Intravitreal anti-vascular endothelial growth factor injections in pregnancy and breastfeeding: a case series and systematic review of the literature.

INTRODUCTION: Anti-vascular endothelial growth factor (anti-VEGF) agents may occasionally need to be considered for sight-threatening macular pathology in pregnant and breastfeeding women. This is controversial due to the dearth of data on systemic side effects for mother and child. We aimed to expand the evidence base to inform management. METHODS: Retrospective case series of pregnant and breastfeeding women treated with intravitreal anti-VEGF injections at Oxford Eye Hospital between January 2015 and December 2022. In addition, we conducted a systematic review and combined eligible cases in a narrative synthesis. RESULTS: We treated six pregnant women with anti-VEGF for diabetic macular oedema(DMO) (n = 5) or choroidal neovascularisation (CNV) (n = 1). Four received ranibizumab whilst two (not known to be pregnant) received aflibercept. Patients known to be pregnant underwent counselling by an obstetric physician. Five pregnancies resulted in live births. Combining our cases with those previously published, treatment of 41 pregnant women (42 pregnancies) are reported. Indications for treatment included CNV (n = 28/41,68%), DMO (n = 7/41,17%) and proliferative diabetic retinopathy (n = 6/41,15%). Bevacizumab (n = 22/41,54%) and ranibizumab (n = 17/41,41%) were given more frequently than aflibercept (n = 2/41,5%). Many (n = 16/41,40%) were unaware of their pregnancy when treated. Most pregnancies resulted in live births (n = 34/42,81%). First trimester miscarriages (n = 5/42,12%) and stillbirths (n = 3/42,7%) mostly occurred in women with significant risk factors. CONCLUSION: Intravitreal anti-VEGF injections may not necessarily compromise obstetric outcomes, although clear associations cannot be drawn due to small numbers and confounders from high rates of first trimester miscarriages in general and inherently high-risk pregnancies. It may be worth considering routinely investigating pregnancy and breastfeeding status in women of childbearing age prior to each injection, as part of anti-VEGF treatment protocols.

Best practice recommendations for medically assisted reproduction in patients with known cardiovascular disease or at high risk of cardiovascular disease.

Increasing numbers of people are seeking assisted conception. In people with known cardiac disease or risk factors for cardiac disease, assisted conception may carry increased risks during treatment and any subsequent pregnancy. These risks should be assessed, considered and minimized prior to treatment.

Endocrine disease in pregnancy.

Endocrine disease is common in pregnancy. Most pre-existing endocrine conditions, if well controlled, have little impact on maternal or fetal morbidity. Uncontrolled endocrine conditions in pregnancy, whether poorly controlled pre-conception or newly diagnosed, are associated with a variety of adverse fetal outcomes and maternal morbidity. Also, transplacental transfer of maternal antibodies can have adverse fetal or neonatal consequences. The initial diagnosis of many conditions is hindered by the overlap of symptoms that occur in normal pregnancy and those that suggest specific endocrine pathologies, and also by the changes in reference ranges for common biochemical measurements that occur as a result of physiological changes in pregnancy. This article summarises the common endocrine disorders in pregnancy and describes how pregnancy can alter their investigation, treatment and ongoing management, as well as the potential effects on the fetus.

Gastrointestinal and liver disease in pregnancy.

Gastrointestinal (GI) conditions are common in women of childbearing age. They often present before pregnancy but can arise de novo during pregnancy. The physiological changes that occur during pregnancy can influence the differential diagnosis of common GI presentations, affect the interpretation of diagnostic tests and restrict the use of diagnostic or therapeutic procedures. In this article, we summarise the clinical features, investigation and management of common GI and liver conditions that are incidental to pregnancy, and describe the specific features of pregnancy-related disorders that are less frequently encountered by general physicians. Newer developments in areas that are increasingly encountered in obstetric medical practice, including pregnancy after bariatric procedures, are also described.

Non-alcoholic fatty liver disease in pregnancy.

Non-alcoholic fatty liver disease (NAFLD) is now the commonest liver pathology in the UK; however, relatively little is known about its course in pregnancy or the effect it has on maternal or fetal outcomes. Described here is a 24-year-old woman in her first pregnancy who presented with non-specific symptoms and raised alanine aminotransferase with ultrasonography of her liver showing changes of steatosis and suspicious for cirrhosis, leading to a diagnosis of NAFLD. The case illustrates the need for the clinician to have awareness of this increasingly prevalent condition and for multidisciplinary management.

Haematinic deficiency in pregnancy: another HELLP mimic.

Haematinic deficiency is not uncommon in pregnancy. Folate deficiency is more common than B12 deficiency because of the increased uptake of folate in pregnancy, and the fact that B12 stores take much longer to deplete. Described here are five cases of anaemia in pregnancy secondary to severe haematinic deficiency with subsequent management and pregnancy outcomes. In the majority of cases, the women were proteinuric, but systemically well and normotensive. Thrombotic thrombocytopenic purpura and HELLP were both considered, but the identification of very abnormal folate levels of less than 3 µg/L in all and low B12 deficiency in the majority made haematinic deficiency the most likely diagnosis. They all received high dose folic acid, parenteral vitamin B12 and oral iron and made good haematological recoveries. Adequate antenatal correction of vitamin deficiency like this avoids bone marrow suppression and helps minimise poor obstetric outcomes associated with pre-existing anaemia including post-partum haemorrhage.

Patient Care Pathways for Pregnancy in Rare and Complex Rheumatic Diseases: Results From an International Survey.

OBJECTIVE: To map existing organizational care pathways in clinical centers of expertise that care for pregnant women affected by rare and complex connective tissue diseases (rcCTDs). METHODS: An international working group composed of experts in the field of pregnancy in rcCTDs co-designed a survey focused on organizational aspects related to the patient's pathway before, during, and after pregnancy. The survey was distributed to subject experts through referral sampling. RESULTS: Answers were collected from 69 centers in 21 countries. Patients with systemic lupus erythematosus and/or antiphospholipid syndrome were followed by more than 90% of centers, whereas those with disorders such as IgG4-related diseases were rarely covered. In the majority of centers, a multidisciplinary team was involved, including an obstetrician/gynecologist in 91.3% of cases and other healthcare professionals less frequently. Respondents indicated that 96% of the centers provided routine pre-pregnancy care, whereas the number of patient visits during pregnancy varied across centers. A formalized care pathway was described in 49.2% of centers, and 20.3% of centers had a predefined protocol for the monitoring of pregnant patients. Access to therapies during pregnancy also was heterogeneous among different centers. CONCLUSION: In international referral centers, a high level of care is provided to patients with rcCTDs before, during, and after pregnancy. No significant discrepancies were found between European and non-European countries. However, this work highlights a potential benefit to streamlining the care approaches across countries to optimize pregnancy and perinatal outcomes among patients with rcCTDs.

COVID-19 in pregnancy: A UK perspective.

COVID-19 infection in pregnancy can cause respiratory and obstetric complications,1 however emerging evidence on its impact in pregnancy is limited. This article aims to review data collected and analysed so far over the course of the coronavirus pandemic, that examine demographic associations, patterns of disease, severity and outcomes of COVID-19 in pregnancy in the UK. Hospital admission, for which black and minority ethnic background and raised body mass index are risk factors, is associated with maternal mortality and admission to intensive care and is more likely in the late second or third trimester.2 Vaccination is safe in pregnancy3 and is protective against severe COVID-19 and admission to intensive care,4, 5 Maternal SARS CoV-2 is associated with a greater risk of stillbirth, preterm birth, small for gestational age (SGA) and preeclampsia.6 Efforts to reduce the incidence of COVID-19 in pregnancy, including vaccination, are therefore likely to reduce preventable complications from this disease.

Considerations for women with COVID-19 admitted to hospital.

The number of pregnant women being admitted with severe COVID-19 infection and dying has increased with each wave of the pandemic. These women often present unique challenges to the medical and obstetric teams given the changes in physiology that occur in pregnancy, affecting assessment and management, as well as the practical difficulties such as the ideal location of care. Whilst the basis of treatment remains the same, there are nuances to caring for pregnant women that need considerable thought and multidisciplinary collaboration. Obstetricians, neonatologists, midwives, intensivists, anaesthetists and physicians may all be involved at some point, depending on the gestation and severity of illness. Implementing a COVID-19 in pregnancy guideline or checklist for your hospital will help ensure pregnant women are managed in a safe and timely manner. Here described are some key recommendations to help in the management of pregnant women admitted with COVID-19.

Haemophagocytic lymphohistiocytosis in pregnancy.

Haemophagocytic lymphohistiocytosis is a life-threatening systemic inflammatory syndrome defined by persistent fever, cytopenia and multi-organ dysfunction. Primary haemophagocytic lymphohistiocytosis classically presents in childhood as a result of genetically abnormal perforin or inflammasome function, leading to the aberrant release of pro-inflammatory cytokines causing a hyperinflammatory state. Secondary haemophagocytic lymphohistiocytosis is an acquired phenomenon occurring at any age as a result of immune dysregulation to a specific trigger such as infection, haematological malignancy or autoimmune disease. Secondary haemophagocytic lymphohistiocytosis occurring in the pregnant woman represents a diagnostic challenge and carries a significant mortality. This has led to its first inclusion in the fourth Mothers and Babies: Reducing Risk through Audits and Confidential Enquiries across the United Kingdom annual maternal report in 2017. This article presents an overview of haemophagocytic lymphohistiocytosis, reviews the literature on haemophagocytic lymphohistiocytosis in pregnancy, suggests diagnostic pathways and explores the safety and efficacy of existing and potential treatment strategies for haemophagocytic lymphohistiocytosis occurring during pregnancy.

Rhombencephalitis in Pregnancy-A Challenging Case of Probable Listeria Infection.

Rhombencephalitis refers to inflammation of the brainstem and cerebellum, and can be caused by infections, autoimmune disorders or paraneoplastic syndromes. The most common infective cause is the bacterium Listeria monocytogenes. Listeria monocytogenes is the predominant species to cause human listeriosis, and is commonly due to the ingestion of contaminated foods. Symptoms include a mild gastroenteritis, fever (often with extreme temperature variations), headache, and myalgia. In more severe cases, invasive disease may lead to bacteraemia and neurolisteriosis. Pregnant women are more susceptible to listeriosis, which is believed to be due to pregnancy-related immune modulation. Maternal-neonatal infection with adverse pregnancy outcomes include neonatal listeriosis, spontaneous miscarriage and intrauterine fetal demise. Diagnosis may be challenging due to initial nonspecific symptoms and low sensitivity and specificity of confirmatory diagnostic laboratory tests. Here, we describe a case of rhombencephalitis in pregnancy, attributed to Listeria, and review the clinical features, diagnosis and multidisciplinary management. Lastly, we describe the immunological response to Listeria monocytogenes and show in vitro pro-inflammatory effects of Listeria monocytogenes on peripheral blood mononuclear cells and placental explants.

Tachycardia in pregnancy: when to worry?

Tachycardia in pregnancy is common, and distinguishing between physiological and pathological causes can be a challenge. Understanding the cardiovascular changes that take place in pregnancy can help to direct investigations. The finding of a persistent tachycardia, regardless of symptoms, should always prompt clinical review and consideration of investigations (such as blood tests, electrocardiography and echocardiography), where indicated. Treatment of tachyarrhythmias in pregnancy differs very little from a non-pregnant adult, and unstable arrhythmias should follow Resuscitation Council UK guidelines. Pregnant women with pathological arrhythmias need to be cared for under a multidisciplinary team, including obstetricians, obstetric anaesthetists, specialist midwives, cardiologists and obstetric physicians.

Severe hypertension in pregnancy.

Severe hypertension in pregnancy is defined as a sustained systolic blood pressure of 160 mmHg or over or diastolic blood pressure of 110 mmHg or over and should be assessed in hospital. Severe hypertension before 20 weeks' gestation is rare and usually due to chronic hypertension; assessment for target organ damage and exclusion of secondary hypertension are warranted. The most common cause of severe hypertension in pregnancy is pre-eclampsia, which presents after 20 weeks' gestation. This warrants more rapid control of blood pressure due to the risk of haemorrhagic stroke, and intravenous antihypertensive agents may be required. Treatment is determined by licensing, availability and clinician experience, with no high-level evidence to guide prescribing. Labetalol is the agent most commonly used, both orally and intravenously, in pregnancy in the UK. Severe hypertension is a risk factor for sustained hypertension after pregnancy. Hypertension in pregnancy is associated with increased cardiovascular risk.

Iron deficiency anaemia in pregnancy: A contemporary review.

Iron deficiency anaemia is a global health problem, which particularly affects pregnant women. Iron deficiency anaemia during pregnancy is associated with increased maternal and perinatal morbidity and mortality. Maternal iron deficiency may also be associated with neurocognitive deficits in infants. Iron requirements increase during pregnancy and are influenced by hepcidin, the master regulator of iron homeostasis. The enduring global burden of maternal anaemia suggests that currently employed iron supplementation strategies are suboptimal. Recent developments in our understanding of systemic and placental iron homeostasis may improve therapeutic effectiveness by altering the dose and frequency of oral iron. Intravenous iron appears to be a safe treatment to correct maternal anaemia rapidly but research on patient-centred outcomes and cost-effectiveness is needed. Future trials should be adequately powered to assess outcomes relevant to pregnant women.

Loeys-Dietz syndrome in pregnancy.

Loeys-Dietz syndrome is a recently described condition which causes cardiovascular, craniofacial, neurocognitive and skeletal abnormalities due to mutations in components of the transforming growth factor-ß signalling pathway. Associated vascular abnormalities include vessel tortuosity and an increased incidence of vascular dissection. Pregnancy increases the risk of aortic dissection compared to non-pregnant individuals and an underlying condition such as Loeys-Dietz syndrome increases this further. While aortic dissection is well described in pregnancy in Loeys-Dietz syndrome, some women can have uncomplicated deliveries, particularly when the risks of the condition are actively managed. Such pregnancies should be considered high-risk, and women should be counselled and managed accordingly. Here we describe two pregnancies in one woman, both with successful outcomes, followed by a summary of the key management principles.

Antisynthetase syndrome in pregnancy: A case and review of the literature.

Antisynthetase syndrome is a rare autoimmune, multisystem, inflammatory condition, characterised by autoantibodies against aminoacyl tRNA synthetases. The predominant features are myositis and interstitial lung disease but other symptoms such as Raynaud's phenomenon may also be present. Described here is a 36-year-old woman with antisynthetase syndrome who planned and underwent a successful pregnancy, during which a multidisciplinary team approach secured a good outcome for both mother and baby.

Loeys-Dietz syndrome and pregnancy: The first ten years.

The physiological and haemodynamic changes that occur in pregnancy and the postpartum period increase the risk of aortic dissection. Loeys-Dietz syndrome results from mutations in the genes encoding components of the TGF-ß signalling pathway; aortic pathology is of particular concern in this condition but other vascular abnormalities can also be present. Significant maternal morbidity and mortality has been described in patients with Loeys-Dietz syndrome, but successful and uncomplicated pregnancies are still possible. Nevertheless, all patients with this condition should, at present, be treated as very high risk in pregnancy and the postpartum period, until reliable risk prediction tools become available. This review summarises the recent advances in the understanding of the pathophysiology of this condition, and the management strategies currently advocated.