HIV in pregnancy

HIV in pregnancy

I. What Every Physician Needs to Know

Most women infected with human immunodeficiency virus (HIV) are in their reproductive years and the majority of the disease is acquired via heterosexual transmission. In the United States, approximately 6,000 women infected with HIV give birth every year. HIV infection can be transmitted from mother to child in utero (~30%), intrapartum (~70%), or with breast feeding. The treatment goals during pregnancy are to provide appropriate care for the HIV-infected pregnant woman and to prevent mother-to-child transmission of the disease. Care should be taken to choose the appropriate antiretroviral regimen to avoid adverse effects on maternal and fetal health.

II. Diagnostic Confirmation: Are You Sure Your Patient Has an HIV Infection?

The American Congress of Obstetricians and Gynecologists (ACOG) and the Centers for Disease Control (CDC) recommend an opt-out HIV screening protocol. While women can refuse HIV testing, it is a part of routine prenatal blood tests and all pregnant women should have their HIV serostatus evaluated.

Until recently, standard serology testing for HIV infection has started with the ELISA (enzyme-linked immunosorbent assay), which is repeated if positive. HIV-1 Western blot testing is performed next to confirm the diagnosis in the setting of repeatedly positive ELISA tests. The serology test result is positive for HIV infection only when antibodies of at least 2 of the HIV antigens (p24, p41, and gp120) are detected.

Although serology testing with ELISA followed by confirmatory testing with Western blot is both sensitive and specific for diagnosis of established HIV-1 infection, it is not able to detect acute HIV infection (AHI) because of the time lag between exposure and development of antibodies. Antibodies to HIV infection do not develop until 3-7 weeks after inoculation. Thus, during this diagnostic window, the pregnant woman with AHI might be mistakenly determined to be HIV-negative with standard serology testing. In addition, HIV-2 infection is often being misclassified as HIV-1 infection by the HIV-1 Western Blot test.

The CDC now recommends initial screening with an HIV-1/2 antigen/antibody combination immunoassay. Confirmation of HIV infection is then performed with an HIV-1/HIV-2 antibody differentiation immunoassay and HIV-1 nucleic acid test. The advantage of this method is early diagnosis of acute HIV-1 infection as well as detection of HIV-2. In addition, HIV infection can be diagnosed with this method days to weeks before a Western blot test would have become positive, by assessing for the p24 antigen (detectable 15 days after infection) and for immunoglobulin M (IgM) antibodies (detectable 3-5 days after the p24 antigen turns positive). The availability of this new testing modality will have an important impact on reducing perinatal transmission of HIV by detecting acute infections, which have a high risk of vertical transmission.

B. Prevalence

Women comprise 20% of the 50,000 newly diagnosed HIV infection patients in the United States and account for 23% of those with existing infections. There are multiple risk factors for women acquiring HIV infection: intravenous (IV) drug use, employment as a sex worker, male sex partners who use IV drugs or who are infected with HIV, acquisition of a sexually transmitted infection within the past year, or having multiple sex partners since the last HIV test.

Over the past decade, the demographics of those infected with HIV and AIDS have shifted dramatically. Most of these women are diagnosed during their reproductive years, the majority being women of color who acquired the infection through heterosexual contact.

D. Physical Examination Findings

Physical examination during the initial prenatal visit should include:

• Vital signs, maternal weight, documentation of fetal heart tones

• General physical examination (including fundoscopy, breast exam)

• Pelvic examination (including careful evaluation for any discoloration, condylomata, ulcerative lesions, cervical, vaginal, or perineal lesions, vaginal discharge, or bleeding)

• Uterine size/fundal height

E. What Diagnostic Tests Should Be Performed?

The HIV-1 Western blot and HIV-1 immunofluorescence assay are no longer recommended for laboratory diagnosis of HIV-1 infection. Testing for HIV infections should begin with an HIV-1/HIV-2 antigen/antibody combination immunoassay. This detects HIV-1 and HIV-2 antibodies and the HIV-1 p24 antigen. Reactive specimens will undergo confirmatory testing with an additional HIV-1/2 immunoassay to differentiate between HIV-1 and HIV-2 antibodies.

In situations when a reactive specimen on the initial combination immunoassay is non-reactive or indeterminate on the HIV-1/2 antibody differentiation assay, then an HIV-1 nucleic acid test (HIV-1 NAT) should be performed for confirmation. A positive HIV-1 NAT confirms acute HIV infection, while a negative HIV-1 NAT indicates no infection.

Positive results from the above testing should confirm the diagnosis of HIV, and targeted medical care for the infection is recommended.

1. What Laboratory Studies Should Be Ordered to Help Establish the Diagnosis? How Should the Results Be Interpreted?

Aside from the standard pregnancy specific laboratory tests, the following additional tests are considered in the care of HIV-infected women:

1. HIV viral load and CD4 count (total and percentage)

• Viral load at initial visit; 2-4 weeks after starting or changing antiretroviral (ARV) medication; every 4 weeks until the viral load is undetectable; and then every 3 months

• Viral load results at 34-36 weeks will guide determination of the route for delivery

• CD4 count at initial visit and at least every 3 months

2. Genotype – if never taken antiretroviral medication (ARV-naive) or failure of suppression of HIV RNA while on ARV agents – at initial visit and as indicated.

3. Cytomegalovirus immunoglobulin G (Ig G) – at initial visit.

4. Toxoplasmosis Ig G – at initial visit.

5. Hepatitis A virus (HAV) IgG – at initial visit.

6. Hepatitis B virus [HBV surface antigen (HBsAg)] – at initial visit.

7. Hepatitis C virus (HCV) antibody – at initial visit.

8. Tuberculosis – purified protein derivative (PPD) skin testing or interferon-gamma release assay – at initial visit.

9. Complete blood count – at initial visit and every 3 months or more frequently, based on ARV regimen or symptoms.

10. Chemistries and liver function tests – at initial visit and every 3 months or more frequently, based on ARV regimen or symptoms. If on nucleoside analog transcriptase inhibitors (NRTIs), monitor electrolytes and hepatic enzymes monthly in third trimester.

11. Assessment of human leukocyte antigen (HLA)-B*5701 in patients where use of abacavir is being considered.

2. What Imaging Studies Should Be Ordered to Help Establish the Diagnosis? How Should the Results Be Interpreted?

• All pregnant women should have an obstetric ultrasound examination as early as possible during the gestation (preferably in first trimester or early second trimester) to confirm fetal viability and gestational age. Accurate dating of the pregnancy is important to avoid the potential risk of iatrogenic premature delivery as planning for scheduled cesarean delivery at 38 weeks (and not 39 weeks) is optimal for HIV-infected women with a high viral load.

• In the second trimester: women who were on a combination ARV regimen during first trimester will need a targeted ultrasound exam for fetal anatomy.

• The indications for non-stress testing are unchanged in HIV-infected women and should be guided by other underlying maternal disorders, ultrasound findings, and standard obstetrical indications.

In the third trimester: Serial ultrasound examination for evaluation of fetal interval growth might be considered in women receiving protease inhibitors (PI) due to their possible association with fetal growth restriction.

A. Immediate Management

An HIV-infected woman may face myriad challenges, including medical, psychological, social, and practical issues. Thus, a multidisciplinary approach is required for her optimal care. Communication between the obstetrician and the primary HIV specialist with consultation from a maternal-fetal medicine specialist is indicated.

Of importance, the HIV-infected woman should receive detailed counseling about the risk of vertical transmission of the HIV infection. Management options to decrease the risk of vertical transmission should be discussed in detail, including the three-part zidovudine prophylaxis regimen, either alone or in combination with other antiretroviral medications (i.e., antiretroviral therapy during the antepartum period, in the intrapartum period, and for neonatal zidovudine therapy); cesarean delivery for women with a viral load greater than 1,000 copies/milliliter (mL); other potential obstetrics interventions; and avoidance of breast feeding.

Potential risks, benefits, and alternatives of management options should also be included in the detailed counseling.

Antiretroviral therapy

HIV viral load impacts the rate of mother-to-child transmission of HIV infection. Proper use of ARV therapy in combination with other obstetric interventions can suppress the viral load and reduce perinatal transmission to less than 2%, although there is no threshold of viral load level below which transmission does not occur. As such, current U.S. Public Health Service guidelines recommend that ARV should be offered to all HIV-infected pregnant women, including those who do not require ARV treatment for their own health, regardless of viral load. The primary goal of therapy should be to reduce the patient’s viral load to undetectable levels for the duration of the pregnancy.

Resistance testing should be conducted before starting antiretroviral therapy, but the results should not delay treatment initiation. Rather, the treatment can be modified if necessary based on the results of resistance testing. It is important to note that although resistance testing may not be successful with viral loads less than 1,000 copies/mL, it should nonetheless be performed for viral loads greater than 500 copies/mL. Resistance testing should not delay the beginning of ARV therapy; rather, therapy may be modified following the results of testing.

The initial monotherapy with zidovudine (ZDV) from Protocol Pediatric Acquired Immunodeficiency Disease Syndrome Clinical Trial Group (PACTG) 076 has been expanded to include a combination of other ARVs in the antepartum period. Potent combination ART regimens are chosen, comprised of nucleoside and nucleotide analogue transcriptase inhibitors (NRTI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) or protease inhibitors (PI).

It is not recommended to use ZDV monotherapy alone for prophylaxis. However, in the few women whose HIV ribonucleic acid (RNA) levels are below 1,000 copies/mL on no ART and who decline potent combination ART for fear of fetal exposure, ZDV monotherapy might be an option.

A few important notes about safety of antiretroviral therapy during pregnancy:

Nucleoside and Nucleotide analogue reverse transcriptase inhibitors (NRTIs)

The NRTIs are classified by the Food and Drug Administration (FDA) as either pregnancy category “B” or “C”. They are generally well tolerated and cross the placenta. Individually, stavudine (d4T) (Class B) and didanosine (ddI) (Class B) have good safety records in pregnancy. However, fatal cases of lactic acidosis and liver failure have been reported when used together. Also, stavudine has pharmacologic antagonism with ZDV and should not be used in combination to avoid overlapping toxicities.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Limited data is available on the use of NNRTIs during pregnancy. Caution should be taken with efavirenz, which has been associated in some case reports and animal studies with neural tube defects. It should be avoided in the first trimester, and women on efavirenz should be counseled to avoid pregnancy. However, if a pregnant patient has been achieving effective suppression of her viral load with an antiviral regimen that includes efavirenz, it should not be discontinued. If a woman who is taking efavirenz becomes pregnant, she should undergo a targeted anatomy ultrasound at 18 to 20 weeks gestation. If viral genotyping reveals contraindicated medications as the only option for viral load suppression, the patient must receive extensive counseling regarding the risks and benefits of treatment.

Hepatotoxicity and skin rash have been reported to be associated with the use of nevirapine, but more recent data either do not show this association or show a weak association among pregnant women. If nevirapine is used, the patients should be monitored for liver toxicity at baseline and at intervals during treatment, and other alternatives should be considered in the setting of elevated baseline transaminases. Single-dose nevirapine during labor is not associated with liver toxicity.

Protease inhibitors (PIs)

Generally classified as pregnancy category “B” or “C”, there is continued conflicting data reporting increased risk of preterm birth in women receiving combination ARV regimens including PIs. However, the clear advantages of PIs for improving maternal health and in reducing the risk of vertical transmission of HIV appear to outweigh the small risk of preterm birth, and thus PIs should be included in combination ARV regimens.

Specific situations:

1. For women who are not on antiretroviral medication but need treatment for their own health:

Pregnant women who met the guidelines’ criteria for initiation of ARV in non-pregnant adults should be started on combination ART. Therapy should continue after delivery. Because treatment is indicated for the woman’s own health and the potential benefit of therapy to the mother appears to outweigh the potential risks to the fetus, therapy should begin promptly, even if during the first trimester. However, medications with known teratogenic effects are best avoided.

2. For women who do not require antiretroviral medication treatment for their own health:

These women require ARV only for prophylaxis against vertical transmission of HIV infection. As they do not meet the requirements for initiation of ARV for their own health, they should be counseled on the benefits of ARV prophylaxis.

A three-drug ARV combination for prophylaxis of perinatal transmission is also recommended. These women are at a low risk for disease progression if therapy is delayed; therefore, initiation of prophylaxis can begin after the first trimester to avoid potential adverse fetal risks. However, recent data supports better efficacy in reducing in utero transmission with earlier initiation of treatment.

3. For women who previously received antiretroviral medication or prophylaxis but are not currently taking any medication:

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 had effectively suppressed viral load, these antiretroviral medications can be used again, but drugs with teratogenic potential or adverse maternal effects should be avoided. Consultation with a specialist is helpful to guide appropriate ARV choices for women who previously received the regimen for their own health.

4. For women who are currently receiving antiretroviral medication:

Generally, women on ART for their own health should have the medications evaluated for safe use during pregnancy. Those who tolerate the regimen well without adverse effects or toxicity and achieve adequate viral suppression should continue that treatment during pregnancy.

Opportunistic infection prophylaxis

The decision of when to initiate prophylaxis against opportunistic infection during pregnancy is as follows:

• For those with cluster of differential 4 (CD4) count below 200 cells/cubic millimeter (mm³⁾: Start Pneumocystis jiroveci pneumonia (PCP) prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) at 1 double strength (DS) tablet every day. Aerosolized pentamidine can be used as substitute.

• For those with CD4 count below 100 cells/mm³ and positive serology for toxoplasmosis: Start toxoplasmosis encephalitis prophylaxis with TMP-SMX at 1 DS tablet every day.

• For those with CD4 count below 50 cells/mm³: Start Mycobacterium avium complex (MAC) prophylaxis with Azithromycin at 1,200 milligrams (mg) every week.

Routine prophylaxis is not recommended for cryptococcosis.

Screening for other sexually transmitted infections (STI)

Current standards require all pregnant women to undergo STI screening for syphilis, gonorrhea, and chlamydia with prompt treatment of any positive tests. As co-infection of syphilis with HIV has been linked to increased risk of vertical HIV transmission, early identification and treatment of syphilis is important for prevention of both congenital syphilis and HIV.

Screening for cervical dysplasia is also important for all pregnant women. HIV positive women have a higher incidence of cervical dysplasia, genital warts, and intraepithelial neoplasia. However, cancer is infrequently encountered even in the setting of immunosuppression. The guidelines for pap smear screening for cervical dysplasia recommend yearly pap testing for HIV positive women, starting within 1 year after the initiation of sexual intercourse or age 21, whichever is earlier, and repeated 6-12 months later. Yearly pap testing for women with HIV should continue until 3 negative results, after which pap screening every 3 years is recommended. Because of the high prevalence of human papillomavirus (HPV) in younger populations, HPV co-testing is only recommended for women over the age of 30. Women with negative co-testing can undergo repeat co-testing every 3 years.

Vaccination

Up to date vaccination records are a key part of prenatal care in both HIV-infected and HIV-uninfected women. While some vaccines, particularly live attenuated vaccines, such as measles-mumps-rubella and varicella, should be avoided in pregnant patients, there are no vaccination restrictions specific to HIV-infected pregnant women. In addition to routine vaccines such as hepatitis A and hepatitis B, pregnant women with HIV should receive an annual influenza vaccine and pneumococcal vaccine as well as a tetanus, diphtheria, and pertussis (Tdap) vaccination each pregnancy. The H1N1 vaccine should be administered to all pregnant women regardless of HIV status.

Tuberculosis testing

In the developing world it is common to find co-infection with HIV and tuberculosis (TB). Such co-infection can lead to increased severity of TB, reactivation TB, and diminished response to purified protein derivative (PPD) skin testing. The threshold for a positive PPD in an HIV-positive woman is only 5 millimeters (mm) of induration, measured perpendicular to the long axis of the arm. Chest radiography should be performed on all positive PPD results during pregnancy, as there is minimal fetal radiation exposure from chest x-rays.

Laboratory tests to monitor therapy response and management adjustments

HIV-infected pregnant women should undergo viral load monitoring at the initial visit and monthly until it is undetectable, and every 3 months after an undetectable level is attained. When ARV regimens are changed, patients should undergo repeat viral load testing in 2-4 weeks. In patients where therapy adherence to therapy is a concern, more frequent testing is recommended.

Once appropriate therapy has been initiated, viral load should decrease by at least one log 10 copies/mL after one month with target suppression generally taking 16-24 weeks.

The viral load should be reassessed around 34-36 weeks gestation to help guide decision making as to the mode of delivery.

HIV-infected pregnant women should have CD4 monitoring at the initial visit and every 3 months. Physiologic hemodilution during pregnancy can result in a stable CD4 percentage with changes in absolute CD4 count. Although CD4 percentage is a better indicator of the immune status of a pregnant woman, absolute CD4 count is frequently used because guidelines for initiating treatment are based on these values.

If a woman has a viral load greater than 500-1000 copies/mL, suboptimal viral suppression while on ARV, or persistent viral rebound after suppression, drug-resistance testing should be performed. In the setting of virologic failure, patients should be on ARV or have discontinued medication no greater than 4 weeks prior to resistance testing. Genotypic testing is more affordable, faster, and more sensitive than phenotypic testing when there is a mixture of wild-type and resistant viruses.

Liver function should be monitored on all women receiving ART. Pregnant women require more frequent monitoring of transaminase levels when initiating nevirapine. Abnormal baseline transaminase levels may be a better predictor of risk of nevirapine-associated hepatotoxicity than CD4 count. Women taking ZDV should undergo routine hematologic monitoring. Further monitoring should be determined by the specific agents being taken.

Scheduled cesarean delivery for women with greater than 1000 copies/mL HIV RNA viral load

ACOG currently recommends that all HIV-infected women with viral loads above 1,000 copies/mL should be counseled regarding the potential benefits of scheduled cesarean delivery to further reduce the risk of vertical transmission beyond what has been achieved by the highly potent antiretroviral regimen.

However, the benefit of scheduled cesarean delivery for women with viral loads below 1,000 copies/mL who are on combination ARV has not been demonstrated. Routine cesarean delivery in the setting of viral loads less than 1,000 copies/mL is not recommended in the absence of other obstetric indications due to the higher complication risk in this population. Discussion of cesarean delivery should begin as early as possible in pregnancy with counseling tailored to each patient’s risks and needs. Consultation and follow-up visits with maternal-fetal medicine and infectious disease specialists should be scheduled.

Planned cesarean delivery circumvents many of the risks for transmission of HIV associated with normal delivery and labor, including microtransfusions during contractions and exposure to cervicovaginal secretions in the birth canal. The risk of vertical transmission in HIV-infected women on highly active antiretroviral regimens can be reduced by up to 80% through the use of elective cesarean delivery prior to rupture of membranes.

For healthy, non-HIV infected women, ACOG greatly discourages scheduled delivery before 39 completed weeks of gestation to avoid neonatal morbidities associated with earlier delivery. However, in HIV-infected women, a younger gestational age of 38 weeks is chosen to avoid the possibility of spontaneous labor or rupture of membranes. Because of this, obstetricians should be aware of the potential risk of neonatal respiratory morbidities or other morbidities associated with earlier delivery. The benefits of scheduled cesarean delivery in reducing vertical transmission is unclear after the occurrence of spontaneous labor or rupture of membranes; thus care should be individualized in these cases after counseling the patient about the risks and benefits of each delivery mode, while taking care to expedite delivery regardless of method to decrease the chance of vertical transmission.

Studies have shown that HIV-infected women experience increased rates of complications following cesarean delivery than their HIV-negative counterparts, likely due to their immunosuppressed status. The increased risks to the mother, mostly from infection, must also be discussed prior to planning a scheduled cesarean delivery. However, the majority of studies evaluating the efficacy of prophylactic antibiotics for the prevention of infectious morbidity following cesarean delivery were performed when such antibiotics were given only after cord clamping.

ACOG currently recommends administration of prophylactic antibiotics at least 30 minutes prior to cesarean delivery. Further studies are needed to evaluate whether this change in timing has impacted morbidity and mortality, and because of this prophylactic antibiotics are recommended prior to scheduled cesarean delivery for HIV-infected women.

Overall, when compared to the cost of caring for a child with perinatally acquired HIV, scheduled cesarean delivery at 38 weeks is cost-effective in spite of the increased postpartum morbidity.

Intrapartum management

Intrapartum prophylaxis with zidovudine (one of the three-part regimen of the PACTG Protocol 076 to decrease vertical transmission) is no longer indicated for women who are compliant with antiretroviral therapy and with viral loads less than 1,000 copies/mL in the late third trimester. This practice is discontinued due to the lack of available randomized clinical trials supporting zidovudine (ZDV) prophylaxis in women with suppressed viral loads of less than 1,000 copies/mL. Furthermore, available studies reported a very low risk of vertical transmission in women who did not receive intrapartum prophylaxis with ZDV but who had a viral load of less than 1,000 copies/mL.

However, intrapartum prophylaxis with ZDV to prevent vertical transmission is recommended for:

• Women who do not achieve suppression of viral loads to less than 1,000 copies/mL by the late third trimester

• Women with unknown viral load levels

• Women with HIV who went untreated during the antepartum period

• Women who test positive on rapid HIV testing upon admission for delivery

The ZDV prophylaxis consists of continuous intravenous ZDV during labor, regardless of the antepartum antiviral regimen. The loading dose is 2 milligram/kilogram (mg/kg) IV over 1 hour followed by continuous infusion of 1 mg/kg/hour until delivery. In the event of a scheduled cesarean section, ZDV should be initiated 3 hours prior to delivery. Serum medication levels have been shown to be lower with oral ZDV than with intravenous administration, but in cases of limited availability of IV medication, a 600 mg loading dose of oral ZDV and 400 mg every 3 hours thereafter can be considered.

Women on antiretroviral regimens should continue their medications on schedule during labor and before the scheduled cesarean delivery. Women on combination regimens including ZDV should stop oral ZDV while intrapartum ZDV prophylaxis is being infused, but should continue the other oral antiretroviral components of their regimen. If stavudine is part of the antepartum regimen, it should be stopped during labor because stavudine may antagonize ZDV.

Other intrapartum management issues

Women who are resistant to zidovudine

Women with ZDV-resistant strains of HIV should still have ZDV prophylaxis if clinically indicated. ZDV serves not only to reduce maternal viral load, but also as pre-exposure and post-exposure prophylaxis for the infant. Wild-type virus also appears to be more readily transmitted to infants when compared to ZDV-resistant virus, so ZDV can have a protective effect for the infant even when the mother will see no benefit from treatment. ZDV is one of the only nucleosides metabolized to its triphosphate (the active form) in the placenta. Furthermore, it has one of the best profiles for central nervous system (CNS) penetration, which can help reduce a potential site for transmitted HIV. ZDV should not be used if there is a documented hypersensitivity to the medication.

Other obstetric interventions

During labor, in an effort to decrease the risk of vertical transmission, certain obstetrical procedures that would cause contamination of the baby with maternal blood or secretions are best avoided in HIV-infected women. Such procedures include: placement of fetal scalp electrode, intrauterine pressure catheter, operative vaginal delivery with vacuum or forceps, and episiotomy.

In the event of spontaneous rupture of membranes during early labor, oxytocin can be administered to hasten delivery. The duration of prolonged rupture of membranes has been shown to further increase the risk of perinatal transmission of HIV. However, this increase in the risk of vertical transmission from prolonged membrane rupture was not determined to be clinically significant based on the results of a meta-analysis of 4,721 deliveries. This report estimated that for each hour after membranes are ruptured, the risk of vertical transmission increases by 2% over the baseline transmission risk. For example, for a woman on ARV therapy with a suppressed viral load of fewer than 1,000 copies/mL, it is assumed that her baseline vertical transmission risk is 2%. At one hour after membrane rupture, if she is still undelivered, her risk of vertical transmission would increase to 2.04%, and if she remains undelivered with ruptured membranes for 8 hours, her risk would be increased to 2.32%. Therefore, although expediting delivery with oxytocin augmentation is indicated (as with all term women with spontaneous rupture of membranes), cesarean delivery after membrane rupture for the purpose of reducing perinatal HIV transmission is not recommended in women with a suppressed viral load.

Delayed cord clamping has shown benefit to term infants, and there is no clear reason to alter this practice in HIV-infected women.

Postpartum hemorrhage, antiretroviral drugs, and methergine use

Uterine atony causing postpartum hemorrhage is typically treated with methergine or other ergot alkaloids. However, PIs are potent CYP3A4 inhibitors, and therefore methergine co-administration is not recommended in this setting due to the risk of exaggerated vasoconstriction.

The availability of alternative treatments such as prostaglandin F-2 alpha, misoprostol, and oxytocin should be chosen for any woman taking PIs. If these alternatives are unavailable and the risk of hemorrhage outweighs the risk of vasoconstriction, methergine can be used at a low dose and for as short a duration as possible.

When CYP3A4 inducers are part of an ARV regimen (nevirapine, efavirenz), uterotonic agents may have a diminished effect. In these instances, additional uterotonic agents may be necessary.

XI. Special Considerations in the Management of HIV Infection

Preterm premature rupture of membranes

Rupture of membranes greater than 4 hours is associated with an increased risk of perinatal transmission of HIV. HIV-infected women who experience preterm premature rupture of membranes (PPROM) must therefore choose between increased risk of perinatal transmission and severe prematurity (from immediate delivery after PPROM).

Two studies have explored expectant management in PPROM and in both studies perinatally acquired transmission of HIV was limited to women who received no antenatal antiretroviral therapy or received treatment only in the antepartum period with ZDV monotherapy. Though both studies were small (7 women in one, 18 in another), there were no cases of perinatally acquired HIV among women who received antenatal antiretroviral therapy regardless of the duration of rupture of membranes.

While these results are encouraging, the studies are too small to determine the efficacy of expectant management of PPROM. Further studies are necessary to guide management of HIV-infected women with PPROM prior to 34 weeks.

Invasive antenatal testing in HIV pregnant women

In the era prior to common use of potent combination ARV therapy, invasive testing such as amniocentesis and chorionic villus sampling (CVS) were associated with dramatic increases in the risk of perinatal HIV transmission. Between 1984 and 1996 the transmission rate of HIV was 30% among women who underwent amniocentesis compared with a rate of 16.2% among women who did not undergo amniocentesis.

Between 1997 and 2000, after the advent of potent combination drugs, there were zero transmissions among 18 women who underwent amniocentesis. While data is still limited, there does not appear to be an increased rate of transmission of HIV with invasive procedures in women on highly active ARV.

However, some experts consider invasive procedures to be too risky to be safely offered to HIV-infected women. If absolutely required, effective combination ARV prior to any invasive testing is strongly encouraged to maximally reduce the viral load in an effort to reduce the risk of transmission.

Women with detectable viral loads requiring invasive perinatal testing should consider consultation with an expert, and any procedures should be performed under ultrasound guidance with care taken to avoid traversing the placenta, thus minimizing the risk of transmission.

C. When is the Patient Ready for Discharge?

Postpartum care

Vertical transmission can occur via breastfeeding, and as such it is contraindicated in the United States (U.S.), where safe alternatives are available. Other potential considerations leading to the discouragement of breastfeeding among HIV-infected mothers include ARV toxicity or development of ARV resistance in the breastfeeding infant. However, lack of breastfeeding allows a more rapid return to fertility, with some women ovulating within 6 weeks of delivery. As such, adequate contraception must be discussed, particularly in women on efavirenz-containing regimens due to the risk of teratogenicity. A “dual protection” strategy is recommended, which consists of a barrier method in combination with a highly effective form of contraception such as intrauterine device (IUDs), implants, and injectables. While oral contraceptives (OCs) or etonorgestrel-containing implants may interact with many ARV drugs (particularly amprenavir/fosamprenavir), depot medroxyprogesterone acetate (Depo-provera, Depot medroxyprogesterone acetate (DMPA) does not appear to alter ARV pharmacokinetics.

Few studies address other non-oral contraceptives in women on ARV therapy, although some data suggest that the estrogen patch can interact with lopinavir/ritonavir. Considerations must be made for drug interactions, and differing serum concentrations of hormonal contraceptives in combination with ARV drugs that affect the pharmacokinetics of the contraceptives should be taken into account. Sterilization is appropriate only when a woman is certain that she desires no further children, and sterilization counseling should be similar between HIV-infected and HIV-uninfected women.

Women with indications to start ARV therapy (symptomatic HIV infection or low CD4 count) or with CD4 counts between 350 and 550 cells/mm³ should be encouraged to continue their ARV regimen postpartum. Women with CD4 counts greater than 550 cells/mm³ should consider continuation of ARV therapy to reduce the risk of horizontal transmission. Discussion with an HIV specialist regarding continuation of ARV therapy after delivery should be initiated as early as possible for women who do not meet these criteria.

Potential benefits of ARV therapy include improved maternal health and reduced (though not eliminated) risk of horizontal transmission to partners. Other benefits may include lower instances of AIDS defining events and mortality among women who continue ARV therapy, though more research needs to be done on this subject. Women on NNRTI-containing regimens who wish to discontinue their ARV regimen postpartum should be instructed to discontinue the NNRTI and continue other medications for at least 7 days; the optimal interval is unknown.

Efavirenz can prolong NNRTI concentrations for more than 3 weeks. As such, women on efavirenz-containing regimens should either discontinue efavirenz and continue their other ARV medications for at least 3 weeks or substitute a PI for the NNRTI for at least 30 days after discontinuation of efavirenz. If a woman is not on an NNRTI, all ARV medications may be discontinued simultaneously.

Adherence to ARV therapy can be challenging for new mothers, and efforts to simplify regimens may improve outcomes. Significant decreases in compliance with ARV therapy have been shown in the postpartum period; therefore, making arrangements for patient follow-up prior to discharge from the hospital is advisable. Doses of certain medications, particularly PIs, may require adjustment in the postpartum period. New mothers should also be evaluated regularly for signs of depression and substance abuse as these can impact adherence. In some cases, a temporary cessation of ARV therapy may be necessary to address underlying substance abuse issues. Patients must be counseled regarding the risks of virologic failure, development of resistance, and worse long-term outcomes associated with poor medication adherence.

Newly diagnosed HIV in the postpartum period should be evaluated rapidly. Breastfeeding should be stopped unless confirmatory Western blot testing is negative, and children and partners should receive HIV testing. In other regards, the evaluation and management should not differ from other newly HIV-infected patients.

XIII. Patient Counseling

As understanding of HIV has progressed and effective treatments have become widespread, the guidelines regarding reproductive counseling of HIV-infected patients have evolved. In 1994 the Ethics Committee of the American Society for Reproductive Medicine (ASRM) encouraged counseling sero-discordant or HIV positive couples about donor sperm, adoption, and not having children. With the progress of modern medicine, many options are now available to such couples who desire children.

Current guidelines for discordant couples with an HIV-infected woman discuss homologous insemination. As approximately 1 in 500-1,000 episodes of unprotected intercourse results in horizontal transmission of HIV, some couples attempt to time unprotected intercourse with ovulation, but there are now alternatives to this still-risky method. If the male is HIV-infected there are methods of sperm preparation that can reduce the rate of HIV infection to 1%, which greatly reduces the risk to both mother and child. Intrauterine insemination and intracytoplasmic sperm injection have been shown to be both safe and effective means of achieving pregnancy among sero-discordant couples.

Pre-exposure prophylaxis (PrEP), or the medication of HIV-negative partners to maintain sufficient blood levels of ARV drugs and therefore prevent acquisition of HIV, has been shown to minimize the risk of horizontal transmission of the virus to sero-discordant partners. A combination of daily tenofovir and emtricitabine has been approved by the United States Food and Drug Administration for PrEP, and current guidelines recommend starting therapy for 1 month prior to unprotected intercourse and continuing for 1 month after conception attempts. It is advisable for the seronegative partner to be tested for HIV before starting PrEP and every 3 months thereafter. PrEP can be continued during pregnancy or while breastfeeding, but pregnant HIV-negative patients with a sero-discordant partner should be encouraged to consistently use condoms due to the demonstrated increase in HIV acquisition during pregnancy and the theoretical risk of increased perinatal virus transmission among acutely infected individuals.

What's the Evidence?

Connor, EM, Sperling, RS, Gelber, R. “Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group”. N Engl J Med. vol. 331. 1994. pp. 1173-80.

Garcia, PM, Kalish, PA, Pitt, J. “Maternal levels of plasma HIV type 1 RNA and the risk of perinatal transmission. Women and Infants Study group”. New England Journal of Medicine. vol. 341. 1999. pp. 385-393.

“American College of Obstetrics and Gynecology: ACOG Committee Opinion. Human immunodeficiency virus and acquired immunodeficiency syndrome and women of color”. Obstet Gynecol. vol. 112. 2008. pp. 413-6.

Tuomala, RE, Shapiro, DE, Mofenson, LM, Bryson, Y, Culnane, M, Hughes, MD. “Antiretroviral therapy during pregnancy and the risk of an adverse outcome”. N Engl J Med. vol. 346. 2002. pp. 1863-70.

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“American College of Obstetrics and Gynecology: ACOG Committee Opinion No. 389, December 2007. Human immunodeficiency virus”. Obstet Gynecol. vol. 110. 2007. pp. 1473-8.

Mwapasa, V, Rogerson, SJ, Kwiek, JJ. “Maternal syphilis infection is associated with increased risk of mother-to-child transmission of HIV in Malawi”. AIDS. vol. 20. 2006. pp. 1869-77.

“American College of Obstetrics and Gynecology: Scheduled cesarean delivery and the prevention of vertical transmission of HIV infection”. Obstet Gynecol. vol. 234. 2000.

Ekouevi, DK, Inwoley, A, Tonwe-Gold, B. “Variation of CD4 count and percentage during pregnancy and after delivery: implications for HAART initiation in resource-limited settings”. AIDS Res Hum Retroviruses. vol. 23. 2007. pp. 1469-1474.

Kind, C, Rudin, C, Siegrist, CA, Wyler, CA, Biedermann, K, Lauper, U. “Prevention of vertical HIV transmission: additive protective effect of elective Cesarean section and zidovudine prophylaxis. Swiss Neonatal HIV Study Group”. AIDS. vol. 12. 1998. pp. 205-10.

Louis, J, Landon, MB, Gersnoviez, RJ, Leveno, KJ, Spong, CY, Rouse, DJ. “Perioperative morbidity and mortality among human immunodeficiency virus infected women undergoing cesarean delivery”. Obstet Gynecol. vol. 110. 2007. pp. 385-90.

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Cavasin, H, Dola, T, Uribe, O, Biswas, M, Do, M, Bhuiyan, A, Dery, M, Dola, C. “Postoperative infectious morbidities of cesarean delivery in human immunodeficiency virus-infected women”. Infect Dis Obstet Gynecol. vol. 2009. 2009. pp. 827405

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Wertz, J, Cesario, J, Sackrison, J, Kim, S, Dola, C. “Acute HIV infection in pregnancy: The case for third trimester rescreening”. Case Reports in Infectious Diseases. vol. Volume 2011.

Melekin, VV, Shepherd, BE, Jenkins, CA. “Postpartum discontinuation of antiretroviral therapy and risk of maternal AIDS-defining events, non-AIDS defining events, and mortality among a cohort of HIV-1 infected women in the United States”. AIDS Patient Care STDS. vol. 24. 2010. pp. 279-86.

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