Changes in Circulating ProAMH and Total AMH during Healthy Pregnancy and Post-Partum: A Longitudinal Study.

Circulating Anti-Müllerian hormone (AMH) is derived from the gonads, and is a mixture of the prohormone (proAMH), which does not bind to AMH receptors, and receptor-competent AMH. The functions of a hormone are partially defined by the factors that control its levels. Ovarian reserve accounts for 55~75% of the woman-to-woman variation in AMH level, leaving over 25% of the biological variation to be explained. Pregnancy has been reported to decrease circulating AMH levels, but the observations are inconsistent, with the effect of pregnancy on the bioactivity of AMH being unknown. We have therefore undertaken a longitudinal study of circulating proAMH and total AMH during pregnancy. Serum samples were drawn at 6-8 gestational time-points (first trimester to post-partum) from 25 healthy women with prior uneventful pregnancies. The total AMH and proAMH levels were measured at each time-point using ELISA. The level of circulating total AMH progressively decreased during pregnancy, in all women (p<0.001). On average, the percentage decline between the first trimester and 36-39 weeks' gestation was 61.5%, with a standard deviation of 13.0% (range 30.4-81.2%). The percentage decline in total AMH levels associated with maternal age (R = -0.53, p = 0.024), but not with the women's first trimester AMH level. The postpartum total AMH levels showed no consistent relationship to the woman's first trimester values (range 31-273%). This raises the possibility that a fundamental determinant of circulating AMH levels is reset during pregnancy. The ratio of proAMH to total AMH levels exhibited little or no variation during pregnancy, indicating that the control of the cleavage/activation of AMH is distinct from the mechanisms that control the total level of AMH.

The lupus anticoagulant: results from 2257 patients attending a high-risk pregnancy clinic.

Routine investigation for recurrent pregnancy loss includes measurement of antiphospholipid antibodies under the perception that the lupus anticoagulant (LAC) is prevalent in this population. Our tertiary clinic sees ~250 new patients with recurrent pregnancy loss annually, in addition to those with systemic lupus erythematosus and/or antiphospholipid syndrome. We measure LAC using a 4-assay panel that expands on the 2 assays recommended by the International Society on Thrombosis and Haemostatis (ISTH) guidelines. Of 2257 patients tested for LAC during a 6-year period, 62 (2.7%) repeatedly tested positive. Only 5 patients (0.2%) had both a history of early recurrent miscarriage and LAC positivity. Patients with LAC had a significantly more frequent history of thrombosis (35.5% vs 2.4%). LAC was absent in an overwhelming majority of women with exclusively early recurrent pregnancy loss but was associated with sporadic stillbirth. Among our panel of assays, none was predominant, and an increasing number of positive assays was associated with an increased history of morbidity. Therefore, our results do not support the ISTH contention that 2 assays are sufficient to identify and describe patients with LAC. We found that a confirmed, repeated LAC was very infrequent even in a high-risk setting.

Anticardiolipin antibodies and recurrent early pregnancy loss: a century of equivocal evidence.

In 1987, Nigel Harris cautioned against over-diagnosing the antiphospholipid syndrome (APS). In what was a rather prophetic editorial titled 'The Syndrome of the Black Swan', he suggested that while patients with APS do indeed exist, they are probably much more unusual than many medical professionals might like to believe. He expressed concern that the value of studying antiphospholipid antibodies (aPLs) as interesting non-organ specific autoantibodies, would become lost in a 'sea of over-interpreted and over-reported laboratory and clinical findings'. It is our contention that 25 years later, this prediction has come to pass, particularly with respect to one type of aPL and its relation to a clinical event, namely anticardiolipin antibodies and early recurrent pregnancy loss. In this commentary, we trace the evolution of the current dogma and propose that reevaluation of available data from an alternative perspective results in quite a different understanding, the acceptance of which would necessitate not only a revision of the classification criteria for APS but also the subsequent revision of many diagnoses.

Low molecular weight heparin and aspirin for recurrent pregnancy loss: results from the randomized, controlled HepASA Trial.

OBJECTIVE: To compare live birth rates in women with recurrent pregnancy loss (RPL) and either autoantibodies or a coagulation abnormality, treated with low molecular weight heparin plus aspirin (LMWH/ASA) or ASA alone, and to place our results in context with other randomized clinical trials (RCT) with similar cohorts. METHODS: The HepASA Trial was an RCT including patients with a history of RPL and at least 1 of the following: antiphospholipid antibody (aPL), an inherited thrombophilia, or antinuclear antibody. Treatment groups were stratified by aPL status and history of early versus late pregnancy losses. Patients received either LMWH/ASA or ASA alone. The primary outcome was live birth; secondary outcomes included adverse events and bone loss at the spine and femoral neck. Literature over the past 20 years was reviewed to identify comparable RCT. RESULTS: Over 4 years, 859 women with RPL were screened: 88 (10.2%) fulfilled inclusion criteria, became pregnant and were randomized to receive either LMWH/ASA or ASA alone. aPL were present in 42 (47.7%) patients in each group. The trial was stopped after 4 years when an interim analysis showed no difference in live birth rates in the 2 groups, and a lower rate of pregnancy loss in the ASA only group than expected. In the LMWH/ASA group, 35/45 (77.8%) had a live birth versus 34/43 (79.1%) in the ASA only group (p = 0.71). Neither number of prior losses nor aPL status was correlated with pregnancy outcome. There were no cases of pregnancy related thrombosis in either group. Mean change in BMD did not differ by treatment group at either the lumbar spine (p = 0.57) or femoral neck (p = 0.15). RCT since 2000 for aPL positive women with RPL and similar inclusion criteria report a mean live birth rate of 75% with either LMWH or ASA. CONCLUSION: LMWH/ASA did not confer incremental benefit compared to ASA alone for this population. Regardless of treatment regimen, number of prior losses, or aPL positivity, almost 80% of women in our RPL cohort had a successful pregnancy outcome. These findings contribute to a growing body of literature that contests the emerging standard of care comprising LMWH/ASA for this population.

Prostaglandin E2 inhibits BMP signaling and delays chondrocyte maturation.

While cyclooxygenases are important in endochondral bone formation during fracture healing, mechanisms involved in prostaglandin E2 (PGE2) regulation of chondrocyte maturation are incompletely understood. The present study was undertaken to determine if PGE2 effects on chondrocyte differentiation are related to modulation of the bone morphogenetic protein (BMP) signaling pathway. In primary murine sternal chondrocytes, PGE2 differentially regulated genes involved in differentiation. PGE2 induced type II collagen and MMP-13, had minimal effects on alkaline phosphatase, and inhibited the expression of the maturational marker, type X collagen. In BMP-2-treated cultures, PGE2 blocked the induction of type X collagen. All four EP receptors were expressed in chondrocytes and tended to be inhibited by BMP-2 treatment. RCJ3.1C5.18 chondrocytes transfected with the protein kinase A (PKA) responsive reporter, CRE-luciferase, showed luciferase induction following exposure to PGE2, consistent with activation of PKA signaling and the presence of the EP2 and EP4 receptors. Both PGE2 and the PKA agonist, dibutyryl cAMP, blocked the induction of the BMP-responsive reporter, 12XSBE, by BMP-2 in RCJ3.1C5.18 chondrocytes. In contrast, PGE2 increased the ability of TGF-beta to activate the TGF-beta-responsive reporter, 4XSBE. Finally, PGE2 down-regulated BMP-mediated phosphorylation of Smads 1, 5, and 8 in RCJ3.1C5.18 cells and in primary murine sternal chondrocytes. Altogether, the findings show that PGE2 regulates chondrocyte maturation in part by targeting BMP/Smad signaling and suggest an important role for PGE2 in endochondral bone formation.

Incidence of postpartum thrombosis and preterm delivery in women with antiphospholipid antibodies and recurrent pregnancy loss.

OBJECTIVE: To determine the frequency of preterm deliveries and postpartum thrombotic events (TE) in pregnancies resulting in live birth in women with antiphospholipid antibodies (aPL) and a history of recurrent pregnancy loss (RPL) but without prior TE. METHODS: We reviewed the pregnancy outcomes of women referred to our clinic with a history of RPL. Prepregnancy investigation of RPL included history of TE and aPL positivity (anticardiolipin IgG and lupus anticoagulant). We recorded use of anticoagulation therapy during and after pregnancy, obstetric outcome, gestational age at delivery, and postpartum course. Included in our study were women with unexplained RPL with no history of TE attending our clinic who subsequently had pregnancies that resulted in a live birth. RESULTS: Over a 5-year period, 260 women with RPL and no history of TE had a live birth at our clinic. Eighty-seven (33.5%) were positive for aPL and 173 (66.5%) were negative for aPL. Twenty-four percent of deliveries in the aPL-positive group occurred before 37 weeks' gestation compared to 9.8% of deliveries in the aPL-negative group (p = 0.004; 95% CI 0.052-0.234). There were no antepartum TE in either group. One woman in the aPL-positive group (1.1%) had a deep vein thrombosis 3.5 weeks postpartum while receiving prophylactic anticoagulant therapy, compared to none in the aPL-negative group. CONCLUSION: A significantly higher proportion of aPL-positive patients had preterm deliveries compared to aPL-negative patients, but pregnancy-related TE was infrequent: 99.0% of aPL-positive women with a history of RPL and no prior TE who had a live birth at our clinic had an uneventful pregnancy, delivery, and postpartum course.

Postpartum management of women at increased risk of thrombosis--results of a Canadian pilot survey.

OBJECTIVE: To determine current practice patterns in the postpartum management of women at increased risk of thrombosis. METHODS: Physicians affiliated with the University of Toronto departments of Obstetrics and Gynecology, Rheumatology, Hematology, and Obstetric Medicine who provide care to pregnant women were mailed a questionnaire that presented 6 clinical scenarios involving postpartum management of a woman at risk for thrombosis, with (1) recurrent pregnancy loss and antiphospholipid antibody syndrome (APS) treated with aspirin (ASA) in the pregnancy; (2) 2 pregnancy losses and a low titer antiphospholipid antibody (aPL) treated with ASA and low molecular weight (LMW) heparin with placental insufficiency; (3) known APS and pregnancy loss treated with LMW heparin and delivered by cesarean section; (4) a previous 17 week fetal death and aPL; (5) a previous deep vein thrombosis while on oral contraception; and (6) systemic lupus erythematosus and secondary APS with a history of a stillbirth. Physicians were asked whether they would recommend postpartum coagulation, and if so to choose from a list of treatment options. RESULTS: Of the 71 questionnaires mailed, 44 were returned (62%). Three physicians replied that their practices do not include patients similar to those presented in the cases and chose not to respond to the clinical scenarios. Percentages of responders recommending treatment in each scenario were 29% for Case 1, 49% for Case 2, 63% for Case 3, 41% for Case 4, 51% for Case 5, and 58% for Case 6. Recommendation for treatment differed among medical specialties, with rheumatologists being less likely to treat in all cases. Prophylactic heparin was selected as the treatment of choice most frequently by those recommending anticoagulation 70% (84/120). CONCLUSION: Postpartum treatment recommendations for women at increased risk of thrombosis are variable across different practitioner specializations demonstrating clinical equipoise regarding therapy. More definitive research is needed and broader study of physicians involved in the care of these patients is planned to more accurately describe and understand the decision to treat these patients.

Decrease in pregnancy loss rates in patients with systemic lupus erythematosus over a 40-year period.

OBJECTIVE: To determine if there has been a statistically significant change in pregnancy loss and preterm delivery rates in patients with systemic lupus erythematosus (SLE). METHODS: We analyzed the pregnancy outcomes of our SLE patients over the past 3 years and reviewed the literature over the past 40 years. We extracted pregnancy loss and preterm delivery data from reports of postdiagnosis SLE pregnancies. Studies were grouped into 5-year periods and weighted according to sample size. Group means, calculated for each study period, were plotted using linear regression to determine significance, and compared with population norms for the same periods. RESULTS: The rate of loss in SLE pregnancies over the past 40 years decreased from a mean of 43% in 1960-1965 to 17% in 2000-2003 (r2 = 0.648). This approximates the pregnancy loss rate in the general US population. Preterm deliveries were not uniformly reported and were rarely stratified into spontaneous or physician-initiated. Prior to 1980, it was not possible to derive group means for each time period. From 1980 to 2002, however, there was a trend toward a decrease in preterm births in SLE pregnancies, although they continue to be more frequent in SLE than in the general population. CONCLUSION: Improvements in disease management and perinatal monitoring have resulted in a significant decrease in pregnancy loss in SLE over the last 40 years and a trend toward decreased preterm deliveries over the last 20 years in comparison to the general population. These advances highlight the importance of collaboration between rheumatologists and perinatologists. Given these data, the description of SLE-associated pregnancy could be revised to reflect a more positive prognosis for mother and fetus.

Antiphospholipid syndrome in systemic lupus erythematosus: is the whole greater than the sum of its parts?

This article compares the manifestations of systemic lupus erythematosus (SLE) in the presence and absence of antiphospholipid antibodies (aPLs), the hallmark autoantibodies of antiphospholipid syndrome (APS). The combination of SLE and APS appears to be of greater concern than either entity alone. APS complicates SLE by adding a vaso-occlusive factor to the inflammatory component that adversely affects the prognosis of those who have lupus and aPLs. The increase in both morbidity and mortality when both are present has significant therapeutic implications. Anticoagulation may be a safer and more appropriate therapeutic option than instituting a regimen of corticosteroids and immunosuppressive agents with all their attendant adverse effects. It falls upon the physician to clearly define the disease entity and fully evaluate the disease process.

Differential regulation of EP receptor isoforms during chondrogenesis and chondrocyte maturation.

Regulation of chondrogenesis and chondrocyte maturation by prostaglandins has been a topic of interest during recent years. Particular focus on this area derives from the realization that inhibition of prostaglandin synthesis with non-steroidal anti-inflammatory drugs could impact these cartilage-related processes which are important in skeletal development and are recapitulated during bone healing either post-trauma or post-surgery. In addition to reviewing the relevant literature focused on prostaglandin synthesis and signaling through the G-protein coupled EP receptors, we present novel findings that establish the expression profile of EP receptors in chondroprogenitors and chondrocytes. Further, we begin to examine the signaling that may be involved with the transduction of PGE2 effects in these cells. Our findings suggest that EP2 and EP4 receptor activation of cAMP metabolism may represent a central axis of events that facilitate the impact of PGE2 on the processes of mesenchymal stem cell commitment to chondrogenesis and ultimate chondrocyte maturation.

Preterm deliveries in women with systemic lupus erythematosus.

OBJECTIVE: To compare the clinical, laboratory, and demographic variables of women in our clinic with systemic lupus erythematosus (SLE) who have had a pregnancy resulting in a live birth and identify any correlations with either term or preterm delivery. METHODS: Pregnancies in women with SLE from 1999 to 2001 were retrospectively reviewed. We recorded demographic data, disease activity (SLE Disease Activity Index, SLEDAI), obstetric history, prednisone dosage, other medications taken during pregnancy, history of renal disease, and autoantibody status [including antinuclear antibody, anti-DNA, anticardiolipin IgG (aCL), and lupus anticoagulant (LAC)]. Preterm delivery was defined as gestational age at delivery < 37 weeks. We performed a literature survey using PubMed and the key words SLE, pregnancy, and outcome. RESULTS: Of the 72 pregnancies, 28 (38.9%) resulted in preterm deliveries. There were no significant differences in any demographic or disease variables measured comparing term versus preterm delivery groups. More women in the preterm group were taking > or = 10 mg/day prednisone during their pregnancy (50.0% vs 22.2%; p = 0.028), and the mean dose was significantly higher than the term group taking > or = 10 mg/day (24.8 vs 16.7 mg/day; p = 0.047). There was a higher prevalence of women with aCL IgG in the preterm group (p = 0.023). The mean weeks gestation was shorter for women positive for aCL IgG compared to the group negative for aCL (34.9 +/- 4.4 vs 37.5 +/- 3.2 weeks, respectively; p = 0.032). There was no difference in second trimester disease activity between the term and preterm groups (33.3% and 36.4% of each group had a SLEDAI of 0). However, significantly more women in the term group received no medication during their pregnancies compared to women in the preterm group (20.0% vs 0.0%; p = 0.031). CONCLUSION: The rates of preterm deliveries, premature rupture of membranes, intrauterine growth restriction, and aPL in SLE pregnancies vary considerably in published reports, most of which are retrospective analyses. Our rates closely approximate the median values for all measures. We found preterm deliveries to be associated with disease activity (as determined by the use of any medication throughout pregnancy vs no medication, and prednisone dose > or = 10 mg/day) and the presence of aCL IgG but not LAC. Our results suggest that inactive disease rather than controlled disease at the onset of pregnancy may be the determining factor in extending SLE pregnancies to full term, thereby decreasing maternal and fetal morbidity.