Prediction and Prevention of Preterm Birth: A Prospective, Randomized Intervention Trial.

OBJECTIVE: The study aimed to determine if a program of mid-trimester serum proteomics screening of women at low risk for spontaneous preterm birth (sPTB) and the use of a PTB risk-reduction protocol in those whose results indicated an increased risk of sPTB would reduce the likelihood of sPTB and its sequelae. STUDY DESIGN: Prospective comparison of birth outcomes in singleton pregnancies with mid-trimester cervical length ≥2.5 cm and at otherwise low risk for sPTB randomized to undergo or not undergo mid-trimester serum proteomics screening for increased risk of sPTB (NCT03530332). Screen-positive women were offered a group of interventions aimed at reducing the risk of spontaneous PTB. The primary outcome was the rate of sPTB <37 weeks, and secondary outcomes were gestational age at delivery, total length of neonatal stay, and NICU length of stay (LOS). Unscreened and screen-negative women received standard care. The adaptive study design targeted a sample size of 3,000 to 10,000 women to detect a reduction in sPTB from 6.4 to 4.7%. Due to limited resources, the trial was stopped early prior to data unblinding. RESULTS: A total of 1,191 women were randomized. Screened and unscreened women were demographically similar. sPTB <37 weeks occurred in 2.7% of screened women and 3.5% of controls (p = 0.41). In the screened compared with the unscreened group, there were no between-group differences in the gestational age at delivery, total length of neonatal stay, and NICU LOS. However, the NICU LOS among infants admitted for sPTB was significantly shorter (median = 6.8 days, interquartile range [IQR]: 1.8-8.0 vs. 45.5 days, IQR: 34.6-79.0; p = 0.005). CONCLUSION: Mid-trimester serum proteomics screening of women at low risk for sPTB and the use of a sPTB risk-reduction protocol in screen-positive patients did not significantly reduce the rate of sPTB compared with women not screened, though the trial was underpowered thus limiting the interpretation of negative findings. Infants in the screened group had a significantly shorter NICU LOS, a difference likely due to a reduced number of infants in the screened group that delivered <35 weeks. KEY POINTS: · Mid-trimester serum proteomics screening of women at low risk for sPTB and the use of a sPTB risk-reduction protocol in screen-positive patients did not significantly reduce the rate of sPTB, though the trial was underpowered.. · NICU LOS following sPTB was significantly shortened among women who underwent screening and risk-reduction management.. · The use of serum biomarkers may contribute to a practical strategy to reduce sPTB sequelae..

Complement activation predicts adverse pregnancy outcome in patients with systemic lupus erythematosus and/or antiphospholipid antibodies.

OBJECTIVE: Studies in mouse models implicate complement activation as a causative factor in adverse pregnancy outcomes (APOs). We investigated whether activation of complement early in pregnancy predicts APOs in women with systemic lupus erythematosus (SLE) and/or antiphospholipid (aPL) antibodies. METHODS: The PROMISSE Study enrolled pregnant women with SLE and/or aPL antibodies (n=487) and pregnant healthy controls (n=204) at <12 weeks gestation and evaluated them monthly. APOs were: fetal/neonatal death, preterm delivery <36 weeks because of placental insufficiency or preeclampsia and/or growth restriction <5th percentile. Complement activation products were measured on serial blood samples obtained at each monthly visit. RESULTS: APO occurred in 20.5% of SLE and/or aPL pregnancies. As early as 12-15 weeks, levels of Bb and sC5b-9 were significantly higher in patients with APOs and remained elevated through 31 weeks compared with those with normal outcomes. Moreover, Bb and sC5b-9 were significantly higher in patients with SLE and/or aPL without APOs compared with healthy controls. In logistic regression analyses, Bb and sC5b-9 at 12-15 weeks remained significantly associated with APO (ORadj=1.41 per SD increase; 95% CI 1.06 to 1.89; P=0.019 and ORadj=1.37 per SD increase; 95% CI 1.05 to 1.80; P=0.022, respectively) after controlling for demographic and clinical risk factors for APOs in PROMISSE. When analyses were restricted to patients with aPL (n=161), associations between Bb at 12-15 weeks and APOs became stronger (ORadj=2.01 per SD increase; 95% CI 1.16 to 3.49; P=0.013). CONCLUSION: In pregnant patients with SLE and/or aPL, increased Bb and sC5b-9 detectable early in pregnancy are strongly predictive of APOs and support activation of complement, particularly the alternative pathway, as a contributor to APOs.

Detection and confirmation of serum lipid biomarkers for preeclampsia using direct infusion mass spectrometry.

Despite substantial research, the early diagnosis of preeclampsia remains elusive. Lipids are now recognized to be involved in regulation and pathophysiology of some disease. Shotgun lipidomic studies were undertaken to determine whether serum lipid biomarkers exist that predict preeclampsia later in the same in pregnancy. A discovery study was performed using sera collected at 12-14 weeks pregnancy from 27 controls with uncomplicated pregnancies and 29 cases that later developed preeclampsia. Lipids were extracted and analyzed by direct infusion into a TOF mass spectrometer. MS signals, demonstrating apparent differences were selected, their abundances determined, and statistical differences tested. Statistically significant lipid markers were reevaluated in a second confirmatory study having 43 controls and 37 preeclampsia cases. Multi-marker combinations were developed using those lipid biomarkers confirmed in the second study. The initial study detected 45 potential preeclampsia markers. Of these, 23 markers continued to be statistically significant in the second confirmatory set. Most of these markers, representing several lipid classes, were chemically characterized, typically providing lipid class and potential molecular components using MS(2) Several multi-marker panels with areas under the curve >0.85 and high predictive values were developed. Developed panels of serum lipidomic biomarkers appear to be able to identify most women at risk for preeclampsia in a given pregnancy at 12-14 weeks gestation.

Angiogenic factor imbalance early in pregnancy predicts adverse outcomes in patients with lupus and antiphospholipid antibodies: results of the PROMISSE study.

BACKGROUND: Over 20% of pregnancies in patients with systemic lupus erythematosus (SLE) and/or antiphospholipid antibodies (APL) result in an adverse pregnancy outcome (APO) related to abnormal placentation. The ability to identify, early in pregnancy, patients who are destined for poor outcomes would significantly impact care of this high-risk population. In nonautoimmune patients, circulating angiogenic factors are dysregulated in disorders of placentation, such as preeclampsia (PE) and fetal growth restriction. OBJECTIVE: We sought to determine whether early dysregulation of circulating angiogenic factors can predict APO in high-risk SLE and/or APL pregnancies. STUDY DESIGN: We used data and samples from the Predictors of Pregnancy Outcome: Biomarkers in APL Syndrome and SLE (PROMISSE), a multicenter prospective study that enrolled 492 pregnant women with SLE and/or APL from September 2003 through August 2013. Patients were followed through pregnancy from <12 weeks gestation. Circulating levels of soluble fms-like tyrosine kinase-1 (sFlt1), placental growth factor (PlGF), and soluble endoglin were measured monthly and subjects followed up for APO, classified as severe (PE <34 weeks, fetal/neonatal death, indicated preterm delivery <30 weeks) or moderate (PE ≥34 weeks, indicated preterm delivery 30-36 weeks, growth restriction without PE). RESULTS: Severe APOs occurred in 12% and moderate APOs in 10% of patients. By 12-15 weeks, sFlt1, PlGF, and soluble endoglin levels were markedly altered in women who developed severe APO. After adjusting for clinical risk factors, sFlt1 was the strongest predictor of severe APO among 12-15 week measures (odds ratio, 17.3 comparing highest and lowest quartiles; 95% confidence interval [CI], 3.5-84.8; positive predictive value [PPV], 61%; negative predictive value [NPV], 93%). At 16-19 weeks, the combination of sFlt1 and PlGF was most predictive of severe APO, with risk greatest for subjects with both PlGF in lowest quartile (<70.3 pg/mL) and sFlt1 in highest quartile (>1872 pg/mL; odds ratio, 31.1; 95% CI, 8.0-121.9; PPV, 58%; NPV, 95%). Severe APO rate in this high-risk subgroup was 94% (95% CI, 70-99.8%), if lupus anticoagulant or history of high blood pressure was additionally present. In contrast, among patients with both sFlt1 <1872 pg/mL and PlGF >70.3 pg/mL, rate of severe APO was only 4.6% (95% CI, 2.1-8.6%). CONCLUSION: Circulating angiogenic factors measured during early gestation have a high NPV in ruling out the development of severe adverse outcomes among patients with SLE and/or APL syndrome. Timely risk stratification of patients is important for effective clinical care and optimal allocation of health care resources.

The Importance of an Evidence-based Workup for Recurrent Pregnancy Loss.

Choosing an evidence-based workup and treatment for recurrent pregnancy loss is imperative to provide best patient care and create a culture that permits rigorous research into potential (not yet evidence-based) tests and therapeutics. As health sciences technologies become more sophisticated, more precise, and less expensive, new tools may be developed that allow better evaluation and treatment of couples with recurrent pregnancy loss. The goal must remain optimizing value and adhering to evidence-based care.

Predictors of Pregnancy Outcomes in Patients With Lupus: A Cohort Study.

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.

Maternal and fetal morbidity associated with uterine rupture of the unscarred uterus.

OBJECTIVE: We sought to report obstetric and neonatal characteristics and outcomes following primary uterine rupture in a large contemporary obstetric cohort and to compare outcomes between those with primary uterine rupture vs those with uterine rupture of a scarred uterus. STUDY DESIGN: This was a retrospective case-control study. Cases were defined as women with uterine rupture of an unscarred uterus. Controls were women with uterine rupture of a scarred uterus. Demographics, labor characteristics, and obstetric, maternal, and neonatal outcomes were compared. Primary rupture case outcomes were also compared by mode of delivery. RESULTS: There were 126 controls and 20 primary uterine rupture cases. Primary uterine rupture cases had more previous live births than controls (3.6 vs 1.9; P < .001). Cases were more likely to have received oxytocin augmentation (80% vs 37%; P < .001). Vaginal delivery was more common among cases (45% vs 9%; P < .001). Composite maternal morbidity was higher among primary uterine rupture mothers (65% vs 20%; P < .001). Cases had a higher mean estimated blood loss (2644 vs 981 mL; P < .001) and higher rate of blood transfusion (68% vs 17%; P < .001). Women with primary uterine rupture were more likely to undergo hysterectomy (35% vs 2.4%; P < .001). Rates of major composite adverse neonatal neurologic outcomes including intraventricular hemorrhage, periventricular leukomalacia, seizures, and death were higher in cases (40% vs 12%; P = .001). Primary uterine rupture cases delivering vaginally were more likely to ultimately undergo hysterectomy than those delivering by cesarean (63% vs 9%; P = .017). CONCLUSION: Although rare, primary uterine rupture is particularly morbid. Clinicians must remain vigilant, particularly in the setting of heavy vaginal bleeding and severe pain.

Immunotherapy for recurrent miscarriage.

BACKGROUND: Because immunological aberrations might be the cause of miscarriage in some women, several immunotherapies have been used to treat women with otherwise unexplained recurrent pregnancy loss. OBJECTIVES: The objective of this review was to assess the effects of any immunotherapy, including paternal leukocyte immunization and intravenous immunoglobulin on the live birth rate in women with previous unexplained recurrent miscarriages. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (11 February 2014) and reference lists of retrieved studies. SELECTION CRITERIA: Randomized trials of immunotherapies used to treat women with three or more prior miscarriages and no more than one live birth after, in whom all recognized non-immunologic causes of recurrent miscarriage had been ruled out and no simultaneous treatment was given. DATA COLLECTION AND ANALYSIS: The review author and the two co-authors independently extracted data and assessed study quality for all studies considered for this review. MAIN RESULTS: Twenty trials of high quality were included. The various forms of immunotherapy did not show significant differences between treatment and control groups in terms of subsequent live births: paternal cell immunization (12 trials, 641 women), Peto odds ratio (Peto OR) 1.23, 95% confidence interval (CI) 0.89 to 1.70; third-party donor cell immunization (three trials, 156 women), Peto OR 1.39, 95% CI 0.68 to 2.82; trophoblast membrane infusion (one trial, 37 women), Peto OR 0.40, 95% CI 0.11 to 1.45; or intravenous immunoglobulin, (eight trials, 303 women), Peto OR 0.98, 95% CI 0.61 to 1.58. AUTHORS' CONCLUSIONS: Paternal cell immunization, third-party donor leukocytes, trophoblast membranes, and intravenous immunoglobulin provide no significant beneficial effect over placebo in improving the live birth rate.

Cervical length screening: a randomized trial assessing the impact on visit length and patient attitudes.

OBJECTIVES: The purpose of this study was to quantify the time required for transvaginal cervical length measurements during a second-trimester anatomy scan and to evaluate patient attitudes regarding cervical length assessment. METHODS: Consenting women were randomly assigned to one of the following: (1) standard arm-cervix visualized, no prespecified cervical length measurement; (2) sequential arm-3 transabdominal cervical length measurements obtained, transvaginal sonography performed if images were inadequate or if any measurement was 3 cm or less; and (3) screening transvaginal sonography arm-3 transvaginal cervical length measurements obtained. Times were recorded for the entire examination and cervical length evaluation. Participants completed a questionnaire at the end of their visits. RESULTS: Sixty of 230 eligible women enrolled. Demographic characteristics were similar across groups except for body mass index, which was greater in the sequential arm than the screening arm (mean ± SD, 28.5 ± 7.75 versus 24.7 ± 3.89 kg/m(2); P = .03). There were no differences in total examination times between the 3 arms (24.8 ± 8.59 versus 27.8 ± 8.75 versus 28.5 ± 7.78 minutes; P= .39). There were no differences across groups in participant attitudes regarding examination discomfort or embarrassment. CONCLUSIONS: Performing screening transvaginal sonography to measure cervical length did not have a statistically significant impact on the amount of time for completion of the entire examination. Participants had positive responses regarding cervical length assessment by transabdominal and transvaginal sonography.

Prediction of adverse pregnancy outcome by the presence of lupus anticoagulant, but not anticardiolipin antibody, in patients with antiphospholipid antibodies.

OBJECTIVE: To investigate which serologic and clinical findings predict adverse pregnancy outcome in patients with antiphospholipid antibody (aPL) and to test the hypothesis that a pattern of clinical and serologic variables can identify women at highest risk of adverse pregnancy outcome. METHODS: Women enrolled in a multicenter prospective observational study of risk factors for adverse pregnancy outcome in patients with aPL (lupus anticoagulant [LAC], anticardiolipin antibody [aCL], and/or antibody to ß2-glycoprotein I [anti-ß2 GPI]) and/or systemic lupus erythematosus (SLE) were recruited for the present prospective study. Demographic, clinical, serologic, and treatment data were recorded at the time of the first study visit. The relationship between individual and combined variables and adverse pregnancy outcome was assessed by bivariate and multivariate analysis. RESULTS: Between 2003 and 2011 we enrolled 144 pregnant patients, of whom 28 had adverse pregnancy outcome. Thirty-nine percent of the patients with LAC had adverse pregnancy outcome, compared to 3% of those who did not have LAC (P<0.0001). Among women with IgG aCL at a level of ≥40 units/ml, only 8% of those who were LAC negative had adverse pregnancy outcome, compared to 43% of those who were LAC positive (P=0.002). IgM aCL, IgG anti-ß2 GPI, and IgM anti-ß2 GPI did not predict adverse pregnancy outcome. In bivariate analysis, adverse pregnancy outcome occurred in 52% of patients with and 13% of patients without prior thrombosis (P=0.00005), and in 23% with SLE versus 17% without SLE (not significant); SLE was a predictor in multivariate analysis. Prior pregnancy loss did not predict adverse pregnancy outcome. Simultaneous positivity for aCL, anti-ß2 GPI, and LAC did not predict adverse pregnancy outcome better than did positivity for LAC alone. CONCLUSION: LAC is the primary predictor of adverse pregnancy outcome after 12 weeks' gestation in aPL-associated pregnancies. Anticardiolipin antibody and anti-ß2 GPI, if LAC is not also present, do not predict adverse pregnancy outcome.

Aspirin in Pregnancy.

Preeclampsia is associated with significant perinatal morbidity and mortality. Aspirin has been long purported and extensively studied for prevention of preeclampsia. For this reason, the U.S. Preventive Services Task Force, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine recommend its use in pregnancy for preeclampsia prevention in those at high risk. Yet, much controversy exists regarding optimal use in pregnancy with guidelines across global organizations varying. In this narrative review, we summarize the published literature related to the safety, optimal dose, and timing and duration of use of aspirin, as well as other indications for which aspirin has been studied in pregnancy.

Excluding pregnancy-associated deep vein thrombosis with whole-leg ultrasound.

Background: Deep vein thrombosis (DVT) is common in pregnancy, yet data are limited on the best diagnostic strategies in pregnant patients suspected of DVT. Objectives: We conducted a prospective cohort study to evaluate the rate of symptomatic DVT in the 90 days after a negative whole-leg compression ultrasound (CUS) in pregnant women presenting with DVT symptoms. Methods: In this prospective cohort study, we enrolled pregnant patients suspected of DVT between 2011 and 2019 who were referred to the vascular imaging laboratory at a tertiary care center and had anticoagulation held after a negative whole-leg CUS. Primary outcome was objectively confirmed DVT or pulmonary embolism or death due to venous thromboembolism (VTE). Results: Whole-leg CUS yielded normal results in 186 patients (97.9%) and identified DVT in 4 (2.1%). The mean age was 30 and 164 were White. Among the 186 patients with a negative, initial whole-leg CUS who did not receive anticoagulation, there were 2 DVT events identified over the 90-day follow-up period, for an overall rate of 1.1% (95% CI: 0.2-3.4%). The study was terminated before full planned accrual for administrative reasons. Conclusion: The rate of symptomatic DVT is low in pregnant patients who have a single, negative whole-leg CUS and did not receive anticoagulation. Adequately powered studies should prospectively assess whole-leg CUS in a larger population alone and in combination with pre-test probability scores and/or D-dimer to determine its role in the evaluation of suspected DVT in pregnancy.

Pregnancy outcomes in a recurrent preterm birth prevention clinic.

OBJECTIVE: We sought to compare rates of recurrent spontaneous preterm birth (PTB) and neonatal morbidity between women enrolled in a recurrent PTB prevention clinic compared to those receiving usual care. STUDY DESIGN: This was a retrospective cohort study of women with a single, nonanomalous fetus and ≥1 spontaneous PTB <35 weeks. Women enrolled in a recurrent PTB prevention clinic were compared to those receiving usual care. The recurrent PTB prevention clinic was consultative and included 3 standardized visits. Usual-care patients were treated by their primary provider. The primary outcome was recurrent spontaneous PTB <37 weeks. RESULTS: Seventy recurrent PTB prevention clinic and 153 usual-care patients were included. Both groups had similar pregnancy histories. Recurrent PTB prevention clinic patients had increased utilization of resources, had lower rates of recurrent spontaneous PTB (48.6% vs 63.4%, P = .04), delivered later (mean 36.1 vs 34.9 weeks, P = .02), and had lower rates of composite major neonatal morbidity (5.7% vs 16.3%, P = .03). CONCLUSION: Women referred to a consultative recurrent PTB prevention clinic had reduced rates of recurrent spontaneous prematurity and major neonatal morbidity.

Idiopathic recurrent pregnancy loss recurs at similar gestational ages.

OBJECTIVE: To determine whether a correlation exists between gestational ages of idiopathic recurrent pregnancy loss (iRPL). STUDY DESIGN: Cohort of women with iRPL who had an initial loss (qualifying pregnancy [QP]) with precise documentation of gestational age. Outcomes in the immediate next pregnancy (index pregnancy [IP]) were compared between preembryonic (group I), embryonic (group II), or fetal (group III) losses in the QP. RESULTS: Three hundred thirty-four women met inclusion criteria. In their IP, group I had 41% preembryonic, 28% embryonic, and 10% fetal losses. Group II had 14% preembryonic, 53% embryonic, and 9% fetal losses. Group III had 19% preembryonic, 23% embroyonic, and 29% fetal loses. Correlation coefficient for type of loss among the QPs and IPs was 0.14, P = .009. CONCLUSIONS: Women with iRPL tend to have losses recur in the same gestational age period. Causes for RPL may be gestational age specific and should guide further investigations into causes.

An Update on Biologic Agents During Pregnancy.

Most biological agents are safe to use in pregnancy. Biologic agents may be divided into 4 risk categories: minimal, uncertain, moderate, and high. Treatment options should be individualized to each patient's disease activity, response to medication, and adverse effects. Hydroxychloroquine, sulfasalazine, azathioprine, cyclosporine A, and low-dose aspirin are considered safe. Glucocorticoids may increase the risk of gestational diabetes and gestational hypertension/preeclampsia. Nonsteroidal medication should only be used during the first trimester and for a short period during the second trimester. Limited experience with tumor necrosis factor-α inhibitor medications suggests minimal risk. Methotrexate, mycophenolate, and leflunomide are contraindicated during pregnancy.

Thromboprophylaxis and pregnancy outcomes in asymptomatic women with inherited thrombophilias.

OBJECTIVE: Our objective was to evaluate the effect of thromboprophylaxis on pregnancy outcomes in asymptomatic women with inherited thrombophilias. STUDY DESIGN: This was a retrospective cohort study of asymptomatic pregnant women with inherited thrombophilias. Medical records were reviewed for pregnancy events, diagnosis of thrombophilias, and management in subsequent pregnancies. Outcomes in women who were and were not treated with thromboprophylaxis were compared using Fisher's exact test and logistic regression. RESULTS: Fifty-three women had 75 pregnancies subsequent to their diagnosis of thrombophilia. Women treated with heparin had similar rates of live births (86% vs 82%; P = .8, Fisher's exact test) as those not treated. The odds ratio of live birth in all pregnancies for women treated with heparin was compared with untreated women and was 1.9 (95% confidence interval, 0.5-6.3). CONCLUSION: Pregnancy outcomes are often good in asymptomatic women with thrombophilias in the absence of treatment. Treatment of these women during pregnancy should be considered investigational.

Longitudinal profiling of human blood transcriptome in healthy and lupus pregnancy.

Systemic lupus erythematosus carries an increased risk of pregnancy complications, including preeclampsia and fetal adverse outcomes. To identify the underlying molecular mechanisms, we longitudinally profiled the blood transcriptome of 92 lupus patients and 43 healthy women during pregnancy and postpartum and performed multicolor flow cytometry in a subset of them. We also profiled 25 healthy women undergoing assisted reproductive technology to monitor transcriptional changes around embryo implantation. Sustained down-regulation of multiple immune signatures, including interferon and plasma cells, was observed during healthy pregnancy. These changes appeared early after embryo implantation and were mirrored in uncomplicated lupus pregnancies. Patients with preeclampsia displayed early up-regulation of neutrophil signatures that correlated with expansion of immature neutrophils. Lupus pregnancies with fetal complications carried the highest interferon and plasma cell signatures as well as activated CD4+ T cell counts. Thus, blood immunomonitoring reveals that both healthy and uncomplicated lupus pregnancies exhibit early and sustained transcriptional modulation of lupus-related signatures, and a lack thereof associates with adverse outcomes.

Variability in thyroid-stimulating hormone suppression by human chorionic [corrected] gonadotropin during early pregnancy.

OBJECTIVE: The objective of the study was to further explore relationships between human chorionic gonadotropin (hCG), TSH, and free T4 in pregnant women at 11 through 18 wk gestation. STUDY DESIGN: The design of the study was to analyze hCG in comparison with TSH and free T4, in paired first- and second-trimester sera from 9562 women in the First and Second Trimester Evaluation of Risk for Fetal Aneuploidy trial study. RESULTS: hCG is strongly correlated with body mass index, smoking, and gravidity. Correlations with selected maternal covariates also exist for TSH and free T4. As hCG deciles increase, body mass index and percent of women who smoke both decrease, whereas the percent of primigravid women increases (P < 0.0001). hCG/TSH correlations are weak in both trimesters (r2 = 0.03 and r2 = 0.02). TSH concentrations at the 25th and fifth centiles become sharply lower at higher hCG levels, whereas 50th centile and above TSH concentrations are only slightly lower. hCG/free T4 correlations are weak in both trimesters (r2 = 0.06 and r2 = 0.003). At 11-13 wk gestation, free T4 concentrations rise uniformly at all centiles, as hCG increases (test for trend, P < 0.0001), but not at 15-18 wk gestation. Multivariate analyses with TSH and free T4 as dependent variables and selected maternal covariates and hCG as independent variables do not alter these observations. CONCLUSIONS: In early pregnancy, a woman's centile TSH level appears to determine susceptibility to the TSH being suppressed at any given hCG level, suggesting that hCG itself may be the primary analyte responsible for stimulating the thyroid gland. hCG affects lower centile TSH values disproportionately.

Maternal thyroid hypofunction and pregnancy outcome.

OBJECTIVE: To estimate whether maternal thyroid hypofunction is associated with complications. METHODS: A total of 10,990 patients had first- and second-trimester serum assayed for thyroid-stimulating hormone (TSH), free thyroxine (freeT4), and antithyroglobulin and antithyroid peroxidase antibodies. Thyroid hypofunction was defined as 1) subclinical hypothyroidism: TSH levels above the 97.5th percentile and free T4 between the 2.5th and 97.5th percentiles or 2) hypothyroxinemia: TSH between the 2.5th and 97.5th percentiles and free T4 below the 2.5th percentile. Adverse outcomes were evaluated. Patients with thyroid hypofunction were compared with euthyroid patients (TSH and free T4 between the 2.5th and 97.5th percentiles). Patients with and without antibodies were compared. Multivariable logistic regression analysis adjusted for confounders was used. RESULTS: Subclinical hypothyroidism was documented in 2.2% (240 of 10,990) in the first and 2.2% (243 of 10,990) in the second trimester. Hypothyroxinemia was documented in 2.1% (232 of 10,990) in the first and 2.3% (247 of 10,990) in the second trimester. Subclinical hypothyroidism was not associated with adverse outcomes. In the first trimester, hypothyroxinemia was associated with preterm labor (adjusted odds ratio [aOR] 1.62; 95% confidence interval [CI] 1.00-2.62) and macrosomia (aOR 1.97; 95% CI 1.37-2.83). In the second trimester, it was associated with gestational diabetes (aOR 1.7; 95% CI 1.02-2.84). Fifteen percent (1,585 of 10,990) in the first and 14% (1,491 of 10,990) in the second trimester had antithyroid antibodies. When both antibodies were positive in either trimester, there was an increased risk for preterm premature rupture of membranes (P=.002 and P<.001, respectively). CONCLUSION: Maternal thyroid hypofunction is not associated with a consistent pattern of adverse outcomes. LEVEL OF EVIDENCE: II.