatal Depression Scale

Note. Ns for some characteristics don’t add up to the column N because of missing values

Table 2.

Associations of infertility with pregnancy-related anxiety and pregnancy and postpartum depression symptoms

	Pregnancy-Related Anxiety	High Perinatal EPDS Score	High Postpartum EPDS Score
Infertility at index pregnancy	N=1,918	N=1,603	N=1,395
	OR (95% CI)	OR (95% CI)	OR (95% CI)
Model 1	1.12 (0.79, 1.60)	0.87 (0.56, 1.35)	1.06 (0.67, 1.67)
Model 2	1.14 (0.79, 1.65)	0.94 (0.60, 1.47)	1.14 (0.71, 1.81)
Model 3	1.00 (0.68, 1.46)	0.93 (0.59, 1.48)	1.07 (0.66, 1.73)
Model 4	1.14 (0.78, 1.65)	0.83 (0.52, 1.33)	0.99 (0.60, 1.61)
Model 5	1.03 (0.69, 1.53)	0.93 (0.57, 1.51)	1.01 (0.60, 1.69)

Note. The outcomes of Pregnancy-Related Anxiety, Perinatal EPDS, and Postpartum EPDS were run as separate factors/outcomes

Note. Infertility at index pregnancy is dichotomized as 0 = No history of impaired fertility, 1 = Infertility at index pregnancy

OR: Odds ratio, CI: Confidence intervals, EPDS: Edinburgh Postnatal Depression Scale

Model 1: Unadjusted

Model 2: Model 1 + categorical age (<35 years and ≥35 years)

Model 3: Model 2 + reproductive characteristics (pre-pregnancy body mass index category, smoking, polycystic ovarian syndrome, thyroid disease, nulliparous

Model 4: Model 2 + life hardships (history of physical abuse, history of financial hardship, history of depression, partner support, and friend/family support)

Model 5: Model 3 + Model 4 (fully adjusted)

Conclusion

We observed no association of infertility at index pregnancy with anxiety or depressive symptoms during pregnancy or postpartum, which reinforces what previous studies have found among women who received infertility treatment to conceive.^5–7 Strengths of this study include adjustment for potential confounders and mediators, use of validated instruments, and use of multiple imputation for covariate data. Infertility treatments and reproductive medicine is continually evolving, and a limitation is the age of the data. We did not explore if differences in mental health outcomes exist based on infertility treatment utilization, or type of treatments received, which is an area for future research. While the study was adequately powered to identify clinically relevant differences, it was not sufficiently powered to detect more modest associations. Nonetheless, results echo what similar studies have found when examining associations between infertility and depression, which is encouraging that women with infertility who go on to have live birth are not more at risk for developing anxiety and depression in pregnancy and postpartum than women without infertility.

Attestation Statement:

• The subjects in this trial have not concomitantly been involved in other randomized trials (If applicable).

• Data regarding any of the subjects in the study has not been previously published unless specified: Findings have not yet been presented at a meeting. Abstract was accepted for presentations at the American Society for Reproductive Medicine (ASRM) 2023 Scientific Congress & Expo to be held October 14–18, 2023 in New Orleans, Louisiana, and the Revitalizing Women’s Healthcare Together Conference co-sponsored by the Institute of Restoration Reproductive Medicine of America (IRRMA) and FACTS About Fertility to be held September 29–30, 2023 in Minneapolis, Minnesota. Abstract was accepted for a poster presentation to the Sigma Theta Tau Region 15 Annual Research Symposium to be held October 6, 2023 in Chestnut Hill, MA.

• Data will be made available to the editors of the journal for review or query upon request.

Data Sharing Statement:

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