HIV in Pregnancy
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The reduction in mother-to-child transmission of human immunodeficiency virus (HIV) is regarded as one of the most effective public health initiatives in the United States. In the absence of treatment, the risk of vertical transmission of HIV is as high as 25-30%. With the implementation of HIV testing, counseling, antiretroviral medication, delivery by cesarean section prior to onset of labor, and discouraging breastfeeding, the mother-to-infant transmission has decreased to less than 2% in the United States.
Before the current treatment era, approximately 2000 babies were infected with HIV each year in the United States alone. [1] That figure now stands at less than 200 infants per year since 2010 (there were 86 perinatal transmissions in the US in 2015).
The rapid clinical implementation of research findings directed toward decreasing perinatal transmission is credited as the key to this accomplishment. In 1994, the Pediatric AIDS Clinical Trials Group (PACTG) protocol 076 demonstrated that the administration of zidovudine during pregnancy and labor and then to the newborn decreased the risk of perinatal transmission of HIV by 68%, from 25.5% to 8.3%. [2] In the late 1990s, the combined use of 3 or more antiretroviral medications was found to be highly successful at suppressing viral replication.
The exact mechanism of mother-to-child transmission of HIV remains unknown. Transmission may occur during intrauterine life, delivery, or breastfeeding. The greatest risk factor for vertical transmission is thought to be advanced maternal disease, likely due to a high maternal HIV viral load. [3] Unfortunately, it has been reported that 30% of pregnant women are not tested for HIV during pregnancy, and another 15-20% receive no or minimal prenatal care, thereby allowing for potential newborn transmission. [4]
Early in the acquired immunodeficiency syndrome (AIDS) epidemic, women were rarely diagnosed with HIV or AIDS, but by 2005, women represented 27% of the estimated 45,669 new diagnosis of HIV/AIDS, with the greatest rise among young women. [5] About 74% of new cases in women in the United States are contracted through heterosexual intercourse, 23% by contaminated needles, and most of the remaining cases by maternal-child transmission. Testing of donated blood has essentially eliminated blood transfusions as a source of infection.
Of women with AIDS, 71% were diagnosed between the ages of 25 and 44, implying that many of them may have been infected as adolescents. In the United States, African American and Hispanic women represent 25% of the female population but account for 76% of the total number of women with AIDS. Furthermore, the rate of HIV diagnosis is 15 times higher in African-American women compared to white women. Women of color account for 80% of newly diagnosed HIV/AIDS cases in the United States. [6]
The Joint United Nations Programme on HIV/AIDS (UNAIDS) has estimated that in 2017, approximately 36.7 million people worldwide (1% of the global adult population aged 15-49 y) were infected with HIV, of which 1.8 million people were newly infected; 64% of all people living with HIV worldwide live in sub-Saharan Africa. New HIV infection rates are declining globally as a result of efforts to strengthen HIV prevention and treatment programs. Worldwide, new infections among children declined 47% since 2010 as coverage of ART provided to pregnant women rose 29% in the same time period. Unfortunately, young women in high-prevalence areas of the world, such as sub-Saharan Africa, continue to remain at high risk for HIV with 26% of new infections occurring in women aged 15-24 years despite this age group making up only 10% of the population. In 2016, AIDS claimed an estimated 1 million lives; of which 120,000 were children. [7]
The Antiretroviral Pregnancy Registry, where clinicians should report cases of exposure to antiviral therapy in pregnancy, contains approximately 18,000 reported exposures and notes no increase in the congenital malformation rate with exposure to antiretroviral medications, even in the first trimester, with the exception of didanosine and nelfinavir. First trimester exposure to efavirenz was previously reported to be associated with neural tube defects, however further meta-analyses and studies have been reassuring and the WHO continues to recommend efavirenz as an alternative in resource-poor settings.
ART may increase the incidence of adverse pregnancy outcomes. Several studies have shown that zidovudine monotherapy had no negative effect on pregnancy.
Although initial data from cohorts in the United States have not shown an increased risk of preterm birth with combination therapy, a European collaborative study showed an increased risk of preterm labor in women infected with HIV who were taking combination antiretroviral therapy, with an odds ratio for preterm birth of 1.8 for combination therapy without a protease inhibitor and 2.6 for combination therapy that included a protease inhibitor. [8]
The Promoting Maternal and Infant Survival Everywhere (PROMISE) trial, published in 2016, was a well-designed randomized controlled trial of 3,490 mostly African women that reported women who initiated ART in pregnancy were more likely to deliver preterm (9</ref>
In another US study of pregnant women infected with HIV, the overall rate of adverse pregnancy outcome, including prematurity, low birth weight, stillbirth, and abnormal Apgar scores, was similar in women who received antiretroviral therapy during pregnancy and those who did not. [10] Of the 2123 women in the study, 1590 received monotherapy, 396 received combination therapy without a protease inhibitor, and 137 received combination therapy with a protease inhibitor; 1143 did not receive antiretroviral therapy.
Rates of prematurity and extreme prematurity did not differ significantly according to antiretroviral regimen. Although the risk of low and very low birth weight was greater in the group receiving a protease inhibitor, the results did not reach statistical significance. Furthermore, this may be a reflection of higher viral load or advanced stage of disease rather than exposure to protease inhibitors. [10]
In a more recent retrospective study (2004-2012) that evaluated US infant growth patterns during their first year of life among those born to perinatally HIV-infected (PHIV) (32 infants, 25 mothers) and nonperinatally HIV-infected (NPHIV) mothers (120 infants, 99 mothers) who received care, infants of PHIV mothers had lower mean length-for-age z-scores (LAZ) that were associated with birth length. Other small-for-gestational age anthropometric parameter associations included those of birth weight and weight-for-age z-scores (WAZ) and those of both birth length and weight with weight-for-length z-scores (WLZ). The investigators also reported an association between delivery HIV RNA level below 400 copies/mL with increased WAZ and WLZ. [11]
A large meta-analysis that included articles from several countries between 1998 and 2006 showed that overall, highly active antiretroviral therapy (HAART) did not increase the risk of prematurity; however, the use of regimens with protease inhibitors seemed to increase prematurity slightly. [12]
A possible association exists between HAART and preeclampsia. [13]
The development of glucose intolerance may be more common in pregnant women with HIV. Originally thought to be associated with protease inhibitors, gestational diabetes appears to be somewhat increased regardless of the medication regimen. As such, during pregnancy, women should be screened and monitored for glucose intolerance. [14]
Preliminary data suggest that women with HIV may suffer from subfertility. Conception in couples who have never conceived may occur in a median of 6 months with 2 acts of intercourse during the ovulatory period of the cycle. With each act, the risk of sexual transmission must be considered even in the presence of an undetectable viral load.
In couples planning a pregnancy where only the female is HIV-infected, assisted insemination at home or with a treatment provider with her partner’s semen is the safest conception option after ART (antiretroviral therapy) has been initiated and maximum viral suppression has been attained.
In couples planning a pregnancy where only the male partner is infected, natural conception carries a risk of sexual transmission to the uninfected female and alternatives to natural conception are the safest options. Safe alternative options include adoption or sperm donation with assisted reproduction techniques. If a couple cannot or declines alternatives to natural conception, counseling regarding pre-exposure prophylaxis(PreP), sperm analysis, sperm washing, and transmission risks should be reviewed. While antiretroviral therapy can reduce viral load in the blood to undetectable levels, semen analysis is recommended prior to attempting conception as HIV-infected men can still have a substantial viral concentration in semen in the presence of an undetectable plasma viral load. If HIV viral load cannot be suppressed, semen washing can be considered with appropriate counseling as it may decrease the HIV RNA and DNA to undetectable levels. After processing and rechecking for residual contamination, the spermatozoa can be used for intrauterine insemination or in vitro fertilization.
Pregnancy does not appear to influence the progression of HIV disease. [15] A large cohort of French women with known seroconversion dates noted a pregnancy-adjusted relative risk of progression from HIV to AIDS of 0.7. [16] Furthermore, pregnancy does not seem to affect survival of women infected with HIV. [17]
For concordant couples (both partners are HIV-infected) who wish to conceive, both partners should attain maximum viral suppression and be screened and treated for genital tract infections before attempting conception. For serodiscordant couples who want to conceive, in addition to above, counseling should include the recommendation to only attempt conception once antiretroviral therapy (ART) is started and viral loads are undetectable. Additionally, NIH guidelines include educating patients regarding PrEP in serodiscordant couples. Recommendations regarding periconception administration of antiretroviral PrEP for HIV-uninfected partners are an additional tool to reduce the risk of sexual transmission and are continually evolving. The current guidelines include information on counseling, laboratory testing, and monitoring of individuals on PrEP and the importance of reporting uninfected women who become pregnant on PrEP to the Antiretroviral Pregnancy Registry. FDA labeling information and perinatal ART guidelines permit off-label using in pregnancy, however safety data regarding teratogenicity are limited. [18, 19, 20]
HIV-infection risk-reduction strategies in conjunction with relatively inexpensive fertility awareness methods (FAMs) may be useful for counseling HIV-serodiscordant couples who want to conceive. [21] Such methods include use of accessible and highly sensitive, but poorly specific, strategies like the calendar method, basal body temperature measurements, and cervicovaginal mucus secretion features. Urinary luteinizing hormone testing has high specificity and cost with less sensitivity. Timed condomless sex has low cost but necessitates understanding how to precisely predict the fertile period in a menstrual cycle. [21]
Approximately 30% of women in the United States are not tested for HIV during pregnancy. Reasons for declining should be explored and patients counseled appropriately. Testing strategies also include reoffering screening in the third trimester to women who declined first-trimester screening or who are in high-risk groups. The Centers for Disease Control and Prevention (CDC) recommends routine third-trimester screening in women with high-risk behaviors or who exhibit signs or symptoms of the disease. [4]
Clinicians who care for women with HIV need to provide family planning services and counseling regarding optimizing health status. This includes making a primary treatment goal of attaining an undetectable viral load prior to conception. Preconception care should include modifying current ART regimens to optimize viral suppression, encouraging compliance to medication regimens, cessation of smoking, and updating immunizations. Stressing the importance of taking their medication regularly to decrease the possibility of developing antiretroviral drug resistance may encourage women to comply with therapy. Cigarette smoking, concurrent use of drugs (cocaine, heroin), and unprotected intercourse have been associated with increased risk of perinatal transmission.
It is encouraging to note there has been a substantial reduction in substance use in the past 2 decades. [22] In a retrospective study over a 23-year period (1990-2012) that evaluated data from two prospective cohort studies (Women and Infants Transmission Study, Surveillance Monitoring for Antiretroviral Therapy Toxicities Study), investigators noted a dramatic decrease in substance use among 5451 HIV-infected pregnant women (1990: 82%; 2012: 23%). There was a significant decline in use of each substance between 1990 and 2006, when it reached a plateau, which the investigators suggested may have been caused by an epidemiologic transition of the HIV epidemic among US women. [22] Substance use was inversely associated with receiving antiretroviral therapy. Women with multiple pregnancies with substance use in their previous pregnancy were at higher risk of substance use in their next pregnancy. [22]
Unfortunately, 15% of women infected with HIV receive no or minimal prenatal care, and 20% do not initiate prenatal care until late in the third trimester. Even in the absence of antepartum treatment, intrapartum and early neonatal prophylaxis can reduce the mother-to-child transmission risk. Women with HIV should be extensively counseled regarding the ability to decrease the risk of perinatal transmission with ART. In women of reproductive age who are being treated with ART, the current regimen’s effectiveness, an individual’s hepatitis B (HBV) status, the potential for teratogenicity, and possible adverse outcomes for mother and fetus should all be considered.
All women who do not desire pregnancy should be counseled regarding contraceptive methods, including hormonal contraception and long-term reversible contraceptive methods. Emergency contraception options should be reviewed and made available to HIV-infected women who do not desire contraception.
In pregnancy, the initial history should assess the status of the patient’s HIV disease (eg, CD4+ T-cell count, viral load), the need for beginning or altering antiretroviral medication, and ways to reduce perinatal transmission. A careful review of the medical and surgical history, gynecologic history, high-risk habits, and previous obstetric history should be done at the first prenatal visit. Women with HIV should be screened for current and past exposure to intimate partner violence and depression and referral made to supportive and mental health services if indicated.
During pregnancy, a complete physical examination must be performed. Knowledge of the normal physiologic changes of pregnancy, such as an enlarged thyroid gland and a systolic murmur, is important to differentiate from disease process. HIV infection can affect essentially all body systems.
The American Congress of Obstetrics and Gynecology (ACOG) recommends routine HIV screening for women aged 19-64 years and targeted screening for at-risk women outside of this age reference. All pregnant women should have their HIV serostatus evaluated when they first present for prenatal care.
Women should have the right to refuse testing after being informed that HIV testing will be drawn as part of their routine prenatal panel. This opt-out approach to prenatal screening, as advocated by the Institute of Medicine and the National Institute of Health, is associated with higher testing rates among pregnant women. However, some states have laws that prohibit this approach and mandate that patients sign consent forms for testing, known as the opt-in approach. [23]
The most common screening test is an enzyme-linked immunosorbent assay (ELISA), which looks for the presence of antibodies. If this test result is positive, the ELISA is repeated to eliminate laboratory error prior to proceeding to a confirmatory test by Western blot. The ELISA has 98% sensitivity. False-negative results may occur early in the disease, and false-positive results have been reported after certain vaccines. Repeat testing several months later usually confirms seronegativity in such cases. A positive test is sent for Western blot.
For the Western blot, specific viral proteins are separated by electrophoresis, and reaction of antibody to 3 proteins must occur for the test to be considered positive. Indeterminate results occur when 1 or 2 of the proteins are present. In low-risk populations, indeterminate results usually revert to negative over several months. Western blot has a false-positive rate of 1 in 20,000.
For pregnant women infected with HIV, in addition to the standard prenatal assessment, continued assessment of HIV status is important. A complete blood count to assess anemia and white blood cell count as well as renal and liver function tests should be included. Initial evaluation includes CD4+ counts, which help determine the degree of immunodeficiency.
Viral load, determined by plasma HIV RNA copy number (copies/mL) assesses the risk of disease progression. The viral load is important in decisions regarding maternal treatment and delivery management; however, because perinatal HIV transmission can occur even at low or undetectable HIV RNA copy numbers, the viral load is not used to decide whether to start antiretroviral medications. Moreover, newer guidelines now recommend initiation of ART for all HIV-infected individuals, regardless of CD4 count, to reduce the morbidity and mortality associated with HIV infection and the risk for all modes of transmission.
If a viral load is detected, antiretroviral drug resistance studies (HIV genotype) should be sent but providers should not wait for results before initiation of ART. In general, pregnancy has not been associated with a risk of rapid progression of HIV. [17] With appropriate therapy, the viral load should drop by 1 log within the first month and become nondetectable within 6 months after initiating treatment. The higher the viral load, the longer the decrease may take; however, if the viral load persists or increases at 6 months, treatment failure must be considered.
Other laboratory studies should include a lipid profile, which is not usually obtained in pregnancy. Although cholesterol normally increases in pregnancy, baseline values are required, as certain medications have been associated with increased triglyceride and cholesterol levels.
Initial obstetric ultrasonography for viability and dating is important for determining treatment and planning delivery. Potential teratogenicity is highest during the first trimester, and some patients may consider delaying treatment until after the first 12 weeks of pregnancy. In women who are severely ill, the risks and benefits of this delay must be weighed. A targeted ultrasonography may be warranted depending on medication exposure.
Hepatitis B surface antigen status testing is recommended for all pregnant women. HIV-infected pregnant women who screen negative for HBV (i.e., HBsAg-negative, anti-HBc-negative, and anti-HBs-negative) should receive the HBV vaccine series. In the case of acute hepatitis B infection (HBV), the risk of vertical transmission also varies with gestational age, with an 80-90% risk of transmission to the offspring if the infection occurs in the third trimester. [23] Women who are co-infected with HIV and chronic hepatitis B may require different management in pregnancy. Current guidelines recommend tenofovir disoproxil fumarate plus lamivudine or emtricitabine. [24]
Co-infection with HIV and hepatitis C virus (HCV) is common and may range from 17-54%. [25] The diagnosis of hepatitis C is confirmed by identification of the hepatitis C antibody via an ELISA test. False-negative HCV test results may occur if the CD4 count is very low. More specific tests, (eg, hepatitis C viral RNA detection by polymerase chain reaction) are available. High maternal viral titers have been associated with an increased risk of vertical transmission.
Chronic carriers of HBV or HCV should receive education on the importance of informing sexual partners, household contacts, and needle-sharing contacts and review precautions to decrease transmission.
Evaluation of opportunistic infectious disease states should be performed in accordance with current guidelines. Assessment of the need for prophylaxis against Pneumocystis jiroveci pneumonia (PCP),Mycobacterium avium complex (MAC) infection, and reactivation toxoplasmosis is necessary based on CD4 counts. Though routine toxoplasmosis titers are not recommended for all pregnant women in the United States, baseline titers should be obtained for HIV-infected women and suppressive therapy is recommended in women with low CD4 counts and a positive IgG. For women with low CD4 counts, prophylaxis for PCP is with trimethoprim-sulfamethoxazole (TMP-SMX). Due to potential teratogenicity, aerosolized pentamidine may be substituted in the first trimester, as it is not absorbed systemically. Atovaquone administration is also an oral alternative to TMP-SMX in the first trimester. For prophylaxis of MAC, azithromycin is used in place of clarithromycin because of potential teratogenicity. Cytomegalovirus should not be routinely screened for in HIV-infected pregnant patients, however assessment for re-infection or reactivation of disease is the same as for non-pregnant HIV-infected individuals.
Screening for other maternal sexually transmitted diseases is recommended in pregnancy. For example, screening for maternal syphilis is important not only for the prevention of congenital syphilis but also because maternal syphilis has been associated with an increased risk of mother-to-child transmission of HIV. [26]
Vaginal speculum examination should be performed to obtain cervical cytology smear and assays for gonorrhea and chlamydia as vaginal swabs are preferred over testing other sites in HIV-infected individuals. All sexually transmitted diseases should be treated promptly. Genital warts and vulvar intraepithelial neoplasia are more common among HIV-seropositive than HIV-seronegative women, but wart regression is as common in women with HIV as those without and cancer is infrequent. [27] Women infected with HIV have a higher incidence of cervical dysplasia.
Vaccinations should be kept updated. During pregnancy, live attenuated vaccines (eg, measles-mumps-rubella [MMR], varicella, Bacille Calmette-Guérin [BCG] vaccines) should be avoided. Inactivated annual influenza, H1N1, and tetanus vaccines should be administered to all pregnant women, including women who are HIV positive. Hepatitis A and B vaccines (if non-immune) and pneumococcal vaccines should be administered to HIV-positive pregnant women.
Co-infection with HIV and tuberculosis is very common in developing nations. Immunosuppression from HIV infection contributes not only to a higher rate of tuberculosis reactivation but also to an increased disease severity.
Tuberculosis skin testing should be performed and a 5-mm purified protein derivative (PPD) result interpreted as positive. Alternatively, interferon (IFN)-gamma release assays have been shown to be safe and reliable in pregnancy to screen for latent tuberculosis. [41] If screening test is positive, chest radiography can be performed during pregnancy because radiation risk is exceedingly low.
For women who present in labor and have not had prenatal testing, rapid testing should be offered. Unlike the ELISA, the rapid HIV test is a blood or saliva antibody test and results are usually available within an hour. The rapid test is reported to have a high negative predictive value (100%) and to be highly sensitive and specific (approaching 100%); however, the positive predictive value in pregnancy varies from 44-100%. [4] Patients who test positive in labor by ELISA should be treated as HIV positive until confirmatory results are available.
Mother-to-child transmission is linked to viral load. As such, antepartum antiretroviral therapy should be offered to all pregnant women infected with HIV to reduce the risk of perinatal transmission to below 2%. [28] Combination antiretroviral therapy should be offered in all cases.
If a pregnant woman has received antiretroviral medication in the past but is not currently on any medication, the choice of regimen may vary according to the history of prior use, the indication for stopping treatment in the past, gestational age, and resistance testing. In this setting, if there is no resistance to the drugs and the regimen suppressed viral load, antiretroviral medication can be used again, but avoid drugs with teratogenic potential or adverse maternal effects.
If a patient who is on an ART regimen presents for prenatal care, continuing her treatment during the first trimester is reasonable, provided that care is taken to avoid medications that are contraindicated in early pregnancy (stavudine, didanosine, full-dose ritonavir). HIV antiretroviral drug resistance testing is recommended if a viral load is detectable. Considerations of drugs not usually used early in pregnancy may be necessary if drug resistance is confirmed and the patient receives extensive counseling regarding risk and benefits.
In an HIV-infected pregnant woman who has never been exposed to antiretroviral medication, ART regimen determination is similar to non-pregnant patients however certain medications should be avoided (dolutegravir, elvitegravir, and tenofovir alafenamide). ART should be started as soon as possible, including during the first trimester. Again, recommendations are for drug-resistance testing and care to avoid medications that may potentially cause adverse maternal and fetal effects.
If prenatal HIV testing was not performed and a rapid HIV test returns preliminarily positive, the patient should be treated and managed as high-risk for transmission. Certainly, the gestational age and obstetrical scenario may dictate the treatment options available, but as the exposure risk to antiretroviral medication is minimal to both mother and fetus, antiretroviral therapy should be initiated. [4]
The patient with a positive rapid test must be counseled regarding the possibility of a false-positive screen, and the results should be documented as preliminary in the medical chart. If this test was performed on arrival in labor, treatment with the ZDV protocol through labor is recommended, followed by avoiding breastfeeding and administration to the neonate until confirmatory testing on the mother becomes available.
Treatment of women infected with HIV should not be withheld because of pregnancy. Although the decision regarding starting or maintaining current antiretroviral therapy is based on the same criteria as in nonpregnant patients, several considerations must be taken into account because of potential effects on the fetus.
The regimen chosen should also take into account prior therapy and response to that regimen, as well as resistance testing. Gestational age and potential fetal and neonatal toxicity must also be taken into account when selecting a regimen.
The mechanism of action with which these drugs reduce perinatal transmission includes lowering maternal viral load; however, as these drugs cross the placenta, there appears to be prenatal prophylaxis as well. The third component, prophylaxis of the newborn, further decreases the risk of perinatal transmission.
The antiretroviral drugs used in pregnancy fall broadly into 3 categories: the nucleoside and nucleotide analogue reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs). Additionally, raltegravir is an integrase inhibitor with a growing body of data that is reassuring in pregnancy. There are insufficient data to allow recommendations regarding the use of entry inhibitors in pregnancy.
Guidelines for perinatal ART were revised in January 2017 regarding which agents are considered preferred, alternative, or to be used under special circumstances. Combination regimens, usually including 2 NRTIs with either an NNRTI or 1 or more protease inhibitors (PIs) are recommended. For further information, see Table 1 and refer to updated guidelines (published annually).
Table 1. ART agents during pregnancy [18] (Open Table in a new window)
ART Class
Preferred*
Alternate
Special Circumstances
Insufficient Data to Recommend
NRTIs
tenofovir disoproxil fumarate + emtricitabine or lamivudine
abacavir + lamivudine
zidovudine + lamivudine
didanosine (not recommended)
stavudine (not recommended)
tenofovir alafenamide
NNRTIs
efavirenz
rilpivirine
nevirapine (not recommended, ART naive)
etravirine
PIs
atazanavir + ritonavir
darunavir + ritonavir
lopinavir + ritonavir
indinavir
nelfinavir
saquinavir
darunavir + cobicistat
atazanavir + cobicistat
fosamprenavir
tipranavir
dolutegravir
elvitegravir/ cobicistat
elvitegravir/ cobicistat/ emtricitabine/ tenofovir
alafenamide
Entry and Fusion Inhibitors
–
–
–
enfuvirtide
maraviroc
Pharmacoenhancers
–
ritonavir
cobicistat
Nucleotide analogue reverse transcriptase inhibitors
The NRTIs are generally well tolerated and cross the placenta with a variable safety profile depending on the agent used. These drugs do bind to mitochondrial DNA gamma polymerase and may cause mitochondrial dysfunction manifesting as cardiomyopathy, neuropathy, lactic acidosis, and liver dysfunction. Genetic susceptibility to these drugs may play a role, and the effects usually resolve with cessation of the medication. [1]
The combination of didanosine and stavudine has been associated with lactic acidosis and hepatic failure leading to fatalities and should be used with caution or only in cases where other NRTIs cannot be used due to resistance or toxicity. Finally, ZDV and stavudine have overlapping toxicities and are antagonistic and should be avoided in combination. [28]
Non-nucleoside reverse transcriptase inhibitors
Five NNRTIs are FDA approved: delavirdine (Rescriptor), efavirenz (Sustiva), etravirine (Intelence), nevirapine (Viramune), and rilpivirine (Edurant). Although less information is available regarding NNRTI use in pregnancy, nevirapine and efavirenz both cross the placenta. The most common side effect is rash, which can occur in up to 17% of patients on nevirapine.
Use of efavirenz was previously not recommended in the first trimester because of reported cases of fetal neural tube defects, however, based on additional data the NIH now classifies this drug as an acceptable alternative agent.
Severe nevirapine-associated skin rash and hepatic toxicity have been reported in pregnancy. The potentially fatal hepatotoxicity appears to be increased in women, during pregnancy, and in patients with a CD4+ T-cell count greater than 250 cells/mL. Because of these significant complications, nevirapine should not be used as first-line therapy unless no other option is available.
In women whose CD4+ T-cell counts were below 200 cells/mL and who were previously exposed to peripartum single-dose nevirapine, ritonavir-boosted lopinavir plus tenofovir-emtricitabine was superior to nevirapine plus tenofovir-emtricitabine for initial antiretroviral therapy. [29]
In children previously exposed to single-dose nevirapine for perinatal prevention of HIV transmission, zidovudine and lamivudine plus ritonavir-boosted lopinavir for antiretroviral treatment resulted in better outcomes than treatment with zidovudine and lamivudine plus nevirapine. [30]
Protease inhibitors
Protease inhibitors do not cross the placenta easily, and no teratogenic effects have been noted in animals.
Also see the Medscape Drugs & Diseases topic Antiretroviral Therapy for HIV Infection.
In any pregnant woman infected with HIV who presents in labor, every effort should be made to continue her ART regimen on schedule in the peripartum period as much as possible to provide maximal virologic effect and to minimize the chance of developing drug resistance. All HIV-infected women with HIV RNA >1,000 copies/mL (or unknown HIV RNA) near delivery should be administered IV zidovudine (ZDV) during labor, in addition to their regular antepartum regimen and regardless of mode of delivery. IV ZDV is no longer required for HIV-infected women receiving combination ART regimens who have HIV RNA ≤1,000 copies/mL near delivery. [18]
ZDV is given intravenously during labor at a dose of 2 mg/kg infused over 1 hour, followed by a continuous infusion of 1 mg/kg throughout labor. This regimen, along with maternal antepartum and infant zidovudine, reduced perinatal transmission by 66% overall. [18] If the patient is having a planned cesarean delivery, the IV infusion should begin 3 hours before the procedure. [28, 31]
Women with documented drug resistance to ZDV or whose antepartum regimen did not include ZDV should still be given the intravenous ZDV protocol during labor and delivery or before cesarean delivery. [31] Furthermore, the other antiretroviral agents must be continued on schedule throughout the intrapartum or preoperative period. Stavudine is the only agent that can antagonize ZDV and should be stopped prior to the IV infusion of ZDV. [28]
In patients attempting a vaginal delivery, amniotomy performed in the setting of ART and virologic suppression is not associated with increased risk of perinatal transmission and can be performed for standard obstetric indications. Amniotomy in the setting of viremia, routine use of fetal scalp electrodes for fetal heart rate monitoring, operative delivery with vacuum devices or forceps and episiotomy are generally avoided given the potential increased risk of transmission.
ART is now recommended for all HIV-infected individuals to reduce the risk of disease progression and to prevent HIV sexual transmission. Antepartum ART regimens in general should be continued postpartum, however decisions regarding continuation should be made in consultation with the patient and her HIV care provider. Such decision-making should occur in the outpatient setting and careful documented before delivery given the immediate postpartum period poses its own unique challenges to medication adherence.
Infant ART prophylaxis [18]
All HIV-exposed infants should receive zidovudine in the following doses for the first six weeks of life:
< 30 weeks’ gestation: 2 mg/kg PO BID; after age 4 weeks, advance to 3 mg/kg PO BID
>30 to < 35 weeks’ gestation: 2 mg/kg PO BID; after age 2 weeks, advance to 3 mg/kg PO BID
>35 weeks’ gestation: 4 mg/kg PO BID
Initiate as soon after delivery as possible (preferably within 6-12 hours) and continue through age 6 weeks and administer birth through 6 weeks. For infants unable to tolerate IV doses, the IV dose is 75% of the oral dose while maintaining the same dosing interval. A simplified weight-band dosing for infants ≥ 35 weeks is also published and available via the NIH guidelines.
Additional prophylaxis with nevirapine is needed for HIV-exposed infants of women who did not receive antepartum ART at the following weights and dosages:
Birth weight 1.5-2 kg: 8 mg/dose PO
Birth weight >2 kg: 12 mg/dose PO
Administer 3 doses in the first week of life; 1st dose 48 hours after birth, give 2nd dose 48 hours after 1st dose, and 3rd dose 96 hours after 2nd dose.
Three-drug infant combined ART prophylaxis regimens are under investigation, however some experts are already using these in clinical practice (please refer to current guidelines available via the NIH).
The current recommendation for treating women co-infected with HIV and HBV is to treat these women with tenofovir, lamivudine, telbivudine or emtricitabine. [32] All four have shown activity against HBV. A meta-analysis found that the use of lamivudine effectively prevents mother-to-child transmission, even in pregnant women who have a high degree of HBV infectiousness in late pregnancy. [33]
Women receiving treatment should be advised of the signs and symptoms of liver toxicity, and regular follow-up of transaminase levels is warranted. The infant should receive hepatitis B immunoglobulin and start the 3-dose series of hepatitis B vaccine within the first 12 hours of life. [18]
Pregnancy does not appear to alter the course of HCV infection; however, co-infection with HIV does appear to increase the risk of perinatal transmission of HCV. As such, a 3-drug antiviral combination is recommended regardless of the viral load. As with HBV co-infection, patients should be made aware of the signs and symptoms of liver toxicity, and transaminases should be assessed according to current guidelines.
As with HIV, prolonged rupture of membranes may increase the risk of perinatal HCV transmission; however, the data remain inconclusive regarding the use of cesarean section delivery to decrease the risk of transmission. As such, delivery recommendations are based on the HIV status. Infants can be evaluated by testing HCV RNA at 2 and 6 months of age or HCV antibody after 15 months of age. [18]
Cesarean delivery must be discussed and the patient counseled regarding the possibility of an unnecessary surgical procedure should the final HIV result be negative. [18] Care should be individualized according to clinical scenario.
Early studies regarding cesarean delivery and transmission risk showed conflicting results. Cesarean delivery before the onset of labor may prevent microtransfusion that occurs with uterine contractions, and avoiding vaginal delivery eliminates exposure to virus in the cervicovaginal secretions and blood at time of delivery.
In the late 1990s, prospective cohort studies noted a decrease in mother-to-child transmission in women on zidovudine (ZDV) who underwent elective cesarean delivery compared with women who did not take ZDV prophylaxis. [34, 35] In 1999, results from a large meta-analysis of individual patient data from 15 prospective cohort studies demonstrated a 50% reduction of vertical transmission with the use of elective cesarean delivery for women with HIV, after adjusting for antiretroviral therapy, maternal stage of disease, and infant birth weight.
Of note, vertical transmission risk did not change when the study group was limited to those women who had rupture of membranes shortly before surgery. The transmission risk was decreased by about 80% for women who had both an elective cesarean delivery and were taking antiretroviral medication. [36]
In the same year, ACOG issued an opinion that elective cesarean delivery should be discussed and offered to all pregnant women who were HIV positive at 38 weeks’ gestation to avoid the potential risk of spontaneous labor and rupture of membranes. [31]
These studies did not adjust for viral load and were performed before HAART came into use. In patients on HAART with an undetectable viral load (< 1000 copies), the risk of transmission is very low, and whether cesarean delivery offers any further benefit remains unknown.
This led to an updated ACOG statement in 2000, stating that women infected with HIV whose viral loads are greater than 1,000 copies/mL should be counseled regarding the potential benefit of scheduled cesarean delivery to further reduce the risk of vertical transmission of HIV beyond that achieved with antiretroviral therapy alone. [31] However, data are insufficient to demonstrate a benefit for neonates of women with viral loads less than 1,000 copies/mL.
Longer duration of ruptured membranes may be associated with a higher rate of mother-to-child transmission. The International Perinatal HIV group meta-analysis found that the risk of vertical transmission increased by 2% for every increase of 1 hour in the duration of ruptured membranes. If cesarean delivery is performed after the onset of labor or rupture of membranes, the benefit of surgery is likely lost as available data indicate no reduction in the transmission rate if cesarean delivery is performed after the onset of labor or rupture of membranes. In this scenario, a decision regarding the route of delivery should be individualized. [31, 36]
Operative risk may outweigh the potential benefit of further reducing HIV transmission. In a study by Louis et al that compared the outcome of cesarean section in 378 women infected with HIV and in more than 54,000 uninfected women, HIV-infected women had a higher rate of intraoperative need for blood transfusion as well as increased incidence of postpartum endometritis, sepsis, pneumonia, admission to the intensive care unit, and maternal death. [37]
In the HIV-infected group, morbidity and mortality were associated with infection and related to immune function, with the greatest risk being for women with a CD4 count less than 200 cells/mL. [37]
Because morbidity is increased in women infected with HIV who undergo cesarean delivery, prophylactic antibiotics should be administered. Scheduled cesarean delivery should be discussed and recommended for women with viral loads greater than 1000 copies/mL, whether or not they are taking antiretroviral therapy.
Discussion of the recommendation of scheduled cesarean delivery in women with high viral loads should begin as early as possible in pregnancy with every pregnant woman infected with HIV, to give her an adequate opportunity to consider the recommendations and plan for the procedure. The risks, which appear to be greater for the mother, must be balanced with the benefits expected for the neonate. The patient’s autonomy must be respected when making the decision to perform a cesarean delivery, because the potential for maternal morbidity is significant.
Consultation and follow-up with specialists in infectious disease and maternal-fetal medicine is recommended.
During pregnancy, a healthy, well-balanced diet is recommended, and this recommendation is not altered by HIV. Certain foods need to be limited and avoided during all pregnancies. Alcohol should be avoided. Generally, eating fish low in mercury content is recommended. Caffeine must also be limited, as well as foods high in nitrites and soft cheeses. Current available evidence suggests that vitamin A supplementation during pregnancy (not to exceed 10,000 IU in the first trimester) improves birth weight. [38] Light exercise is recommended in pregnancy, and this recommendation is not altered by HIV infection. Walking and swimming are excellent programs during pregnancy. Women should discuss their exercise routine with their physician.
Currently, no vaccine is available for HIV; therefore, prevention is crucial to decreasing the risk of transmission. [39] Women must be counseled on methods to avoid transmission to others, including safe sex practice and avoiding donation of blood or organs.
Regular use of latex condoms and avoidance of unprotected intercourse is important. Treatment of genital tract infections and inflammation in both partners is important to avoid mucosal breaks. The frequent use of nonoxyynol-9 vaginal gel has been associated with increased risk of HIV acquisition in the high-risk population. Women should not share toothbrushes or razors, as small amounts of blood may be present.
In areas of the world where safe alternatives are available, breastfeeding is not recommended. This also applies to women on antiretroviral therapy. [5] Passage of antiretrovirals into breast milk has been shown for several agents, including zidovudine and lamivudine. [18]
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ART Class
Preferred*
Alternate
Special Circumstances
Insufficient Data to Recommend
NRTIs
tenofovir disoproxil fumarate + emtricitabine or lamivudine
abacavir + lamivudine
zidovudine + lamivudine
didanosine (not recommended)
stavudine (not recommended)
tenofovir alafenamide
NNRTIs
efavirenz
rilpivirine
nevirapine (not recommended, ART naive)
etravirine
PIs
atazanavir + ritonavir
darunavir + ritonavir
lopinavir + ritonavir
indinavir
nelfinavir
saquinavir
darunavir + cobicistat
atazanavir + cobicistat
fosamprenavir
tipranavir
dolutegravir
elvitegravir/ cobicistat
elvitegravir/ cobicistat/ emtricitabine/ tenofovir
alafenamide
Entry and Fusion Inhibitors
–
–
–
enfuvirtide
maraviroc
Pharmacoenhancers
–
ritonavir
cobicistat
Ashley T Peterson, MD Fellow in Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Tufts Medical Center; Clinical Instructor, Department of Obstetrics and Gynecology, Tufts University School of Medicine
Ashley T Peterson, MD is a member of the following medical societies: American Congress of Obstetricians and Gynecologists, American Institute of Ultrasound in Medicine, Massachusetts Medical Society, Society for Maternal-Fetal Medicine
Disclosure: Nothing to disclose.
Linda C Kleeman, MD Assistant Professor, Department of Obstetrics and Gynecology, Tufts Medical Center; Course Director, Maternal-Fetal Medicine Acting Internship, Tufts University School of Medicine
Linda C Kleeman, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists, Society for Maternal-Fetal Medicine
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Ronald M Ramus, MD Professor of Obstetrics and Gynecology, Director, Division of Maternal-Fetal Medicine, Virginia Commonwealth University School of Medicine
Ronald M Ramus, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists, American Institute of Ultrasound in Medicine, Medical Society of Virginia, Society for Maternal-Fetal Medicine
Disclosure: Nothing to disclose.
Teresa Marino, MD Assistant Professor, Attending Physician, Division of Maternal-Fetal Medicine, Tufts Medical Center
Disclosure: Nothing to disclose.
HIV in Pregnancy
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