Continuing Education Activity

Several thousand HIV positive pregnant women give birth in the US annually. With proper management, these women can achieve viral suppression to undetectable levels and have a normal conception, pregnancy, and vaginal delivery. This activity outlines the evaluation and management of HIV in pregnant women and highlights the role of the interprofessional team in managing patients with this condition.

Objectives:

• Identify the etiology of the perinatal spread of HIV in pregnant women.
• Summarize the evaluation of women with HIV.
• Outline the management options available for HIV in pregnant women.

Introduction

The study of HIV during pregnancy holds great significance because many women are first diagnosed with HIV during pregnancy. Similarly, it is equally important in cases where one or both partners are HIV positive and wish to conceive. During the recent years, universal HIV prenatal testing, antiretroviral therapy (ART), scheduled cesarean delivery for HIV positive women with elevated viral loads, appropriate ART for infants and avoidance of breastfeeding have shown encouraging results, and the Centers for Disease Control and Prevention now aims to eliminate HIV transmission from mother to child by reducing its incidence to <1 infection per 100,000 live births.

Etiology

HIV disease in humans can be caused by infection with either HIV-1 or HIV-2. HIV-1 is more prevalent of the two, has higher infectivity, virulence, and greater spread through heterosexual sex. The transmission rate of HIV from mother to child (vertical transmission) is 20% to 25% for HIV-1 versus about 5% for HIV-2.[1] Vertical transmission of HIV is possible not only throughout pregnancy but also during childbirth and breastfeeding. Together this is termed as the perinatal transmission of HIV.

Epidemiology

According to one estimate, around 5,000 HIV positive women give birth in the United States every year.[2] Following current recommendations regarding HIV and pregnancy, both the United States and Europe have witnessed a steep decline in perinatal HIV transmission to 1% or less.[3] In the United States, black infants have 5 times increased incidence of perinatal HIV compared to white infants.[2] According to a report by the Centers for Disease Control and Prevention, only 44 HIV positive infants were born in the United States in the year 2016, with the incidence of perinatal HIV transmission being as low as 1.1 out of 100,000 live births.[4] Globally, with the increasing availability of ART to pregnant women, the number of new HIV cases among children has decreased by 47% since 2010 according to the Joint United Nations Programme on HIV/AIDS (UNAIDS).

History and Physical

History and physical in HIV-positive pregnant women should focus on identifying health issues in the mother who may directly or indirectly affect the health of the fetus. Special consideration should be given to any history of opportunistic infections, sexually transmitted infections, substance abuse, and vaccination status. New symptoms like fever should immediately alert the physician to the possibility of an undiagnosed opportunistic infection.

Physical examination should aim to pick up signs like thrush, which may be an indicator of an advanced HIV infection. Special attention should also be paid to signs of other STIs which may be present along with HIV. A thorough examination should be performed to look for any stigmata of liver disease.

Evaluation

Following investigations are required to assess the infection and follow up with treatment:

• Gestational age estimation

Ultrasound estimation in the first trimester is preferred over the LMP method for calculating the expected date of delivery (EDD).[5] Especially important in HIV positive pregnant women because some of them may require early delivery in order to diminish the risk of perinatal transmission of the virus.

• CD4 cell counts

Done on the first visit and then every trimester during pregnancy. 

One physiological effect of pregnancy is a fall in the absolute CD4 count, but the percentage CD4 count remains unchanged and may be monitored instead. However, absolute CD4 counts are still used to check, e.g., ART response.[6]

• Viral load measurement

According to the Panel of Antiretroviral Guidelines for Adults and Adolescents, viral load should be assessed at the time of the initial visit, again at the time of starting ART, two weeks after starting ART and then monthly until the patient achieves complete suppression of the virus after which it can be reduced to testing once every three months for the remaining pregnancy duration. At 34-36 weeks, another estimation of the viral RNA load is made to decide the mode of delivery and gestational age for delivery.

• Drug resistance testing

In the United States, the Panel on Treatment of HIV-infected Pregnant Women and Prevention of Perinatal Transmission recommends doing drug resistance testing before ART initiation and modification in all cases where the HIV RNA levels are >500 to 1000 copies/mL which is the threshold for drug resistance testing.

In cases where a pregnant HIV positive woman has never received ART, especially if she is presenting late in her pregnancy, ART should be started before the drug resistance testing results are available and can be later modified accordingly.

• ART toxicity monitoring

The Panel of Antiretroviral Guidelines for Adults and Adolescents in the United States suggests doing CBC, BUN, creatinine, and liver function tests before starting ART. These should then be repeated every three to six months. Additionally, urinalysis is recommended before starting a tenofovir-containing ART regimen and then every six months.

• HLA-B*5701 testing

This should be done if abacavir-containing ART regimen is to be initiated

• Gestational diabetes screening

For HIV positive pregnant women on ART regimens containing protease inhibitors, GDM screening should be performed earlier than the usual recommended age of 24-28 weeks because protease inhibitors tend to increase glucose intolerance in HIV-infected individuals.[7]

• Viral hepatitis testing

Because of frequent coinfection, HIV positive pregnant women are screened for both HBV and HCV. In addition to the usual anti-HCV IgG and IgM, a patient with CD4 counts below 100/microL, and having a history of HCV risk factors should be given PCR testing for HCV RNA because serological testing for HCV can be falsely negative.

If the patient is HBV-negative, give them the recombinant HBV vaccination (considered safe in pregnancy). If HBV infection is confirmed, antivirals having activity against both HIV and HBV can be given.

Educate HCV negative patients about the risk factors for HCV. Acute HCV infection during pregnancy in HIV infected women increases the risk of vertical transmission of HCV to the fetus.[8]

• Tuberculosis testing

Testing for tuberculosis is recommended for all patients with diagnosed HIV infection.[9] It can be safely done in HIV infected pregnant women if it has not been previously performed or if HIV is diagnosed for the first time during pregnancy. This is especially important because latent tuberculosis is more likely to transition into active infection in individuals who are HIV positive.[10]

• STI screening

Because of the risk of stillbirth, low birth weight, premature preterm rupture of membranes, and preterm delivery, HIV positive pregnant women are screened for syphilis, gonorrhea, chlamydia, and trichomonas infection. Syphilis infection of HIV infected pregnant women has been found to increase vertical transmission risk of HIV.[11]

• Toxoplasma and CMV testing

Unlike in HIV-negative women, serological testing for Toxoplasma gondii is recommended in HIV infected pregnant women. If T. gondii IgG is positive and CD4 count below 100/mL, then suppressive therapy is started.

Most HIV positive pregnant women have already been exposed to CMV, so no CMV serological testing is recommended.[12] At present, there are no recommended drugs to prevent congenital CMV infection. Only active CMV infection in HIV infected pregnant women is treated.

• Vaccination assessment

In addition to the Tdap and influenza immunizations routinely given during pregnancy, HIV positive pregnant women should also receive pneumococcal and Hepatitis A & B (according to past infection status) vaccinations.

• General Counselling

This should include counseling about modifiable behaviors, which can lead to increased chances of perinatal HIV transmission, e.g., tobacco, alcohol, illicit drug use, unprotected sex in a non-monogamous relationship. Regular condom use should be encouraged.

• Psychiatric evaluation

Evaluate the patient for any history of difficulty adhering to medication regimens, depression, anxiety, and domestic/intimate partner violence. These should prompt the need for supportive care.

• Evaluation for opportunistic infections

TMP-SMX is given to pregnant patients with CD4 cell count below 100/mL (Toxoplasma gondii and PCP) and 200/miroL (PCP) for prophylaxis against these opportunistic infections. This is done after discussing the possible teratogenicity risk of TMP-SMX with the patient.[13][14]

Azithromycin is used as a prophylaxis against disseminated Mycobacterium avium complex infection in pregnant patients with CD4 cell count <50/mL.

Treatment / Management

The treatment protocols vary from the time of conception until birth.

• Preconception Management and Counseling

Counseling should be tailored according to the needs and HIV status of partners wishing to conceive. According to the CDC guidelines, in serodiscordant couples, where the partner with HIV is on ART and has an undetectable viral load, unprotected sexual intercourse is associated with no risk of sexual transmission of HIV.[15][16] Two plasma viral load readings below detectable levels, recorded at least three months apart, are required to show successful (sustained) viral suppression.

In serodiscordant couples wishing to conceive where viral suppression status is unknown, or it has not been successfully attained, the partner without HIV can be given pre-exposure prophylaxis, and unprotected sexual intercourse can be limited to peak fertility period in each cycle. This is done to limit the sexual transmission of HIV.[17][18]

Starting ART before conception not only prevents sexual transmission between partners, it also reduces perinatal transmission of HIV.[19]

To further eliminate the chances of sexual transmission of HIV, HIV positive women with HIV negative partners and wishing to conceive, may receive assisted insemination. If an HIV positive man and an HIV negative woman wish to conceive, sperm preparation techniques combined with intrauterine insemination or in vitro fertilization may be considered. A sperm donor may also be used in such cases.

Genital tract inflammation, as seen in genital tract infections, increases HIV viral shedding.[20] It is therefore recommended to screen both partners for genital tract infections before trying to conceive.

Both HIV and ART are associated with increased infertility. So infertility works up in such couples should be started early, ideally, after failure to conceive after six months of unprotected sex.[21][22]

In couples where both partners are HIV positive, it is recommended to start ART and attain sustained viral suppression before trying to conceive.

Pregnant HIV negative women with HIV positive partners should be screened for HIV on initial visits unless they decide to opt-out of it. They should receive counseling about regular condom use and ART adherence in their partner. Such women (living with HIV positive partners) should ideally be tested for HIV every trimester.

Counseling for HIV negative men trying to conceive with HIV positive partners should include the importance of pre-exposure prophylaxis (PrEP) and antiretroviral therapy (ART) adherence in their partner. Such men should be tested for HIV at least every three months during the period when they are having unprotected sex with their partners in order to try to conceive.

• Antepartum Management

In addition to the routine assessment for all pregnant women, HIV positive pregnant women should be assessed as described above under ‘evaluation.’

ART not only prevents the perinatal transmission of HIV but also inhibits the sexual (secondary) transmission of the virus. The level of viral RNA in the blood and genital tract secretions of the mother is diminished by strict adherence to the ART regimen.[23]

ART should be started as soon as a diagnosis of HIV is made in a pregnant patient or as soon as pregnancy is diagnosed in an HIV positive woman who is still untreated. This should be done regardless of the patient’s CD4 count or HIV RNA levels. A combined antepartum, intrapartum, and postpartum (neonatal prophylaxis) approach should be adopted when administering ART to minimize the perinatal spread of HIV.[24][25][24]

Before initiating ART, the patient must be informed about its possible side effects on the mother or fetus and interactions of ART drugs with other medications.[26] The importance of strict adherence to ART should also be stressed.[27]

While choosing an ART regimen for pregnant women, a combination regimen is usually preferred over a single agent.[28] At least one NRTI agent with significant trans-placental transfer should be added to the regimen to maximize the fetus’s pre-exposure prophylaxis.[29] The principles dictating the selection of ART regimen in pregnant women are the same as in non-pregnant HIV patients except certain regimens, which are avoided because of limited data about their dosing in pregnant women.

For treatment-naïve patients, two NRTIs with a third integrase inhibitor or protease inhibitor is the preferred regimen, keeping in view the results of the patient’s drug resistance testing. Patient’s tolerability, adherence, and comorbid conditions are also important factors affecting regimen selection. Tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) or abacavir-lamivudine are generally used NRTI combinations. Tenofovir is avoided in patients with significant renal failure. Zidovudine-lamivudine, despite extensive use and demonstrated safety in pregnancy, is still only an alternative drug in the US. This is because it requires twice-daily dosing and causes headaches and anemia in the mother, along with congenital heart defects in the fetus.[30] Popular third drug choices include the once-daily dose of the highly virologic integrase inhibitor dolutegravir (DTG) (associated with a small increased risk of neural tube defects (NTDs) with use at the time of conception) or twice-daily dosing of another highly virologic integrase inhibitor raltegravir (more prone to drug resistance).[31] Another popular choice of a third agent is a protease inhibitor e.g., once-daily dosing of atazanavir-ritonavir (can cause indirect hyperbilirubinemia in mother) or twice-daily dosing of darunavir-ritonavir. However, there is a small risk of preterm birth with protease inhibitors, and they often require boosting due to the pharmacokinetic changes in pregnancy.

Didanosine, stavudine, and full-dose ritonavir regimens must be discontinued during pregnancy even if the patient has successfully attained sustained viral suppression.[32][33]

For women who become pregnant while on ART with sustained viral suppression, continuing the same regimen during pregnancy is strongly encouraged. This is true even when the agents in their present regimen are not preferred during pregnancy. Patient’s tolerability and adherence and dose adjustments (especially for protease inhibitors) to account for pharmacokinetic changes in pregnancy are still of utmost importance. Women on cobicistat-containing regimens at the time of pregnancy are encouraged to switch to an alternative drug because cobicistat’s levels decrease during pregnancy, and there is a risk of loss of the previously sustained suppression of the virus.[34] Women on dolutegravir should be counseled about the small risk of NTDs with DTG.[35] In the US, The Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission guidelines dictate the continuation of DTG in such cases.

For women who become pregnant while on ART but without sustained suppression of the virus should be evaluated about drug adherence, and resistance testing should be done. Agents not usually recommended for use during pregnancy may be prescribed in this case. Once-daily dosing is preferred, and if there is still no viral suppression, repeat drug resistance testing should be done.[36]

Women who were previously on ART but not currently taking it should be evaluated thoroughly about past drug regimens, virologic efficacy, past drug tolerability, and past resistance testing. Again, agents not usually preferred in pregnancy may be used in such cases. Patient adherence should be stressed, and viral response closely monitored.

For women with high viral load (treatment naïve or experienced) presenting late in pregnancy, the use of integrase inhibitors e.g., dolutegravir, has been found to result in a rapid decrease in HIV RNA load.[37]

If an ART regimen has to be stopped during pregnancy e.g., due to drug toxicity, hyperemesis gravidarum, acute illness or lack of availability of drugs, all component drugs of the regimen must be discontinued together[38], and the priority should be to restart an ART regimen as soon as possible again.[39][38]

• Intrapartum Management

Women with HIV RNA viral load >1000 copies/mL or unknown levels near delivery are delivered via scheduled cesarean section at 38 weeks.[40]  Cesarean section is not indicated when HIV RNA viral load <1000 copies/mL, and the patient is on ART. HIV positive women are found to have a higher complication rate from cesarean section than HIV negative women.[41] For women whose HIV RNA is <1000 copies/mL, the timing of vaginal delivery should follow the standard OB/GYN indications. If a scheduled cesarean delivery is performed for routine indications (other than HIV prevention) and HIV RNA is <1000 copies/mL, it should be performed at 39 weeks.[42]

If a woman with HIV RNA >1000 copies/mL presents before 37 weeks with ruptured membranes or spontaneous labor, her individualized management plan should be decided after consulting with a perinatal HIV expert if a woman presenting with ruptured membranes has HIV RNA <1000 copies/mL, there is no increased risk of perinatal HIV transmission, and there is no indication for cesarean delivery.

Artificial rupture of membrane for obstetrical indications can only be done if the patient is on ART with sustained viral suppression, though it should be used as a last alternative due to the risk of transmission of the virus due to injury to the fetus during the procedure. It must be avoided in women with detectable viral loads. Fetal scalp electrodes, forceps, or vacuum-assisted delivery should be avoided in all HIV positive women.

In the case of uterine atony and postpartum hemorrhage, methergine should be avoided if the patient’s ART regimen has a cytochrome CYP3A4 enzyme inhibitor e.g., cobicistat.[43] An added dose of methergine is needed in patients taking CYP3A4 enzyme inducers, e.g., efavirenz.

Routine ART regimen should be continued during the intrapartum management phase. If HIV RNA > 1000 copies/mL at the time of delivery, then IV zidovudine (ZDV) infusion should be started 3 hours prior to the scheduled cesarean section in addition to oral administration of routine ART regimen.[44] If the routine ART regimen consists of ZDV, it can be stopped during this period of IV ZDV infusion. ZDV infusion must be given whenever HIV RNA> 1000 copies/mL at the time of delivery, even if ZDV was not a part of the routine ART regimen due to ZDV resistance. ZDV rapidly crosses the placenta and builds ART drug levels in the fetus’s system before it is exposed to the mother’s genital secretions and blood during delivery, which contains HIV.[45]

If a woman presents in labor with unknown HIV status, offer her an opt-out screening option for HIV. The initial test is a combination immunoassay for HIV-1 and HIV-2 and an HIV RNA assay. If this initial test is positive, immediately start IV ZDV infusion. Women with positive initial tests are tested with antibody immunoassay, which differentiates HIV-1 and HIV-2 antibodies.

• Postpartum Management

Comprehensive care plans involving OB/GYN, primary care, HIV specialists, pediatric care, mental health, and supportive care must be provided to HIV positive women in the postpartum period. ART for the mother and the newborn must be provided before hospital discharge, and the first follow-up visit to the HIV-care provider must happen within 2-4 weeks of discharge. These measures are of particular importance to women who have HIV diagnosed during delivery/labor and maximize the chances of successful viral suppression.[46]

Postpartum depression is particularly important in HIV positive women, and all HIV positive women in postpartum must be screened for it.[47] Postpartum adherence to ART is often challenging, and the continuation of postpartum ART must be stressed. In the postpartum phase, the choice of ART should be carefully tailored according to factors like the desire for future pregnancies, choice of contraceptives, and any potential drug interactions. Patients must be counseled about contraceptive use and PrEP for their partners (in serodiscordant couples) and informed about the earlier return of ovulation in the absence of breastfeeding.[48] HIV positive women can safely use all methods of contraception.[49][50]

In the US official guidelines by the Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Infection state that breastfeeding must be avoided by HIV positive women because viral transmission through breast milk is possible despite ART suppression and also because of the risk of ART drug toxicity to the infant via breast milk. Women must be counseled about the various pharmacological and non-pharmacological options available to deal with painful breast engorgement when not breastfeeding.[51][52]

• Newborn Management

Infants born to HIV positive mothers should be given ART post-exposure prophylaxis within 6 to 12 hours of delivery. Infants born to mothers with viral suppression should receive ZDV for four weeks unless the mother had genital ulcers or excessive bleeding or other STIs at the time of delivery, in which case the infant should receive the same care as that given to an infant born to a mother without viral suppression. Infants born to mothers with no viral suppression (HIV RNA>50copies/mL) should receive a two-drug (ZDV and nevirapine) or three-drug (ZDV, lamivudine, and either nevirapine or raltegravir) for six weeks.[45] if the HIV status of the mother is unknown, give a rapid HIV antigen-antibody test to the mother. At the same time, the infant should be given two or three-drug prophylaxis (same as in high-risk infants). This prophylaxis can be stopped if the testing reveals that HIV is not present in the mother.

A CBC with differential is performed before starting ART in infants. If abnormalities are detected on it, then ART may need to be stopped, a decision that should be made after consultation with pediatric HIV experts. As a general rule, hemoglobin and neutrophil counts should be measured every four weeks if an infant is receiving ZDV and lamivudine regimen.

TMP-SMX prophylaxis against PCP is started after 4 or 6 weeks ART prophylaxis has finished in an infant born to a mother who is HIV positive unless definite test results are available to rule out HIV infection in the newborn. In infants <18 months, viral assays (HIV RNA or HIV DNA nucleic acid tests or NATs) are used to diagnose HIV. No antigen-antibody assays should be used. All infants born to HIV positive mothers are tested with NATs at 14 to 21 days, 1 to 2 months, and 4 to 6 months. If an infant is at high risk of HIV transmission (e.g., no viral suppression in the mother), additional NATs should be performed at birth and at 2 to 3 months.

In utero or neonatal exposure to HIV or ART drugs must be documented in a child’s long-term medical records even if the child is HIV negative. This is important because many such children have mitochondrial abnormalities leading to the development of disorders of the heart and nervous system in later life.[53]

Differential Diagnosis

The differential diagnosis for acute HIV infection in pregnancy can include infectious mononucleosis (IM), syphilis, rubella, toxoplasmosis, viral hepatitis, disseminated gonococcal infection, or an autoimmune disease of new-onset.

Prognosis

In the absence of any treatment, the risk of vertical transmission of HIV during pregnancy, delivery, or breastfeeding is as high as 25 to 30%. However, with rigorous testing, preconception counseling, good ART adherence, scheduled cesarean delivery, and infant prophylaxis, the rate of vertical transmission is as low as <1 to 2% in the US.[54]

Complications

In untreated HIV positive women, the risk of developing opportunistic infections increases with the fall in CD4 cell counts. Opportunistic infections like CMV and toxoplasmosis can cross the placenta and infect the fetus leading to congenital abnormalities. Also, untreated HIV infection has high chances of being passed on to the newborn in utero, during delivery, or by breastfeeding.

ART regimens themselves are also associated with many complications. Dolutegravir is associated with NTDs, while protease inhibitors have been found to cause preterm birth.[33] ZDV can cause hematological abnormalities in the infant.[55] Similarly in utero exposure to HIV or ART drugs can also cause mitochondrial dysfunction later on in the child’s life.[53][35]

Deterrence and Patient Education

Patients’ reasons for opting out of HIV testing during their initial prenatal visit should be explored. Testing should again be offered in the third trimester to women who opt out in the first trimester or those included in high-risk groups according to the CDC (e.g., IV drug users and their sexual partners, women who are sex workers, sexual partners of HIV-infected persons, and women with a new or more than one sexual partner during this pregnancy)

HIV positive women must be counseled about the need to achieve sustained viral suppression before conception and the importance of ART adherence in minimizing both vertical and secondary sexual transmission of the virus to their partners. They should also be counseled against unsafe sexual practices, alcohol and tobacco use, and illicit drug abuse.[49]

Patients must be educated about the various available methods of contraception, the availability of PrEP for their HIV-negative partners, the need to avoid breastfeeding, and how to alleviate painful breast engorgement in the absence of lactation.[51][52]

Enhancing Healthcare Team Outcomes

Managing HIV in pregnant women requires an interprofessional team of healthcare professionals that includes a nurse, laboratory technologists, pharmacists, social workers, and a number of physicians in different specialties. Without proper management, the rate of perinatal transmission of HIV from mother-to-child is high.[1][Level V]

The moment an HIV positive woman expresses her desire to have a child, the clinic physician and nurse are required to assess her readiness as follows:

• The nurse orders her CD4 cell counts and viral load measurements and coordinates with the laboratory technologists.
• The physician assesses her adherence to the ART regimen and consults with the pharmacist about the need to switch regimens in case one of the drugs is contraindicated in pregnancy.[56] [Level V]
• The primary care physician or HIV specialist consults OB/GYN specialists, and together they coordinate to care for the special needs of an HIV positive pregnant patient.
• Mental health physician is consulted to evaluate the patient for any domestic violence, depression or anxiety as these could affect her ART adherence and jeopardize the health and ensure the wellbeing of both the mother and the child.
• OB/GYN specialist plans the mode and timing of delivery [Level V] and coordinates with the patient’s HIV specialist, mental health physician and HIV pediatric specialist to improve the patient’s ART adherence postpartum, screen for postpartum depression and provide ART prophylaxis and testing to the newborn.

The management of HIV positive pregnant patient does not end with the delivery of the baby. ART regimens for both the mother and the child have to be decided before hospital discharge. Future contraception options have to be discussed. Counseling about breastfeeding needs to be done. The patient’s family support and home environment need to be assessed by a social worker. Only by working as an interprofessional team can we minimize the perinatal transmission of HIV.[54][57] [Level V]