Systemic lupus erythematosus is associated with an increased frequency of spontaneous preterm births: systematic review and meta-analysis.

OBJECTIVE: Preterm birth is one of the most frequent complications of pregnancy in women with systemic lupus erythematosus. The high indicated preterm birth proportion due to hypertensive disorders of pregnancy and/or fetal growth restriction is well known, and preventive measures and screening for early detection are performed. The risk of spontaneous preterm birth is less well recognized. This study aimed to determine the proportions of spontaneous and indicated preterm birth in pregnancies of women with systemic lupus erythematosus. DATA SOURCES: A systematic literature search using Pubmed, Embase, Web of Science, and Google Scholar was performed in June 2021. STUDY ELIGIBILITY CRITERIA: Studies in pregnant women with systemic lupus erythematosus reporting spontaneous and indicated preterm birth rates were selected. Original research articles published from 1995 to June 2021 were included. METHODS: Quality and risk of bias of the included studies were assessed using the Newcastle-Ottawa quality assessment scale. To estimate the pooled event rates and 95% confidence intervals, meta-analysis of single proportions with a random-effects model was performed. RESULTS: We included 21 articles, containing data of 8157 pregnancies in women with systemic lupus erythematosus. On average, 31% (95% prediction interval, 0.14-0.50) of the pregnancies resulted in preterm birth, including 14% (95% prediction interval, 0.04-0.27) spontaneous and 16% (95% prediction interval, 0.03-0.35) indicated preterm birth. CONCLUSION: In pregnant women with systemic lupus erythematosus, spontaneous and indicated preterm birth proportions are high. This information should be applied in (prepregnancy) counseling and management in pregnancy. The knowledge obtained by this meta-analysis paves the way for further research of associated risk factors and development of interventions to reduce spontaneous preterm birth in systemic lupus erythematosus pregnancies.

Does placental abruption cause neonatal anemia?

INTRODUCTION: Placental abruption can result in serious perinatal morbidity and mortality. However, it is not clear whether placental abruption could lead to neonatal anemia, as a direct relation has not been described yet. The objective of this study is to investigate whether there is a relation between occurrence of placental abruption and neonatal anemia. MATERIAL AND METHODS: All women with a clinical diagnoses of placental abruption between January 2016 and April 2021 in Amsterdam UMC, from both the VU University Medical Center and Amsterdam Medical Center, were included. Demographic data and delivery outcomes were collected retrospectively using the medical files. The primary outcome was neonatal anemia, defined as hemoglobin levels less than the fifth percentile for gestational age. RESULTS: A total of 65 mothers and 65 neonates were included in our study. Average gestational age was 30 + 5 weeks. Mean hemoglobin level of the neonates at birth was 16.5 g/dl (10.2 mmol/L) with hemoglobin levels comparable to the reference curve. Two neonates (3.6%) were diagnosed with anemia based on their hemoglobin level at birth, and six (9.2%) neonates received a blood transfusion within 24 h after birth. CONCLUSIONS: With this study, we found that the hemoglobin levels of the neonates born after placental abruption are comparable to the reference curve and do not show more neonates than expected below the fifth percentile for gestational age. It remains unclear whether there is fetal blood loss during a placental abruption but our results suggest that at least a big amount of fetal blood is not lost, since we did not found a large number of anemic neonates. Severe neonatal anemia in the case of placental abruption does not need to be expected.

Corrigendum to "Maternal and Perinatal Outcome in Women with Systemic Lupus Erythematosus: A Retrospective Bicenter Cohort Study".

[This corrects the article DOI: 10.1155/2017/8245879.].

Patients' perspective on aspirin during pregnancy: a survey.

OBJECTIVE: To elucidate patients' knowledge and counseling perspective on aspirin reducing the risk of hypertensive disorders of pregnancy (HDP). METHODS: A quantitative survey was performed including women who are members of the patient orgasnization Dutch HELLP Foundation due to a history of HDP. RESULTS: Awareness of the risk-reducing effect of aspirin on HDP was present in 51.9% of the 189 women. The majority was informed by their gynecologist (89.8%) and preferred to be informed by a gynecologist (79.4%), at the postpartum checkup (42.3%) or in the consecutive pregnancy (30.7%), both orally and written (62.4%). CONCLUSION: Half of the women with a history of HDP were aware of the risk-reducing effect of aspirin in a consecutive pregnancy.

The relationship of a Prothrombin G20210A mutation or a factor V Leiden mutation and on-aspirin platelet (re-)activity.

INTRODUCTION: The interplay between platelets and pro-thrombotic factors may have been under-investigated in the identification of aspirin users at high risk for cardiovascular event reoccurrences. There is growing evidence that a Prothrombin G20210A (FII) or a Factor V Leiden (FVL) mutation might increase platelet activity. Subsequently, this study assessed on-aspirin platelet (re-)activity in non-pregnant participants with a FII - or a FVL mutation in comparison with non-pregnant data derived from controls. METHODS: This study was conducted with data derived from the follow-up FRUIT-RCT. This is a unique cohort namely, participants without a history of cardiovascular disease or thrombotic events, but who are a carrier of a pro-thrombotic mutation. All participants were instructed to ingest aspirin once daily for 10 days. Platelet (re-)activity was measured by the PFA Closure Time (PFA-CT), the VerifyNow (VN-ARU), and serum Thromboxane B2 (sTxB2) levels. RESULTS: In total, eight participants with a FII-, 15 with a FVL mutation, and 21 controls were included. The FII mutation carriers demonstrated significantly higher on-aspirin platelet (re)-activity (PFA-CT, -92 sec.; VN-ARU, +37 ARU) vs. controls. The FVL carriers demonstrated similar on-aspirin platelet (re-)activity vs. controls. The sTxB 2 levels were similar in either of the carrier groups vs. controls. CONCLUSION: We feel these data are suggestive of increased on-aspirin platelet (re-)activity, as measured by the PFA-200 and the VerifyNow, in non-pregnant carriers of a FII-mutation, but not in carriers of FVL-mutation. Interestingly, this increased on-aspirin platelet (re-)activity is present in spite of low sTxB2 levels.

Resistance of aspirin during and after pregnancy: A longitudinal cohort study.

OBJECTIVES: The objective of this study is to investigate possible changes in aspirin resistance during and after pregnancy over time. STUDY DESIGN: A longitudinal cohort study in obstetric high risk women with an indication for aspirin usage during pregnancy to prevent placenta mediated pregnancy complications. MAIN OUTCOME MEASURES: Aspirin resistance measured in the first, second and third trimester of pregnancy and at least three months postpartum by four complementary test: PFA-200, VerifyNow®, Chronolog light transmission aggregometry (Chronolog LTA) and serum thromboxane B2 (TxB2) level measurements. Correlation between the devices was investigated. RESULTS: In total, 23 pregnant women participated in the present study. Aspirin resistance according to the PFA-200, VerifyNow®, Chronolog LTA and serum TxB2, was 30.4%, 17.4%, 26.1% and 23.8% respectively. Resistance by any device was 69.6%. Aspirin resistance measured by the VerifyNow®, Chronolog LTA, serum TxB2 and aspirin resistance by any device during pregnancy was demonstrated more frequently than aspirin resistance after pregnancy. Correlation between the different devices was weak. CONCLUSION: Aspirin resistance was found in a considerable part of the participants. Considerable variation between participants, within participants over time and between the different devices was found. Prevalence of aspirin resistance during pregnancy differs from after pregnancy. More research on aspirin resistance and clinical obstetric outcome is needed.

Peptide hormone ELABELA enhances extravillous trophoblast differentiation, but placenta is not the major source of circulating ELABELA in pregnancy.

Preeclampsia is a frequent gestational hypertensive disorder with equivocal pathophysiology. Knockout of peptide hormone ELABELA (ELA) has been shown to cause preeclampsia-like symptoms in mice. However, the role of ELA in human placentation and whether ELA is involved in the development of preeclampsia in humans is not yet known. In this study, we show that exogenous administration of ELA peptide is able to increase invasiveness of extravillous trophoblasts in vitro, is able to change outgrowth morphology and reduce trophoblast proliferation ex vivo, and that these effects are, at least in part, independent of signaling through the Apelin Receptor (APLNR). Moreover, we show that circulating levels of ELA are highly variable between women, correlate with BMI, but are significantly reduced in first trimester plasma of women with a healthy BMI later developing preeclampsia. We conclude that the large variability and BMI dependence of ELA levels in circulation make this peptide an unlikely candidate to function as a first trimester preeclampsia screening biomarker, while in the future administering ELA or a derivative might be considered as a potential preeclampsia treatment option as ELA is able to drive extravillous trophoblast differentiation.

Maternal and Perinatal Outcome in Women with Systemic Lupus Erythematosus: A Retrospective Bicenter Cohort Study.

OBJECTIVE: To investigate disease activity around and during pregnancy and pregnancy outcome in women with systemic lupus erythematosus (SLE) considering antiphospholipid antibody status. Moreover, differences between first and consecutive pregnancies were examined. METHODS: Pregnancies > 16 weeks gestation of SLE patients receiving joint care from rheumatologists and gynecologists in two tertiary centers in the Netherlands between 2000 and 2015 were included. Disease activity, flare rate, and pregnancy outcomes and complications were assessed. RESULTS: Ninety-six women (84% Caucasian) with 144 pregnancies were included. The median SLE(P)DAI score was 2 before, during, and after pregnancy. Flare rates were 6.3%, 20.1%, and 15.3%, respectively. Severe hypertensive disorder of pregnancy, intrauterine fetal death, preterm birth, and small-for-gestational age infants occurred in 18.1%, 4.1%, 32.7%, and 14.8%, respectively. Complication rates were similar in the first and consecutive pregnancies. Half of the women did not experience any pregnancy complication whereas 42.7% developed a complication during all pregnancies. Mean number of pregnancies was 2.4 and live births 1.7. CONCLUSION: In this SLE population with low disease activity, pregnancy complications were present irrespective of antiphospholipid antibody status. Furthermore, there were no differences in complication rates between the first and consecutive pregnancies as seen in healthy mothers. This information is useful for patient counseling.

Low-molecular-weight heparin and aspirin use in relation to pregnancy outcome in women with systemic lupus erythematosus and antiphospholipid syndrome: A cohort study.

OBJECTIVE: To relate anticoagulant use to pregnancy complications in women with systemic lupus erythematosus (SLE) and primary antiphospholipid syndrome (APS). METHODS: All ongoing pregnancies, 184, in two Dutch tertiary centers between 2000 and 2015. RESULTS: LMWH and aspirin was prescribed in 15/109 SLE women without antiphospholipid antibodies (aPL), 5/14 with aPL, 11/13 with APS, 45/48 with primary APS. Main complications in the four treatment groups (no anticoagulant treatment, aspirin, LMWH, aspirin and LMWH) included hypertensive disorders of pregnancy (9.4%, 23.3%, 50%, 18.4%, respectively, p = 0.12) and preterm birth (16.7%, 34.3%, 75%, 36.8%, respectively, p < 0.001). CONCLUSION: Maternal and perinatal complications occurred frequently, despite LMWH and aspirin use.

Post-pregnancy aspirin resistance appears not to be related with recurrent hypertensive disorders of pregnancy.

OBJECTIVE: The FRUIT-RCT concluded that low-molecular-weight heparin added to aspirin compared to treatment with aspirin alone is beneficial in the prevention of early-onset hypertensive disorders of pregnancy (HD) in women with inheritable thrombophilia and prior HD and/or a small-for-gestational age (SGA) infant leading to delivery before 34 weeks gestation. The aim of this study is to answer the question whether aspirin resistance is associated with recurrent HD. STUDY DESIGN: Women with and without recurrent HD matched for age, study arm, and chronic hypertension were invited for this follow-up study 6-16 years after they participated in the FRUIT-RCT. Aspirin resistance was tested after 10days of aspirin intake using three complementary tests: PFA-200, VerifyNow® and serum thromboxane B2 (TXB2). An independent t-test, Mann-Whitney U test, Fisher's Exact test and Chi2 test were used for the statistical analyses. RESULTS: Thirteen of 24 women with recurrent HD and 16 of 24 women without recurrent HD participated. The prevalence of laboratory aspirin resistance was 34.5% according to the PFA-200, 3.4% according to the VerifyNow® and 24.1% according to TXB2. The prevalence of aspirin resistance by any test was 51.7%. Aspirin resistance per individual test did not differ between women with and without recurrent HD. Aspirin resistance measured by any test occurred more frequently in women without recurrent HD (p<0.01), irrespective of low-molecular-weight heparin. CONCLUSIONS: No relation could be demonstrated between recurrent HD and aspirin resistance per test, measured up to 16 years after pregnancy. On the contrary, complementary aspirin resistance measurements were encountered more frequently in women without recurrent HD.

Low-molecular-weight heparin and recurrent placenta-mediated pregnancy complications: a meta-analysis of individual patient data from randomised controlled trials.

BACKGROUND: Placenta-mediated pregnancy complications include pre-eclampsia, late pregnancy loss, placental abruption, and birth of a small-for-gestational-age (SGA) neonate. These complications are leading causes of maternal, fetal, and neonatal morbidity and mortality in high-income countries. Affected women are at high risk of recurrence in subsequent pregnancies; however, effective strategies to prevent recurrence are absent. Findings from our previous study-level meta-analysis suggested that low-molecular-weight heparin reduced the risk of recurrent placenta-mediated pregnancy complications. However, we identified significant heterogeneity in the results, possibly due to trial design or inclusion criteria. To identify which patients benefit from, and which outcomes are prevented by, low-molecular-weight heparin, we did an individual patient data meta-analysis. METHODS: We did a systematic review in May, 2013, which identified eight eligible randomised trials done between 2000 and 2013 of low-molecular-weight heparin to prevent recurrent placenta-mediated pregnancy complications. We excluded studies on the basis of the wrong population, the study being ongoing, inability to confirm eligibility of participants, intervention stopped too early, and no response from the principal investigator. We requested individual patient data from the study authors for eligible women (women pregnant at the time of the study with a history of previous pregnancy that had been complicated by one or more of the following: pre-eclampsia, placental abruption, birth of an SGA neonate [<10th percentile], pregnancy loss after 16 weeks' gestation, or two losses after 12 weeks' gestation) and recoded, combined, and analysed the data for our meta-analysis. The primary outcome was a composite of early-onset (<34 weeks) or severe pre-eclampsia, birth of an SGA neonate (<5th percentile), late pregnancy loss (≥20 weeks' gestation), or placental abruption leading to delivery, assessed on an intention-to-treat basis. We assessed risk of bias with the Cochrane Risk of Bias tool. This study is registered with PROSPERO, number CRD42013006249. FINDINGS: We analysed data from 963 eligible women in eight trials: 480 randomly assigned to low-molecular-weight heparin and 483 randomly assigned to no low-molecular-weight heparin. Overall, the risk of bias was not substantial enough to affect decisions regarding trial inclusion. Participants were mostly white (795/905; 88%) with a mean age of 30·9 years (SD 5·0) and 403/963 (42%) had thrombophilia. In the primary analysis, low-molecular-weight heparin did not significantly reduce the risk of recurrent placenta-mediated pregnancy complications (low-molecular-weight heparin 62/444 [14%] versus no low-molecular-weight heparin 95/443 (22%) absolute difference -8%, 95% CI -17·3 to 1·4, p=0·09; relative risk 0·64, 95% CI 0·36-1·11, p=0·11). We noted significant heterogeneity between single-centre and multicentre trials. In subgroup analyses, low-molecular-weight heparin in multicentre trials reduced the primary outcome in women with previous abruption (p=0·006) but not in any of the other subgroups of previous complications. INTERPRETATION: Low-molecular-weight heparin does not seem to reduce the risk of recurrent placenta-mediated pregnancy complications in at-risk women. However, some decreases in event rates might have been too small for the power of our study to explore. FUNDING: Canadian Institutes of Health Research.

Cardiovascular risk factors in women with inheritable thrombophilia a decade after single or recurrent hypertensive disorder of pregnancy.

OBJECTIVE: To described cardiovascular risk factors in women with inheritable thrombophilia 8-19 years after early-onset hypertensive disorders of pregnancy (HD) with or without recurrent HD. METHODS: Women with recurrent HD were compared with women with single HD, for physical examination and cardiovascular parameters in serum. RESULTS: Systolic blood pressure, diastolic blood pressure, and albumin: creatinine ratio were higher in women with recurrent HD compared with women with single HD (p = 0.046, p = 0.029, and p = 0.008, respectively). In both groups 72.7% had an increased cardiovascular risk. CONCLUSION: Women with inheritable thrombophilia after single or recurrent HD have a high cardiovascular risk.

Hypertensive Disorders of Pregnancy Appear Not to Be Associated with Alzheimer's Disease Later in Life.

BACKGROUND: After hypertensive disorders of pregnancy, more subjective cognitive complaints and white matter lesions are reported compared to women after normal pregnancies. Both have a causal relationship with Alzheimer's disease (AD). AIM: To investigate if women whose pregnancy was complicated by hypertensive disorders have an increased risk of AD. METHODS: A case-control study in women with AD from the Alzheimer Center of the VU University Medical Center Amsterdam and women without AD. Paper and telephone surveys were performed. RESULTS: The response rate was 85.2%. No relation between women with (n = 104) and without AD (n = 129) reporting pregnancies complicated by hypertensive disorders (p = 0.11) was found. Women with early-onset AD reported hypertensive disorders of pregnancy more often (p = 0.02) compared to women with late-onset AD. CONCLUSION: A reported history of hypertensive disorders of pregnancy appears not to be associated with AD later in life.