Pregnancy outcomes and iron status in ß-thalassemia major and intermedia: a systematic review and meta-analysis.

ABSTRACT: Advancements in orally bioavailable iron chelators and MRI methods have improved life expectancy and reproductive potential in thalassemia major (TM) and thalassemia intermedia (TI). Pregnancy is associated with adverse maternal and neonatal outcomes, frequency of which has not been well delineated. This systematic review aims to provide risk estimates of maternal and fetal outcomes in TM and TI and explore pregnancy's impact on iron homeostasis. Fifteen studies (429 participants, 684 pregnancies) were included. Meta-analysis revealed a higher thrombosis risk in TI (3.7%) compared to TM (0.92%), unchanged from prepregnancy. Heart failure risks in the earlier years appeared similar (TM 1.6% vs TI 1.1%), and maternal mortality in TM was 3.7%, but with current management, these risks are rare. Gestational diabetes and pre-eclampsia occurred in 3.9% and 11.3% of TM pregnancies, respectively. Caesarean section rates were 83.9% in TM and 67% in TI. No significant difference in stillbirth, small for gestational age neonates, or preterm birth incidence between TM and TI was observed. In TM pregnancies, red cell requirements significantly increased (from 102 to 139 ml/kg/year, P = 0.001), and 70% of TI pregnancies required blood transfusions. As expected, increased transfusion alongside chelation cessation led to a significant increase in serum ferritin during pregnancy (TM by 1005 ng/mL; TI by 332 ng/mL, P < 0.0001). Deterioration in iron status was further reflected by an increase in liver iron concentration (from 4.6 to 11.9 mg/g dry weight, P < 0.0001), and myocardial T2-star (T2∗) magnetic resonance imaging decreased (from 36.2 ± 2.5 ms to 31.1 ms) during pregnancy. These findings emphasize the elevated maternal risk of iron-related cardiomyopathy during pregnancy and labor, stressing the importance of cardiac monitoring and postpartum chelation therapy resumption.

Blood pressure thresholds for the diagnosis of hypertensive disorders of pregnancy in sickle cell disease.

In this retrospective cohort study of singleton pregnancies in people with sickle cell disease (SCD) delivered at two academic centres between 1990 and 2021, we collected demographic and SCD-related data, pregnancy outcomes, and the highest systolic and diastolic blood pressure (SBP and DBP) at seven time periods. We compared the characteristics of subjects with new or worsening proteinuria (NWP) during pregnancy to those without. We then constructed receiver operating characteristic (ROC) curves to determine the blood pressure (BP) that best identifies those with NWP. The SBP or DBP thresholds which maximized sensitivity and specificity were 120 mmHg SBP (sensitivity: 55.2%, specificity: 73.5%) and 70 mmHg DBP (sensitivity: 27.6%, specificity: 67.7%). The existing BP threshold of 140/90 mmHg lacked sensitivity in both genotype groups (HbSS/HbSß0 : SBP = 21% sensitive, DBP = 5.3% sensitive; HbSS/HbSß+ : SBP = 10% sensitive, DBP = 0% sensitive). Finally, percent change in SBP, DBP and MAP were all poor tests for identifying NWP. Existing BP thresholds used to diagnose hypertensive disorders of pregnancy (HDP) are not sensitive for pregnant people with SCD. For this population, lowering the BP threshold that defines HDP may improve identification of those who need increased observation, consideration of early delivery and eclampsia prophylaxis.

Natural history of blood pressure in sickle cell disease pregnancy.

In this retrospective cohort study of singleton pregnancies in people with sickle cell disease (SCD) delivered at two academic centres between 1990 and 2021, we collected demographic and SCD-related data, pregnancy outcomes, and the highest systolic and diastolic blood pressure (SBP and DBP) at seven time periods. We compared blood pressure values and trajectories in the composite cohort and in each genotype group to control values in a non-SCD pregnancy dataset. There were 290 pregnancies among 197 patients with SCD. Sixteen per cent (n = 47) of pregnancies had a hypertensive disorder of pregnancy (HDP); the rates did not differ by genotype. The mean SBP and DBP were lower in the HbSS/HbSß0 group than in the non-SCD control group at all timepoints. Mean SBP and DBP trajectories were similar between the HbSS/HbSß0 group and non-SCD controls, whereas the mean SBP and DBP in the HbSC/HbSß+ group decreased between the first and second trimesters and plateaued between the second and third trimesters. There were no differences in blood pressure trajectory by haemoglobin >/< 10 gm/dL or by chronic transfusion status. Overall, pregnant people with SCD have lower blood pressure than unaffected pregnant people, raising the possibility that HDP are underdiagnosed, particularly in people with HbSS/HbSß0 .

Impact of mutations on pregnancy outcome in patients with myeloproliferative neoplasms.

The impact of driver and other somatic mutations on pregnancy outcomes is unknown. The purpose of this study was to report the management and outcome of pregnancies in a cohort of myeloproliferative neoplasms (MPN) patients, particularly to evaluate the impact of somatic mutations. The cohort included consecutive patients with MPN who had a least one confirmed pregnancy. The primary outcome was live births. Secondary outcomes were thrombotic and major bleeding events. Between 2010 and 2021, 29 pregnancies occurred in 24 individuals with MPN. Aspirin was used in 24 cases (83%) and interferon alfa in five (17%). There were 24 live births (83%). There were three thrombotic events, two antepartum and one postpartum. Miscarriages and thrombotic events occurred in JAK2-mutated and triple negative, but not CALR-mutated, MPN. Additional somatic mutations were rare, and there were no apparent associations with pregnancy loss or complications. While JAK2 V617F is associated with an increased risk of thrombosis, its impact on pregnancy outcome has been inconsistently reported. The association between triple negative MPN and adverse pregnancy outcome has not previously been reported. While limited by small numbers, this study underscores the importance of describing driver and other mutations to direct optimal antenatal care in individuals with MPN.

Postpartum Hemorrhage in Women with von Willebrand Disease: Consider Other Etiologies.

OBJECTIVE: Higher rates of postpartum hemorrhage (PPH) have been reported for women with von Willebrand disease (VWD). Comprehensive multidisciplinary care reduces these rates; thus PPH may not be secondary to VWD. METHODS: We conducted a retrospective review for the period of 2009-2018, including all VWD pregnancies at 2 tertiary care academic hospitals to determine rates, etiology, and timing of PPH. RESULTS: A total of 63 women with 80 pregnancies were included. Three women had twin pregnancies. Sixty-six pregnancies (82.5%) involved type 1 VWD; 4 (5.0%), type 2 (unclear subtype); 3 (3.8%) type 2A; 3 (3.8%) type 2B; and 2 (2.5%), type 2M. Median age of patients was 32.9 years (range 19-43 y). Most patients were blood type O (65%), and 33 of 80 pregnancies (41.3%) were nulliparous. The mean bleeding assessment score was 8 (range 0-16). Thirty-seven pregnancies (46.3%) received prophylactic hemostatic treatment prior to delivery. Seventy-four percent of pregnancies were delivered vaginally, and 88% received epidural anaesthesia. The majority of pregnancies (78.8%) had von Willebrand factor (VWF) levels assessed during the third trimester, with most (71.3%) achieving VWF levels above 1.00 IU/mL. Four pregnancies (5.2%) were complicated by primary PPH; uterine atony in 2 and placenta previa in 1. Delayed postpartum bleeding occurred in 5 pregnancies (6.3%). CONCLUSION: Multidisciplinary care of pregnancies with VWD improves outcomes. Rates of primary and delayed PPH in this study are lower than previously described and are similar to those of women without VWD. In women with VWD, uterine etiologies for primary PPH need to be considered, in a manner similar to the assessment of women without VWD, to ensure hemostasis is achieved.

Adverse outcome of acute splenic sequestration crisis in pregnancy.

BACKGROUND: Acute splenic sequestration crisis, characterized by abrupt fall in hemoglobin, splenomegaly, hypovolemia, and often thrombocytopenia, occurs infrequently in adults with sickle cell disease and extremely rarely during pregnancy. CASE: A 25-year-old woman with HbSC presented at 33 weeks' gestation with vaso-occlusive pain. Sudden worsening of abdominal pain and non-reassuring fetal surveillance on day 3 of admission led to emergent delivery. Acute splenic sequestration crisis was the diagnosis of exclusion based on clinical presentation and intra-operative hemoglobin of 37 g/L. Five- and 10-minute Apgar scores were 4. Neonatal brain magnetic resonance imaging revealed significant diffuse white matter abnormalities. CONCLUSION: Acute splenic sequestration crisis in pregnancy must be considered in the differential diagnosis for this patient population as it can evolve rapidly and lead to maternal and fetal compromise.

Physician experiences in management of COVID-19-associated coagulopathy in pregnancy: Communication from the ISTH SSC Subcommittee on Women's Health Issues in Thrombosis and Haemostasis.

BACKGROUND: Coronavirus disease 2019 (COVID-19) occurs following infection with the potentially fatal, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus. Infection can be complicated by coagulopathy, at times featuring thrombocytopenia and thrombosis alongside other coagulation abnormalities, also termed COVID-19-associated coagulopathy (CAC). Data concerning CAC in pregnancy are limited. Better understanding of physician experiences is essential to identify current practice patterns and knowledge gaps. OBJECTIVES: To determine physician experiences and practice patterns regarding CAC in pregnancy. METHODS: Self-administered survey using the RedCap online platform; supported by the ISTH Subcommittee on Women's Health Issues in Thrombosis and Hemostasis. RESULTS: Seventy-five respondents fully or partially completed the survey. Of 1546 reported cases, disease severity was specified in 1298. Sixty-four percent of COVID-19 infections were mild, whereas 4% were severe. Of all cases, 1% developed CAC, with 65% classified as severe. The most frequent abnormalities included thrombocytopenia, elevated C-reactive protein, D-dimer, and lymphopenia. Low molecular weight heparin was the anticoagulant of choice in CAC and was provided by 77% of respondents, with 60% using standard prophylactic dosing. Thrombosis occurred in seven anticoagulated patients who were receiving standard prophylactic (four) or weight-based (three) dosing. Disease severity and additional thrombosis risk factors dictated anticoagulation duration. CONCLUSION: In the select population reported by our survey, CAC appears to be uncommon in pregnancy. Anticoagulation practices vary and may not reflect current guidelines. Venous thromboembolism was observed in some CAC patients despite prophylactic anticoagulation (including standard and weight-adjusted dosing). Urgent research is required to determine appropriate anticoagulant dosing and duration in pregnant women with COVID-19 infection.

The Pathophysiology of Hypercoagulability and Infertility.

Alongside an interplay of a multitude of factors, attainment of a favorable pregnancy outcome is predicated on successful implantation, which in itself is a complex process anchored by balanced interchange with the hemostatic system. Among other etiologies, failure of implantation can result in infertility, and lead affected couples to consider assisted reproductive technology (ART) in an effort to fulfill their desire for procreation. Given the critical role of the hemostatic system in the process of implantation, documentation of a hypercoagulable state during controlled ovarian stimulation in the context of in vitro fertilization, as well as the potential association of its derangement in the setting of thrombophilia, with infertility, ART, ovarian hyperstimulation syndrome, and failure of implantation are explored. Additionally, current evidence addressing the relationship between ART and thromboembolism is examined, as is the role of therapy with heparin and aspirin to decrease thrombotic risk and improve ART-related pregnancy outcomes. Evidence-based recommendations from relevant professional societies are summarized.

Expecto Patronum! Leveraging the Positive Force of COVID-19 Vaccines for Pregnant and Lactating Individuals.

For over a year, the world has been gripped by the coronavirus disease 2019 (COVID-19) pandemic, which has had far-reaching effects on society. The integrity of national health care systems has also been challenged, owing to shifts in guidance and misinformation. Although initial reports suggested that pregnant people were not at increased risk of severe COVID-19, current data arising from the "third wave" paint a much more concerning picture. In addition, pregnant and lactating people were excluded from vaccine trials, which has hindered the ability of health care professionals to provide evidence-based counselling regarding the safety and efficacy of the available vaccines in these populations. This commentary reviews the current data on the safety of COVID-19 vaccines in pregnancy. The evidence is clear that the risks of hospitalization and severe maternal and potentially fetal morbidity from COVID-19 in pregnancy far outweigh the very minimal risks of COVID-19 vaccination in pregnancy.

Patient- and Health-Care-Provider-Reported Outcomes to Consider in Research on Pregnancy-Associated Venous Thromboembolism.

BACKGROUND: Venous thromboembolism (VTE) in pregnancy can have numerous adverse impacts on patients and health care systems. Ongoing research aimed at improving maternal and fetal/neonatal outcomes is hampered by the lack of patient perspective in determining which outcomes are considered important to assess the effectiveness of interventions. OBJECTIVES: The objective of this study was to elicit outcomes from those who experienced or were at risk for pregnancy-associated VTE (health service users, HSUs) and health care providers (HCPs) involved in their care. METHODS: Canadian HSUs and HCPs were recruited using convenience and purposive sampling, respectively. Individual, semistructured interviews aimed specifically at eliciting pregnancy-related outcomes were conducted until data saturation was attained. Interviews were audio-recorded and transcribed verbatim. Written transcripts were de-identified and interpretatively analyzed in duplicate to obtain outcomes related to participant experiences. Outcomes were grouped based on a taxonomy developed for medical research and compared between and across interviews with patients and HCPs, and with those obtained through a systematic review of the published literature. RESULTS AND CONCLUSION: We interviewed 10 HSUs and eight HCPs and elicited 52 outcomes, 21 of which have not been reported in the literature. Although the majority of elicited outcomes were in the clinical/physiological core outcome area, both HSUs and HCPs highlighted the importance of outcomes related to functioning/life impact and general wellbeing of mother and baby. These outcomes representing the perspectives of HSUs and HCPs should be considered while conducting trials on pregnancy-associated VTE.

COVID-19 susceptibility in pregnancy: Immune/inflammatory considerations, the role of placental ACE-2 and research considerations.

SARS-CoV-2 is a new virus, to which herd immunity has not yet developed and both molecular and serological testing are not without flaws. The virus evokes a state of severe and widespread inflammation, and stimulates both innate and adaptive immune response. The angiotensin-converting enzyme 2 (ACE2), which acts as the SARS-CoV-2 receptor, is present in endothelial cells and has been noted within the human placenta. There are questions about whether pregnancy would increase the susceptibility of pregnant women to COVID-19 and disease severity within this population. In this report, we highlight physiological and immune/inflammatory considerations that may explain the susceptibility and disease pathology in response to SARS CoV-2 during pregnancy, explore testing considerations in asymptomatic individuals, discuss the potential role and of placental ACE2 receptor in the pathogenesis of COVID-19 in pregnancy and in pregnancy outcomes, and finally share our perspective with respect to an urgently needed change concerning involvement of pregnant women in research addressing COVID-19.

COVID-19 coagulopathy in pregnancy: Critical review, preliminary recommendations, and ISTH registry-Communication from the ISTH SSC for Women's Health.

BACKGROUND: Novel coronavirus (SARS-CoV-2), which causes COVID-19, has thus far affected more than 15 million individuals, resulting in more than 600 000 deaths worldwide, and the number continues to rise. In a large systematic review and meta-analysis of the literature including 2567 pregnant women, 7% required intensive care admission, with a maternal mortality ~1% and perinatal mortality below 1%. There has been a rapid increase in publications on COVID-19-associated coagulopathy, including disseminated intravascular coagulopathy and venous thromboembolism, in the non-pregnant population, but very few reports of COVID-19 coagulopathy during pregnancy; leaving us with no guidance for care of this specific population. METHODS: This is a collaborative effort conducted by a group of experts that was reviewed, critiqued, and approved by the International Society on Thrombosis and Haemostasis Subcommittee for Women's Health Issues in Thrombosis and Hemostasis. A structured literature search was conducted, and the quality of current and emerging evidence was evaluated. Based on the published studies in the non-pregnant and pregnant population with a moderate to high risk of bias as assessed by Newcastle-Ottawa scale and acknowledging the absence of data from randomized clinical trials for management of pregnant women infected with SARS-CoV-2, a consensus in support of a guidance document for COVID-19 coagulopathy in pregnancy was identified. RESULTS AND CONCLUSIONS: Specific hemostatic issues during pregnancy were highlighted, and preliminary recommendations to assist in the care of COVID-19-affected pregnant women with coagulopathy or thrombotic complications were developed. An international registry to gather data to support the management of COVID-19 and associated coagulopathy in pregnancy was established.

Placental histopathology in sickle cell disease: A descriptive and hypothesis-generating study.

INTRODUCTION: Abnormal placental development is a unifying factor amongst many adverse pregnancy outcomes (APOs) in Sickle Cell Disease (SCD). Our aim was to describe placental histopathologic findings in women with SCD and their relationship with APOs, and to explore the association between antenatal sonographic findings and placental pathology. METHODS: Retrospective single-centre case series of all pregnant women with SCD (January 2000-December 2017), pregnancy beyond 20 weeks' gestation, and available placenta histopathology. APOs included intrauterine fetal death, early neonatal death, preterm birth, small for gestational age, and hypertensive disorders of pregnancy. Review of images for mid-pregnancy ultrasound and one proximal to delivery was completed, blinded to clinical outcomes and histopathology results. Gross and histopathologic findings were reviewed and characterized per published classification. RESULTS: Of 72 placentas, abnormalities were present in 69%, with Maternal Vascular Malperfusion (MVM) noted in 40%. APOs were encountered in 61% overall and in 79% of those with MVM. Neither SCD genotype nor severe maternal anemia had an influence on histopathologic placental features. Presence of high-resistance uterine artery waveforms at mid-trimester ultrasound was strongly associated with APOs and with abnormal findings on placental histopathology, most notably MVM. MVM was strongly associated with small for gestational age infants, preterm birth, and stillbirth. DISCUSSION: MVM is the predominant lesion in placentas of women with SCD and is strongly associated with APOs. Mid-trimester ultrasound can identify a subset of women at risk. Future research into advanced imaging modalities to aid in antenatal diagnosis alongside investigations of potentially beneficial therapies is needed.

COVID-19 and acute coagulopathy in pregnancy.

We present a putative link between maternal COVID-19 infection in the peripartum period and rapid maternal deterioration with early organ dysfunction and coagulopathy. The current pandemic with SARS-CoV-2 has already resulted in high numbers of critically ill patients and deaths in the non-pregnant population, mainly due to respiratory failure. During viral outbreaks, pregnancy poses a uniquely increased risk to women due to changes to immune function, alongside physiological adaptive alterations, such as increased oxygen consumption and edema of the respiratory tract. The laboratory derangements may be reminiscent of HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome, and thus knowledge of the COVID-19 relationship is paramount for appropriate diagnosis and management. In addition to routine measurements of D-dimers, prothrombin time, and platelet count in all patients presenting with COVID-19 as per International Society on Thrombosis and Haemostasis (ISTH) guidance, monitoring of activated partial thromboplastin time (APTT) and fibrinogen levels should be considered in pregnancy, as highlighted in this report. These investigations in SARS-CoV-2-positive pregnant women are vital, as their derangement may signal a more severe COVID-19 infection, and may warrant pre-emptive admission and consideration of delivery to achieve maternal stabilization.

Impact of Perinatal Primary Hyperparathyroidism on Maternal and Fetal and Neonatal Outcomes: Retrospective Case Series.

OBJECTIVE: We sought to describe the maternal, fetal, and neonatal outcomes of primary hyperparathyroidism in a contemporary setting through a retrospective case series conducted in a tertiary referral centre focused on women diagnosed with primary hyperparathyroidism prior to conception, in the antepartum period, or within 6 weeks postpartum. METHODS: A retrospective chart review was conducted and data were abstracted to case report forms. Summary statistics are reported. RESULTS: From 2000 to 2017, 19 women (23 pregnancies) with primary hyperparathyroidism were identified. Most women (79%) were symptomatic at presentation, though often with non-specific manifestations. While 14% of pregnancies involved maternal/obstetric complications, fetal/neonatal complications were observed in 45%. Mild hypercalcemia was identified in 57% of women, with accompanying hypophosphatemia and hypomagnesemia in 46% and 36% of women, respectively. Surgical intervention was performed for 89% women, and no complications were encountered. Normal calcium levels achieved through treatment before conception did not fully eliminate adverse outcomes. CONCLUSION: Rates of perinatal complications in our series are more reassuring than the ubiquitously quoted rates from small and dated studies. The diagnosis of primary hyperparathyroidism may be easily missed during pregnancy, owing to its non-specific presentation. A high index of suspicion and measurement of ionized calcium levels is encouraged, especially for patients with excessive nausea and vomiting, nephrolithiasis, atypical presentations of hypertensive disorders, or isolated polyhydramnios. Mild degrees of calcium derangement do not preclude adverse perinatal outcomes. Surgery appears to be safe, even in the third trimester. The attenuated rate of complications noted in our series may have been the result of the high proportion of surgery, though this will require verification via meta-analysis or future prospective work.