HIV AIDS and pregnancy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ujjwal Rastogi, M.B.B.S. [2]; Ammu Susheela, M.D. [3]

Overview

Approximately one out of four HIV positive women are unaware of their disease, which puts them at high risk of passing the virus to their children. Mother-to-child transmission is the most common way children become infected with HIV. Approximately all AIDS cases in U.S. children are because of mother-to-child transmission. HIV transmission is reduced from 25% to less than 2% in women taking antiretroviral therapy (ART) before and during birth, and if their babies are given therapy after birth. Accordingly, universal “opt-out” HIV testing is recommended for all pregnant women early in every pregnancy. Triple therapy should be administered to all pregnant women diagnosed with HIV. However, regardless of the antenatal ART regimen, zidovudine should be administered to the mother as an intravenous infusion during labor, and to the neonate orally for 6 weeks after birth.

Epidemiology and Demographics

According to the Joint United Nations Programme on HIV/AIDS (UNAIDS), 19.2 million women are living with HIV/AIDS throughout the world. In many countries, the rate of HIV infection in women is rising faster than in any other group.

Source: https://www.cdc.gov/

Mother to Child Transmission

• HIV transmission from mother to child during pregnancy, labor, delivery or breast feeding is known as perinatal transmission of HIV .
• It is one of the most common route of transmission in children.
• Not all women who have HIV will give it to their children. Without treatment or breastfeeding about 25% (1 in 4) of pregnant women with HIV will transmit the virus to their babies.
• HIV transmission is reduced from 25% to less than 2% in women taking ART before and during birth, and if their babies are given therapy after birth. Before the current ART era, each year in the United States alone, approximately 2000 babies were infected with HIV. Despite increasing HIV prevalence, the HIV infected infants are approximately 300 per year.
• Since the mid-1990s, HIV testing and preventive interventions have resulted in more than a 90% decline in the number of children perinatally infected with HIV in the United States.

Prevention Challenges

• The main challenge to preventing mother-to-child HIV transmission remains the fact that too many women don’t know they are HIV positive and they are not being routinely tested when pregnant.
• At the same time, many women are not aware that the right treatment can reduce the risk of passing the virus to their children.
• Other important challenges include:
  • Sexual Contact with HIV-infected Men : The risk factors for women have changed. Earlier in the epidemic, more women were exposed to HIV through injection drug use. During the 1990s, women were increasingly likely to become infected through sexual contact with HIV-infected men. This is why women should know their own -- and their partners’ -- HIV status and risk factors.
  • Lack of Prenatal Care : Women at highest risk for HIV often don’t get prenatal care or don’t have access to ongoing care during their pregnancy. These women are more likely to enter the delivery room not knowing their HIV status, and have not taken the antiretroviral drugs that can treat their own disease and reduce the risk of transmitting to their infant.
  • Problems with Treatment : Many HIV-infected women and their infants still do not receive the correct drugs and other treatment or do not take the drugs properly. They may not get treatment or medical care. They may not live close to an HIV specialist who can make sure they receive proper treatment and care. Or they simply don’t have the information and resources to make decisions about their future.

Counseling

Pregnant women who are HIV-infected should be counseled concerning their options (either on-site or by referral), given appropriate antenatal treatment, and advised not to breastfeed their infants.

Recommendations

Centers for Disease Control and Prevention gives the following recommendations:

• HIV-infected pregnant women should receive HIV prevention counseling as recommended. This counseling should include discussion of the risk for perinatal HIV transmission, ways to reduce this risk, and the prognosis for infants who become infected. HIV-infected pregnant women should also be told the clinical implications of a positive HIV antibody test result and the need for and benefit of HIV-related medical and other early intervention services, including how to access these services.
• HIV-infected pregnant women should be counseled regarding antiretroviral therapy during pregnancy to improve their health and prevent perinatal transmission. Medical care and management of HIV-infected persons, especially pregnant women, can be complicated because of the need for combination therapy with multiple drugs, management of common side effects, careful monitoring of viral load and drug resistance, prophylaxis for and treatment of opportunistic infections, and monitoring of immune status. Health-care providers who are not experienced in the care of pregnant HIV-infected women are encouraged to obtain referral for specialty care from providers who are knowledgeable in this area.
• HIV-infected pregnant women should receive information regarding all reproductive options. Reproductive counseling should be non-directive. Health-care providers should be aware of the complex concerns that HIV-infected women must consider when making decisions regarding their reproductive options and should be supportive of any decision.

HIV Testing

HIV testing is recommended for all pregnant women. HIV testing is provided to pregnant women in two ways:

1. Opt-in : In areas with opt-in testing, women may be offered HIV testing. Women who accept testing will need to sign an HIV testing consent form.
2. Opt-out : In areas with opt-out testing, HIV testing is automatically included as part of routine prenatal care. With opt-out testing, women must specifi­cally ask not to be tested and sign a form refusing HIV testing. The Centers for Disease Control and Prevention (CDC) recommends that opt-out testing be provided to all pregnant women.

CDC Recommendations

• In the 2006 Revised Recommendations for HIV Testing of Adults, Adolescents, and Pregnant Women in Health-Care Settings, the CDC recommends:
  • Universal “opt-out” HIV testing for all pregnant women early in every pregnancy
  • A second test in the third trimester in certain geographic areas or for women who are known to be at high risk of becoming infected (e.g., injection-drug users and their sex partners, women who exchange sex for money or drugs, women who are sex partners of HIV-infected persons, and women who have had a new or more than one sex partner during this pregnancy)
  • Rapid HIV testing at labor and delivery for women without a prenatal test result
  • Exploration of reasons that women decline testing

Treatment

The risk of HIV transmission from mother to infant had declined to low levels with the use of ART in USA and Europe. The risk for perinatal HIV transmission can be reduced to <2% through the use of antiretroviral regimens and obstetrical interventions (i.e., zidovudine or nevirapine and elective cesarean section at 38 weeks of pregnancy) and by avoiding breastfeeding.

Therapeutic Goals of ART in Pregnancy

• Reduction of perinatal transmission of infection.
• Treatment of maternal HIV disease.

ART Regimen

Preferred agents include the following:

• NRTI - Zidovudine, lamivudine.
• NNRTI - Nevirapine.
• Protease inhibitor - Lopinavir/ritonavir.

Salient Features

• Therapy should consist of 2 NRTI's with either an NNRTI or PI, guided by resistance testing.
• Regardless of the antenatal ART regimen, zidovudine should be administered to mother and neonate as follows:
  • Mother : IV infusion during labor.
  • Neonate : Orally for 6 weeks following birth.

• ART consisting of lopinavir/ritonavir in combination with zidovudine/lamivudine is preferred in most cases.
• Efavirenz should not be used during first trimester due to its teratogenic effect; while in second and third trimester, it should only be used , if it has clear benefits over other alternatives.
• Nevirapine regimen has shown to cause hepatic failure and death in few patients.
  • Nevirapine-based regimens should be initiated in women with CD4 counts >250 cells/mm³ only if the benefits clearly outweigh the risks because of the drug’s potential for causing hepatic toxicity/hypersensitivity reaction.
  • Women who become pregnant while receiving nevirapine-containing regimens and who are tolerating the regimen well can continue on the therapy regardless of CD4 count.

Important trials

• In a randomized control trial of 530 patients protease inhibitor-based HAART has shown to increased preterm delivery (21.4% vs 11.8%, P = .003 with NRTI therapy); However ART regimen had no effect on infant hospitalizations and mortality.
• In a randomized controlled trial involving patients from seven African countries, ritonavir-boosted lopinavir plus tenofovir–emtricitabine was found superior to nevirapine plus tenofovir–emtricitabine for initial ART in women with prior exposure to peripartum single-dose nevirapine.

Recommendations for the Treatment of HIV-Infected Pregnant Women

Grading of Recommendations and Levels of Evidence

Strength of recommendation	Level of evidence
A. Strong	I. One or more randomized trials with clinical outcomes and/or validated laboratory endpoint
B. Moderate	II. One or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes
C. Optional	III. Expert opinion based on evaluation of other evidence

Although pregnancy is not an adequate reason to defer therapy for HIV infection, unique considerations exist regarding use of antiretroviral drugs during pregnancy, including the potential need to alter dosing because of physiologic changes associated with pregnancy, the potential for adverse short- or long-term effects on the fetus and infant, and the effectiveness in reducing the risk for perinatal transmission.

• Obstetric providers should adhere to best obstetric practices, including offering scheduled cesarean section at 38 weeks to reduce risk for perinatal HIV transmission.

• All pregnant women who require therapy for their own health should receive a combination antepartum antiretroviral (ART) drug regimen containing at least three drugs for treatment, which will also reduce the risk of perinatal transmission.

• Combination antepartum drug regimens are also recommended for prevention of perinatal transmission in women who do not yet require therapy for their own health.

• ART prophylaxis is more effective when given for a longer than a shorter duration. Therefore, ART drugs should be started as soon as possible in women who require treatment for their own health (AI), and without delay after the first trimester in women who do not require immediate initiation of therapy for their own health, although earlier initiation can be considered in these women as well.

• In the absence of antepartum administration of ART drugs, ART drugs should be administered intrapartum in combination with infant ART prophylaxis to reduce the risk of perinatal transmission (AI); if antepartum and intrapartum ART drugs are not received, infant ART prophylaxis should be provided (see Infant Antiretroviral Prophylaxis) (AI).

• Adding single-dose intrapartum/newborn nevirapine to the standard antepartum combination ART regimens used for prophylaxis or treatment in pregnant women in the United States is not recommended. This is because the drug does not appear to provide additional efficacy in reducing transmission and it may be associated with development of nevirapine resistance (AI).

• To eliminate the risk for postnatal transmission, HIV-infected women in the United States should not breast-feed. Support services for use of appropriate breast milk substitutes should be provided when necessary. UNAIDS and World Health Organization recommendations for HIV and breast-feeding should be followed in international settings. Thus breastfeeding is not recommended for HIV-infected women in the United States—including those receiving combination antiretroviral therapy (ART)—because safe, affordable, and feasible alternatives are available (AII).

• To optimize medical management, positive and negative HIV test results should be available to a woman's health-care provider and included on her confidential medical records and those of her infant. After informing the mother, maternal health-care providers should notify the pediatric-care providers of the impending birth of an HIV-exposed infant and any anticipated complications. If HIV is first diagnosed in the infant, health-care providers should discuss the implications for the mother's health and help her obtain care. Women should also be encouraged to have their other children tested for HIV. Children can be infected with HIV for many years before complications occur. Providers are encouraged to build supportive health-care relationships that promote discussion of pertinent health information. Confidential HIV-related information should be disclosed or shared only in accordance with prevailing legal requirements.
• After receiving their test results, HIV-infected pregnant women should receive counseling, including assessment of the potential for negative effects (e.g., discrimination, domestic violence, psychological difficulties). Counseling should also include information on how to minimize these consequences, assistance in identifying supportive persons in their own social networks, and referral to appropriate psychological, social, and legal services. HIV-infected women should be counseled regarding the risk for transmission to others and ways to decrease this risk. They also should be told that discrimination based on HIV status or AIDS in housing, employment, state programs, and public accommodations (including physicians' offices and hospitals) is illegal.

• Health-care providers should follow the Public Health Service Task Force recommendations for using antiretroviral drugs to treat pregnant HIV-1 infected women and reduce perinatal HIV-1 transmission in the United States, which address treating pregnant women who do not receive health care until near the time of delivery.

Antepartum Care

Monitoring of the Woman and Fetus during Pregnancy

• CD4 cell count should be monitored at the initial antenatal visit (AI) and at least every 3 months during pregnancy (BIII). Monitoring of CD4 count may be performed every 6 months in patients on antiretroviral treatment (ART) for more than 2–3 years who are adherent to therapy, clinically stable, and have sustained viral suppression (BIII).
• Plasma HIV RNA levels should be monitored at the initial visit (AI); 2–4 weeks after initiating (or changing) antiretroviral (ARV) drug regimens (BI); monthly until RNA levels are undetectable (BIII); and then at least every 3 months during pregnancy (BIII). HIV RNA levels also should be assessed at approximately 34–36 weeks’ gestation to inform decisions about mode of delivery.
• Genotypic ARV drug resistance testing should be performed at baseline in all HIV-infected pregnant women with HIV RNA levels >500–1,000 copies/mL, whether they are ARV-naive or currently on therapy (AIII). Repeat testing is indicated following initiation of an ARV regimen in women who have suboptimal viral suppression or who have persistant viral rebound to detectable levels after prior viral suppression on an ARV regimen (AII).
• Monitoring for complications of ARV drugs during pregnancy should be based on what is known about the adverse effects of the drugs a woman is receiving (AIII).
• First trimester ultrasound is recommended to confirm gestational age and, if scheduled cesarean delivery is necessary, to guide timing of the procedure.
• Given the limited data on the effect of combination ARV drugs on the fetus, most experts would recommend second trimester ultrasound to assess fetal anatomy for women who have received combination ARV regimens during the first trimester, particularly if the regimen included efavirenz (BIII).
• In women on effective combination ARV regimens, no perinatal transmissions have been reported after amniocentesis, but a small risk of transmission cannot be ruled out. If amniocentesis is indicated in HIV-infected women, it should be done only after initiation of an effective combination ARV drug regimen and, if possible, when HIV RNA levels are undetectable (BIII). In women with detectable HIV RNA levels in whom amniocentesis is deemed necessary, consultation with an expert should be considered.

Intrapartum Care

Intrapartum Antiretroviral Therapy/Prophylaxis

• Intrapartum intravenous zidovudine is recommended for all HIV-infected pregnant women, regardless of their antepartum regimen, to reduce perinatal transmission of HIV (AI).
• For women who are receiving a stavudine-containing antepartum regimen, stavudine should be discontinued during labor while intravenous zidovudine is being administered (AI).
• Women who are receiving an antepartum combination antiretroviral (ARV) drug regimen should continue this regimen on schedule as much as possible during labor and before scheduled cesarean delivery (AIII).
• Women receiving fixed-dose combination regimens that include zidovudine should receive intravenous zidovudine during labor while other oral ARV components are continued (AIII).
• For women who have received antepartum ARV drugs but have suboptimal viral suppression near delivery (i.e., HIV RNA >1,000 copies/mL), scheduled cesarean delivery is recommended (AI). The addition of single-dose intrapartum/newborn nevirapine is not recommended (AI).
• Women of unknown HIV status who present in labor should undergo rapid HIV antibody testing (AII). If the results are positive, a confirmatory HIV test should be done as soon as possible and maternal/infant ARV drugs should be initiated pending results of the confirmatory test (AII). If the confirmatory HIV test is positive, infant ARV drugs should be continued for 6 weeks (AI); if the test is negative, the infant ARV drugs should be stopped.
• Intravenous zidovudine is recommended for HIV-infected women in labor who have not received antepartum ARV drugs and infant combination ARV prophylaxis is recommended for 6 weeks (AII).

Transmission and Mode of Delivery

• Scheduled cesarean delivery at 38 weeks’ gestation is recommended for women with HIV RNA levels >1,000 copies/mL near the time of delivery, irrespective of administration of antepartum antiretroviral (ARV) drugs, and for women with unknown HIV RNA levels near the time of delivery (AII).
• Scheduled cesarean delivery is not routinely recommended for prevention of perinatal transmission in pregnant women receiving combination ARV drugs with plasma HIV RNA levels <1,000 copies/mL near the time of delivery. Data are insufficient to evaluate the potential benefit of cesarean delivery in this group, and given the low rate of transmission in these patients, it is unclear whether scheduled cesarean delivery would confer additional benefit in reducing transmission. This decision should be individualized based on discussion between the obstetrician and the mother (BII).
• It is not clear whether cesarean delivery after rupture of membranes or onset of labor provides benefit in preventing perinatal transmission. Management of women originally scheduled for cesarean delivery who present with ruptured membranes or in labor must be individualized based on duration of rupture, progress of labor, plasma HIV RNA level, current ARV regimen, and other clinical factors (BII).
• Women should be informed of the risks associated with cesarean delivery; the risks to the woman should be balanced with potential benefits expected for the neonate (AIII).

Other Intrapartum Management Considerations

• Generally avoid artificial rupture of membranes unless there are clear obstetric indications because of a potential increased risk of transmission (BIII).
• Routine use of fetal scalp electrodes for fetal monitoring should be avoided in the setting of maternal HIV infection unless there are clear obstetric indications (BIII).
• Operative delivery with forceps or a vacuum extractor and/or episiotomy should be performed only if there are clear obstetric indications (BIII).
• The antiretroviral drug (ARV) regimen a woman is receiving should be taken into consideration when treating excessive postpartum bleeding resulting from uterine atony:
  • In women who are receiving a cytochrome P (CYP) 3A4 enzyme inhibitor such as a protease inhibitor (PI), methergine should only be used if no alternative treatments for postpartum hemorrhage are available and the need for pharmacologic treatment outweighs the risks. If methergine is used, it should be administered in the lowest effective dose for the shortest possible duration (BIII).
  • In women who are receiving a CYP3A4 enzyme inducer such as nevirapine or efavirenz, additional uterotonic agents may be needed because of the potential for decreased methergine levels and inadequate treatment effect (BIII).

Postpartum Care

Recommendations for Postpartum Follow-up of HIV infected Women and Perinatally Exposed Children

• HIV-infected women should receive ongoing HIV-related medical care, including immune-function monitoring, recommended therapy, and prophylaxis for and treatment of opportunistic infections and other HIV-related conditions. HIV-infected women should receive gynecologic care, including regular Pap smears, reproductive counseling, information on how to prevent sexual and drug-related transmission of HIV, and treatment of gynecologic conditions according to published recommendations. Obstetrical providers should ensure that HIV-infected women are introduced or referred to another provider to continue their care after pregnancy.
• HIV-infected women (or their children's guardians) should be informed of the importance of follow-up for their children. Children whose HIV infection status is unknown require early diagnostic testing and prophylactic therapy to prevent PCP pending determination of their status.
  • Infected children require follow-up care to determine the need for prophylactic therapy and antiretroviral treatment and to monitor disorders in growth and development that often occur before age 24 months.
  • Uninfected children who are exposed to antiretroviral therapy should be assessed for potential short- and long-term side effects.
• Identification of an HIV-infected mother indicates that her family needs or will need medical and social services as her disease progresses. Thus, health-care providers should ensure that referrals to services address the needs of the entire family.

Infants Born to Mothers with Unknown HIV Infection

• For infants born to mothers with unknown HIV status, rapid HIV antibody testing of the mother and/or infant is recommended as soon as possible after birth, with immediate initiation of infant antiretroviral (ARV) prophylaxis if the rapid test is positive (AII). In the setting of a positive test, standard antibody confirmatory testing such as a Western blot also should be performed on mothers (or their infants) as soon as possible. If the confirmatory test is negative, ARV prophylaxis can be discontinued (AIII).
• If the HIV antibody confirmatory test is positive, a newborn HIV DNA polymerase chain reaction (PCR) should be obtained (AIII).
• If the newborn HIV DNA PCR is positive, ARV prophylaxis should be discontinued and the infant promptly referred to a pediatric HIV specialist for confirmation of the diagnosis and treatment of HIV infection with standard combination antiretroviral therapy (ART) (AI).

Postpartum Management

• A complete blood count (CBC) and differential should be performed on newborns as a baseline evaluation (BIII).
• Decisions about the timing of subsequent monitoring of hematologic parameters in infants depend on baseline hematologic values, gestational age at birth, clinical condition of the infants, the zidovudine dose being administered, receipt of concomitant medications, and maternal antepartum therapy (CIII).
• Some experts recommend more intensive monitoring of hematologic and serum chemistry and liver function assays at birth and when diagnostic HIV polymerase chain reaction (PCR) tests are obtained in infants exposed to combination antiretroviral (ARV) drug regimens in utero or during the neonatal period (CIII).
• If hematologic abnormalities are identified in infants receiving prophylaxis, decisions on whether to continue infant ARV prophylaxis need to be individualized. Consultation with an expert in pediatric HIV infection is advised if discontinuation of prophylaxis is considered (CIII).
• Routine measurement of serum lactate is not recommended. However, measurement can be considered if an infant develops severe clinical symptoms of unknown etiology (particularly neurologic symptoms) (CIII).
• Virologic tests are required to diagnose HIV infection in infants <18 months of age and should be performed within the first 14–21 days of life, at 1–2 months, and at 4–6 months of age (AII).
• To prevent Pneumocystis jirovecii pneumonia (PCP), all infants born to women with HIV infection should begin PCP prophylaxis at age 4–6 weeks, after completing their ARV prophylaxis regimen, unless there is adequate test information to presumptively exclude HIV infection.

Long-Term Follow-Up of Antiretroviral Drug-Exposed Infants

• Children with in utero/neonatal exposure to antiretroviral (ARV) drugs who develop significant organ system abnormalities of unknown etiology, particularly of the nervous system or heart, should be evaluated for potential mitochondrial dysfunction (CIII).
• Follow-up of children with exposure to ARVs should continue into adulthood because of the theoretical concerns regarding the potential for carcinogenicity of nucleoside analogue ARV drugs (CIII).