British<scp>HIV</scp>Association guidelines on the management of opportunistic infection in people living with<scp>HIV</scp>: Considerations in pregnancy 2024

AIDS-related complications are a common cause of maternal death worldwide and are responsible for a high proportion of maternal deaths in low-income countries; they are a significant contributing cause of maternal death in high-income countries, although the absolute numbers are small [1, 2]. Their medical management is complicated by the requirement to balance the needs of the mother and the fetus. As opportunistic infections in pregnant women living with human immunodeficiency virus (HIV) in the UK are rare, they should be managed with close collaboration between HIV specialists, obstetricians, neonatologists, paediatricians and pharmacists. Any case of confirmed or suspected opportunistic infection in pregnancy should ideally be discussed within a fetal medicine and infection multidisciplinary team (MDT). If an MDT is not available locally, a national MDT is available and can be contacted ([email protected]; [email protected]; [email protected]; [email protected]; [email protected]). It is important to understand the physiological changes that occur in pregnancy as they can affect the interpretation of test results, clinical findings and the pharmacokinetics of drugs used in pregnant women [1, 3, 4]. Absolute CD4 cell counts characteristically decrease during pregnancy. Furthermore, there is a shift from cell-mediated immunity (Th1 response) towards humoral immunity (Th2 response) which leads to an increased susceptibility to, and severity of, certain infectious diseases in pregnant women, irrespective of HIV infection, including toxoplasmosis, varicella and listeriosis [5]. There are increases in cardiac output, plasma volume, red cell mass and glomerular filtration rate in pregnancy. Absorption of aerosolised medication may be affected by increased tidal volume and pulmonary volume. Placental transfer of drugs, increased renal clearance, altered gastrointestinal absorption and metabolism by the fetus may affect drug levels. Therapeutic drug monitoring should be considered due to altered drug pharmacokinetics in pregnancy, and the potential for complicated multiple interactions between antiretroviral agents and many of the drugs used to treat opportunistic infections [3, 6]. For information about drug safety during pregnancy and breastfeeding, see Appendix 1. While this guidance refers to women and breastfeeding throughout, the writing group fully acknowledges that it is also applicable to pregnant transgender men and gender diverse individuals and also that some may prefer the term chestfeeding to breastfeeding. We endorse the use of person-centered, gender-inclusive language in healthcare settings according to the individual's preferences. Guidance on supporting people living with HIV with opportunistic infections, including in pregnancy, can be found on the British HIV Association (BHIVA) website (https://www.bhiva.org/file/6225e44b53c49/OI-guidelines-supporting-patients.pdf). A full review of these guidelines is due by 2029, with interim updates only if recommendations need updating in line with new data. In general, pregnant women with symptoms suggestive of an AIDS-defining illness should be managed and investigated in the same way as non-pregnant individuals. When choosing an imaging modality for the diagnosis of opportunistic infections in pregnant women, consideration should be given to the need for a rapid diagnosis and the potential harm of the investigation. The potential fetal doses of ionising radiation from different imaging modalities and the risk of childhood cancer were recently outlined by Wiles et al. [7]. Discussion between HIV specialists, obstetricians, senior radiologists and the pregnant woman is recommended. If opportunistic infection in the lung is suspected, a chest X-ray may be carried out with little or no risk to the fetus [7]. An ultrasound scan is a safe option for imaging of the abdomen. A direct computed tomography (CT) scan of the fetus in the pregnant abdomen should be avoided where possible. Magnetic resonance imaging of the fetus and abdomen is considered safe at all stages of pregnancy, although use of gadolinium in pregnancy has been reported to cause an increased risk of inflammatory conditions and should be avoided where possible [8]. CT scans of the brain, thorax or limbs of the mother may be carried out with minimal exposure to the fetus. Modern CT scanners have little radiation scatter to areas outside the scanner itself, so the main radiation scatter that would affect the fetus during a thoracic CT scan would be internally within the body of the mother. The use of contrast with CT scanning is permitted. Pulmonary embolus (PE) is a leading cause of maternal morbidity and death, and suspected PEs need to be investigated and treated promptly. Ventilation and perfusion scans, or in some situations limited ‘perfusion’ scans, are regarded as acceptable for cases of suspected PE in pregnancy. CT pulmonary angiogram (CTPA) scans are also being used more often and are becoming regarded by many as the investigation of choice for the diagnosis of PEs in pregnancy. Although CTPA is associated with low fetal radiation exposure, it does expose the mother's breast tissue to a relatively high radiation dose [7, 9]. There are no specific contraindications for lymph node biopsy, liver biopsy and lumbar puncture in pregnancy. Endoscopic procedures, including bronchoscopy and upper and lower gastrointestinal endoscopy, may also be undertaken if necessary [10]. Where an opportunistic infection has been diagnosed, the fetus should be closely monitored, for example by serial high-resolution ultrasound scans and fetal cardiac monitoring, so that signs of disease, growth retardation, fetal distress or drug toxicity can be detected early [1, 11]. A paediatrician or neonatologist with expertise in HIV and congenital infection should be involved, prior to delivery, in discussions about the management of opportunistic infections in pregnant women. An MDT approach is advised to include risk–benefit discussions about opportunistic infection treatment choices in pregnancy, fetal monitoring and early review of the neonate for signs of congenital infection, drug toxicity and teratogenicity. Congenital infections in the neonate have been described for a variety of opportunistic pathogens affecting the mother. These include Mycobacterium tuberculosis [12, 13], Cryptococcus neoformans [14-16], cytomegalovirus (CMV) [17], Pneumocystis jirovecii [18, 19] and Toxoplasma [20-22]. In some instances, it may be difficult to distinguish between congenital and early postnatal infection. Neonates born to women living with HIV should be assessed by a paediatrician with expertise in HIV and other congenital infections, and where necessary actively screened for congenital infections using appropriate national and local guidelines and assessed for signs of teratogenicity or drug toxicity. The scope, purpose and guideline topics were agreed by the writing group. The search (population, intervention, comparator and outcome [PICO]) questions were set and an independent systematic literature review carried out. The Medline, Embase and Cochrane Library databases were searched and the literature reviewed to address each question. The PICO questions and search strategies are outlined in Appendix 2. Further details of the methodology can be found on the BHIVA website (https://www.bhiva.org/file/5d514ec9b503d/OI-guidelines-methods-general.pdf), including the use of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to assess and grade the evidence. Good practice points (GPPs) are recommendations, based on the clinical judgment and experience of the writing group, with which few clinicians are expected to disagree and for which evidence is unlikely to emerge as they are generally considered to be good practice. From Section 6.2 Antifungal treatment for candidiasis and cryptococcal infection. There is some evidence from case studies that PCP in pregnancy may be more aggressive, with increased morbidity and mortality, than in non-pregnant women [23]. Investigation and diagnosis of PCP in pregnant women is the same as for non-pregnant adults. No large, randomised trials investigating the treatment of PCP have included pregnant and breastfeeding women [24]. Trimethoprim-sulfamethoxazole inhibits bacterial and, to a lesser extent, human folate metabolism. Folate is essential for fetal development and folate deficiency has been associated with an increased risk of neural tube defects and other congenital anomalies [25]. Trimethoprim-sulfamethoxazole has been associated with cardiovascular anomalies and defects of the urinary tract in some studies [26]. Other studies, including a meta-analysis, have not found an increased risk of congenital malformations associated with trimethoprim-sulfamethoxazole use in pregnancy, including in the first trimester [27, 28]. A nested control study from the Quebec Pregnancy Cohort (predominantly in women without HIV) found an increase in the rates of spontaneous abortion in pregnant women who took trimethoprim-sulfamethoxazole in pregnancy (adjusted odds ratio 2.94, 95% confidence interval 1.89–4.57) [29]. However, the benefit of trimethoprim-sulfamethoxazole to treat PCP in pregnancy outweighs any potential harm and it should be used, including in the first trimester. Folic acid at 0.4–5 mg/day is recommended for all pregnant women [30]. Some authors have advocated using higher-dose folic acid replacement to prevent fetal anomalies associated with anti-folate drugs [31]. However, others have reported PCP treatment failure in this context [32]. Therefore, doses above 0.4 mg daily should only be considered in the first trimester of pregnancy and on a case-by-case basis. Steroids should be administered as per standard guidelines for the treatment of PCP in non-pregnant women. Steroids are generally considered safe in pregnancy, although the findings of a systematic review of case–control studies suggested a small increased risk of oral clefts [33]. However, other large population-based studies have not found an association between maternal steroids and congenital anomalies [34, 35]. Alternative options are limited to dapsone with trimethoprim or atovaquone. Clindamycin is generally considered safe in pregnancy, but primaquine can cause both maternal and fetal haemolysis in G6PD deficiency and is therefore not recommended. Dapsone has been used in pregnancy to treat leprosy and malaria and appears to be safe [36, 37]. The risk of haemolysis in neonates with G6PD deficiency seems to be very low [38]. Limited data suggest that atovaqone is safe in pregnancy [39]. Chemoprophylaxis for PCP should be prescribed to pregnant women living with HIV in line with standard guidelines for non-pregnant individuals. It is important to remember that there is a false reduction in absolute CD4 count during pregnancy, especially during the third trimester, and in such circumstances a CD4 percentage less than 14% can be used as an indicator for the need to commence PCP prophylaxis. Trimethoprim-sulfamethoxazole is the preferred prophylactic agent against PCP in pregnancy. There are theoretical concerns over the safety of this drug in the first trimester, especially prior to the closure of the neural tube, and an alternative agent could be considered during this time. Possible alternatives include once daily dapsone, atovaquone or nebulised pentamidine. It is unclear whether congenital Pneumocystis infection can occur, although occasional case reports suggest it may be possible [40, 41]. However, it is recommended that infants born to women treated for PCP in pregnancy should be reviewed by a paediatrician or neonatologist, mainly to rule out any teratogenic effects and/or toxicity of maternal drug treatment. If there are signs of possible Pneumocystis infection, the infant should be urgently reviewed and the case discussed with the local paediatric infectious diseases team. Vaginal candidiasis occurs more frequently in pregnancy; however, although it is supposed that other fungal infections are more common in pregnancy, there is little direct evidence to support this. Investigation of suspected fungal infections should be identical in pregnancy, except for considering the risk associated with radiological procedures (see Introduction). Candidiasis Cryptococcal infection Two case series illustrate that cryptococcal infection in pregnancy is associated with high maternal mortality and frequent stillbirths and miscarriages despite antifungal therapy [42, 43]. There have been no reports of teratogenesis or other adverse pregnancy outcomes with liposomal amphotericin B [44]. Flucytosine has been associated with teratogenesis when used in rats at high doses [45]; however, there are case reports of its use to treat cryptococcal meningitis during the second and third trimesters of pregnancy with healthy fetal outcomes [46, 47]. Although single-dose fluconazole has not been associated with any birth defects in pregnancy [48], specific birth defects associated with continuous daily doses of fluconazole of 400 mg/day or more in the first trimester, including cardiac septal defects, have been suggested by one case report and the finding of a large case–control study [49, 50]. Two studies have also demonstrated a higher risk of spontaneous abortion with fluconazole exposure in the first and second trimesters [51]. Hence national agencies have been re-evaluating guidelines for its use in pregnancy. In one case series, 12 pregnant Ugandan women with cryptococcal meningitis were described, five of whom received fluconazole in the second and third trimesters amphotericin B therapy Although few of these in no congenital were has been associated with teratogenicity in rats and there have been no reports of its use in during pregnancy is also not recommended in pregnancy due to teratogenicity in the findings of one case series suggested it may be safe in The are not considered given evidence of teratogenicity in studies, although no human data are available infection in pregnancy is not to have direct for the should be reviewed if a woman has been treated with antifungal drugs with a potential risk of especially during the first trimester. Congenital cryptococcal infection has been but appears to be born to with cryptococcal in pregnancy should be assessed for cryptococcal by a paediatrician or neonatologist If cryptococcal is suspected, on management should be from a local paediatric infectious diseases team. The risk of of Toxoplasma increases at lower CD4 women with a low CD4 count and a of infection should be for signs of women with Toxoplasma no exposure to infection, should be advised about the risk for and associated risk reduction strategies There is no evidence that is more when it occurs in pregnancy Investigation and diagnosis of in pregnant women is the same as for non-pregnant adults. in pregnancy should be treated in the same way as in non-pregnant individuals. and are the drugs of choice in pregnancy, especially the first trimester is a folic acid of acid mg daily is recommended as as folic acid the of in pregnancy Although some folic acid are human this does not to include A few case reports of defects have been exposure in pregnancy to but no systematic studies are case report described a of the and thoracic and a in an infant to and dapsone in the first trimester. However, an association between the drugs and the has been The safety of during pregnancy has not been although not to a significant teratogenic risk when used as agents study in demonstrated an association with birth defects, but a association could not be as other such as its use in with may have a The the to the fetus during all stages of with maternal is with fetal of maternal levels. may in the neonate for birth when given to the mother are to cause harm to the neonate if administered to that may be in the neonate include and in the neonate has been to maternal at term by authors infants to be especially to the development of has been reported in neonates and in a fetus in exposure to both neonates of the potential toxicity to the these agents should be avoided to these that should not be used of pregnancy and that should be used Clindamycin the of of the maternal and is generally considered safe in pregnancy. Clindamycin is an alternative option when there is to should be the same as for non-pregnant individuals. The of maternal HIV on the risk of congenital infection is the of maternal infection during pregnancy on the risk of HIV is not In the congenital infection is associated with infection in pregnancy. There have been case reports of to neonates during pregnancy in women living with HIV and not in the context of The neonate to be at risk of congenital infection should be reviewed by a paediatrician or neonatologist When clinical findings or are with possible congenital infection, the case should be discussed with a local paediatric infectious diseases to investigation and medical management The main of this guidance is the management of as an opportunistic infection in pregnant women living with A review of the management of all infection and its on the pregnancy is outside the of this There is no evidence to suggest that in pregnant and non-pregnant women It is that of maternal infections are and infections or with a different can to in the mother and congenital in the fetus For pregnant women living with for investigation and treatment of suspected maternal the same as for non-pregnant women. Investigation and for possible in infection of the fetus also the guidance for in women without that infection in the context of HIV has a higher risk of to the fetus pregnant women should be advised about the risk of infections such as that are associated with congenital infection agents including and adverse fetal effects in studies but there is a of and studies in Any therapy for the especially in the first trimester, should be to a risk–benefit with consideration of therapy if for example treatment of to the risk to both the mother and fetus The clinical experience and case report data are available for and its oral We suggest and as treatment for in pregnancy. safety data for the use of and in pregnancy, and use is recommended considering the and has been to be associated with teratogenicity in studies and is also A study specific to women living with HIV) not any increased of adverse pregnancy outcomes or birth defects with when with the use of during pregnancy There is evidence from case reports for the safe use of in the first and second trimesters for pregnant women in the to pregnant women living with there are case report data safe use of in the second and third trimesters to treat maternal disease, with in of congenital infection In one case of maternal and fetal death were to than treatment has been associated with fetal in studies A case report demonstrated the safe use of in the second trimester of pregnancy for a with no adverse fetal effects A case of use in the third trimester for a reported it is unclear whether this to the treatment to the potential for renal monitoring of for should be especially in the second and third has been to be in studies, including and It is associated with fetal tissue and There are no data on the clinical use of in pregnant women and its use is not advised the context of as an opportunistic infection, there is evidence to suggest that at high doses can the of congenital infection maternal infection, especially in the first trimester. is an of review and treatment of infection during pregnancy with or without HIV) with the of congenital infection may be appropriate in some cases and should be discussed with the mother and MDT on a case-by-case There is evidence to suggest that neonates born to women living with HIV not on antiretroviral therapy are at higher risk of congenital infection than born to on data on the and rates of congenital are We for signs of congenital in neonates born to women living with especially born to who have CD4 counts or who are not on These neonates should be assessed for signs and symptoms of congenital infection. according to national guidance should be There is no evidence to support of all infants to The same as for the should be In of the higher risk of all neonates born to with evidence of should be reviewed and investigated for congenital infection with using an appropriate or as as possible birth and within the first of and discussed with the paediatric infectious diseases team. The same for investigation and management of possible congenital should be as for the There is no evidence to suggest that Mycobacterium in pregnant women to that in non-pregnant individuals. and treatment are the same for pregnant women as for other adults. has been associated with birth defects in However, data from the Quebec Pregnancy Cohort not an increased risk of congenital malformations in with exposure to in the first trimester Furthermore, women in who were to in the first trimester no increased risk of congenital malformations However, studies have an increased risk of spontaneous abortion first trimester exposure to et al. in a nested case–control study within the Quebec Pregnancy Cohort not control for the severity of infection, and findings may have been due to maternal infection than drug exposure has not been associated with birth defects in studies and human studies have not any increased risk of congenital malformations in infants in et al. found an increased risk of spontaneous abortion maternal exposure to in pregnancy. However, as for maternal infection may have been the cause of Therefore, is preferred as treatment for in pregnant women and is not recommended. and have been used to treat Mycobacterium tuberculosis in pregnancy without any teratogenic effects being and are therefore considered safe to use when pregnant women with infection. There are no data on the safety of in pregnancy and therefore is preferred when pregnant women Mycobacterium has not been born to women treated for in pregnancy should be reviewed by a paediatrician or neonatologist to drug toxicity or teratogenicity. If there are any concerns possible infection, review with the local paediatric infectious diseases team is recommended. The writing group and for and The writing group also and both of UK for this 1. 2. use in early pregnancy and the risk of birth of during pregnancy and the risk of congenital a based et al. in Pregnancy and A to and et al. therapy of cytomegalovirus infection with review of the The Medline, Embase and Cochrane Library databases were searched for language between and the of the from on and HIV of and on HIV and between and were also The databases were searched using the 1. imaging dose CT scan scan X-ray gadolinium contrast 2. Pneumocystis jirovecii congenital trimethoprim primaquine atovaquone Candidiasis congenital amphotericin B fluconazole Cryptococcal infection congenital amphotericin B congenital (CMV) congenital Mycobacterium congenital Antifungal agents fluconazole amphotericin congenital candidiasis search also limited to randomised systematic and The literature were based on the PICO radiological are safe to use for pregnant women living with HIV and at risk of opportunistic is the treatment for PCP for pregnant women living with For pregnant women living with with a CD4 count is the agent for PCP dose of folic acid should be used for pregnant women trimethoprim-sulfamethoxazole for the treatment of is the treatment for candidiasis for pregnant women living with is the treatment for cryptococcal infection for pregnant women living with is the treatment for for pregnant women living with is the treatment for for pregnant women living with is the treatment for for pregnant women living with

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