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Predictors of Pregnancy Outcomes in Patients With Lupus: A Cohort StudyPredictors of Pregnancy Outcomes in Patients With Lupus

Jill P. Buyon, MD; Mimi Y. Kim, ScD; Marta M. Guerra, MS; Carl A. Laskin, MD; Michelle Petri, MD, MPH; Michael D. Lockshin, MD; Lisa Sammaritano, MD; D. Ware Branch, MD; T. Flint Porter, MD, MPH; Allen Sawitzke, MD; Joan T. Merrill, MD; Mary D. Stephenson, MD, MSc; Elisabeth Cohn, BA; Lamya Garabet, MD; and Jane E. Salmon, MD
[+] Article, Author, and Disclosure Information

This article was published online first at www.annals.org on 23 June 2015.


From New York University School of Medicine, Hospital for Special Surgery, Albert Einstein College of Medicine, and Weill Cornell Medical College, New York, New York; University of Utah Health Sciences Center and Intermountain Healthcare, Salt Lake City, Utah; Oestfold Hospital Trust, Fredrikstad, Norway; University of Toronto, Toronto, Ontario, Canada; Oklahoma Medical Research Foundation and the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Johns Hopkins University School of Medicine, Baltimore, Maryland; and University of Illinois at Chicago, Chicago, Illinois.

Financial Support: The PROMISSE study and all authors except Drs. Sawitzke and Garabet were supported by RO1 AR49772 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. Drs. Lockshin and Salmon received additional support from the Mary Kirkland Center for Lupus Research, and Dr. Salmon also received support from Rheuminations. Dr. Petri received additional support from the National Institutes of Health (NIH AR43727).

Disclosures: Dr. Buyon reports grants from the National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases during the conduct of the study. Dr. Kim reports grants from the National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases during the conduct of the study. Ms. Guerra reports grants from the National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases during the conduct of the study. Dr. Laskin reports grants from the National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases during the conduct of the study. Dr. Petri reports grants from the National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases during the conduct of the study. Dr. Lockshin reports grants from the National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases during the conduct of the study. Dr. Sammaritano reports grants from the National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases during the conduct of the study. Dr. Branch reports grants from the National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases during the conduct of the study. Dr. Porter reports grants from the National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases during the conduct of the study. Dr. Merrill reports grants from the National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases and a subcontract from the principal investigator's funding from the National Institutes of Health during the conduct of the study. Dr. Stephenson reports grants from the National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases during the conduct of the study. Ms. Cohn reports grants from the National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases during the conduct of the study. Dr. Salmon reports grants from the National Institutes of Health, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and Rheuminations during the conduct of the study. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOf InterestForms.do?msNum=M14-2235.

Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer.

Reproducible Research Statement:Study protocol and data set: Because the investigative team is still analyzing the data for biomarkers and genetics, at this time, the authors are not willing to make the protocol or data public except for what is currently published at ClinicalTrials.gov (NCT00198068). Statistical code: Not available.

Requests for Single Reprints: Jill P. Buyon, MD, NYU/Langone Medical Center, 550 First Avenue, MSB 607, New York, NY 10016, or Jane E. Salmon, MD, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021.

Current Author Addresses: Dr. Buyon: NYU/Langone Medical Center, 550 First Avenue, MSB 607, New York, NY 10016.

Dr. Kim: Albert Einstein College of Medicine, 1300 Morris Park Avenue, Belfer Building, Room 1303, Bronx, NY 10461.

Ms. Guerra and Drs. Lockshin, Sammaritano, and Salmon: Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021.

Dr. Laskin: LifeQuest Centre for Reproductive Medicine, 655 Bay Street, Suite 1800, Toronto, Ontario M5G 2K4, Canada.

Dr. Petri: Division of Rheumatology, Johns Hopkins University School of Medicine, 1830 East Monument Street, Suite 7500, Baltimore, MD 21205.

Dr. Branch: University of Utah Health Sciences Center, 30 North 1900 East, Room 2B200 SOM, Salt Lake City, UT 84132.

Dr. Porter: University Hospital, 50 North Medical Drive, Salt Lake City, UT 84132.

Dr. Sawitzke: University of Utah Health Sciences Center, 30 North 1900 East, SOM 4B200, Salt Lake City, UT 84132.

Dr. Merrill: Oklahoma Medical Research Foundation, 825 NE 13th Street, MS 22, Oklahoma City, OK 73104.

Dr. Stephenson: Department of Obstetrics and Gynecology, University of Illinois College of Medicine, 820 South Wood Street, MC 808, Chicago, IL 60612.

Ms. Cohn: 1219 South Lamar Boulevard, Austin, TX 78704.

Dr. Garabet: Oestfold Hospital Trust, Cicignongata 19, 1603 Fredrikstad, Norway.

Author Contributions: Conception and design: J.P. Buyon, M.Y. Kim, M.M. Guerra, M. Petri, M.D. Lockshin, L. Sammaritano, T.F. Porter, J.E. Salmon.

Analysis and interpretation of the data: J.P. Buyon, M.Y. Kim, M.M. Guerra, M. Petri, M.D. Lockshin, L. Sammaritano, D.W. Branch, A. Sawitzke, J.T. Merrill, J.E. Salmon.

Drafting of the article: J.P. Buyon, M.Y. Kim, M.M. Guerra, M. Petri, M.D. Lockshin, T.F. Porter, L. Garabet, J.E. Salmon.

Critical revision of the article for important intellectual content: J.P. Buyon, M.Y. Kim, M.M. Guerra, C.A. Laskin, M. Petri, M.D. Lockshin, L. Sammaritano, T.F. Porter, J.T. Merrill, J.E. Salmon.

Final approval of the article: J.P. Buyon, M.Y. Kim, M.M. Guerra, C.A. Laskin, M. Petri, M.D. Lockshin, L. Sammaritano, D.W. Branch, T.F. Porter, A. Sawitzke, J.T. Merrill, M.D. Stephenson, L. Garabet, J.E. Salmon.

Provision of study materials or patients: J.P. Buyon, C.A. Laskin, M. Petri, M.D. Lockshin, L. Sammaritano, D.W. Branch, T.F. Porter, A. Sawitzke, J.T. Merrill, M.D. Stephenson.

Statistical expertise: M.Y. Kim.

Obtaining of funding: T.F. Porter, J.E. Salmon.

Administrative, technical, or logistic support: M.M. Guerra, T.F. Porter, J.T. Merrill, J.E. Salmon.

Collection and assembly of data: J.P. Buyon, M.M. Guerra, M. Petri, M.D. Lockshin, L. Sammaritano, D.W. Branch, A. Sawitzke, E. Cohn, L. Garabet, J.E. Salmon.


Ann Intern Med. 2015;163(3):153-163. doi:10.7326/M14-2235
Text Size: A A A

Background: Because systemic lupus erythematosus (SLE) affects women of reproductive age, pregnancy is a major concern.

Objective: To identify predictors of adverse pregnancy outcomes (APOs) in patients with inactive or stable active SLE.

Design: Prospective cohort.

Setting: Multicenter.

Patients: 385 patients (49% non-Hispanic white; 31% with prior nephritis) with SLE in the PROMISSE (Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus) study. Exclusion criteria were urinary protein–creatinine ratio greater than 1000 mg/g, creatinine level greater than 1.2 mg/dL, prednisone use greater than 20 mg/d, and multifetal pregnancy.

Measurements: APOs included fetal or neonatal death; birth before 36 weeks due to placental insufficiency, hypertension, or preeclampsia; and small-for-gestational-age (SGA) neonate (birthweight below the fifth percentile). Disease activity was assessed with the Systemic Lupus Erythematosus Pregnancy Disease Activity Index and the Physician's Global Assessment (PGA).

Results: APOs occurred in 19.0% (95% CI, 15.2% to 23.2%) of pregnancies; fetal death occurred in 4%, neonatal death occurred in 1%, preterm delivery occurred in 9%, and SGA neonate occurred in 10%. Severe flares in the second and third trimesters occurred in 2.5% and 3.0%, respectively. Baseline predictors of APOs included presence of lupus anticoagulant (LAC) (odds ratio [OR], 8.32 [CI, 3.59 to 19.26]), antihypertensive use (OR, 7.05 [CI, 3.05 to 16.31]), PGA score greater than 1 (OR, 4.02 [CI, 1.84 to 8.82]), and low platelet count (OR, 1.33 [CI, 1.09 to 1.63] per decrease of 50 × 109 cells/L). Non-Hispanic white race was protective (OR, 0.45 [CI, 0.24 to 0.84]). Maternal flares, higher disease activity, and smaller increases in C3 level later in pregnancy also predicted APOs. Among women without baseline risk factors, the APO rate was 7.8%. For those who either were LAC-positive or were LAC-negative but nonwhite or Hispanic and using antihypertensives, the APO rate was 58.0% and fetal or neonatal mortality was 22.0%.

Limitation: Patients with high disease activity were excluded.

Conclusion: In pregnant patients with inactive or stable mild/moderate SLE, severe flares are infrequent and, absent specific risk factors, outcomes are favorable.

Primary Funding Source: National Institutes of Health.

Figures

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Appendix Figure.

Study flow diagram.

Pregnant women at <12 weeks' gestation with aPL positivity and SLE and healthy control participants were screened. Exclusion criteria included multifetal pregnancy, prednisone use >20 mg/d, blood pressure >140/90 mm Hg, urinary protein-creatinine ratio >1000 mg/g on 24-h or spot urine collection, serum creatinine level >1.2 mg/dL, screening too late in pregnancy, and previous enrollment in PROMISSE. Healthy pregnant women were enrolled if they had ≥1 successful pregnancy, no history of fetal death, <2 miscarriages at <10 weeks' gestation, and no aPLs. The current study included all PROMISSE patients who met American College of Rheumatology criteria for SLE. aPL = antiphospholipid antibody; APO = adverse pregnancy outcome; PROMISSE = Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus; SLE = systemic lupus erythematosus.

* Did not meet criteria for the primary study outcome (elective termination [n = 1], incompetent cervix [n = 2], and premature preterm rupture of membranes [n = 1]). See Table 1.

† Did not meet criteria for the primary study outcome (indicated delivery for poor obstetric history [n = 1], SLE flare [n = 1], bleeding placental abruption [n = 1], termination for complete heart block [n = 1], fetal death due to trisomy 18 [n = 1], and premature preterm rupture of membranes and/or premature labor [n = 15]). See Table 1.

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Figure.

Frequency of APOs in patients and healthy control participants.

Error bars represent 95% confidence bounds. APO = adverse pregnancy outcome; LAC = lupus anticoagulant; PGA = Physician's Global Assessment; PROMISSE = Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus; SGA = small-for-gestational-age (birthweight below fifth percentile); SLE = systemic lupus erythematosus.

* These patients were non-Hispanic white, were LAC-negative, had a PGA score ≤1, had a platelet count ≥100 × 109 cells/L, and were not treated with antihypertensive medications at baseline. They constitute a subset of “all SLE.”

† Because women enrolled in the PROMISSE control group had ≥1 successful pregnancy, no history of fetal death, <2 miscarriages at <10 weeks' gestation, and no underlying medical problems requiring treatment, their pregnancy outcomes were anticipated to be better than those in unselected healthy women, particularly nulliparous women. In addition to the APOs in the graph, the healthy control participants had 10 (5.1%) adverse outcomes that did not meet the study primary outcome definition: 2 genetic terminations at ≤23 wk; 3 premature preterm ruptures of membranes and/or spontaneous preterm births, 2 placental abruptions, and 1 delivery for fetal indications (supraventricular tachycardia and hydrops) at >23 to ≤35 wk; and 3 premature preterm ruptures of membranes and/or spontaneous preterm births at >35 wk (some women had >1 adverse outcome).

‡ From references 27 and 28. Not available for preterm birth as defined in the study.

§ Defined as delivery at <36 wk and indicated by gestational hypertension, preeclampsia, or placental insufficiency.

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Comments

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Antiphospholipids and Uterine artery Doppler are Predictors of Pregnancy Outcomes in Patients with Lupus
Posted on July 20, 2015
Lionel Carbillon, Amelie Benbara, Jeremy Boujenah, Claire de la Hosseraye, Arsene Mekinian
Assistance Publique-Hôpitaux de Paris, University of Paris 13
Conflict of Interest: None Declared
In a recent study, Buyon et al (1) assessed the predictors of adverse pregnancy outcomes (APOs) for patients with inactive or stable active systemic lupus erythematosus (SLE) in a prospective multicentric cohort including 385 patients. They identified diverse baseline predictors of APOs among which the presence of lupus anticoagulant (LAC) and antihypertensive use were the strongest, with an APOs rate as high as 58.0% and a neonatal mortality rate of 22.0%, for the women who were LAC-positive and used antihypertensives.
However, 48 women were classified antiphospholipid (aPL) positive, 34 women had LAC, and this probably mainly explained the 83 prophylactic treatment with heparin (and/or aspirin), that is usually indicated to prevent complications related to placental insufficiency in antiphospholipid syndrome (APS). Thus, the strong correlation of heparin with APOs that was found could actually reflect the link of APOs with APS and the underlying placental disease, but this association is not discussed by the authors, who did not analyze uterine artery Doppler (UAD), a key predictor of APOs in these patients.
The well-established association between the presence of aPL or LAC, and the specific complications of placental insufficiency (fetal death, preterm or small-for-gestational-age birth due to preeclampsia), may be highlighted by the abnormal persistence of high resistance index (RI) measured by UAD at 22-24 gestational age or persistent UAD notch (2, 3).
Caruso et al (2) retrospectively analyzed 28 patients with APS (of whom 46 % had positive anticoagulant). Abnormal UAD with high RI at 18-24 gestational weeks predicted birthweight <1750 g and preeclampsia with a high positive (100% and 50% respectively) and negative (88%and 94% respectively) predictive value. Venkat-Raman et al (3) included 170 patients with APS of whom 32 were LAC positive. They showed that, in the LAC+ patients, abnormal UAD with persistent bilateral notch at 22–24 weeks’ gestation identified SGA and preeclampsia with a high positive (80% and 75% respectively) and negative (94% and 94% respectively) predictive value.
Actually, abnormal UAD strongly correlates to impaired trophoblastic invasion and placental thrombosis in patients with SLE and aPLs. Prophylactic treatment with heparin (and/or aspirin) may improve the uteroplacental blood flow and is a possible confounding factor, but UAD remains predictive of APOs in treated patients and may be used in the indispensable multidisciplinary follow-up of these high risk pregnancies.

REFERENCES
1. Buyon JP, Kim MY, Guerra MM et al. Predictors of Pregnancy Outcomes in Patients With Lupus: A Cohort Study. Ann Intern Med. 2015 Jun 23. doi: 10.7326/M14-2235.
2. Caruso A, De Carolis S, Ferrazzani S, Valesini G, Caforio L, Mancuso S. Pregnancy outcome in relation to uterine artery flow velocity waveforms and clinical characteristics in women with antiphospholipid syndrome. Obstet Gynecol 1993;82:970–7.
3. Venkat-Raman N, Backos M, Teoh TG, Lo WT, Regan L, Venkat-Raman N, et al. Uterine artery Doppler in predicting pregnancy outcome in women with antiphospholipid syndrome. Obstet Gynecol 2001;98:235–42.
Author's Response
Posted on September 24, 2015
Jill P. Buyon, MD, Mimi Y. Kim, ScD, Jane E. Salmon, MD
NYU Medical Center
Conflict of Interest: None Declared
Carbillon and coauthors have commented on our recent paper (1) with a focus on antiphospholipid antibodies and Uterine Artery Doppler (UAD) as predictors of pregnancy outcomes in patients with lupus. They specifically remark on two points, one related to heparin and the other to the use of UAD. With regard to the former, their statement regarding our identification of a strong correlation of heparin with adverse pregnancy outcomes (APOs) is based on bivariate analysis but this association was no longer significant after adjusting for LAC status and other predictors in our multivariate logistic regression model. All medications were prescribed at the discretion of the treating physician, and we fully agree that heparin was likely prescribed for patients thought to be at greatest risk, many of whom had APS. This may, in part, explain the unadjusted association of heparin with APOs.

The goal of our study was to establish risk early in pregnancy with the rationale that this would enable sufficient time to intervene with novel therapies in future studies. While we fully endorse that UAD is informative in at risk pregnant patients, an abnormal finding at 22-24 weeks might be too late to reverse aberrant placentation.


1. Buyon JP, Kim MY, Guerra MM et al. Predictors of Pregnancy Outcomes in Patients With Lupus: A Cohort Study. Ann Intern Med. 2015 Jun 23. doi: 10.7326/M14-2235.

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Summary for Patients

Pregnancy Outcomes in Patients With Lupus

The full report is titled “Predictors of Pregnancy Outcomes in Patients With Lupus. A Cohort Study.” It is in the 4 August 2015 issue of Annals of Internal Medicine (volume 163, pages 153-163). The authors are J.P. Buyon, M.Y. Kim, M.M. Guerra, C.A. Laskin, M. Petri, M.D. Lockshin, L. Sammaritano, D.W. Branch, T.F. Porter, A. Sawitzke, J.T. Merrill, M.D. Stephenson, E. Cohn, L. Garabet, and J.E. Salmon.

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