11.1 Background and epidemiology
AIDS-related complications are a common cause of maternal death worldwide and are responsible for a high proportion of maternal deaths in the developing world; they are a significant contributing cause of maternal death in the developed world, though the absolute numbers are small [1,2]. Their medical management is complicated by the requirement to balance the needs of the mother and the foetus, and the viability of the pregnancy itself.
- •Opportunistic infections in HIV-seropositive pregnant women should be managed with close collaboration between HIV specialists, obstetricians, paediatricians and where possible, specialists in obstetric medicine and materno–foetal medicine (category IV recommendation).
Physiological changes in pregnancy are important to understand as they can impact on the interpretation of test results, clinical findings on examination and the pharmacokinetics of drugs used in pregnant women [1,3,4]. CD4 cell counts characteristically drop during pregnancy. Furthermore there is a shift from cell-mediated immunity (Th1 response) toward 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 . There is an increase in cardiac output (30–50%), plasma volume (24–50%), red cell mass (20–30%) and glomerular filtration rate. Absorption of aerosolised medication may be affected by an increase in tidal volume and pulmonary volume. Placental transfer of drugs, increased renal clearance, altered gastrointestinal absorption and metabolism by the foetus may affect drug levels.
- •Therapeutic drug monitoring (TDM) should always be considered due to altered drug pharmacokinetics in pregnancy, and the potential for complicated multiple interactions between antiretrovirals and many of the drugs used to treat opportunistic infections [3,6].
11.2 Diagnostic considerations in HIV-seropositive pregnant women
In general, pregnant women with symptoms suggestive of an AIDS-defining illness should be managed and investigated in the same way that they would be if they were not pregnant.
There are detailed guidelines relating to the use of X-rays and other imaging techniques in pregnant women [7–11]. If opportunistic infection in the lung is suspected a chest X-ray may be carried out with little or no risk to the foetus as long as an abdominal shield is used and due consideration is given to exposure times and position of the X-ray. Plain abdominal X-rays should generally be avoided.
An ultrasound scan is a safe option for imaging of the abdomen. A direct CT scan of the foetus in the pregnant abdomen is contraindicated and, where possible, should be avoided. MRI scanning of the foetus and abdomen may be considered, although it is recommended to avoid them in the first trimester unless absolutely necessary.
CT scans of the brain, thorax or limbs of the mother may be carried out with minimal exposure to the foetus. Modern CT scanners have little radiation scatter to areas outside the scanner itself, so the main radiation scatter affecting the foetus during a thoracic CT scan would be internally within the body of the mother. The use of contrast with CT scanning is permitted. However, Gadolinium, which is used in MRI scanning, is not recommended as it has been found to be teratogenic in some animal studies, and should be avoided if possible.
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 (VQ) scans, or in some situations limited ‘perfusion’ scans, are regarded as acceptable with suspected PE in pregnancy. CT pulmonary angiogram (CTPA) scans are also being used more and are becoming regarded by many as the investigation of choice for the diagnosis of PEs in pregnancy .
- •When choosing 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. Discussion between HIV specialists, obstetricians and senior radiologist is recommended (category IV recommendation).
Lymph node biopsy, liver biopsy and lumbar puncture have no specific contraindications in pregnancy. Endoscopic procedures, including bronchoscopy and upper and lower GI endoscopy, may both also be undertaken if necessary .
11.3 Diagnostic considerations for the foetus and newborn baby
11.3.1 Foetal monitoring
Where an opportunistic infection is being treated the foetus should be closely monitored, for example by serial high- resolution ultrasound scans and foetal cardiac monitoring, so that signs of disease, growth retardation, foetal distress or possible drug toxicity in the foetus can be detected early [1,13].
11.3.2 Vertical transmission of maternal opportunistic infections to the neonate
Congenital infections in the neonate have been described for a variety of opportunistic pathogens affecting the mother. These include Mycobacterium tuberculosis [14,15], cryptococcal infection [16,17], cytomegalovirus (CMV) , Pneumocystis jirovecii (PCP) [19,20] and toxoplasmosis [21,22]. Vertical transmission is generally assumed to be the route of infection, although in some cases it may not be clear whether the neonate acquired the infection in utero or during the perinatal or postnatal period.
- •Neonates born to HIV-seropositive women should be assessed by a paediatrician, and where necessary actively screened, for congenital opportunistic infections. The placenta should also be examined histologically for signs of infection or disease (category IV recommendation).
11.4 Treatment considerations for specific opportunistic infections
(Letters in parentheses denote US Food and Drug Administration-assigned pregnancy categories .)
11.4.1 Pneumocystis jirovecii (PCP)
Therapeutic options are identical to non-pregnant patients.
- •Trimethoprim-sulphamethoxazole (C/D) is the treatment of choice in pregnancy.
Alternative options are limited to: clindamycin (B) with primaquine (C); dapsone (C) with trimethoprim (C); or atovaquone (C) suspension. Clindamycin is generally considered safe in pregnancy, but primaquine can cause haemolysis. There are limited data on the use of dapsone in pregnancy; however, one review identified mild degrees of haemolysis . Intravenous pentamidine is embryotoxic but not teratogenic, so should be used only if other options are not tolerated.
Steroids should be administered as per standard guidelines for the treatment of PCP in non-pregnant women.
Chemoprophylaxis for PCP should be prescribed to HIV-seropositive pregnant women as per guidelines for non-pregnant individuals. As for most drugs, avoidance of prescribing in the first trimester should be adhered to, other than in exceptional circumstances. It is important to remember that there is a false reduction in absolute CD4 cell counts during pregnancy, especially during the third trimester, and in such circumstances more emphasis should be put on the CD4 percentage as an indicator for the need to commence PCP or indeed any prophylaxis.
Trimethoprim-sulphamethoxazole (C/D) is the preferred prophylactic agent against PCP in pregnancy [25,26]. Concerns remain over the safety of this drug in the first trimester , and during this time an alternative agent could be used if indicated. Possible alternatives include once daily dapsone (C) or nebulised pentamidine (C). The dosing of these agents is the same as for non-pregnant individuals. Other alternatives to these agents include clindamycin (B) and primaquine (C) or atovaquone (C); however, data on their efficacy are not as clear as for the other agents, and data on their safety in pregnancy is not complete.
11.4.2 Cryptococcus neoformans
First-line therapy should be with liposomal amphotericin B (B). There are no reports of teratogenesis with liposomal amphotericin B in the literature .
The addition of flucytosine (C) to amphotericin B requires careful consideration. Teratogenic effects have been reported when used in rats at high doses . However there are case reports of its use to treat cryptococcal meningitis during the second and third trimesters of pregnancy with healthy foetal outcomes [30,31]. Flucytosine should therefore only be used in combination with liposomal amphotericin B when potential benefits outweigh the risks and should be avoided during the first trimester whenever possible.
Most authorities recommend the use of fluconazole (C) during the consolidation phase of treatment for cryptococcal meningitis in non-pregnant individuals. High dose fluconazole treatment should be avoided during the early stages of pregnancy and substituted with liposomal amphotericin B. During the later stages of pregnancy the use of fluconazole as secondary prophylaxis may be considered (see below).
Voriconazole (D) use in rats has been strongly associated with teratogenicity and there are no reports in the literature of its use during pregnancy .
Congenital cryptococcosis has been reported, but appears to be rare .
11.4.3 Candida infections
Treatment of symptomatic vaginal candidiasis during pregnancy should be with topical agents, continued for at least 7 days.
The first episode of oropharyngeal candidiasis may respond to topical treatment with nystatin suspension or amphotericin. Oral fluconazole (100 mg daily for 7 to 10 days) is probably more effective, with fewer relapses  but should be avoided during the first trimester of pregnancy and only used following failure of topical therapy later in pregnancy, as there are four case reports of an unusual cluster of congenital malformations (craniofacial and skeletal) when fluconazole has been used at high doses during the first trimester of pregnancy [34,35]. However, there are over 800 pregnancy outcomes recorded with exposure to low dose fluconazole (≤150 mg) without an increased risk of malformations or miscarriage [36–40] and this provides a suitable alternative after the first trimester.
Oesophageal candidiasis requires systemic therapy. During the first trimester of pregnancy this should be with liposomal amphotericin B (B), for which there are no reports of teratogenesis in the literature . During the later stages of pregnancy, oral fluconazole may be considered. Although caspofungin (C) and voriconazole (D) are effective treatments for oesophageal candidiasis, both are associated with foetal abnormalities in animal studies and are not recommended for use during pregnancy.
11.4.4 Toxoplasma gondii
First line treatment should be with sulphadiazine (B) and pyrimethamine (C). Although some animal studies have shown sulphadiazine to be teratogenic, there is no clear evidence of teratogenicity in humans . If sulphadiazine is continued in the third trimester, there is a risk of neonatal haemolysis and methaemoglobinaemia. Although pyrimethamine is teratogenic in animals, causing cleft palate and neural tube defects, limited human data have not shown an increased risk of birth defects [21,41]. Pyrimethamine is a folate antagonist and should be prescribed with folinic acid.
Alternative options are clindamycin (B) with pyrimethamine (C) or atovaquone (C).
Secondary prophylaxis should be as for the non-pregnant.
All pregnant women should have T. gondii serological status checked. In the non-immunocompromised host, transmission of T. gondii to the foetus usually only occurs during acute infection. However, there have been case reports of transmission following reactivation in HIV-infected women with severe immunosuppression , although this is rare. Where there is evidence of acute infection or symptomatic reactivation in the mother, the foetus should be screened for evidence of perinatal transmission. Studies following up immunocompetent women with acute toxoplasmosis in pregnancy have not shown any conclusive evidence for the effectiveness of spiramycin, or sulphadiazine with pyrimethamine, to prevent congenital foetal infection [41,42].
11.4.5 Cytomegalovirus (CMV)
For systemic disease systemic therapy will be required. However, for patients with single site retinal disease, consideration may be given to providing local intravitreal therapy or implants to reduce foetal exposure to antivirals.
All the available antiviral agents, ganciclovir (C), valganciclovir (C), foscarnet (C) and cidofovir (C), are associated with congenital anomalies in rats and rabbits [43,44]. Ganciclovir is embryotoxic in rabbits and mice and teratogenic in rabbits. There is no published experience of valganciclovir in pregnancy, but the same concerns exist as for ganciclovir. Foscarnet is associated with an increased risk of skeletal anomalies in rats and rabbits, but there is no experience of its use in early human pregnancy. Due to the potential for renal toxicity, careful monitoring of amniotic fluid should be undertaken, especially in the second and third trimester, for oligohydramnios. Cidofovir also has shown evidence of embryotoxicity and teratogenicity in rats and rabbits, and there is no experience of using this drug in pregnancy.
Therefore, the most experience in clinical practice has been with intravenous ganciclovir, and either this agent or oral valganciclovir should be considered first line treatment for CMV disease in pregnancy [45,46].
Infants born to mothers with evidence of active CMV disease should be examined for evidence of congenital infection .
11.4.6 Herpes simplex virus (HSV) and varicella zoster virus (VZV)
Oral aciclovir (B) for either acute attacks or prophylaxis is indicated . No adverse outcomes have been reported to the infant after in utero exposure to this drug [48,49]. There are fewer registry data available for famciclovir (B) or valaciclovir (B), and the manufacturers recommend their use only when potential benefits outweigh the risk .
11.4.7 Mycobacterium tuberculosis
HIV infection and tuberculosis are closely linked; HIV infection increases the risk of reactivation of latent TB by at least 20 fold [51,52]. Both infections most commonly occur in women of childbearing years and therefore, in communities with a high incidence of TB, HIV-seropositive pregnant women are at risk of developing symptomatic tuberculosis. TB and HIV are both independent risk factors for maternal mortality [14,53,54].
Maternal TB infection, not confined to the lymph nodes, has been linked to increased pregnancy complications, including low birth weight, preterm birth and intra-uterine growth retardation [55,56]. These complications are exacerbated when TB is diagnosed late or treatment is interrupted .
Investigation of pregnant women for tuberculosis should be the same as for non-pregnant adults. Although every effort should be made to obtain appropriate specimens for culture and sensitivity testing, treatment for suspected or probable TB should not be delayed, especially when managing an individual approaching the end of her pregnancy, to reduce the risk of transmitting M. tuberculosis to the neonate.
Treatment of TB should be the same as for the non-pregnant. All four first line drugs have a good safety profile in pregnancy and none appears to have teratogenic effects [57,58]. Isoniazid (C) causes hepatotoxicity in pregnant and non-pregnant adults, although one retrospective study, which was not statistically significant, has suggested that this is more common in pregnant women . All pregnant women receiving isoniazid should be aware of potential hepatotoxicity and its symptoms, and their liver function should be checked if clinical symptoms deteriorate. Some authorities recommend regular monitoring of liver function during pregnancy. Pyridoxine should be used, as for all taking isoniazid.
Rifampicin (C) may increase the risk of haemorrhagic disease in neonates. Therefore neonates born to pregnant women taking rifampicin should be given vitamin K. Rifampicin is not known to be teratogenic.
Although pyrazinamide (C) is not recommended for use during pregnancy in the United States, both the WHO and International Union Against Tuberculosis and Lung Disease recommend its routine use for pregnant women being treated for TB . There seems to be little evidence to suggest pyrazinamide is harmful in pregnancy and it should therefore be included in an initial anti-tuberculous regime. If pyrazinamide is omitted, the minimum duration of treatment is nine months.
Ethambutol (B) is not known to be harmful in pregnancy . Ethambutol causes ocular toxicity in adults but visual problems have not been reported in neonates exposed in utero .
Despite FDA category B, there are no data on the use of rifabutin (B) in pregnancy. Rifampicin has been widely used in pregnancy and this drug is therefore preferred .
Managing TB in pregnant HIV-seropositive adults is complicated by drug interactions between antiretroviral therapy and antituberculous therapy, particularly rifampicin. Therapeutic drug monitoring (TDM) is therefore recommended for both antiretrovirals and antituberculous drugs when using the two together , especially in pregnancy. Rifampicin reduces the concentration of ritonavir-boosted protease inhibitors , risking loss of HIV virological control. Rifampicin and saquinavir/ritonavir coadministration can cause severe hepatocellular toxicity and is contraindicated . There is insufficient evidence on the safety of rifabutin in pregnancy to recommend its use, but if reduced dose rifabutin (150 mg on alternate days or three times per week) is used with lopinavir/ritonavir, therapeutic drug monitoring should be used to monitor lopinavir levels in the pregnant woman. Rifampicin and efavirenz can be coadministered, but because of the concern of teratogenic effects of efavirenz in pregnancy it should be used with caution. There is increasing experience to suggest it can be considered after the first trimester. For those already on a regimen containing efavirenz, this should be continued, with dose alterations according to maternal weight and therapeutic drug monitoring. Another option would be to use a triple nucleoside regimen for pregnant women requiring anti-tuberculous therapy. Alternatively AZT monotherapy and planned caesarean section could be considered for those with an HIV VL <10 000 copies/mL and able to discontinue antiretroviral therapy following delivery. Advice on drug interactions with antiretroviral therapy can be found in Section 11.6.
There is limited experience in the management of multi-drug-resistant TB (MDR-TB) during pregnancy and management should be in conjunction with a specialist in this field. Although there is limited experience with many second-line drugs in pregnancy, untreated TB, especially in those infected with HIV, will lead to increased maternal mortality and poor obstetric outcomes [53–56] and the risk of congenital and neonatal TB. There are a number of reports of the successful management of MDR-TB in pregnancy [63–65]. Pregnant individuals infected with MDR-TB should be transferred to a unit with expertise in this field.
11.4.8 Mycobacterium avium complex
Clarithromycin has been associated with birth defects in mice and rats, but two reviews failed to show an increase in major malformations in 265 women exposed in the first trimester [66,67]. There is no evidence for teratogenicity of azithromycin in animal studies. One hundred and twenty-three women were reported to the teratogenicity service in Toronto, Canada, having taken azithromycin during pregnancy (88 in the first trimester). No increase in malformations was seen when compared to those exposed to a non-teratogenic antibiotic .
11.5 Impact of HAART
There are no trial data examining the optimum time to start ART in the context of treating opportunistic infections in pregnancy. However, there is a consensus that in most situations ART should be started as soon as possible.
There have not been any publications describing immune reconstitution inflammatory syndrome (IRIS) relating to opportunistic infections in pregnancy for patients on HAART, but this must at least be a theoretical concern.
11.6 Potential antiretroviral drug interactions
Antiretroviral drugs, especially the NNRTIs and boosted PIs, have several important drug–drug interactions. The following are examples of drugs which are metabolized through cytochrome P450 enzyme system; rifampicin, rifabutin and azole antifungals. They are likely to have significant drug interactions, which may require change in drug dose, additional monitoring or coadministration should be avoided. As data and advice changes frequently, this information should always be interpreted in conjunction with the manufacturer's information (http://www.medicines.org.uk). Other useful web-based reference sources include the Liverpool HIV drug information website (http://www.hiv-druginteractions.org) and the Toronto Clinic website (http://www.hivclinic.ca/main/drugs_interact.html).