Open Journal Systems

MEDICAL SPECIALITIES

Received: October 22^nd 2014

Accepted: March 6^th 2015

Maternal and fetal outcome in Mexican women with rheumatoid arthritis

Miguel A. Saavedra,^a,e Antonio Sánchez,^a Reyna Bustamante,^a Dafhne Miranda-Hernández,^a Jimena Soliz-Antezana,^a Pilar Cruz-Domínguez,^b,e Sara Morales,^d Luis J. Jara^c,e

^aDepartamento de Reumatología, Hospital de Especialidades

^bDivisión de Investigación, Hospital de Especialidades

^cDirección de Educación e Investigación

^dDepartamento de Perinatología, Hospital de Gineco-Obstetricia 3

^a,b,c,dCentro Médico Nacional La Raza, Instituto Mexicano del Seguro Social, Distrito Federal, México

^eUniversidad Nacional Autónoma de México, Distrito Federal

Communication with: Miguel A. Saavedra

Telephone: (55) 5724 5900, extensión 23219

Email: miansaavsa@gmail.com

Objective: To report our experience in maternal-fetal outcome in women with RA in a national medical referral center.

Methods: A retrospective analysis of the records of pregnant women with rheumatoid arthritis attending at a Pregnancy and Autoimmune Rheumatic Diseases Clinic was performed. Maternal-fetal outcomes such as disease activity, preclampsia/eclampsia, rate of live births, abortions, stillbirths, preterm birth, weeks of gestation, birth weight, congenital malformations and use of anti-rheumatic drugs were studied.

Results: We included 73 pregnancies in 72 patients. Disease activity was documented in 47.2% of patients during pregnancy and/or postpartum and 87.7 % of patients received some antirheumatic drug. Preclampsia developed in 8.2 % of cases. The live birth rate was 98.6 %, with preterm delivery in 15.9 % and low weight at term in 17.6% of cases. Cesarean section was performed in 77.1 % of cases. The disease activity was not associated with a higher percentage of maternal-fetal complications.

Conclusions: Our study showed that most patients do not experience significant activity of RA during pregnancy, fetal outcome is satisfactory and disease activity did not appear to influence significantly the obstetric outcome.

Keywords: Rheumatoid arthritis, Pregnancy, Preclampsia.

---

Rheumatoid arthritis (RA) is a systemic autoimmune disease that mainly involves the synovial joints. RA mostly affects women with increased prevalence after age 40, although it can also develop in women of reproductive age. The worldwide prevalence is estimated at around 1%, but it has been reported that in some regions of Mexico this prevalence is higher and it develops on average 10 years earlier compared with the population of the US and Europe.^1,2

Since the first descriptions, it has been reported that pregnancy has a beneficial effect on disease activity, resulting in an improvement of symptoms in up to 90% of cases; however, a high proportion of patients develop a relapse of the disease pospartum.^3,4 More recent studies have reported that using more objective indices to measure disease activity, this beneficial effect is less.^5,6

Pregnancy of women with RA has been linked to various maternal and fetal complications, but published studies have reported results in percentages compared with healthy pregnant women.^7-11 The information generated on this topic in other parts of the world is important; however, in Mexico it is still limited.¹² Therefore, the objective of this work is to report our experience in maternal-fetal outcomes of women with RA in a national medical center of reference.

Methods

A retrospective analysis of medical records of pregnant patients diagnosed with RA (according to EULAR/ACR 2010 criteria)¹³ served consecutively at the Clínica de Embarazo y Enfermedades Reumáticas Autoinmunes (Pregnancy and Autoimmune Rheumatic Diseases Clinic) at the Hospital de Especialidades “Dr. Antonio Fraga Mouret”, Centro Médico Nacional La Raza of the Instituto Mexicano del Seguro Social in the period January 2009 to June 2014. In general, patients were evaluated independently by rheumatologists and obstetrician-gynecologists every 4-6 weeks over the course of gestation and at least once postpartum. The treatment protocol of patients included a complete clinical evaluation, emphasizing the joint manifestations, and the determination of laboratory tests, such as complete blood work, serum creatinine, urea, uric acid, AST, ALT, serum albumin, erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, and general urinalysis. They also collected information about medications the patient was taking before, during, and after pregnancy. The treatment given to each patient was prescribed according to the criteria of the rheumatologist without an established protocol.

In addition to patient demographics, maternal and fetal complications were pulled from the record, which were considered in accordance with the following preset definitions: spontaneous miscarriage (loss of pregnancy before 20 weeks), stillbirth (intrauterine fetal death after 20 weeks of gestation), neonatal death (born alive, died within the first 28 days after birth), premature (born alive before 37 weeks of gestation), child with low birth weight born at term (< 2,500 g in child born ≥ 37 weeks gestation [GW]), congenital malformations (according to World Health Organization Classification of Disease (ICD) codes), preeclampsia (hypertension-systolic blood pressure > 140 mmHg and/or diastolic blood pressure > 90 mmHg and proteinuria > 300 mg in 24-hour urine after the 20th week of pregnancy), eclampsia (preeclampsia criteria plus seizures) and maternal infections. It was considered that the patient had the active disease if the presence of arthritis was documented in her file in more than one joint and/or of there was change of treatment (initiation or increase of dose of a disease-modifying drug and/or prednisone).

Statistical analysis included descriptive statistics of the main clinical and demographic variables, as well as of each of the maternal-fetal complications expressed as mean and standard deviation or percentages. Chi-squared was used to compare the clinical characteristics by trimester according to whether or not there was RA activity. For analysis, each pregnancy was considered as a separate event. A p ≤ 0.05 was considered statistically significant. All data were processed in SPSS version 20.0.

Results

The records of 85 pregnancies in women with RA were reviewed, of which 12 total were excluded (5 lost to follow-up, 4 diagnosed with RA during the pregnancy studied, and 3 with insufficient information). In the end, 73 pregnancies in 72 women were included for analysis. The demographic characteristics of the patients at the time of the pregnancy studied are shown in Table I. The median time of disease progression in the patients was 4.8 years, most were positive for rheumatoid factor, and one-third were in their first pregnancy.

Over the course of the pregnancy, 87.7% of the patients took a drug to control the disease; the most frequently used were prednisone in 60.3% of cases (maximum average dose of 8.3 ± 4.1 mg per day), anti-malarials (mainly chloroquine) in 72.6%, and sulfasalazine (1-3 g per day) in 20.5% of the cases. In addition, two patients received a TNF-blocking agent (etanercept or infliximab) during pregnancy due to the severity of RA activity. Two women had received rituximab within 12 months prior to conception.

42.5% of cases had some maternal-fetal complication. 8.2% of pregnancies developed preeclampsia. Five women had premature rupture of membranes. One patient presented abruption and another underwent hysterectomy for uncontrollable uterine bleeding. We did not observe serious maternal infections. 47.2% of patients had disease activity in at least one trimester or postpartum. This activity was more frequently observed in the second trimester of pregnancy and the postpartum period, compared with the first trimester with a statistically significant difference (Figure 1). In 32.8% of patients, RA activity was observed throughout pregnancy. Comparison of pregnancies affected and unaffected by RA activity showed no differences in the frequency of maternal and fetal complications (data not shown). As expected, patients with disease activity took prednisone more frequently (71.4 versus 51.4%, p = 0.01), at a greater average dose (10.2 ± 5.1 mg versus 6.9 ± 2.5 mg, p = 0.01), or sulfasalazine (37.1 versus 5.4%, p = 0.01) during pregnancy to control RA, compared to patients who did not develop activity. 

The main fetal outcomes are shown in Table II. There were two twin pregnancies whose products were born alive but who were not included in the description of anthropometric measurements. The live birth rate was nearly 100% with no miscarriages or neonatal deaths. Preterm birth was observed in 15.9% of cases, and 77.1% of births were C-sections. In 7 cases fetal distress were documented. One child developed congenital heart block in a mother with positive anti-Ro antibodies and another child was born with clubfoot.

Discussion

Our results show that a high proportion of patients remained free of RA symptoms during pregnancy. Furthermore, in those patients who had disease activity at some point during pregnancy, there was no higher percentage of maternal and fetal complications, and a high rate of live births at term with adequate birth weight was found. However, most of the patients did receive treatment for RA control.

Since the first reports, RA has been associated with improvement of symptoms during pregnancy.³ Our study showed that almost 70% of women had no significant clinical activity in this period. It is noteworthy that most of the patients received treatment for disease control, including low-dose prednisone in 60% of them, which may help control inflammatory joint activity. Also, as previously reported,³ a percentage of patients experienced recurrence of symptoms in the postpartum period. However, follow-up time of the patients was not the same for all, which may explain why the observed proportion of relapse postpartum has not been as high as in other published studies.^4,6

Despite the good clinical development of patients, a third of them showed some degree of disease activity during pregnancy. The majority of patients with articular activity was in the second trimester and postpartum. The improvement of symptoms in the third trimester in most patients has been well documented in other populations.⁶ Recent studies have reported that improvement of RA in pregnancy is perhaps less compared to the initial studies, especially when more objective methods are used to evaluate disease activity.¹⁴ Moreover, the low proportion of our patients with disease activity in the first trimester may be the result of good clinical status prior to conception, which we could not document in all cases. Moreover, the percentage of postpartum reactivation may have been influenced by the use of drugs in patients. It has been suggested that the state of activity pre-pregnancy or negativity for rheumatoid factor or antibodies against citrullinated proteins predict good clinical development over the course of gestation.^6,15 The explanation for the clinical behavior of the disease in this period seems to obey multiple hormonal and immunological factors not fully elucidated and that have undergone several revisions and will not be discussed here.^16-21

The use of antirheumatic drugs in pregnant women is an issue of particular importance due to their teratogenic potential, or the development of long-term complications that are not fully characterized.²² Almost 90% of our patients received some antirheumatic drug for disease control, such as antimalarials, sulfasalazine, and prednisone. Moreover, in some of our patients it was necessary to use doses > 20 mg of prednisone daily or TNF-blocking agents, especially in the only patient included with two pregnancies in this study. In the first of them the patient remained in remission, but in the second she developed severe disease activity throughout the entire pregnancy, which warranted the use of up to 25 mg of prednisone and infliximab in the second trimester of gestation. Nevertheless, the patient had two babies at term without complications. The use of anti-malarials and sulfasalazine is safe during pregnancy, like prednisone, although they have been associated with complications such as premature delivery and intrauterine growth restriction, which seems dependent on the dose administered.⁸ Moreover, there is growing information that the use of biological agents is not associated with increased maternal and fetal complications, but the current recommendation is to administer them only if the benefits clearly outweigh the risks.^22,23

The fetal outcome in our series can be considered satisfactory, as there was a high rate of success in live births, most at term and with good birthweight. Our results are consistent with the observations by some authors^24-26 but not by others.^7-11 Several studies have reported an increased risk of premature delivery, low birth weight, congenital malformations, and birth via cesarean section compared to the general population.^7-11 Some factors associated with the presence of these complications include RA activity and use of prednisone.⁸ However, our results could not confirm these observations since fetal outcome was similar in women with and without disease activity, also no association was found with the use of prednisone. Different methodological designs may explain the difference in results. 

Our study has some limitations. The retrospective nature of our study without a control group does not allow analysis of all the variables that can influence maternal and fetal outcome. We could not find out the clinical status of the disease prior to conception or history of use of antirheumatic drugs before pregnancy and the likely exposure in the first trimester in all patients. Furthermore, the evaluation of our patients did not have an objective method for this purpose although it must be taken into account that when using the DAS28 it is suggested to use DAS28 PCR without the global health component for the evaluation of clinical status of disease activity,¹⁴ and therefore we could not establish the degree of disease activity. However, to our knowledge this is the largest study of pregnant women with RA published in our country.

In conclusion, our study showed that two thirds of patients do not experience significant activity of RA during pregnancy, fetal outcome is satisfactory, and that disease activity does not appear to significantly influence obstetrical outcome. Multidisciplinary approach in this group of patients leads to good maternal-fetal prognosis.

References

1. Mody GM, Cardiel MH. Challenges in the management of rheumatoid arthritis in developing countries. Best Pract Res Clin Rheumatol. 2008;22:621-41.

2. Pascual-Ramos V, Contreras-Yáñez I, Villa AR, Cabiedes J, Rull Gabayet M. Medication persistence over 2 years of follow-up in a cohort of early rheumatoid arthritis patients: associated factors and relationship with disease activity and with disability. Arthritis Res Ther. 2009;11:R26.

3. Golding A, Haque U, Giles J. Rheumatoid arthritis and reproduction. Rheum Dis Clin N Am. 2007;33: 319-43.

4. Barett JH, Brennan P, Fiddler M, Silman AJ. Does rheumatoid arthritis remit during pregnancy and relapse postpartum? Results from a nationwide study in the United Kingdom performed prospectively from late pregnancy. Arthritis Rheum. 1999;42:1219-27.

5. de Man YA, Hazes JMW, van de Geijn FE, Krommenhoek C, Dolhain RJ. Measuring disease activity and functionality during pregnancy in patients with rheumatoid arthritis. Arthritis Care Res. 2007;57:716-22.

6. de Man YA, Dolhain RJE, van de Geijn FE, Willemsen SP, Hazes JMW. Disease activity of rheumatoid arthritis during pregnancy: Results from a Nationwide Prospective Study. Arthritis Care Res. 2008; 59:1241-8.

7. Reed SD, Vollan TA, Svec MA. Pregnancy outcomes in women with rheumatoid arthritis in Washington State. Matern Child Health J. 2006;10:361-10.

8. de Man YA, Hazes JM, van der Heide H, Willemsen SP, de Groot CJ, Steegers EA, et al. Association of higher rheumatoid arthritis disease activity during pregnancy with lower birth weight: results of a national prospective study. Arthritis Rheum. 2009;60: 3196-206.

9. Lin HC, Chen SF, Lin HC, Chen YH. Increased risk of adverse pregnancy outcomes in women with rheumatoid arthritis: a Nationwide population-based study. Ann Rheum Dis. 2010;69:715-7.

10. Wallenius M, Salvesen KÅ, Daltveit AK, Skomsvoll JF. Rheumatoid arthritis and outcomes in first and subsequent births based on data from a national birth registry. Acta Obstet Gynecol Scand. 2014;93: 302-7.

11. Langen ES, Chakravarty EF, Liaquat M, El-Sayed YY, Druzin ML. High rate of preterm birth in pregnancies complicated by rheumatoid arthritis. Am J Perinatol. 2014;31:9-14.

12. Álvarez-Nemegyei J, Cervantes-Díaz MT, Ávila-Zapata F, Marín-Ordoñez J. Desenlace obstétrico antes y después del inicio de la artritis reumatoide. Rev Med Inst Mex Seguro Soc. 2011;49:599-604.

13. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2010;69: 1580-8.

14. de Man YA, Dolhain RJ, Hazes JM. Disease activity or remission of rheumatoid arthritis before, during and following pregnancy. Curr Opin Rheumatol. 2014;26:329-33.

15. de Man YA, Bakker-Jonges LE, Goorbergh CM, Tillemans SP, Hooijkaas H, Hazes JM, et al. Women with rheumatoid arthritis negative for anti-cyclic citrullinated peptide and rheumatoid factor are more likely to improve during pregnancy, whereas in autoantibody-positive women autoantibody levels are not influenced by pregnancy. Ann Rheum Dis. 2010; 69:420-3.

16. Tandon VR, Sharma S, Mahajan A, Khajuria V, Kumar A. Pregnancy and rheumatoid arthritis. Indian J Med Sci. 2006;60:334-44.

17. Vázquez-Del Mercado M, Martín-Márquez BT, Petri MH, Martínez-García EA, Muñoz-Valle JF. Molecular mechanisms in normal pregnancy and rheumatic diseases. Clin Exp Rheumatol. 2006;24:707-12.

18. Ostensen M, Villiger PM. The remission of rheumatoid arthritis during pregnancy. Semin Immunopathol. 2007;29:185-91.

19. Amin S, Peterson EJ, Reed AM, Mueller DL. Pregnancy and rheumatoid arthritis: insights into the immunology of fetal tolerance and control of autoimmunity. Curr Rheumatol Rep. 2011;13:449-55.

20. Hazes JM, Coulie PG, Geenen V, Vermeire S, Carbonnel F, Louis E, Masson P, De Keyser F. Rheumatoid arthritis and pregnancy: evolution of disease activity and pathophysiological considerations for drug use. Rheumatology (Oxford). 2011;50: 1955-68.

21. Förger F, Vallbracht I, Helmke K, Villiger PM, Ostensen M. Pregnancy mediated improvement of rheumatoid arthritis. Swiss Med Wkly. 2012;142: w13644.

22. Ostensen M, Förger F. How safe are anti-rheumatic drugs during pregnancy? Curr Opin Pharmacol. 2013;13:470-5.

23. Ostensen M. Safety issues of biologics in pregnant patients with rheumatic diseases. Ann N Y Acad Sci. 2014;1317:32-8.

24. Morris WI. Pregnancy in rheumatoid arthritis and systemic lupus erythematosus. Aust N Z J Obstet Gynaecol. 1969;9:136-44.

25. Ostensen M, Aune B, Husby G. Effect of pregnancy and hormonal changes on the activity of rheumatoid arthritis. Scand J Rheumatol. 1983;12:69-72.

26. Spector TD, Silman AJ. Is poor pregnancy outcome a risk factor in rheumatoid arthritis? Ann Rheum Dis. 1990;49:12-4.

Enlaces refback

• No hay ningún enlace refback.