Systemic sclerosis (scleroderma) and pregnancy

INTRODUCTION — Systemic sclerosis (SSc; scleroderma) is an uncommon illness with an annual incidence of 1 to 2 per 100,000 individuals in the United States and a peak onset between the ages of 30 and 50 [1,2]. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults".)

Literature on pregnancy in women with SSc was previously scarce, as most cases of this disorder occur in women past their peak reproductive years. However, as a greater number of women are choosing to have children well into their thirties and forties, the incidence of pregnancy in women with SSc is increasing.

This topic will review issues of fertility and pregnancy outcome among patients with SSc, as well as the impact of pregnancy upon disease activity.

FERTILITY — In early reports from the 1950s, women with SSc were thought to have diminished fertility because of the low incidence of pregnancy in those with preexisting disease [3]. Subsequent studies, however, showed mixed results with respect to pregnancy rates and to the frequency of pregnancy difficulties among women with SSc, both prior to and after the diagnosis.

The following findings were noted in different observational studies of women with SSc who were of childbearing age:

●A retrospective analysis of reproductive events prior to the diagnosis of SSC reported a nonsignificant threefold increase in risk of the combined endpoint of infertility and spontaneous abortion compared with controls [4]

●A higher incidence of infertility and a longer time to conceive prior to the diagnosis of SSC compared with healthy controls (odds ratio 2.3 and 2.6, respectively), but not compared with women with primary Raynaud phenomenon [5]

●Significantly more live births prior to the onset of SSc and significantly fewer live births after the onset of SSC compared with women in the general population [6]

●No difference in fertility among women with SSc compared with patients with rheumatoid arthritis and compared with healthy controls [7]

The conclusions that can be drawn from these studies are limited by their reliance upon patient recall and by a failure to usually distinguish whether women had difficulty conceiving or did not desire pregnancy.

SPONTANEOUS ABORTION — Compared with the information available concerning systemic sclerosis (SSc) and fertility, somewhat more conclusive data have been published relating to the rate of spontaneous abortion in women who become pregnant prior to an eventual diagnosis of SSc. Multiple studies (but not all) suggest that such women have an increased risk [4,8,9]. As an example, the rate of spontaneous miscarriage among pregnant women, both prior to and subsequent to a diagnosis of SSc, was assessed in one study of 14 patients [8]. The rate of spontaneous miscarriage was significantly higher among those who became pregnant prior to disease diagnosis when compared with control individuals (22 versus 14 percent). Pregnant patients with preexisting SSc also had a significantly increased rate of spontaneous abortions. A similar risk (relative risk 2.1) was noted in another report of nearly 270 women with SSc [4]. In contrast to these findings, a third study found an increased number of medically induced (but not spontaneous) abortions among patients who became pregnant after disease onset, compared with controls [9]. A 2020 meta-analysis found an increased odds ratio of 1.6 (CI 95% 1.22-2.22) of miscarriage amongst women with SSc compared with the general obstetric population [10].

Thus, miscarriage appears to be more common among those women who go on to develop SSc, but it remains unclear whether spontaneous abortions occur more frequently among those already diagnosed with the disorder. Whether a history of a spontaneous abortion may predispose a woman to subsequently develop SSc is unknown [4]. Data concerning the spontaneous abortion rate among patients with a preexisting diagnosis of SSc are also clouded by the paucity of information regarding medication use during pregnancy [11].

PREGNANCY OUTCOME — Although women with systemic sclerosis (SSc) typically have successful pregnancies, clinicians should be aware that there may be an increased risk of pregnancy complications:

●In a meta-analysis including observational data from articles on SSc and pregnancy outcomes published between 1950 and 2018, pregnancies in women with SSc had a higher risk of miscarriages, intrauterine growth restriction, preterm deliveries, and newborns with low birth weight compared with healthy controls [10].

●In one study, prospectively collected data on 99 women who had 109 births were compared with the general obstetric population (total of 3,939 deliveries) [12]. SSc patients had a significantly increased frequency of preterm delivery, intrauterine growth restriction, and low-birthweight babies. A multivariable analysis showed that corticosteroid use was associated with preterm deliveries, whereas the use of folic acid and the presence of anti-Scl-70 may be protective. However, this study is limited because of the relatively few number of pregnancies in the scleroderma group.

●Another study compared outcomes in women with SSc with those in women with rheumatoid arthritis (RA) and in control individuals [9]. A nonsignificant trend toward an increased rate of premature births among patients with SSc, compared with the other two groups, was observed. In addition, there was an increased incidence of infants small for gestational age born to women with SSc, but there was no statistically significant increase in fetal death [9,13]. An expanded study by the same group of investigators retrospectively obtained reproductive histories in 214 women with SSc and compared them with 167 women with RA and with 105 neighborhood controls [7]. The patients with SSc had more premature births and more infants small for gestational age after disease onset. However, these results are limited because the effects of age and medication use on these results were not analyzed. Immunosuppressive agents used in patients with SSc, including prednisone, may cause premature rupture of the membranes, as well as infants small for gestational age [11].

●In a cross-sectional study of 342 patients with SSC, compared with the healthy control population, adverse pregnancy outcomes (including preterm infants, low birth weight infants, and cesarean sections) were increased in the SSc pregnancies [14].

●In one study of 38 pregnancies in 26 female patients with active and or early disease, of the 33 live births, 60 percent had intrauterine growth restriction and low birth weight [15].

●Using the National Inpatient Sample (NIS) database from 2000 to 2017, the authors reported on 3740 delivery associated hospitalizations in women with SSc. Throughout this time period, the risk of adverse pregnancy outcomes (including fetal death, preterm delivery, hypertensive disorders, intrauterine growth restriction) was statistically significantly higher amongst SSc women compared with the general obstetric population. While fetal death rates improved over time, there was no decline in other adverse pregnancy outcomes [16]. (See "Safety of rheumatic disease medication use during pregnancy and lactation".)

There have been several case reports of SSc involving the cervix and perineum [17,18]. In this setting, vaginal delivery can be difficult, and elective cesarean delivery may be required.

IMPACT OF PREGNANCY UPON DISEASE ACTIVITY — Although the data are limited, pregnancy does not clearly exacerbate systemic sclerosis (SSc) [9,19]. While there are case reports of poor pregnancy outcomes in women with SSc, in one large study that included 99 women with SSC who had 109 births, the disease remained stable in most patients [12]. There were four cases of disease progression which occurred within one year of delivery. All of these women were anti-Scl-70 positive, and three of them had a disease duration of less than three years. By contrast, the Canadian Scleroderma research group reported on 45 women who became pregnant after their diagnosis of SSc and compared them with 153 SSc women who were nulliparous. Disease progression including pulmonary, kidney, and physician global assessment was not different between these two groups [20].

SSc renal crisis — Kidney disease is common in patients with SSc [21] (see "Kidney disease in systemic sclerosis (scleroderma), including scleroderma renal crisis"). In the pregnant patient, however, it is extremely difficult to distinguish kidney dysfunction due to SSc from that resulting from preeclampsia and eclampsia. One review of the literature, for example, found that seven of nine patients initially thought to have preeclampsia actually had kidney biopsy findings more consistent with SSc kidney disease [22] (see "Preeclampsia: Clinical features and diagnosis"). Another possible differential in the postpartum period is hemolytic-uremic syndrome; this disorder cannot be distinguished histologically from SSc kidney. (See "Acute kidney injury in pregnancy".)

Whether pregnancy is associated with an increased incidence of renal crisis among patients with preexisting SSc is unclear. One study of women with SSc found no enhanced incidence of renal crisis in pregnant women when compared with those who did not become pregnant [9].

An extremely high morbidity and mortality has been observed among those who develop renal crisis during pregnancy [13]. The use of angiotensin-converting enzyme (ACE) inhibitors was beneficial in one case report, but ACE inhibitors are contraindicated during pregnancy because of the risk to the fetus [23,24] (see "Adverse effects of angiotensin converting enzyme inhibitors and receptor blockers in pregnancy"). However, in the case of renal crisis during pregnancy, ACE inhibitors may be necessary to control disease, and patients should be counseled accordingly regarding the risk of these medications during pregnancy. Thus, patients with SSc and active kidney disease should be counseled regarding the high morbidity and mortality associated with pregnancy.

OTHER CONSIDERATIONS — Difficulties in delivery secondary to skin fibrosis and the aggravation of relatively minor symptoms may also occur among pregnant patients with systemic sclerosis (SSc). As an example, the increased abdominal pressure in pregnancy may exacerbate dyspepsia due to esophageal dysmotility. Some symptoms, however, may diminish; symptoms of Raynaud phenomenon generally lessen because of the vasodilatation of pregnancy [22].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Systemic sclerosis (scleroderma)".)

SUMMARY AND RECOMMENDATIONS

●Fertility – It is difficult to draw clear conclusions concerning fertility in women with systemic sclerosis (SSc) due to the very limited data that are available. Studies have shown mixed results with respect to pregnancy rates and to the frequency of pregnancy difficulties among women with SSc, both prior to and after the diagnosis. (See 'Fertility' above.)

●Spontaneous abortion – Multiple studies (but not all) suggest that women who become pregnant prior to an eventual diagnosis of SSc have an increased risk of spontaneous abortion. There are some data to suggest that pregnancy after the diagnosis of SSc is associated with higher miscarriage rate. (See 'Spontaneous abortion' above.)

●Pregnancy outcomes – Although women with SSc typically have successful pregnancies, clinicians should be aware that there may be an increased risk of pregnancy complications including an increased risk of premature births and of infants small for gestational age after disease onset; however, the impact of medication use, age, and other risk factors for prematurity on these results is not known. (See 'Pregnancy outcome' above.)

●Impact of pregnancy on SSc – Although the data are limited, pregnancy does not clearly exacerbate SSc. However, extremely high morbidity has been observed among those who develop renal crisis during pregnancy, and patients with SSc and active kidney disease should be counseled regarding the high morbidity and mortality associated with pregnancy. (See 'Impact of pregnancy upon disease activity' above and 'SSc renal crisis' above.)

●Impact of pregnancy on Raynaud phenomenon – Symptoms of Raynaud phenomenon generally lessen during pregnancy because of vasodilatation. However, difficulties in delivery secondary to skin fibrosis and the aggravation of relatively minor symptoms, such as dyspepsia, may occur among pregnant patients with SSc. (See 'Other considerations' above.)