Preterm birth and uterine fibroid necrosis: The clinical presentation illustrated in a case series.

OBJECTIVE: Uterine fibroids increase the risk of preterm birth. The current study highlights uterine fibroid necrosis as a possible cause of (extreme) preterm birth. STUDY DESIGN: Retrospective cohort study in one Dutch academic hospital. Cases were selected from the 526 participants of the MyoFert study (Netherlands Trial Register, NL7990), which included patients who presented between 2004 and 2018 and were between the age of 18 and 45 years at the time of diagnosis of uterine fibroids. Of these participants, 414 women became pregnant. A retrospective chart review of the first pregnancies was performed. The main outcomes were (imminent) preterm birth and signs of fibroid necrosis on ultrasound. In women with signs of fibroid necrosis, the following data were collected systematically: fibroid characteristics, clinical presentation, pregnancy outcome, and postpartum period. RESULTS: In total, 66 women had a preterm birth (16 %, 66/414), of which 25 pregnancies ended between 16 and <24 weeks (38 %, 25/66) and 41 pregnancies ended between 24 and <37 weeks of gestation (62 %, 41/66). Of all women with preterm birth and available ultrasound images, 15 % (7/48) had fibroid necrosis at the time of labour. These seven patients, supplemented with three patients with fibroid necrosis during their first pregnancy and at least one episode of imminent preterm birth, are described in more detail. In these ten patients, the fibroids increased substantially in size during the first and second trimester, leading to severe abdominal pain in all patients and hospital admission in seven patients. Ultrasound examination of the fibroids showed heterogenic changes and focal transonic areas in the fibroid, which are characteristics that indicate fibroid necrosis. In four patients, myomectomy was performed and necrosis was confirmed histologically. CONCLUSION: Fibroid necrosis during pregnancy is likely associated with (imminent) preterm birth. Clinicians are advised to structurally evaluate the myometrium in pregnancy, specifically in women presenting with abdominal pain in the second trimester.

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.

The effect of low-dose aspirin on platelet function during pregnancy compared to placebo: An explorative study.

OBJECTIVES: To evaluate the effect of aspirin 80 mg compared to placebo on platelet function tests in the second and third trimester of pregnancy. STUDY DESIGN: An explorative study was performed to assess laboratory platelet function in a subpopulation of the APRIL trial: a randomized double-blind trial comparing aspirin 80 mg once daily to placebo for the prevention of recurrent preterm birth. Platelet function was measured between 18 and 22, and between 28 and 32 weeks gestational age with three platelet function tests: VerifyNow®, Chronolog light transmission aggregometry (Chronolog LTA) and serum thromboxane B2 (TxB2). Medication adherence was evaluated by pill counts, self-reported diaries and structured interviews. RESULTS: We included 11 women, six in the aspirin and five in the placebo group. In women receiving aspirin, platelet function was significantly lower compared to women receiving placebo for all three tests: VerifyNow® Aspirin Reaction Units (450.5 vs 648.0, p = 0.017); Chronolog LTA (9.5% vs 94.5%, p = 0.009); serum TxB2 levels (11.9 ng/mL versus 175.9 ng/mL, p = 0.030). For all three tests, platelet function did not differ between the second and third trimester of pregnancy in the aspirin group. In the placebo group, serum TxB2 levels were significantly higher in the third trimester. One non-adherent participant in the aspirin group showed results similar to the placebo group. CONCLUSION: Aspirin 80 mg has a clear inhibitory effect on laboratory platelet function during pregnancy compared to placebo. This effect is similar in the second and third trimester of pregnancy.

Long-term outcomes following antenatal exposure to low-dose aspirin: study protocol for the 4-year follow-up of the APRIL randomised controlled trial.

INTRODUCTION: The use of low-dose aspirin by pregnant women to prevent preterm pre-eclampsia is gradually increasing. The administration of aspirin during pregnancy improves perinatal outcome, which could translate into improved child outcome in the long term. However, antenatal exposure to aspirin could have adverse effects on child development that may manifest later in life. The aim of this follow-up study is to assess the long-term effects of antenatal exposure to low-dose aspirin compared with placebo on survival, (neuro)development, behaviour and general health at 4 years corrected age. METHODS AND ANALYSIS: This is a follow-up study of the Dutch double-blind randomised controlled APRIL trial which assessed the effectiveness of treatment with aspirin (80 mg daily) compared with placebo for the prevention of preterm birth in women with a previous spontaneous preterm birth. Treatment was initiated before 16 weeks of gestation and continued until 36 weeks or birth. We aim to follow-up all 379 children born to women who participated in the APRIL trial and survived the neonatal period, at the corrected age of 4 years. The main outcomes are (neuro)development as assessed by the Ages and Stages Questionnaire, and behaviour as assessed by the Strength and Difficulties Questionnaire. Additional outcomes include mortality, growth and general health from birth up to 4 years, and a composite outcome including mortality, abnormal (neuro)development and problem behaviour. Analyses will be performed by intention-to-treat using a superiority design. ETHICS AND DISSEMINATION: Institutional Review Board approval was obtained from the Medical Research Ethics Committee from Amsterdam Medical Center (no. W20 289#20.325). The results will be published in a peer-reviewed journal and presented at conferences. TRIAL REGISTRATION NUMBER: The APRIL trial (NTR5675, NL5553; EudraCT number 2015-003220-31) and the APRIL follow-up study (NL8950) are registered in the Dutch trial register. The study is funded by the Amsterdam Reproduction & Development research institute.

Uterine Fibroids Causing Preterm Birth: A New Pathophysiological Hypothesis on the Role of Fibroid Necrosis and Inflammation.

According to recent studies and observations in clinical practice, uterine fibroids increase the risk of preterm birth. There are several theories on the pathogenesis of preterm birth in the presence of fibroids. One theory proclaims that fibroid necrosis leads to preterm birth, though pathophysiological mechanisms have not been described. Necrotic tissue secretes specific cytokines and proteins and we suggest these to be comparable to the inflammatory response leading to spontaneous preterm birth. We hypothesize that fibroid necrosis could induce preterm parturition through a similar inflammatory response. This new hypothesis generates novel perspectives for future research and the development of preventative strategies for preterm birth. Moreover, we emphasize the importance of the recognition of fibroids and especially fibroid necrosis by clinicians during pregnancy.

The risk of preterm birth in women with uterine fibroids: A systematic review and meta-analysis.

BACKGROUND: Fibroids have been identified as a possible risk factor for preterm birth, however, the magnitude of this risk is unclear. Our objective was to determine the risk of total, spontaneous, and medically indicated preterm birth in women with fibroids. METHODS: A literature search was performed on 9 June 2021. We selected studies reporting on preterm birth in women with and without fibroids. Fibroids had to be diagnosed by routine ultrasound before or during pregnancy. Main outcomes were total preterm birth <37, <34, <32, and <28 weeks of gestation, and spontaneous and medically indicated preterm birth. Two authors independently performed study selection, data extraction and quality assessment. We performed quality assessment with the Newcastle-Ottawa scale. Meta-analyses were presented as Odds Ratios (ORs) with 95% Confidence Intervals (95%CIs). MAIN RESULTS: The search yielded 2078 unique articles of which 11 were included. Meta-analysis for preterm birth <37 weeks of gestation included 256,650 singleton deliveries: 12,309 with fibroids and 244,341 without fibroids. Women with fibroids had a higher rate of preterm birth (11.6% versus 9.0%; OR 1.66, 95%CI 1.29-2.14). Fibroids were also associated with preterm birth <34 (OR 1.88, 95%CI 1.34-2.65), <32 (OR 2.03, 95%CI 1.40-2.95) and <28 (OR 2.24, 95%CI 1.45-3.47) weeks of gestation. Data on type of preterm birth was limited: one study showed a significant association of fibroids with spontaneous preterm birth and another with indicated preterm birth. The main limitations of the included studies were the lack of correction for confounders, the risk of ascertainment bias due to possible underreporting of fibroids, and the substantial heterogeneity between studies. CONCLUSIONS: Our results suggest fibroids are associated with an increased risk of preterm birth, with a stronger risk at earlier gestational ages. We encourage further research to clarify the association between fibroids and preterm birth by systematic myometrial assessment in pregnancy. REGISTRATION: Prospero database [CRD42020186976].

Evaluation of low-dose aspirin in the prevention of recurrent spontaneous preterm labour (the APRIL study): A multicentre, randomised, double-blinded, placebo-controlled trial.

BACKGROUND: Preterm birth is the leading cause of neonatal morbidity and mortality. The recurrence rate of spontaneous preterm birth is high, and additional preventive measures are required. Our objective was to assess the effectiveness of low-dose aspirin compared to placebo in the prevention of preterm birth in women with a previous spontaneous preterm birth. METHODS AND FINDINGS: We performed a parallel multicentre, randomised, double-blinded, placebo-controlled trial (the APRIL study). The study was performed in 8 tertiary and 26 secondary care hospitals in the Netherlands. We included women with a singleton pregnancy and a history of spontaneous preterm birth of a singleton between 22 and 37 weeks. Participants were randomly assigned to aspirin 80 mg daily or placebo initiated between 8 and 16 weeks of gestation and continued until 36 weeks or delivery. Randomisation was computer generated, with allocation concealment by using sequentially numbered medication containers. Participants, their healthcare providers, and researchers were blinded for treatment allocation. The primary outcome was preterm birth <37 weeks of gestation. Secondary outcomes included a composite of poor neonatal outcome (bronchopulmonary dysplasia, periventricular leukomalacia > grade 1, intraventricular hemorrhage > grade 2, necrotising enterocolitis > stage 1, retinopathy of prematurity, culture proven sepsis, or perinatal death). Analyses were performed by intention to treat. From May 31, 2016 to June 13, 2019, 406 women were randomised to aspirin (n = 204) or placebo (n = 202). A total of 387 women (81.1% of white ethnic origin, mean age 32.5 ± SD 3.8) were included in the final analysis: 194 women were allocated to aspirin and 193 to placebo. Preterm birth <37 weeks occurred in 41 (21.2%) women in the aspirin group and 49 (25.4%) in the placebo group (relative risk (RR) 0.83, 95% confidence interval (CI) 0.58 to 1.20, p = 0.32). In women with ≥80% medication adherence, preterm birth occurred in 24 (19.2%) versus 30 (24.8%) women (RR 0.77, 95% CI 0.48 to 1.25, p = 0.29). The rate of the composite of poor neonatal outcome was 4.6% (n = 9) versus 2.6% (n = 5) (RR 1.79, 95% CI 0.61 to 5.25, p = 0.29). Among all randomised women, serious adverse events occurred in 11 out of 204 (5.4%) women allocated to aspirin and 11 out of 202 (5.4%) women allocated to placebo. None of these serious adverse events was considered to be associated with treatment allocation. The main study limitation is the underpowered sample size due to the lower than expected preterm birth rates. CONCLUSIONS: In this study, we observed that low-dose aspirin did not significantly reduce the preterm birth rate in women with a previous spontaneous preterm birth. However, a modest reduction of preterm birth with aspirin cannot be ruled out. Further research is required to determine a possible beneficial effect of low-dose aspirin for women with a previous spontaneous preterm birth. TRIAL REGISTRATION: Dutch Trial Register (NL5553, NTR5675) https://www.trialregister.nl/trial/5553.

Long-term health and neurodevelopment in children after antenatal exposure to low-dose aspirin for the prevention of preeclampsia and fetal growth restriction: A systematic review of randomized controlled trials.

OBJECTIVE: To evaluate the long-term effects of antenatal aspirin exposure on child health and neurodevelopmental outcome beyond the perinatal period. STUDY DESIGN: PubMed, Embase.com, the Cochrane Library and Web of Science were systematically searched from inception through 5 November 2020. We performed a cited-reference search and ClinicalTrials.gov was searched on 20 October 2020 to identify trial results that were not reported elsewhere. We included randomized controlled trials reporting on health-related outcomes in children (aged > 28 days) exposed to aspirin versus placebo or no treatment during pregnancy. Studies with any dose or duration of aspirin use were included. We excluded studies evaluating other antiplatelet agents or non-steroidal inflammatory drugs. Two authors independently performed study selection, data extraction and quality assessment. Quality assessment was performed using the Cochrane RoB2 tool for the original randomized controlled trials and the QUIPS for the follow-up studies. Results are presented as relative risks (RR) with 95% confidence intervals (95%CI). RESULTS: The search yielded 6,907 unique records. Two studies were included, containing 4,168 children at age 12 months and 5,153 children at 18 months. Children were exposed to aspirin 50-60 mg versus placebo or no treatment. At 12 months, post-neonatal mortality was lower after allocation to aspirin (0.2% versus 0.5%; RR 0.28, 95%CI 0.08-0.99) in a single study. At 18 months, fewer children were found to have (gross and fine) motor problems (RR 0.49, 95%CI 0.26-0.91) after antenatal aspirin exposure in one study. No differences were found in mortality rate; the proportion of children with a short stature or low weight; or respiratory, hearing or visual problems at 18 months. Both included studies had a high risk of bias. CONCLUSION: The two included studies showed evidence of potential benefit of antenatal low-dose aspirin on mortality and neurodevelopment up to the age of 18 months. Our findings support the current application of low-dose aspirin in pregnant women at risk for preeclampsia and fetal growth restriction. However, further follow-up research of children who were exposed to low-dose aspirin during pregnancy is of utmost importance to exclude potential long-term harm.

Significant reduction in umbilical artery metabolic acidosis after implementation of intrapartum ST waveform analysis of the fetal electrocardiogram.

BACKGROUND: Although the evidence regarding the benefit of using ST waveform analysis of the fetal electrocardiogram is conflicting, ST waveform analysis is considered as adjunct to identify fetuses at risk for asphyxia in our center. Most randomized controlled trials and meta-analyses have not shown a significant decrease in umbilical metabolic acidosis, while some observational studies have shown a gradual decrease of this outcome over a longer period of time. Observational studies can give more insight into the effect of implementation of the ST technology in daily clinical practice. OBJECTIVE: To evaluate the change in frequency of perinatal intervention and adverse neonatal outcome after the implementation of ST waveform analysis of the fetal electrocardiogram from 2000 to 2013. STUDY DESIGN: This retrospective longitudinal study was conducted in a tertiary referral center. A total of 19,664 medium- and high-risk singleton pregnancies with fetuses in cephalic presentation, a gestational age of ≥36 weeks, and the intention to deliver vaginally were included. ST waveform analysis of the fetal electrocardiogram was implemented in the year 2000 and by 2010 all deliveries were monitored using this technology. Data were collected on the following perinatal outcomes: fetal blood sampling, mode of delivery, umbilical cord blood gases, Apgar scores, neonatal encephalopathy, and perinatal death. Longitudinal trend analysis was used to detect changes over time in all deliveries monitored by cardiotocography either alone or in adjunct to ST waveform analysis of the fetal electrocardiogram. Logistic regression was used to correct for possible confounders. RESULTS: The umbilical artery metabolic acidosis rate declined from 2.5% (average rate of 2000 + 2001 + 2002) to 0.4% (average of 2011 + 2012 + 2013) (P < .001), which represents an 84% decrease. This decrease largely occurred between 2006 and 2008, during the Dutch randomized trial on fetal electrocardiogram ST waveform analysis. At this time, approximately 20% of deliveries were monitored using this method. Furthermore, there were significant reductions in fetal blood sampling rate (P < .001). Overall cesarean and vaginal instrumental deliveries decreased significantly (P < .001), but not for fetal distress. There were no changes in the Apgar scores. The incidence of neonatal encephalopathy was significantly lower in the second part of the study (odds ratio 0.39, 95% confidence interval 0.17-0.89). CONCLUSION: There was an 84% decrease in the incidence of umbilical artery metabolic acidosis in all deliveries between 2000 and 2013. The neonatal encephalopathy rate, fetal blood sampling rate, and the total number of cesarean and vaginal instrumental deliveries also decreased.

Radioembolization: Is Prophylactic Embolization of Hepaticoenteric Arteries Necessary? A Systematic Review.

PURPOSE: To study the effectiveness of prophylactic embolization of hepaticoenteric arteries to prevent gastrointestinal complications during radioembolization. METHODS: A PubMed, Embase and Cochrane literature search was performed. We included studies assessing both a group of patients with and without embolization. RESULTS: Our search revealed 1401 articles of which title and abstract were screened. Finally, eight studies were included investigating 1237 patients. Of these patients, 456 received embolization of one or more arteries. No difference was seen in the incidence of gastrointestinal complications in patients with prophylactic embolization of the gastroduodenal artery (GDA), right gastric artery (RGA), cystic artery (CA) or hepatic falciform artery (HFA) compared to patients without embolization. Few complications were reported when microspheres were injected distal to the origin of these arteries or when reversed flow of the GDA was present. A high risk of confounding by indication was present because of the non-randomized nature of the included studies. CONCLUSION: It is advisable to restrict embolization to those hepaticoenteric arteries that originate distally or close to the injection site of microspheres. There is no conclusive evidence that embolization of hepaticoenteric arteries influences the risk of complications.