Racial disparities in pregnancy outcomes among women with rheumatic diseases: A systematic literature review

Abstract

Objective:

There is a limited understanding of racial disparities in adverse pregnancy outcomes (APO) among women with rheumatic diseases. The aim of our study was to conduct a systematic literature review to evaluate the impact of race on APO in women with rheumatic diseases.

Methods:

Databases were searched to find reports of APO stratified by race among women with rheumatic diseases. The initial searches were conducted in July 2020 and updated in March 2021. Of the final included articles, the full text was reviewed, and data was extracted from each study using a standard data abstraction form.

Results:

Ten studies with a total of 39,720 patients met our eligibility criteria. There was a greater propensity for APO in racial minorities with rheumatic diseases compared to their White counterparts. Among women with systemic lupus erythematosus (SLE), Black women had the highest odds of APOs, particularly those with a concomitant diagnosis of antiphospholipid syndrome. Pooled meta-analysis could not be done due to multiple factors, including heterogeneity between studies.

Conclusion:

Racial minorities with rheumatic diseases are more prone to APO compared to their White counterparts. One limitation is the lack of standardized criteria for APO, which prohibited direct comparison between studies. There is also a paucity of data looking at APOs among women with rheumatic diseases other than SLE. Further research is needed to explore the drivers of these racial disparities to guide targeted solutions for those in the greatest need.

INTRODUCTION

Rheumatic diseases predominantly affect women with over 70% of prevalent cases in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) [1]. Moreover, these diseases commonly affect women of child-bearing age. Women with rheumatic diseases have been found to have a higher frequency of adverse pregnancy outcomes (APOs) [2, 3]. In a study by Sugawara et al, pregnancies with rheumatic diseases were more likely to encounter preterm delivery and emergency cesarean section compared to the general obstetric population [4].

Racial disparity is a contributor to the prevalence of APOs in both women with rheumatic diseases and the general population. The 2015 National Vital Statistics Report demonstrated that Hispanic births had a higher incidence rate of preterm birth and term low birth rate compared to non-Hispanic White births. Additionally, non-Hispanic Black births were 1.5 times more likely to encounter preterm birth and more than twice as likely to have term low birth weight [5]. In a study that utilized the Nationwide Inpatient Sample, Black and Hispanic women with SLE had higher rates of cesarean section delivery, fetal growth restriction, and preterm labor, with preterm labor occurring in only 14.3% of White women with SLE compared to 24.7% and 20.6% in Black and Hispanic patients, respectively [6]. Thus, race and rheumatic diseases are independently associated with adverse birth outcomes. Yet, the overall association of race with adverse birth outcomes in women with rheumatic diseases is unknown. Prior studies have investigated aspects of this issue; however, limitations of rheumatic disease type and race ascertainment prevent single studies from synthesizing a complete analysis. The aim of this study was to conduct a systematic literature review of observational studies of women with rheumatic diseases focusing on the association between race and APOs.

PATIENTS AND METHODS

This systematic review was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) guidelines [7].

Data sources and search strategies

A trained research librarian (DL) developed a systematic search strategy in PubMed and then translated it to create comparable strategies for Embase and CINAHL Complete. The search strategies (Supplemental Table 1) incorporated controlled vocabulary terms and text words appropriate to each database to represent the concepts of race and ethnicity, pregnancy and birth outcomes, and rheumatic diseases. The three databases were originally searched from inception to July 28, 2020, and the searches were updated on March 14, 2021. Search results were limited to English-language publications, and conference abstracts from Embase were included only if they were published between 2015 and 2021.

Identification of eligible studies

The studies retrieved from the searches were divided among three reviewers (GS, MS, IH), who evaluated them against a set of a priori inclusion and exclusion criteria. Inclusion criteria consisted of 1) women with rheumatic diseases, 2) study evaluating adverse birth/maternal outcomes, 3) race as predictors of adverse pregnancy outcomes, and comparisons among different races. Exclusion criteria were conference abstracts published prior to 2015, non-English studies, and the following study designs: basic science, reviews, meta-analysis, and animal studies.

Data abstraction and quality assessment

The full text of eligible articles was reviewed independently by three reviewers (GS, IH, MS), and data was extracted from each study using a standard data abstraction form. Variables extracted from each study included characteristics (such as location and study period), type of rheumatic disease(s), whether race was used as a predictor of adverse outcomes, and exposure/outcomes ascertainment (type of study, how race was reported, how maternal/birth outcomes were determined, and what race comparisons were performed). The completed data abstraction forms were compared and any discrepancies between reviewers were resolved by an independent reviewer (NS) after thorough discussions. The Newcastle-Ottawa scale was used to assess study quality [8].

RESULTS

A total of 1,540 articles were identified after elimination of duplicates. Study abstracts were screened against the inclusion and exclusion criteria resulting in the removal of 1,477 articles (Figure 1). The most common reason for exclusion was lack of adverse maternal/birth outcomes. Other reasons included articles that were case reports, case series, or reviews, non-English articles, and studies not based on rheumatic diseases. After undergoing the exclusion process, a full-text review was done on 27 articles. Seventeen of these articles were further excluded due to race not being utilized as a predictor of APOs (n=11), lack of race comparisons (n=2), less recognized race (n=2), single race study (n=1), and duplicate study (n=1). Ten studies were utilized in the qualitative analysis. Due to considerable heterogeneity between the study populations, a meta-analysis could not be conducted.

Figure 1.

PRISMA Flow Diagram showing study selection process

Characteristics of the included studies

The characteristics of included studies are summarized in Table 1. The systematic literature review identified eight cohort studies (two prospective and six retrospective) and two cross-sectional studies. The study period spanned from 2003 – 2019 and a total of 39,720 patients were included in the qualitative analysis. Sample sizes of the studies ranged from 102 – 21,165 patients. Seven studies were conducted in North America, one in Spain, one in Malaysia, and one was multi-national. Races represented were White (non-Hispanic), Asian, Black, and Hispanic. Seven studies looked at patients with SLE with or without antiphospholipid syndrome (APS) [6, 9–14], two with SLE and rheumatoid arthritis (RA), and one with juvenile rheumatoid arthritis [15]. Seven studies assessed only fetal outcomes, and three assessed both maternal and fetal outcomes. The number of APOs evaluated was highly variable, ranging from preterm birth as the only assessed outcome [16] to ten different outcomes [6]. Individual APOs and their definitions are included in Table 1.

Table 1.

Characteristics of Included Studies

Author last name/Publication year	Continent/Country	Rheumatic disease studied	Study period	Race/ethnicity	Maternal or infant or both outcomes	Adverse Pregnancy Outcomes (APO)	Total n	Race Comparisons Performed
Kaplowitz 2017 [9]	North America	SLE, APS	Sept 2003 - July 2014	White (non-hispanic), African American, Hispanic, Asian, American Indian	Infant	Fetal death after 12 weeks of gestation, neonatal death before hospital discharge due to complications of prematurity, preterm delivery before 36 weeks gestation due to pregnancy-induced hypertension, preeclampsia, placental insufficiency, and small for gestational age (SGA) neonate	402	White vs Black, White vs Hispanic, White vs Asian
Buyon 2015 [10]	North America	SLE	Sept 2003 - Dec 2012	Non Hispanic White, Hispanic White, African American, Asian, other	Infant	Fetal death after 12 weeks’ gestation unexplained by chromosomal abnormalities, anatomical malformation, or congenital infection; neonatal death before hospital discharge due to complications of prematurity, placental insufficiency, pre-term delivery or termination of pregnancy at less than 36 weeks due to gestational hypertension, preeclampsia, or placental insufficiency; and SGA neonate, defined as one with a birthweight below the fifth percentile without anatomical or chromosomal abnormalities.	385	NonHispanic White (yes vs. no)
Clowse 2016 [6]	US	SLE	2008 – 2010	White, Black, Hispanic	Both	Preterm labor, preeclampsia, fetal growth restriction, stillbirth, premature rupture of membranes, chorioamnionitis, cervical incompetence, placental abruption, postpartum hemorrhage, gestational diabetes mellitus	10,605	White vs Black, White vs Hispanic
Andrade 2008 [11]	US (Alabama, Texas, Puerto Rico)	SLE	Unknown - June 1 2005	Hispanic- Texan, Hispanic- Puerto Rican, African American, Caucasian	Infant	Miscarriage or abortion (<20 weeks), a stillbirth (≥ 20 weeks) and/or a moderate to severe preterm baby (<34 weeks)	102	No direct race comparison
Vinet 2011[12]	Multiple (US, Canada, UK, Sweden)	SLE	Unknown	White, Black, Asian, Other	Infant	Standardized incidence ratio (SIR) of observed to expected live births	339	White vs Black, White vs Asian, White vs Other
Shaharir 2020 [13]	Malaysia	SLE	Jan 2016 - Dec 2019	Malay, Chinese, Indian	Both	APO includes early pregnancy loss (first 13 weeks), late pregnancy loss (after 13 weeks), intra-uterine death (fetal loss >= 20 weeks), intrauterine growth restriction (below 10th percentile), premature birth (before 37 weeks), preeclampsia, maternal death	153	Malay vs Chinese Malay vs Indian
Mohammed 2016 [15]	US	JRA	2011 – 2012	Caucasian, African American, Hispanic	Infant	Preterm birth (delivery > 22 wks AND <37 weeks), SGA	8,273,987 mothers (of which 1236 had JRA)	P-values for race comparisons within JRA group
Manzano-Gamero 2018 [14]	Spain	SLE and SLE plus APS	Sept 2013 - Oct 2014	Caucasian, Roma	Infant	Fetal death, abortion	150	Roma vs Caucasian
Anastasiou 2020 [17]	US (California)	SLE and RA	2016 – 2017	Caucasian, African American	Both	Intrauterine fetal demise, preeclampsia/eclampsia	11,100 SLE 10,065 RA	White vs Black
Sabih 2020 [16]	US (California)	SLE and RA	2007 – 2012	White, Black, Hispanic, Asian	Infant	Preterm Birth (less than 37 weeks)	2,309 with RA and 2,874 women with SLE	White vs Black White vs Hispanic White vs Asian Black vs Hispanic Black vs Asian Asian vs Hispanic

Abbreviations: APS- antiphospholipid syndrome; JRA- Juvenile rheumatoid arthritis; RA- rheumatoid arthritis; SLE- systemic lupus erythematosus; UK- United Kingdom; US- United States

Relationship between race and APOs

Four of the five studies directly comparing Black and White patients found Black patients had a higher rate of APOs [6, 9, 16, 17]. They included women with SLE (with and without APS) and RA. Both maternal and infant APOs were evaluated. Kaplowitz et al found that among women with SLE but without APS, Blacks had higher odds of APOs compared to Whites (OR 2.7 [95% CI 1.3–5.5]) using an unadjusted logistic regression model. After adjusting for age, socioeconomic status, and other clinical variables, the difference between both races was no longer statistically significant (OR for Black women versus White women = 1.9 [95% CI 0.8 – 4.5]). Women with SLE and APS had higher odds of APOs than those with just SLE, within all racial groups. Even after adjustment for the exact variables as before, Black women with SLE and APS had significantly higher odds of APOs than White women (OR 22.2 [95% CI 2.1–232.8]). The study by Vinet et al [12] looked at favorable pregnancy outcomes, such as the number of live births in women in SLE rather than APOs. They found that Black women had increased live birth rates (standardized incidence ratio 1.47 [95% CI 1.08–2]) compared to White, Asian, and other races.

Three studies directly compared Hispanic and White patients [6, 9, 16] and all found that Hispanic patients had a higher rate of APOs in women with SLE (with and without APS) and RA. Clowse et al [6] found that Hispanic women with SLE had higher rates of preeclampsia, preterm labor, fetal growth restriction, and postpartum hemorrhage after adjusting for various clinical and socioeconomic factors.

Asian patients were included in five studies, but only three of them carried out comparisons with other races [9, 12, 13]. Kaplowitz et al [9] found that in SLE patients with and without APS, Asians had higher odds of APOs compared to White patients without APS. This was true for both the unadjusted and adjusted logistic regression models although the confidence interval did not exclude the absence of effect (OR 5.5 [95% CI 0.9–35.5] and OR 6.1 [95% CI 0.8– 47.1], unadjusted and adjusted, respectively). Shaharir et al found that Indian patients with SLE had a higher rate of APOs (90.5%) compared to Chinese (58.8%) or Malay (58.9%) patients (p<0.05). Vinet et al [12] found that Asian ethnicity was associated with the fewest live birth rates compared to Black and White patients (standardized incidence ratio 0.5 [95% CI 0.28–0.89]). Table 2 shows the methodological quality of all studies using the Newcastle-Ottawa scale. Most studies were of moderate to high quality.

Table 2.

Risk of bias assessment for included cohort studies per the Newcastle Ottawa Scale

		Selection			Comparability		Outcome
Studies	Representativeness of exposed cohorts	Selection of the nonexposed cohort	Ascertainment of exposure	Demonstration that outcome of interest was not present at start of study	Comparability of cohorts on the basis of the design or analysis		Assessment of outcome	Was follow up long enough	Adequacy of follow up of cohorts
					Controls for Age	Controls for any additional factor
Kaplowitz	*	*	*	*	*	*	*	*	*
Buyon	*	*	*	*	*	*	*	*	*
Clowse	*	*	*	*	*	*	*	*	*
Andrade	*	*	*	*	*		*	*	*
Vinet	*	*	*	*	*	*	*	*	*
Shahrir	*			*			*	*	*
Mohamed	*	*	*	*	*	*	*	*	*
Manzano-Gamero	*			*	*	*	*	*	*
Anastasiou	*	*	*	*	*	*	*	*	*
Sabhi	*	*	*	*	*	*	*	*	*

A study can be awarded a maximum of one star (*) for each item within the Selection and Outcome categories. A maximum of two stars can be given for Comparability

DISCUSSION

This systematic literature review highlights the greater propensity for APO in racial minorities with rheumatic diseases compared to their White counterparts. Most of the studies that met inclusion criteria examined outcomes among women with SLE [6, 9–14]. Studies frequently diverged in variables that were adjusted for or served as independent variables in models, including clinical variables, age, insurance status, socioeconomic status, medical conditions, and medication use. Few studies focused on racial disparities in APOs among women with RA.

Among women with SLE, Black women had the highest odds of APOs, particularly with a concomitant diagnosis of SLE and APS. Additionally, among Hispanic patients, with and without APS, the rate of APOs was higher in SLE and RA, with higher rates of preeclampsia, preterm labor, fetal growth restriction, even after adjustment for various clinical and socioeconomic factors. These studies highlight the racial disparities in APOs regardless of other variables; however, this could have been attributed, in some cases, to socioeconomic differences, such as fewer years of education, as described in the LUMINA study by Andrade et al, which did not find a clear correlation with ethnicity per se but did find fewer years of education as an important determinant of APOs. Furthermore, Black and Hispanic women have been found to have higher rates of renal involvement, which was also found to be an independent predictor of APOs.

Two studies focused on women with RA [18, 19] and one focused on pregnancy outcomes in women with juvenile rheumatoid arthritis (JRA) [15]. Mohammed et al [15] observed that White mothers with JRA were the least likely to have a preterm birth (OR 1.78 [95% CI 1.41–2.42]) and that Hispanic women were the most likely (OR 4.43 [95% CI 2.97–6.62]). Sabih et al [19] concluded that Black women with RA were significantly more likely to have preterm birth than White, Hispanic, or Asian women at 1.3–1.5 times the rate. While Sabih et al only looked at preterm birth as an APO, Mohammed et al evaluated preterm birth and poor fetal birth as outcomes; only preterm birth showed a significant difference. In the study by Anastasiou et al [18], while measuring intrauterine fetal demise (IUFD) and preeclampsia/eclampsia, they found no significant difference between White and Black women. Additionally, they concluded that differences between IUFD and preeclampsia/eclampsia were only prevalent in SLE and not RA.

As evidenced in our study, racial disparities in birth outcomes among women with RA have been understudied, leading to a scarcity of data and an inability to pool data given high heterogeneity. In addition, all the RA studies focused on only a few APOs, limiting the breadth of evidence collected.

While conducting this systematic review, we found several studies that were closely related to our subject matter but were not eligible to be included in the review due to the racial groups studied or the type of study not meeting inclusion criteria. As an example, in the study by Feld et al [20], Jewish and Arab SLE patients were compared and there was an insignificant difference in the likelihood of APO. The authors cited several possible reasons for this outcome, including that Israeli healthcare is public resulting in equal access to all patients. Another study by Mbuli et al [21] observed that neonates born to Black African mothers had significantly lower rates of survival compared to neonates born to mothers of mixed ancestry (5.6% vs 94.4%; p=0.001). Njagu et al [22] conducted a meta-analysis consisting of three cohort studies that included women with SLE. In these studies, race was classified as White or non-White and each study was analyzed individually. Researchers concluded that there was a higher risk of fetal loss among non-White women than their White counterparts (OR 1.96 [95% CI 1.05–3.77]). In addition, researchers considered the effect of lupus nephritis on adverse birth outcomes, as Black and Hispanic women have a higher prevalence of lupus nephritis. Although a history of nephritis had no effect on fetal loss, White women with a history of nephritis had increased risk of preeclampsia (OR 3.57 [95% CI: 0.92–13.92]) and among Non-white women, those with a history of nephritis had an increased rate of high disease activity during pregnancy (OR 3.22 [95% CI 1.40–7.43]). Finally, Kharbanda [23] et al studied a cohort of Indian patients with systemic sclerosis (SSc) and compared results with SSc cohorts of Italian [24] and Brazilian patients [25]. They noted higher rates of spontaneous abortion than the Italian cohort (OR 5.8 [95% CI 1.2–27]), an increased frequency of lower section cesarean section (LSCS) (OR 9.4 [95% CI 1.16–76]), and a lower rate of live births (60 vs 90%, OR 0.05 [95% CI 0.003–0.5]); their rates were comparable to Brazilian cohort of women with SSc.

One potential hypothesis for explaining these racial disparities could be that they reflect differences in socio-economic status (SES) among the different racial groups, which ultimately leads to APOs (Figure 2). To this extent, after Kaplowitz et al [9] adjusted for SES variables in women with SLE without aPL, there were no longer significant differences in odds of APO for any of the minority women, suggesting that, indeed, SES variables had a significant influence on pregnancy outcomes, just as they do for other health outcomes in SLE [26]. However, among women with SLE with APS, neither clinical nor SES factors accounted for the elevated rates of APO, suggesting that other factors such as genetics or increased stress levels likely play a role in this association. Among women with RA, it has been shown that RA disease severity in early pregnancy is predictive of preterm delivery and small for gestational age (SGA) [27]. Greenberg et al [28] showed that among patients with RA, disparities persist in disease activity and clinical outcomes for minority groups versus patients who are White. It remains plausible that this differential disease activity by racial group could account for the racial differences in APOs in patients with RA.

Figure 2.

Conceptual framework explaining potential factors driving adverse pregnancy outcomes in women with rheumatic diseases

Our study has several strengths. No restrictions were set on the study period which allowed for a wide range of studies to be examined. We tried to evaluate racial disparities in a wide range of rheumatic diseases and for any pregnancy outcomes, although most of the identified studies focused on women with SLE.

Our study also has a few limitations. A primary shortcoming was the high heterogeneity of studies with significant differences in the methodology of the studies, the outcomes recorded, and the intention of the study, which precluded doing a quantitative analysis. The definition of an APO varied in many of our included studies. While many studies included several of the same infant and mother outcomes (such as preeclampsia, hypertension, prematurity, or abortion), no studies shared the exact same definitions. Moreover, several studies only examined a single birth outcome, such as expected to observed live births or preterm birth. Thus, we are unable to analyze the impact of race on a specific APO.

In summary, in this systemic literature review, racial minorities with rheumatic diseases were more likely to experience an APO compared to White women. However, the majority of the available APO data exists in women with SLE and RA, and studies on APO in other rheumatic conditions are sparse. There are also inconsistencies in how APOs are defined and measured. Standardizing the definition for APO in association to rheumatological diseases might allow direct comparison between studies. Recognizing these disparities between the different racial groups is critical to design future studies to understand the drivers of these disparities and facilitate the formulation of targeted solutions to help those in the greatest need.