Effect of anti-TNF biologic exposure during pregnancy on villitis of unknown etiology diagnoses in patients with autoimmune disease

Abstract

Tumor necrosis factor-α (TNF-α) antagonists are highly effective in controlling autoimmune diseases. This has led to speculation that they might also be useful in treating inflammatory placental conditions, such as chronic villitis of unknown etiology (VUE). VUE affects 10–15% of term placentas and is associated with recurrent fetal growth restriction (FGR) and pregnancy loss. We aimed to evaluate outcomes in patients with autoimmune diseases with and without anti-TNF-α biologic exposure during gestation. This retrospective cohort study compared pregnant women with autoimmune disease taking anti-TNF-α biologics (n=89) to pregnant women with autoimmune disease but not taking a biologic (n=53). We extracted data on all patients meeting our inclusion criteria over a 20-year period. Our primary outcome was the diagnosis of VUE by histology. Our secondary outcomes were maternal and neonatal complications such as preeclampsia, FGR and neonatal intensive care admission. Kruskal-Wallis and chi-squared tests were performed as appropriate for statistical analysis. Maternal characteristics were comparable between groups and there was no increase in adverse pregnancy outcomes based on anti-TNF-α treatment. Exposure to anti-TNF-α therapy had no significant effect on the incidence of VUE or other obstetric complications. Within the cohort exposed to anti-TNF-α biologics during pregnancy, the rate of VUE was 9.3%, which is comparable to the reported general population risk. Our data support the safety profile of biologic use in pregnancy.

Introduction

Autoimmune diseases mainly affect women of reproductive age [1]. They are also associated with adverse pregnancy outcomes, especially in uncontrolled disease [2–4]. Inflammatory processes, in conditions such as rheumatoid arthritis and inflammatory bowel disease, are driven by tumor necrosis factor-α (TNF-α) mediated pathways [5]. The advent of biologic therapy, especially anti-TNF-α, heralded a new era of treatment for autoimmune disease. Different anti-TNF-α therapies have distinct mechanisms of action to suppress the activity of TNF-α [6]. Increasingly, women are conceiving and carrying pregnancies whilst using anti-TNF-α biologic therapy. Maternal and fetal benefits from optimal disease control outweigh potential pharmacological risks. This is reflected in international consensus guidelines on pregnancy management of women with autoimmune disease [7–9]. Recent meta-analysis has confirmed the safety of anti-TNF- α in pregnancy [10].

There is increasing evidence that TNF-α is also linked to other pro-inflammatory conditions of pregnancy, such as villitis of unknown etiology (VUE) [11–14], preeclampsia [15, 16] and recurrent pregnancy loss [17]. The important role of TNF- α in placental inflammation is supported by data from animal studies. In a mouse model designed to simulate VUE, induced intrauterine inflammation was strongly associated with increased expression of type 1 cytokines, including TNF- α [18]. Specific TNF-α driven inflammation in the context of brucella infection has also been observed in animal models [19].

VUE is defined as the presence of inflammation in the placental villi in the absence of identifiable etiology, such as viral or acute infections [20]. Inflammation is predominantly lymphohistiocytic, and is diagnosed in 10–15% of term placentas [21]. The majority of cases of VUE will result in an uncomplicated live birth; however, there is a recognized association between VUE and adverse outcomes such as FGR and stillbirth [22]. Up to 55% of patients will have a recurrent diagnosis in a subsequent pregnancy [23, 24]. VUE is hypothesized to be the result of maternal immune targeting of the haploidentical fetus [25–27].

Currently, there are no clinical recommendations regarding therapeutic management following a VUE diagnosis for patients interested in pursuing another pregnancy [28]. Biologic therapies have not been tested as a treatment strategy for VUE but may represent an opportunity to blunt this inflammatory immune response in pregnancy. However, very little is known about the placental effects of biologic exposure in the pregnant populations taking these drugs to control their autoimmune disease. The objective of this study was to test the hypothesis that biologic therapy taken during pregnancy dampens TNF-α mediated inflammatory pathways resulting in decreased incidence of VUE in the placenta.

Materials and Methods

This study was approved by Mayo Clinic Institutional Review Board (#22–006101). We conducted a retrospective cohort study that examined all pregnancies to patients with autoimmune disease who delivered between January 2002 and January 2022, at a Midwest tertiary hospital with corresponding local delivery units.

Using a specialized bioinformatic search engine (Informatics for Integrating Biology and the Bedside – i2b2.org), we extracted all medical records meeting inclusion criteria. The search strategy included all women aged 18–45 years with a coding of ‘pregnancy’ and mention of a biologic therapy one year before or after their pregnancy. We extracted variables on obstetric history including FGR, stillbirth, preeclampsia, and preterm birth. A description of our diagnostic criteria for these complications can be found in Table 1. We also collected biologic therapy type, duration, and placental pathology results. Complications of autoimmune disease were determined using a composite of hospital admission, emergency steroids, or change of therapy. All data were extracted from the digital medical record (Epic). Placental histology was evaluated by perinatal pathologists and detailed in the digital medical record. All extracted data were collected and stored in a password protected REDCap database [29, 30].

Table 1.

Baseline characteristics of study patients.

	Biologics (N=89)	No biologics (N=53)	Total (N=142)	P value1
Age, years: Median (IQR)	32 (6.0)	30 (6.0)	31 (6.0)	0.37
Race 2				0.69
Asian	1 (1.1%)	0 (0.0%)	1 (0.7%)
Black or African American	1 (1.1%)	1 (1.9%)	2 (1.4%)
White	87 (97.8%)	52 (98.1%)	139 (97.7%)
Ethnicity				0.06
Non-Hispanic or Latino	89 (100.0%)	51 (96.2%)	140 (98.6%)
Hispanic or Latino	0 (0.0%)	2 (3.8%)	2 (1.4%)
Smoker				0.69
Never	57 (64.0%)	32 (60.4%)	89 (62.7%)
Current	15 (16.9%)	12 (22.6%)	27 (19.0%)
Former	17 (19.1%)	9 (17.0%)	26 (18.3%)
BMI, kg/m2: Median (IQR) 3	26 (9.7)	30 (9.0)	28 (9.0)	0.07
Parity				0.85
Primiparous	11 (12.4%)	6 (11.3%)	17 (12.0%)
Multiparous	78 (87.6%)	47 (88.7%)	125 (88.0%)
Previous pregnancy complications 4
At least one previous pregnancy complication	43 (48.3%)	25 (47.2%)	68 (47.9%)	0.89
Pregnancy loss < 24 weeks	34 (38.2%)	23 (43.4%)	57 (40.1%)	0.54
Preterm birth (< 37 weeks)	8 (9.0%)	2 (3.8%)	10 (7.0%)	0.24
Stillbirth	1 (1.1%)	0 (0.0%)	1 (0.7%)	0.44
Gestational diabetes	2 (2.2%)	5 (9.4%)	7 (4.9%)	0.06
Preeclampsia	4 (4.5%)	3 (5.7%)	7 (4.9%)	0.76
HELLP syndrome	0 (0.0%)	2 (3.8%)	2 (1.4%)	0.06
Congenital abnormalities	0 (0.0%)	1 (1.9%)	1 (0.7%)	0.19
Fetal growth restriction	5 (5.6%)	1 (1.9%)	6 (4.2%)	0.29
Autoimmune disease
Rheumatoid arthritis	22 (24.7%)	18 (34.0%)	40 (28.2%)	0.24
Psoriasis/ psoriatic arthritis	5 (5.6%)	9 (17.0%)	14 (9.9%)	0.03
Systemic lupus erythematosus	2 (2.2%)	0 (0.0%)	2 (1.4%)	0.27
Inflammatory bowel disease	62 (69.7%)	18 (34.0%)	80 (56.3%)	<0.0001
Sjögren’s syndrome	0 (0.0%)	1 (1.9%)	1 (0.7%)	0.19
Hashimoto’s thyroiditis	1 (1.1%)	1 (1.9%)	2 (1.4%)	0.71
Myasthenia gravis	0 (0.0%)	1 (1.9%)	1 (0.7%)	0.19
Crohn’s disease	52 (58.4%)	13 (24.5%)	65 (45.8%)	0.0001
Ulcerative colitis	12 (13.5%)	5 (9.4%)	17 (12.0%)	0.47
Other AD5	3 (3.4%)	8 (15.1%)	11 (7.7%)	0.01
Type of biologic
Infliximab	27 (30.3%)	0 (0.0%)	27 (19.0%)
Etanercept	5 (5.6%)	0 (0.0%)	5 (3.5%)
Adalimumab6	33 (37.1%)	0 (0.0%)	33 (23.2%)
Certolizumab pegol	23 (25.8%)	0 (0.0%)	23 (16.2%)
Golimumab	1 (1.1%)	0 (0.0%)	1 (0.7%)
Vedolizumab6	1 (1.1%)	0 (0.0%)	1 (0.7%)

Abbreviations: HELLP- hemolysis, elevated liver enzymes, low platelets; AD- autoimmune disease

¹- P-values for continuous variables were calculated using the Kruskal Wallis test. P-values for categorical variables were calculated using the Chi-square test.

²- Race and ethnicity are self-reported in the medical record.

³– One patient in Biologics group missing BMI

⁴- Definitions of obstetric conditions are as follows:

Pregnancy loss- loss of pregnancy before 24 weeks gestation

Preterm birth- live birth before 37 weeks gestation

Stillbirth- delivery of fetus with no signs of life at 24 weeks or greater gestation if gestation is known, or, weight greater than or equal to 500g if gestation is unknown.

Gestational diabetes- evidence of new onset impaired glucose tolerance after 20 weeks gestation

Preeclampsia- new hypertension with evidence of multi-systemic signs after 20 weeks gestation

HELLP syndrome- evidence of hemolysis, elevated liver enzymes and thrombocytopenia in the context of preeclampsia

Congenital abnormalities- structural or functional anomalies that occur during intrauterine life

Fetal growth restriction- estimated fetal weight or abdominal circumference <10^th percentile for gestational age

⁵– Other AD: Ankylosing spondylitis (n=5), other spondyloarthopathies (n=2), juvenile idiopathic arthritis (n=1), mixed connective tissues disorder (n=1), uveitis (n=1), Hidradenitis suppurativa (n=1)

⁶- One subject was exposed to both adalimumab and vedolizumab (monoclonal antibody therapy) during pregnancy.

The descriptive characteristics of patients were summarized as median (IQR) and compared using the Kruskal-Wallis test for continuous variables. Categorical variables are summarized using counts or percentages and compared using the chi-square test. The univariate association of each characteristic with the binary outcome of biologic exposure (yes/no) were quantified with odds ratios and the associated 95% confidence intervals. Statistical analyses were performed using SAS Version 9.4 (SAS Institute, Cary, NC).

Results

142 women with a diagnosis of autoimmune disease completed a pregnancy during the study period. Of these, 89 had anti-TNF-α biologic exposure during pregnancy and 53 had no exposure to biologic therapy during pregnancy. Short-term courses of steroids were prescribed for patients at similar rates in both the biologic and non-biologic cohort (18% and 18.9%, OR 0.94, p=0.89). Maternal characteristics between the biologic and non-biologic group were comparable (Table 1). Much of our cohort was white, did not smoke, had a BMI >25kg/m² and were multiparous. The two groups had similar rates of previous pregnancy complications such as pregnancy loss, stillbirth, and preeclampsia. Autoimmune diseases in our cohort included inflammatory bowel disease (n=80, 56.3%), rheumatoid arthritis (n=40, 28.2%), psoriasis/psoriatic arthritis (n=14, 9.9%), systemic lupus erythematous (n=2, 1.4%), Sjögren’s syndrome (n=1, 0.7%), Hashimoto’s thyroiditis (n=2, 1.4%) and myasthenia gravis (n=1, 0.7%). Patients with inflammatory bowel disease were more likely to be prescribed a biologic, whereas patients with psoriasis or psoriatic arthritis were more likely to be in the non-biologic group (p≤0.0001; p=0.03 respectively). Additionally, patients with other autoimmune disease, which included mainly spondyloarthopathies and associated conditions, were more likely to be in the non-biologic group (p=0.01) Other than these exceptions, distribution of the different inflammatory conditions was comparable between groups. Of the 89 patients who had biologic exposure during pregnancy, adalimumab was the most prescribed therapy (n=33, 23.2%), followed by infliximab (n=27, 19.0%), certolizumab pegol (n=23, 16.2%), etanercept (n=5, 3.5%), and golimumab (n=1, 0.7%). All these biologic therapies are TNF-α specific antagonists. One patient in the cohort received adalimumab as well as an anti-lymphocyte monoclonal antibody (vedolizumab). Additionally, five patients received only non-TNF-α based biologic therapies (interleukin inhibitor ustekinumab, n=1 and anti-lymphocyte monoclonal antibody vedolizumab, n=4). We performed statistical analysis including and excluding these five additional cases, and the results were comparable. Therefore, we present here the results for the cohort on anti-TNF-α specific biologic therapy.

In the studied pregnancies, exposure to biologic therapy did not lead to significant differences in the risk of developing preeclampsia, congenital abnormalities, or FGR (Table 2). However, patients exposed to biologics were less likely to develop gestational diabetes (OR 0.27 [0.08, 0.93], p=0.03), which may reflect the slightly lower average BMI in the group taking biologics. There were no differences in mode of delivery risk when taking a biologic (p=0.58). For the neonate, exposure to biologic therapy was not associated with increased risk of stillbirth, preterm birth, low APGAR scores (1 and 5 minutes) or risk of neonatal intensive care admission. There was also no difference in risk based on the sex of the fetus, and newborn weights were comparable regardless of treatment (p=0.45). Of the 142 pregnancies studied (Table 2), 10 patients (12%) with autoimmune disease had hospital admissions, 26 patients (36.9%) were prescribed emergency steroids and 6 patients (7.5%) had a change of therapy due to autoimmune disease flares. There was no statistical difference in autoimmune complications between the two cohorts based on therapy received.

Table 2.

Odds ratios for biologic exposure.

	Biologics (N=89)	No Biologics (N=53)	Odds Ratio	P value6
Current pregnancy complications 1
Preeclampsia	9 (10.1%)	2 (3.8%)	2.87 (0.60, 13.8)	0.17
Gestational diabetes	4 (4.5%)	8 (15.1%)	0.27 (0.08, 0.93)	0.03
Congenital abnormalities	2 (2.2%)	1 (1.9%)	1.20 (0.11, 13.5)	0.89
Fetal growth restriction	3 (3.4%)	2 (3.8%)	0.89 (0.14, 5.50)	0.90
Mode of delivery				0.58
Spontaneous vaginal delivery	24 (27.6%)	18 (35.3%)	Referent
Planned C/S	22 (25.3%)	9 (17.6%)	1.83 (0.68, 4.92)
Emergency C/S	19 (21.8%)	9 (17.6%)	1.58 (0.58, 4.31)
Induced labor	22 (25.3%)	15 (29.4%)	1.10 (0.45, 2.70)
Pregnancy outcomes
Livebirth	86 (98.9%)	53 (100.0%)	-	0.43
Fetal sex				0.29
Female	44 (50.6%)	21 (41.2%)	Referent
Male	43 (49.4%)	30 (58.8%)	0.68 (0.34, 1.38)
Gestational age in days: Mean (SD)2	270.3 (14.8)	270.3 (13.0)	1.00 (0.98,1.03)	0.79
Preterm birth (< 37 weeks)	15 (16.9%)	9 (17.0%)	0.99 (0.40,2.45)	0.87
Fetal weight (g): Mean (SD)3	3273.6 (603.3)	3384.8 (528.9)	-	0.45
<10th percentile weight (<2773g)4	19 (21.3%)	7 (13.2%)	1.78 (0.69, 4.58)	0.23
APGAR at 1 minute: Mean (SD)5	7.8 (1.5)	7.7 (2.1)	1.02 (0.83, 1.25)	0.39
APGAR at 5 minutes: Mean (SD)5	8.6 (0.9)	8.7 (1.0)	0.83 (0.55, 1.26)	0.20
Neonatal complications 1
NICU admission	7 (7.9%)	3 (5.7%)	1.42 (0.35, 5.76)	0.61
Special care admission	2 (2.2%)	1 (1.9%)	1.19 (0.11, 13.51)	0.89
Neonatal death < 28 days	0 (0.0%)	0 (0.0%)	-
Congenital abnormalities	1 (1.1%)	0 (0.0%)	-	0.44
No neonatal complications	80 (89.9%)	49 (92.5%)	0.73 (0.21, 2.48)	0.61
Autoimmune complications
Hospital admission due to AD	9 (10.1%)	1 (1.9%)	5.85 (0.72,47.54)	0.06
Use of emergency steroids due to AD	16 (18.0%)	10 (18.9%)	0.94 (0.39,2.26)	0.89
Change of therapy during pregnancy due to AD	5 (5.6%)	1 (1.9%)	3.10 (0.35, 27.23)	0.29
Placenta sent for pathology	43 (48.3%)	23 (43.4%)		0.576
Placental weight (g): Median (IQR)7	445.5 (387.5, 535)	460.5 (398, 523)	~	0.52
Appropriate for GA	27 (75.0%)	17 (77.8%)		0.20
Small for GA	7 (19.4%)	1 (5.6%)
Large for GA	2 (5.6%)	3 (16.7%)
Placental outcomes			-	0.32
VUE	4 (9.3%)	0 (0.0%)
No VUE	39 (91.7%)	23 (100.0%)

Abbreviations: C/S – cesarean section; NICU- neonatal intensive care unit; AD – autoimmune disease; VUE – villitis of unknown etiology; GA – gestational age

¹- Definitions of obstetric/ neonatal conditions are as follows:

Gestational diabetes- evidence of new onset impaired glucose tolerance after 20 weeks gestation

Preeclampsia- new hypertension with evidence of multi-systemic signs after 20 weeks gestation

Congenital abnormalities- structural or functional anomalies that occur during intrauterine life

Fetal growth restriction- estimated fetal weight or abdominal circumference <10^th percentile for gestational age

Congenital abnormalities- structural or functional anomalies that occur during intrauterine life

²- Missing value for gestational age from 6 charts in the biologic cohort and 4 charts in the non-biologic cohort.

³- Fetal weight was compared using the Kruskal-Wallis test. Missing value for fetal weight from 10 charts in the biologic cohort and 5 charts in the non-biologic cohort.

⁴- < 10^th percentile is a categorical variable so compared with Chi-Square test. This variable was set up based on the fetal weight being less than 2773 grams.

⁵- Missing value for APGAR at 1 and 5 minutes from 6 charts in the biologic cohort and 5 charts in the non-biologic cohort

⁶- P-value calculated with Chi-square test unless noted otherwise.

⁷– Comparison conducted using the Kruskal-Wallis test. Missing for 45 charts in the Biologics group and 31 in the No Biologics.

Of the 142 pregnancies studied, 66 women (46.4%) had their placenta evaluated by pathology. There were no differences noted in placental weights based on exposure to biologics, and nearly all placentas were appropriate weight for gestational age. There was a noted, but non-significant difference in biologics and small for gestational age placentas compared to no biologics (p=0.2) Of these, only 4 patients had a diagnosis of VUE and no other immune mediated pathologies, such as chronic histiocytic intervillositis or massive perivillous fibrin deposition, were noted in this cohort. There was no statistical difference in rates of VUE between the groups taking a biologic compared to those in the non-biologic group (p=0.32). Within the cohort who took biologics during pregnancy, the rate of VUE was 9.3%. In the cohort not exposed to a biologic, there were no reported cases of villitis.

In a subanalysis of the women with placental data, we compared three groups: 1) women with villitis/biologic use (n=4); 2) no villitis/biologic use (n=39); and 3) no villitis/no biologic use (n=23). In this cohort, 63.6% (n=42) had biologic exposure before 14 weeks gestation, 60.6% (n=40) had biologic exposure between 14–32 weeks gestation, and 40.9% (n=27) had biologic exposure beyond 32 weeks gestation. Among the three groups, there were no differences in risk based on mode of delivery, livebirth, preterm birth, preeclampsia, gestational diabetes, fetal growth restriction or congenital abnormalities (Table 3). APGAR scores at 1 and 5 minutes and rate of neonatal intensive care admission were comparable.

Table 3.

Comparison of villitis of unknown etiology stratified by biologic exposure.

	VUE/biologic use (N=4)	No VUE/biologic use (N=39)	No VUE/No biologic use (N=23)	P value
Current pregnancy complications
Preeclampsia	1 (25.0%)	7 (17.9%)	2 (8.7%)	0.53
Gestational diabetes	0 (0.0%)	3 (7.7%)	5 (21.7%)	0.20
Congenital abnormalities	0 (0.0%)	1 (2.6%)	1 (4.3%)	0.87
Fetal growth restriction	1 (25.0%)	2 (5.1%)	1 (4.3%)	0.26
Mode of delivery				0.88
Spontaneous vaginal delivery	0 (0.0%)	9 (23.1%)	6 (26.1%)
Planned C/S	1 (25.0%)	6 (15.4%)	4 (17.4%)
Emergency C/S	2 (50.0%)	11 (28.2%)	5 (21.7%)
Induced labor	1 (25.0%)	13 (33.3%)	8 (34.8%)
Pregnancy outcomes
Livebirth	4 (100.0%)	38 (97.4%)	23 (100.0%)	0.70
Fetal sex				0.86
Female	2 (50.0%)	24 (61.5%)	13 (56.5%)
Male	2 (50.0%)	15 (38.5%)	10 (43.5%)
Gestational age in days: Mean (SD) 2	250.0 (31.0)	268.4 (16.4)	266.2 (16.4)	0.19
Preterm (< 37 weeks)	1 (25.0%)	8 (20.5%)	4 (17.4%)	0.92
Fetal weight: Mean (SD)2	2597.5 (985.6)	3163.4 (675.0)	3282.0 (631.8)	0.22
<10th percentile weight (<2773g)	1 (25.0%)	8 (20.5%)	3 (13.0%)	0.71
APGAR at 1 minute: Mean (SD) 3	7.0 (3.4)	7.4 (1.7)	7.3 (2.5)	0.67
APGAR at 5 minutes: Mean (SD) 3	8.8 (1.3)	8.3 (1.2)	8.4 (1.3)	0.59
Neonatal complications
NICU admission	1 (25.0%)	5 (12.8%)	3 (13.0%)	0.79
Special care admission	0 (0.0%)	2 (5.1%)	1 (4.3%)	0.89
Neonatal death < 28 days	0 (0.0%)	0 (0.0%)	0 (0.0%)
Congenital abnormalities	0 (0.0%)	1 (2.6%)	0 (0.0%)	0.70
No neonatal complications	3 (75.0%)	32 (82.1%)	19 (82.6%)	0.93
Autoimmune complications
Hospital admission due to AD	0 (0.0%)	3 (7.7%)	0 (0.0%)	0.34
Use of emergency steroids due to AD	0 (0.0%)	6 (15.4%)	5 (21.7%)	0.53
Change of therapy during pregnancy due to AD	0 (0.0%)	3 (7.7%)	0 (0.0%)	0.34

Abbreviations: HELLP- hemolysis, elevated liver enzymes, low platelets; C/S- cesarean section; NICU- neonatal intensive care unit; AD- autoimmune disease; VUE – villitis of unknown etiology

¹- Definitions of obstetric/ neonatal conditions are as follows:

Gestational diabetes- evidence of new onset impaired glucose tolerance after 20 weeks gestation

Preeclampsia- new hypertension with evidence of multi-systemic signs after 20 weeks gestation

Congenital abnormalities- structural or functional anomalies that occur during intrauterine life

Fetal growth restriction- estimated fetal weight or abdominal circumference <10^th percentile for gestational age

Congenital abnormalities- structural or functional anomalies that occur during intrauterine life

²- Fetal weight was compared using the Kruskal Wallis test. Missing value for 1 patient in No VUE/biologic use

³- Missing value for 1 patient in the No VUE/No biologic use

Discussion

Treatment strategies for controlling maternal autoimmune diseases have found success with biologic therapy. Elevated levels of TNF-α are found in autoimmune conditions including rheumatoid arthritis, Crohn’s disease, systemic lupus erythematous (SLE) and antiphospholipid syndrome [5, 31]. TNF-α has also been associated with pregnancy loss and preeclampsia, as well as demonstrating a possible role in VUE [5, 32]. TNF-α upregulates expression of ICAM-1 on syncytiotrophoblast cells, which can result in inappropriate trafficking of T cells into the intervillous space, a hallmark of chronic placental inflammation [33]. It is posited, that TNF-α upregulation in women with autoimmune disease may lead to higher levels of pro-inflammatory cytokines and chemokines in syncytiotrophoblasts and consequent VUE [34]. Most anti-TNF-α therapies can enter the placental circulation, with detectable levels observed in infant blood for up to 7 months after delivery [5, 35]. Certolizumab is pegylated and lacks an IgG Fc region, meaning that both its size and its lack of binding to the FcRn receptor prevent trans-placental passage [36–39].

A recent meta-analysis examining biologic exposure during pregnancy found no increase in obstetric or neonatal adverse events [10]. Generally, biologic therapy should be continued in pregnancy as the benefits of controlled disease outweigh the risks [5, 10, 40–42]. Our data support this as we observed no difference in adverse pregnancy outcomes between those taking or not taking a biologic. We add additional data to the body of evidence suggesting that biologic therapy is safe for use during pregnancy. Our cohorts had low rates of pregnancy complications such as preeclampsia and FGR in both the biologic and non-biologic groups, comparable to the background population risk. It has been reported that women with autoimmune disease have higher rates of obstetric complications [2, 3]. The low rates we report likely reflect well-controlled disease in a medically engaged population at a tertiary hospital. This is supported by our observations of low hospital admissions and therapy escalation due to autoimmune flares during the pregnancies studied. Cohorts of pregnant patients without controlled disease would be an important comparator group for a future study.

Our study uniquely evaluated placental health and inflammatory pathologies following biologic exposure. VUE is a complex and poorly understood inflammatory condition that resembles a maternal allograft response to the fetus [25–27]. VUE is diagnosed histologically after birth and is characterized by the presence of maternal CD8+ T cell infiltration into the fetal villi and stroma in the absence of infection [28]. Prevalence of VUE is between 10–15% of all pregnancies [23], and there remains a significant recurrence rate in subsequent pregnancies [23, 24, 43, 44]. There are currently no methods to predict or prevent VUE, making this a difficult diagnosis for management and counseling of patients considering a pregnancy following VUE. Anti-inflammatory treatment strategies, including aspirin, intravenous immunoglobulins, and corticosteroids, have been utilized for recurrent VUE in small case series and demonstrate favorable fetal outcomes [44–48]. Other studies have trialed biologic therapy as a treatment for recurrent pregnancy loss, which can be associated with VUE, and showed promising results [49]. However, clinical trials directly aimed at addressing the usefulness of biologics or other anti-inflammatory strategies in prevention of recurrent VUE have not been undertaken. While our results did not demonstrate an effect of biologics on reduction of VUE, our cohort was small and not focused on a population concerned with VUE recurrence. However, our results can be used to further reassure that biologic use during pregnancy is not associated with adverse pregnancy outcomes so studies directly testing anti-TNF-α for prevention of recurrent villitis are a reasonable next step.

As clinical guidelines for VUE are lacking, this could represent a new treatment option for providers and patients concerned about recurrence. Previously, autoimmune disease has been associated with increased incidence of placental inflammatory lesions, including VUE [12, 31, 49]. One study demonstrated that women with SLE had chronic villitis lesions at a rate of 28% compared to a control rate of 5.5% [31]. Autoimmune diseases are associated with upregulation of cytokines including TNF-α, which can lead to placental inflammation [5]. We might therefore expect higher incidence of placental inflammation in both our biologic and non-biologic group given the presence of maternal autoimmune diseases. However, rates of VUE in our study were comparable to background population risk of 10–15% [23]. Again, this may reflect well controlled autoimmune disease in our cohort.

Amongst the 4 cases of VUE in our cohort, the women were exposed to certolizumab pegol (n=3) and infliximab (n=1). Since certolizumab does not cross the placenta [41], this may show reduced effectiveness or increased rates of inflammation compared to biologics known to cross the placental barrier. Overall, the rate of VUE in the biologic exposed group is 9.3%, a very low rate for a cohort with autoimmune disease. However, with no cases of VUE in the non-biologic group, we can only make very modest conjecture about the effectiveness of different TNF-α biologics as it relates to development of placental inflammation. Given TNF-α is likely an important pro-inflammatory driver in many of the described mechanisms promoting VUE [25–27, 33, 50], further research examining its role, as well as the usefulness of anti-TNF-α modulation during pregnancy, may illuminate immunological mechanisms driving VUE, its short- and long-term effects to child health and development and lead to the discovery of useful tools to control or prevent it.

Some limitations to our retrospective design are that we could only include placental pathology reports on tissues sent for analysis at the time of delivery. The protocol at our institution is to send tissue for histologic evaluation only if specific maternal and fetal risk factors were present at the time of delivery [51]. Isolated autoimmune disease was not a sufficient risk factor to merit placental analyses at our center, therefore, less than half of placentas in each group were sent for histology. Only patients with additional risk factors had their placentas sent for analysis. This could introduce a selection bias in our cohort that may skew our sample towards pathological findings; however, as both groups had the same risk factors, our data did not reflect this. Newly published recommendations suggest that maternal autoimmune disease should be a criterion for pathology review [52]; therefore, it is possible these questions surrounding autoimmune disease and immune mediated pathologies will be easier to address in the future. Additionally, our cohort of patients with autoimmune disease was mainly white, making it impossible to draw conclusions about outcomes in a more racially diverse population. Another potential limitation is that there is little data on rates of VUE between patients with different autoimmune diseases. Since there was some skew in the autoimmune disease types by biologic exposure, this may be a confounding factor. For the purposes of the study, we assumed VUE risk is similar between patients with different autoimmune diseases but future studies that directly address this would be important.

Further, only a small portion of each placenta is sampled for evaluation, which could lead to missed diagnoses [53]. To mitigate this risk, our organization utilizes the guidelines developed by the College of American Pathologists and the Amsterdam Working Group for standardization of reporting [20]. Nevertheless, it is possible that pathologic areas were not analyzed, although this limitation would apply equally to both groups. Lastly, while we are pleased to present unique data on placental outcomes following biologic exposure, our numbers remain small due to the limited number of patients who had biologic treatment during their pregnancy and met criteria for pathologic review in our single study center. It is important that further study is conducted in higher numbers and across other centers to expand our understanding of placental outcomes following biologic exposure.

Conclusions

This study suggests that biologic exposure during gestation is not associated with an increased incidence of adverse pregnancy complications, adding to the growing body of evidence that use of biologics is safe during pregnancy. We also did not find evidence that biologic therapy alters the diagnosis of VUE in the placenta; however, further research is warranted to address this question in pregnant patients specifically at risk of recurrence.

Data Availability:

De-identified data will be provided by the corresponding author upon reasonable request.