Pregnancy outcomes, fertility, and family planning in women with psoriatic arthritis

Abstract

Objective

To quantify pregnancy outcomes and the frequency and cause of infertility among women with psoriatic arthritis.

Methods

Women with psoriatic arthritis aged 20–50 years completed a questionnaire about prior pregnancies, infertility, and family planning. Patient-reported pregnancy outcomes were validated by chart review.

Results

In 40 women with psoriatic arthritis, 67% of 70 pregnancies were live births. Patient-reported preterm birth and preeclampsia were more common after psoriatic arthritis diagnosis but were significantly over-reported. Most women reported no or mild joint pain during pregnancy and few took medications for psoriatic arthritis. Infertility was reported by 36% of women who were ever pregnant or ever tried to become pregnant, primarily due to polycystic ovary syndrome.

Conclusion

The patient-reported pregnancy outcomes in this retrospective survey were not supported by chart review, making prospective studies essential to understand the interaction of psoriatic arthritis and pregnancy. Infertility, particularly due to polycystic ovary syndrome, appears to be an important issue in this population.

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis. While reports of rheumatoid arthritis (RA) and pregnancy can be found in the literature since 1940s, only a small number of studies focus on pregnancy in women with PsA. Pregnancy data are limited for PsA due to its late onset (average age of 44 years) and rarity in the general population.^1,2 This leaves fewer pregnancies occurring each year compared to RA, which has a higher prevalence, and lupus, which has a younger age of onset.

The largest published study to date is a prospective study of 42 pregnancies in 29 women with PsA which found relatively stable arthritis during pregnancy, with the majority of women experiencing either stable low activity or improvement. Postpartum, 40% had worsened arthritis, but the majority remained stable or improved.³ When compared to age-matched non-pregnant women with PsA, pregnant women had a 2.1 times increased chance of stable low or improvement during pregnancy. A retrospective analysis of 16 pregnancies in women with PsA reported moderate-to-severe disease activity in 57% of patients during pregnancy and 71% of patients postpartum, compared to 29% pre-pregnancy.⁴ There is a bit more data for psoriasis in pregnancy, with modest increases in preterm birth, low-birth weight infants, and caesarean deliveries compared to women without psoriasis.^5–7

The primary objective of this study was to determine pregnancy outcomes for women with PsA, comparing pregnancies that occurred prior to and following diagnosis, and to validate these patient-reported outcomes using chart review. This study was also designed to identify a range of hypothesis-generating components to the reproductive health of women with PsA, as these topics have been previously largely unexplored. For this reason, a broad range of secondary objectives were studied, including patterns of medication use in pregnancy, changes in arthritis and psoriasis during and following pregnancy, the frequency and causes of infertility, and factors influencing a woman’s decisions about family size.

Patients and methods

Women with PsA between the ages of 20 to 50 years, seen in the Duke Rheumatology Clinic, were invited to participate following informed consent between February and October 2016. Participants were identified through the Duke DEDUCE (Duke Enterprise Data Unified Content Explorer) system, which searches the Duke electronic medical record (EMR) EMR system for patients matching our entry criteria, using International Classification of Diseases (ICD)-9 and ICD-10 codes (696.0, L40.50, L40.52, L40.53, L40.54, and L40.59). In addition, rheumatology clinic schedules were reviewed daily to identify eligible women. Charts of potential participants were reviewed to confirm whether a diagnosis of PsA had been assigned by a Duke University rheumatologist or dermatologist. Eligible patients were then invited to participate via letter and in clinic. A total of 100 women were identified, of which 40 participated; of the 60 non-participants, 5 were excluded for not meeting inclusion criteria, we were unable to contact 2 due to inaccurate contact information, 4 declined, and 49 did not respond to repeated requests for participation. This study complies with the Declaration of Helsinki and was approved by Duke Health Institutional Review Board (Pro00061025).

All participants completed a computer-based survey via REDCap (Research Electronic Data Capture),⁸ which included questions about infertility, intentions and goals for childbearing, menstrual history, and polycystic ovary syndrome (PCOS). Women who had been pregnant provided information about time to conception, number of pregnancies, and pregnancy outcomes. Basic information about PsA was also collected, including when psoriasis started, when arthritis developed, and the medications used previously and currently.

Pregnancy history

Pregnancy outcomes of interest included miscarriage, stillbirth, elective termination, and live births. Among live births, participants were asked if they delivered more than three weeks before their due date and how many weeks before term, if preterm birth occurred, preeclampsia, and if their infant had any congenital anomalies. A composite variable of “adverse pregnancy outcome” was created and defined as pregnancy loss (excluding elective terminations), preterm birth, and/or an infant with congenital anomalies. Among pregnancies occurring after the diagnosis of PsA, patients were asked about medications taken for PsA during pregnancy, including disease-modifying antirheumatic drugs (DMARDs), tumor necrosis factor (TNF) inhibitors, nonsteroidal anti-inflammatory drugs, steroids, topical therapy, and other biologics. Pregnancy outcomes were unavailable for one pregnancy.

Psoriasis activity and arthritis activity during and following pregnancy were determined by a general patient-reported assessment for whether each symptom improved, stayed the same, or worsened. Participants were asked to compare pre-pregnancy disease activity to disease activity during pregnancy and disease activity during pregnancy to the postpartum period.

Validation of patient-reported data through chart review

Women were asked to sign a medical release for each delivery in order to validate patient-reported live birth outcomes. Medical release forms for live deliveries were obtained for 38 of the 47 live births, for which 27 hospital-derived delivery data were obtained. Of these 27 records, 16 were births after the diagnosis of PsA. Twenty deliveries were considered unconfirmed due to no medical release form being completed (n = 7), no records sent from the hospital (n = 9), and medical records being unavailable (n = 4). The reported and documented pregnancy outcomes were compared for accuracy.

Infertility

Infertility was based on self-report and defined as (1) being unable to get pregnant after 12 months of trying or (2) a reported physician diagnosis of infertility. Time to conception greater than 12 months was defined as subfertility. PCOS was based on participants’ report. In addition, we collected data on consequences of PCOS: participant-reported diabetes, pre-diabetes, or insulin resistance; irregular menstrual cycles; adult acne; hair loss on head; obesity (body mass index (BMI) of 30 kg/m² or greater); and Ferriman–Gallwey score, with a total score 8 or more defined as hirsutism.^9,10

Family size

Participants were asked the number of children they would ideally have, if PsA affected the number of children they decided to have, and to identify factors that influenced their decision to have children.

Analysis

Pregnancy outcomes, patterns of medication use, disease activity during pregnancy, patient-reported infertility, reasons for infertility, PCOS, family size, and effect of PsA on the number of children a patient had were reported as counts and frequencies. To measure the effect of PsA on pregnancy outcomes, patient-reported pregnancy outcomes prior to the diagnosis of PsA were compared to pregnancy outcomes after diagnosis by Fisher’s exact test.

To determine the accuracy of patient-reported pregnancy outcomes, outcomes were compared to the medical record on the day of delivery. Measures of concordance included the percentage agreement (where the patient-reported outcome matched what was reported in the medical record) and a kappa statistic. In addition, the sensitivity and specificity of patient-reported outcomes were calculated using medical records as the “gold standard.” All analyses were performed in SAS 9.4 (Cary, NC).

Results

The questionnaire was completed by 40 women with PsA. The majority (92%) were white, non-Hispanic with a high level of education (40% completed college and another 30% had either started or finished a graduate degree); 62.5% were married. The average age at the time of the study was 37.4 (standard deviation (SD) 7.9) years, and the age at diagnosis was 30.9 (SD 8.4) years.

Pregnancy

Pregnancy outcomes

Reported pregnancies occurred between the years 1983 and 2016, with 70% occurring after 1999. Pregnancy outcomes following PsA diagnosis were worse than those prior to diagnosis (Table 1), particularly the rates of miscarriage (30%) and preterm birth (48%), though these differences were not statistically significant. The composite variable of adverse pregnancy outcomes, however, was significantly higher after PsA diagnosis, with 69% of pregnancies resulting in a pregnancy loss (excluding elective terminations), preterm birth, and/or an infant with congenital anomalies after diagnosis but only 34% prior to diagnosis (p = 0.01). The mean maternal age prior to PsA diagnosis was 27.3 (SD 7.3) years, compared to 30.4 (SD 7.1) years after PsA diagnosis (p = 0.08).

Table 1.

Differences in pregnancy outcomes: before and after psoriatic arthritis diagnosis.

	Overall	Prior to diagnosis	After diagnosis	p
Number of pregnancies	70	33	37
Live births	47 (67%)	24 (73%)	23 (62%)	0.4a
Miscarriage	15 (21%)	4 (12%)	11 (30%)	0.09
Stillbirth	1 (1%)	0 (0%)	1 (3%)	1.0
Ectopic pregnancies	1 (1%)	1 (3%)	0 (0%)	0.5
Elective termination	6 (9%)	4 (12%)	2 (5%)	0.4
Number of live births	47	24	23
Preterm birth	16 (34%)	5/24 (21%)	11/23 (48%)	0.07
Preeclampsia	11/46 (24%)	5/23 (22%)	6/23 (26%)	1.0
Caesarean section	20/46 (43%)	12/23 (52%)	8/23 (35%)	0.4
Congenital anomalies	4/49b (8%)	2/24 (8%)	3/25b (12%)	1.0
NICU visit	10/49b (20%)	3/24 (13%)	7/25b (28%)	0.3
Adverse pregnancy outcomec	34/64 (53%)	10/29 (34%)	24/35 (69%)	0.01
Medical records obtained (among live births)	27/47 (57%)	11/24 (46%)	16/23 (70%)	0.1
Mean maternal age, years (SD)	28.9 (7.3)	27.3 (7.3)	30.4 (7.1)	0.08

Note: SD: standard deviation; NICU: Neonatal Intensive Care.

^aA value of p for overall difference in pregnancy outcomes between groups: 0.2, after removing elective terminations, p = 0.1.

^bTwo twin deliveries.

^cComposite variable including pregnancy loss (excluding elective terminations), preterm birth, and/or an infant with congenital anomalies.

Congenital anomalies prior to PsA diagnosis included urinary reflux and the infant being born deaf, and anomalies after PsA diagnosis included urinary reflux, club feet, and a heart murmur. Two of the mothers were not taking any treatment for PsA or psoriasis prior to or during pregnancy; the mother of the infant with a heart murmur was taking only sulfasalazine during pregnancy. One stillbirth occurred to a mother after the diagnosis of PsA at 28 weeks; no PsA or psoriasis medications were taken during pregnancy. The mother reported the fetus had multiple anomalies, including absence of both kidneys and the bladder.

Validation of patient-reported pregnancy outcomes

Among the 27 live births with delivery records available, all births were confirmed as being live, and the 11 patient-reported caesarean sections were also confirmed (100% agreement). Lower agreement was found with preterm births and preeclampsia (Table 2). Of the 26 delivery records with data available on gestational age at delivery, 10 were patient-reported to be delivered preterm, but just 3 actually delivered prior to 37 weeks on record review (73% agreement; kappa: 0.35; sensitivity: 100%; specificity: 70%). The majority of patients who inaccurately reported preterm birth delivered in the 37th week of gestation. Of the 20 delivery records with data available on preeclampsia, 6 were patient-reported to have preeclampsia, but just 2 had a diagnosis of preeclampsia in the records (80% total agreement; kappa: 0.41; sensitivity: 100%; specificity: 78%).

Table 2.

Validation of preterm birth and preeclampsia through medical chart review.

	Gold standard: medical record
	Preterm	Term	Total
Outcome: preterm birtha
Patient-reported
Preterm	3	7	10
Term	0	16	16
Total	3	23	26
	Gold standard: medical record
	Preeclampsia	No Preeclampsia	Total
Outcome: preeclampsiab
Patient-reported
Preeclampsia	2	4	6
No preeclampsia	0	14	14
Total	2	18	20

^aFor the outcome of preterm birth, medical record confirmation available for 26/27 live births. Overall agreement = 73%, kappa = 0.35, sensitivity = 100%, and specificity = 70%.

^bFor the outcome of preeclampsia, medical record confirmation available for 20/27 live births. Overall agreement = 80%, kappa = 0.41, sensitivity = 100%, and specificity = 78%.

Medication use in pregnancy

Most women did not take medication for either psoriasis or arthritis during pregnancy, with only 13% of pregnancies exposed to any medications, including TNF inhibitors (9%), corticosteroids (4%), and DMARDs (3%). No differences in pregnancy outcomes were observed by medications taken during pregnancy, though the power for this analysis is limited. There were nine pregnancies that ended in the year 2011 or later, when we would expect TNF inhibitors to be more routinely used during pregnancy. Of these, two (25%) were on no medications, one was on steroids only (12.5%), one was on sulfasalazine only (12.5%), and four were on etanercept (50%). The pregnancy outcome was a live birth for seven of these eight pregnancies, with one miscarriage occurring to a woman taking etanercept.

Patient-reported disease activity during pregnancy

The majority of women with PsA at the time of pregnancy reported no joint pain (33%) or mild joint pain (49%) during pregnancy. While 50% reported no change in arthritis when pregnant, 28% reported improvement and 22% reported worsening (Figure 1). Following pregnancy, 58% noted no change, only 9% improved, and 33% worsened. No differences in pregnancy or live birth outcomes were observed by the reported level of joint pain reported during pregnancy.

Figure 1.

Psoriatic arthritis disease activity during and after pregnancy. During pregnancy, 33% experienced no arthritis, 48% mild arthritis, 12% moderate arthritis, and 6% severe arthritis. For psoriasis, 23% experienced no symptoms, 60% mild psoriasis, 10% moderate psoriasis, and 7% experienced severe psoriasis.

Similarly, most women reported mild (60%) or no (23%) psoriasis activity in pregnancy. While more than half of women reported no change in skin disease during or following pregnancy, 42% reported an improvement in skin psoriasis with pregnancy.

Infertility

Among the 28 women who had ever been pregnant or tried to become pregnant, 36% reported infertility (Table 3). The leading patient-reported cause of infertility was PCOS (50%), followed by unexplained or unknown infertility (30%). Other reasons included male factors, ovulatory dysfunction, premature ovarian failure or premature menopause, uterine fibroids, and elevated prolactin (10% each). Some women reported multiple causes for infertility.

Table 3.

Infertility in women with psoriatic arthritis (n = 40).

	n = 40
	n (%)
Ever tried to become pregnant	25/39 (64%)
Age when first tried to become  pregnant, mean in years (SD)	28.9 (5.0) of 22
Ever pregnant	27 (68%)
Number of planned pregnancies	n = 30
Time to conceive, months, mean (SD)	6.1 (7.6)
After diagnosis	5.8 (8.8)
Time to conceive >12 months, n (%)	4 (13%)
After diagnosis	2 (12%)
Frequency of intercourse per month  when trying to conceive, mean (SD)	10.6 (5.7)
Infertilitya	10/28 (36%)
Reasons for infertility or inability  to get pregnantb	n = 10
Polycystic ovary syndrome	5 (50%)
Male factor	1 (10%)
Elevated prolactin	1 (10%)
Premature ovarian failure/ premature menopause	1 (10%)
Problem with ovulation	1 (10%)
Uterine fibroids/uterine septum	1 (10%)
Unexplained or unknown	3 (30%)
Co-morbidities potentially associated with infertility	n = 40
Polycystic ovary syndrome	8/39 (21%)
Diabetes	7 (18%)
Pre-diabetes/insulin resistance	6 (15%)
Irregular menstrual cycles	25/39 (64%)
Patient-reported hirsutism	12 (30%)
Adult acne	25/39 (64%)
Hair loss on head	12 (30%)
Obese (BMI ≥ 30 kg/m2)	20/39 (51%)
BMI, kg/m2, mean (SD)	32.4 (9.1)

Note: BMI: body mass index; SD: standard deviation.

^aAmong women who have ever been pregnant or tried to become pregnant (n = 28). Not all women who try to become pregnant do become pregnant, and not all women who become pregnant actively tried to become pregnant.

^bWomen may have more than one reason for infertility; therefore, percentages do not total to 100%.

Women with PsA appeared to have several risk factors for infertility. The average BMI was 32.4 kg/m² (SD 9.1), with only 25% of women having a BMI in the normal range. PCOS was present in 21% of women with PsA, 18% reported diabetes, and an additional 15% reported pre-diabetes or insulin resistance.

Among the 30 planned pregnancies in the cohort, it took an average of 6.1 months (SD 7.6) to conceive, with no differences observed prior to or after PsA diagnosis. Subfertility, defined as a time to conceive of more than 12 months, was reported in 13% of women who had ever been pregnant. The average age when trying to conceive was 28.9 years (SD 5.0).

Family size

Women with PsA reported wanting, on average, 2.7 children. Factors influencing a woman’s decision to have children included concerns around their health (60%), financial considerations (45%), job/school demands (38%), fatigue (20%), and pain (20%). Among those with concerns about their health, pain, or fatigue, there was no observed difference in the desired number of children.

As women with PsA are typically diagnosed at an older age, many women had finished having children prior to diagnosis. Among those who were diagnosed prior to finishing having children, 29% reported their diagnosis led them to want fewer children than before. Reasons for wanting fewer children included concerns over being able to care for children (67%), rheumatic medications harming the baby (78%), disease flaring after delivery (56%), and PsA worsening because of pregnancy (56%).

Discussion

While our primary analysis identified a higher frequency of patient-reported adverse pregnancy outcomes, this difference was invalidated through chart review. Despite pregnancy loss and caesarean delivery being accurately reported, preterm delivery and preeclampsia were strongly over-reported, leading us to question the finding of more adverse events after PsA diagnoses.

The majority of women reported minimal-to-mild arthritis and skin disease during and following pregnancy and very few took medications for PsA during this period. Arthritis did not appear to change dramatically in pregnancy, while many women reported improvements in skin disease during pregnancy. Disease activity did not change postpartum for most women, with similar numbers reporting improvement and worsening of both skin and joint activity. PsA changes during pregnancy have been the subject of speculation but with limited data. A recent prospective cohort study of PsA pregnancies with physician-measured disease activity found that arthritis activity did not change dramatically in pregnancy or following delivery.³ Psoriasis, on the other hand, has been reported to improve with pregnancy and worsen postpartum.^11–13

We observed an unexpectedly high rate of infertility of 36%. We recently published a study that used similar methods of 75 women with and 75 women without RA, and we found that 19% of both groups of women reported infertility.¹⁴ Among women with PsA, PCOS was the primary cause of infertility, and we observed a high prevalence of patient-reported PCOS and consequences of PCOS, including obesity, diabetes, and pre-diabetes, and irregular menstrual cycles. A high prevalence of PCOS has been previously reported among women with psoriasis.¹⁵ Despite the frequency of PCOS, the women in this study did not report a prolonged time to conception nor a high rate of subfertility. We know of no prior research of infertility among women with PsA; however, two recent studies have found women with RA take longer to conceive than healthy women.^16,17

In addition to infertility, personal choice, largely due to concerns driven by awareness of the difficulties involved in caring for a family while experiencing active disease and of the potential toxicity of medications to a developing fetus, also limits family size.¹⁸ Not surprisingly, women with PsA frequently reported concerns over their health. Almost one-third of women said their diagnosis led them to want fewer children, primarily due to concerns over being able to care for a child, medications taken for PsA harming a baby, disease flaring during or after pregnancy, and PsA being worse in the future because of pregnancy. Similar findings have been reported in women with RA.¹⁹

A key limitation of this study was the retrospective design and patient-reported data, which could contribute to recall bias. In an effort to quantify the impact of this study design on the accuracy of the results, we sought to validate the reported pregnancy outcomes with delivery data. One complicating factor was our difficulty in obtaining these records, some several decades old, from distant hospitals, where records were lost or unavailable despite multiple attempts. This led to a smaller number of records than expected. Our survey question of “delivery more than 3 weeks prior to the due date” resulted in over-reporting of preterm birth, with the majority of women who delivered in the 37th week reporting an early delivery. In addition, the date of pregnancy outcomes ranged over a 33-year period, with only eight occurring during the window of time when TNF-inhibitor use during pregnancy was considered routine clinical care.

Prior studies have documented the challenges of self-reported preterm birth, particular in the years following delivery. A Canadian study of almost 3000 live births found excellent agreement between patient-reported preterm birth at four months postpartum compared to electronic medical records, with a kappa of 0.87, and 96% of women reported within one week of the exact gestational age.²⁰ In contrast, a study of 151 birth records obtained an average six years after the pregnancy ended found a kappa of 0.44 for preterm birth, similar to our estimate of 0.35.²¹

Preeclampsia is difficult for patients to accurately report, even soon after delivery, and low agreement with patient-reported and verified preeclampsia has been previously reported, with positive predictive values ranging from 50% to 59%.^22,23 Our observed positive predictive value of 33% was lower than these two previous reports, likely due to the length of time since the pregnancy.

An additional limitation was the relatively small number of pregnancies in our study and the generalizability of these study participants. All women with PsA attended a university rheumatology clinic in the Southeast of the United States. The high level of education of the women in our study is reflective of the area. Data were self-reported by participants, and we were unable to confirm reports of infertility. In addition, the response rate in our PsA cohort was low, with only 40% of invited women agreeing to participate. We do not have characteristics of women who opted out of our study, and it is possible that women who chose to participate self-selected based on certain characteristics relating to our study objectives. Finally, the study was powered to include 100 pregnancies in 40 women based on pregnancy rates from a prior study of women with RA.¹⁸ This cohort of 40 women only had 70 pregnancies, underpowering our analysis.

In conclusion, the patient-reported pregnancy outcomes of preterm birth and preeclampsia in this retrospective survey were not validated by chart review. The majority of women reported minimal PsA activity and medication use during and following pregnancy, with few flares during pregnancy. Over one-third of women with PsA reported infertility, with PCOS being the primary cause of infertility. Future research focusing on a prospective cohort of women with PsA, with real-time patient and physician assessments of disease activity and collection of pregnancy outcomes, will provide clarity about the role the disease plays in pregnancy outcomes and infertility.

Declaration of conflicting interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MEBC is a paid consultant for UCB Pharma. AME and GM have no conflicts of interest to disclose.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Janssen Scientific Affairs, LLC.

Informed consent

Written informed consent was obtained from the patient(s) for their anonymized information to be published in this article.

Ethical approval

This study was approved by Duke Health Institutional Review Board (Pro00061025).

Guarantor

MEBC is the guarantor of this study.

Contributorship

All authors contributed to the design and conduct of the study; data collection and management; interpretation of the data; and preparation, review, or approval of the manuscript. AME wrote the first draft of the manuscript. All authors reviewed and edited the manuscript and approved the final version of the manuscript.