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This chapter should be cited as follows:
Brillo E, Buonomo E, et al, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.416623

The Continuous Textbook of Women’s Medicine SeriesObstetrics Module

Volume 6

Pregnancy complaints and complications: clinical presentations

Volume Editor: Professor Gian Carlo Di Renzo, University of Perugia, Italy

Chapter

Human Immunodeficiency Virus (HIV) in Pregnancy

First published: August 2021

AUTHORS

Eleonora Brillo, BMid, MSN, PhD stud
Center for Research in Perinatal and Reproductive Medicine, University of Perugia, Perugia; Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy
Ersilia Buonomo, MD, PhD
Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy
Valentina Tosto, MD
Center for Research in Perinatal and Reproductive Medicine, University of Perugia, Perugia, Italy

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INTRODUCTION

The human immunodeficiency virus (HIV) is a virus that uses ribonucleic acid (RNA) as its genetic material. It contains two copies of a single-stranded RNA genome and is the cause of the acquired immunodeficiency syndrome (AIDS), the last stage of HIV disease.1 HIV belongs to the family of retroviruses and two serotypes of HIV can be distinguished in HIV-1 and HIV-2. In HIV there are three major classes: M (main), N (new), and O (outlier). The M class is the most widespread and has nine subtypes (“clades”) and many recombinant forms. HIV-1 is the most common and virulent, and originated in Central Africa, whereas HIV-2 is less virulent and transmissible and is common in West Africa.1

The HIV virus targets the immune system weakening the human defense against infections as the virus destroys and impairs the immune system leading to immunodeficiency.2 It usually takes about 1–4 weeks from the time of exposure to the primary seroconversion illness. In addition, it takes 1–3 months from the time of infection to the development of anti-HIV antibodies and it is common to get a false negative result in early infection.

Certain people have a rapid onset of disease and progression to AIDS, for example within 3–5 years, and a smaller group does not seem to progress to AIDS.3

HIV continues to be a public health problem globally with high mortality and morbidity rates. There were approximately 38 million people living with HIV at the end of 2019, as a result, there is a need for interventions to contain the spread of the virus. In the same year, 68% of adults and 53% of children living with HIV were receiving antiretroviral therapy.4

HIV-infected pregnant women are at risk of transmitting HIV infection to their children during pregnancy, labor, and the postpartum period because HIV can cross the placenta, is present in the blood, cervical secretions, and breast milk.5

Since the first case of pediatric acquired immunodeficiency syndrome (AIDS) was described in 19826 until the development of effective preventive strategies, the rate of HIV perinatal transmission was 15–25% among formula-fed infants and 25–40% among breastfed infants.7

In the early 1990s, a therapy to reduce intrauterine and intrapartum mother-to-child transmission of HIV-1 up to 70% among not breastfed infants was finally discovered. Therapy consisted of the maternal administration of zidovudine monotherapy during pregnancy (orally) and labor (intravenously), as well as zidovudine administration (orally) to the newborn.8 As a result, international guidelines initially recommended that mothers use a single drug.9,10

The risk of transmission was reduced still further through a maternal therapy combined with two or three antiretrovirals.11 Consequently, immediate initiation of life-long highly active antiretroviral therapy has been recommended internationally for HIV-infected pregnant or breastfeeding women regardless of their CD4 T lymphocyte (CD4) cell counts with a consequent significant reduction in the risk of vertical HIV transmission.12

In recent years, thousands of cases of perinatal HIV infection have been avoided thanks to the adoption of routine prenatal screening for HIV and the use of effective therapies.13

The early diagnosis, the routine use of combination antiretroviral treatment, and other interventions during the periods of pre-pregnancy planning, pregnancy, labor, delivery and postpartum (e.g., avoidance of breastfeeding and elective cesarean delivery in women with viremia substantially) remarkably reduce the risk of vertical HIV transmission to below 5–1%.5,14

TRANSMISSION

HIV is mainly transmitted through sexual fluids such as vaginal fluids or semen, blood, or through breast milk. HIV can be termed as a sexually transmitted infection (STI) that can be associated with other bacterial and viral STI that cause genital ulcers or mucosal inflammation. STI are a marker of risky sexual behaviors. Of the transmitted founder virus, 80% can be detected at the time of infection and only a maximum of two or three viral variants are transmitted. Factors that affect the risk of transmission include the type of sexual encounter, viral load of the HIV-positive partner, and the use or the type of protective equipment used such as barrier method or pre-exposure prophylaxis (PrEP).15 The risk of receiving blood transfusion containing HIV depends on the prevalence of HIV viremia in the donor population, the likelihood of donation during the pre-antibody phase of viremia, the sensitivity of the screening test to detect HIV antibodies if in fact present, and the number of units of blood received.16

Maternal transmission is during pregnancy, childbirth, or postnatal.

Transmission to pregnant and nonpregnant women

Most of the women, regardless of pregnancy status, acquire HIV via heterosexual intercourse, followed by injection drug use as the second most common infection route.17

Women are more susceptible to HIV infection during pregnancy as well as periconception and early postpartum periods up to 6 months.18,19

In high HIV burden settings, women continue to acquire HIV during pregnancy and breastfeeding resulting in a high risk of HIV transmission to the fetus.20 About 50% of HIV-infected pregnant women were exposed to HIV through heterosexual contact, 8% through injection drug use, 8% through other ways (such as blood transfusion), while in all of the remaining women (about one-third of women) the route of HIV exposure was unknown.21

Transmission to fetus, newborn or infant

Intrauterine transmission is thought to be responsible for 25–40% of the vertically infected infants.21 This kind of transmission is thought to occur just before childbirth shortly before delivery.22 However, the risk of vertical HIV transmission in the absence of treatment is lower in the antepartum period than during intrapartum period and breastfeeding.23

Postpartum transmission by mothers to newborns and infants probably takes place only during breastfeeding24 through the breast milk in which the virus is secreted.25

Risk factors for vertical HIV transmission are:

  • Higher viral load;
  • Advanced disease in the mother (immunologically or clinically);
  • Other STI in the mother;
  • Prolonged rupture of membranes and other labor and delivery events and procedures at high probability of fetus/newborn contact with maternal bodily fluid (e.g., ≥second-degree perineal laceration, episiotomy, and others).26

SIGNS AND SYMPTOMS

Patients with HIV infection experience at least more than one symptom of the acute retroviral syndrome. However, in the first few weeks after initial infection, subjects may experience no symptoms or an influenza-like illness. Fever and flu are common in acute HIV infections, although nonspecific rash, mucocutaneous ulcers, oropharyngeal candidiasis, and meningism are more specific and raise the index of suspicion.27 Consequently, the presence of fever can be an indication of a possible undiagnosed opportunistic infection. The primary HIV infection symptoms also include joint pain, skin rash, sore throat, and swollen lymph nodes.

Nevertheless, the symptoms of HIV vary depending on the stage of HIV disease because the infection progressively weakens the immune system: beginning with stage 1 that is asymptomatic and can end with stage 4.28

As a result, an HIV-infected subject can develop other signs and symptoms. Chronic HIV infection signs and symptoms that can last for over a decade include fever, fatigue, diarrhea, weight loss, oral thrush, shingles, and persistent generalized lymphadenopathy.1 Without treatment, HIV-infected patients could also develop severe illnesses such as severe bacterial infections, tuberculosis, cryptococcal meningitis, and cancers such as Kaposi's sarcoma and lymphomas.

Clinicians should give consideration to any history of opportunistic infections, sexually transmitted infections, substance abuse, and vaccination status.29 The physical examination aims at picking signs such as thrush that is an indicator of an advanced HIV infection, or signs of other sexually transmitted infections that could be present along with HIV.

PREGNANCY-ASSOCIATED COMPLICATIONS

In the United States, around 5000 HIV women give birth every year.30 It is important to identify the health issues of the mother which can directly or indirectly affect the fetus. Vertical HIV transmission increases the risks of adverse pregnancy outcomes in addition to reducing the quality of birth of infants. Studies indicate that maternal HIV infections can increase the risk for stillbirth, neonatal death, low birth weight, preterm birth, as well as small gestational age. However, progression stages of HIV, antiretroviral therapy, CD4 cell counts, viral load, and injection drug use determine the impact of maternal HIV infection on the fetus.30

Sometimes the adverse pregnancy outcomes may be placentally insufficient due to HIV infections causing vascular damage or endothelial injury triggered by antiretroviral, as a result, it leads to in-utero fetal hypoxia and nutrition deficiency. The destruction of CD4 cells makes HIV-positive women become immunocompromised which makes them susceptible to urogenital tract infections that can lead to pregnancy complications.

PREVENTION AND TREATMENT

HIV is seen as the most dreaded pathogen due to the inability to find a cure. However, with antiretroviral therapy, it is now possible to control HIV.

HIV infection causes the depletion of CD4 cells in the peripheral blood that have a significant role in the activation of the cell-mediated and humoral immune system. The depletion continues over several years until the patients succumb to AIDS which is the last stage of HIV infection. HIV has a complex pathogenesis and it is a host-specific infection that complicates treatment. As a result, HIV infection is managed through different combinations of available drugs collectively known as antiretroviral therapy.31 The goal is to prevent HIV from multiplying and the six classes of drugs used depend on the phase of the HIV life cycle the drugs inhibit. The management of HIV infections should include a collaborative team for effective verification of the chosen regimen, checking for drug interactions, dosing, and assuming patient counseling.1

Interventions to curb the epidemic include education, care, and support for the general population as well as building targeted interventions for the population at high-risk of HIV transmission.32 More tools are available for HIV prevention in addition to various strategies such as practising abstinence which is a 100% effective way of HIV prevention, using condoms correctly during sex and taking PrEP for people at high-risk of HIV acquisition. It is also important that people are tested and treated for other sexually transmitted diseases as this can lower the chances of getting HIV. People with HIV should aim to reduce the viral load in their blood especially by taking antiretroviral therapy to prevent transmission to others. Other preventive measures include protective measures for those who inject drugs.33

Prevention and treatment in couples who are trying to conceive

Couples with differing HIV statuses should routinely receive sexual health counseling and care with the prescription of an antiretroviral therapy to achieve serum HIV RNA viral load beneath the laboratory level of detection before trying to conceive because this is critical to preventing HIV transmission to sexual partners and their babies.34

Healthcare providers should warn HIV-infected individuals: (1) to protect their sexual partners through additional forms of prevention for at least the first 6 months from the beginning of antiretroviral treatment and until an HIV RNA level of <200 copies/ml is achieved; (2) to maintain HIV RNA levels <200 copies/ml with antiretroviral therapy as to prevent HIV transmission to sexual partners.34

A HIV-negative partner who is planning a pregnancy with a HIV-infected partner, should receive oral PrEP, if indicated.20,35,36 Oral combination tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) has been approved as PrEP by the US Food and Drug Administration (FDA). The PrEP should be started 1 month to 20 days before condom-less sex exposure and continued for another month after such exposures to minimize risks of seroconversion.36 If a HIV-infected partner has an undetectable HIV-RNA level, PrEP may be optional because of no risk of sexual HIV transmission in these conditions.35 The HIV uninfected partner using PrEP should be counseled regarding signs and symptoms of acute retroviral syndrome as well as advised about the importance of daily adherence to PrEP and routinely receive PrEP follow-up that should also include: (1) HIV diagnostic testing (with an antigen/antibody combination immunoassay), that should be conducted at baseline and then every 3 months; and (2) renal function and HBV testing, that should be conducted at the baseline and then the renal function testing repeated every 6 months in nonpregnant women.19 Women who assume PrEP should be counseled regarding benefits and potential risks of PrEP to mother and fetus/infant during periconception, pregnancy, postpartum/breastfeeding periods benefits.

In HIV-infected women who have never used adequate therapy, an early use of antiretroviral therapy increases the uptake of antiretroviral therapy, decreases the time required to achieve linkage to care and virologic suppression for individual patients, and reduces the risk of HIV transmission.34 The choice of antiretroviral therapy regimen must be carefully considered by the clinician taking into account drug resistance profile, pharmacokinetic and safety data in pregnancy, tolerability and potential adherence, presence of comorbidities.

HIV-infected women who decide to get pregnant should receive counseling before conception in order to discuss the importance of compliance with antiretroviral therapy to achieve sustained viral suppression before conception and throughout pregnancy.

Healthcare providers should discuss the benefits (reducing maternal disease progression and risk of vertical HIV transmission) and risks of adverse maternal and neonatal outcomes with the use of antiretroviral therapy. For example, they should warn of the risk of neural tube defects (NTDs) in infants born to women who received dolutegravir (DTG) around the time of conception with the person of childbearing potential, to allow the person to make informed decisions about care19,37 (see Box 1 for consideration on DTG). There is no evidence that folate supplementation prevents DTG-associated NTDs, but as all the other women, even for women who take DTG and who might conceive, at least 400 μg of folic acid daily is recommended.

Prevention and treatment in pregnant women

Pregnant women continue to become infected during pregnancy and this must be absolutely avoided through the established HIV prevention strategies: risk assessment; counseling to reduce risk; sexually transmitted infections screening and treatment; early HIV testing for mother and their partner (sexual partner and drug injection partner); condom promotion if partner with suspected HIV infection or HIV exposure or confirmed HIV-positivity; provision of antiretroviral therapy to partners if HIV-positive; repeat HIV testing at substantial risk of HIV infection. To these strategies could be added oral PrEP in HIV-negative women at continuing substantial risk of HIV infection and transmission to fetuses/newborns (and antiretroviral drugs administration as postexposure prophylaxis for newborns). WHO recommend PrEP even during the first trimester because the existing safety data support the use of PrEP in pregnancy in women at high risk of infection for themselves and their babies because the benefits of preventing HIV infection outweigh any potential risks of PrEP. As a result, PrEP can be started or continued during pregnancy as part of combination prevention approaches.20 In pregnant women assuming PrEP, a PrEP follow-up should be performed and also include: (1) HIV testing, that should be performed at the first visit in pregnancy and repeated in the second and third trimester or more frequent when clinically indicated; (2) renal function and HBV testing, that should be conducted at the baseline and then the renal function testing should be repeated every 3 months in pregnant women. Healthcare providers should educate individuals about the importance of daily adherence to PrEP,  the symptoms associated with acute HIV infection, and the ineffectiveness of the PrEP against other STI.19

HIV-infected women who are taking antiretroviral therapy should continue it during pregnancy, provided that it is effective, well tolerated, safe. A change in therapy is indicated when antiretroviral therapy is not recommended for use in pregnancy because of toxicity. In this case, women should stop taking their antiretroviral therapy and switch to other antiretroviral drugs recommended for use in pregnancy and based on the results of resistance testing (see Table 1 for antiretroviral therapy).

Discontinuing or altering an effective antiretroviral therapy is not recommended if safe in pregnancy because this could cause: (1) an increase in viral load; (2) a disease progression; (3) a worsening of the immune state; (4) an increased risk of perinatal HIV transmission.47

Women who acquire HIV during pregnancy (acute infection) or near conception (recent infection) have a greater risk of transmitting HIV to their infant than women who became infected with HIV before pregnancy20 and need to initiate therapy promptly, regardless of CD4 and HIV RNA level (see Table 1 for antiretroviral therapy).

Generally, a new antiretroviral therapy needs 8–12 weeks to achieve viral suppression if women are adherent to therapy and have no resistance mutations to the antiviral therapy (more time is required when viral load is high or CD4 count is low, less time is required when integrase strand transfer inhibitors are used).

Box 1 Indications for antiretroviral therapy.

Choosing antiretroviral therapy, what to take in consideration:

  • comorbidities/HIV-related illnesses
  • prior and current antiretroviral therapy use (if applicable)
  • prior and current antiretroviral drug-resistance test results
  • prior and current toxicities/adverse effects caused by previous antiretroviral therapies
  • prior and current adherence to antiretroviral therapies
  • antiretroviral drug-resistance appears to be more common in women acquired HIV-infection perinatally than in another period38
  • antiretroviral therapy should be identified with the aim of maximally suppressing viral replication, which is the most effective strategy for minimizing risk of vertical HIV transmission and preventing development of antiretroviral drug-resistance
  • antiretroviral therapy is recommended during pregnancy considering pharmacokinetics, adverse effects, advantages, safety for pregnant women and fetuses, drug interactions of the individual antiretroviral drugs and drug combinations in the antiviral therapy19
  • preferred, alternative, insufficient data in pregnancy to recommend, not recommended drugs or drug combinations19
  • drugs not recommended because of toxicity: stavudine, didanosine, treatment dose ritonavir
  • drugs not recommended for initial use because of concerns about viral breakthrough during pregnancy
  • restrictions on the use of DTG (indicated beyond the first trimester for the risk of NTDs39,40) have been removed by the Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission and DTG has become a preferred antiretroviral drug throughout pregnancy, irrespective of trimester, and for women who are trying to conceive*
  • pregnant women have relatively similar DTG levels than nonpregnant women41,42
  • women during postpartum have higher DTG levels than during pregnancy41,42 and that DTG passes into breastmilk leading to higher plasma concentrations in infants43

Starting, changing or restarting antiretroviral therapy in pregnancy, what is request:

  • baseline antiretroviral drug-resistance genotype evaluations or assays should be performed before starting/changing antiretroviral therapy44,45 when HIV RNA levels are at least 500–1000 copies/mL (i.e., values assumed as minimal threshold for antiretroviral drug resistance testing, although it can be successful even when HIV RNA <1000 copies/mL, identifying emerging antiretroviral drug resistance at an early stage), but in women who are not already receiving antiretroviral therapy, it should be initiated before results of antiretroviral drug-resistance testing are available (the initial antiretroviral therapy can later be modified, if necessary, based on resistance assay results)
  • plasma HIV RNA levels, that should be monitored at:
    • the initial antenatal visit
    • 2–4 weeks after initiating/changing antiretroviral therapy
    • every month until undetectable HIV RNA levels, (IV) at least every 3 months during pregnancy
    • 34–36 weeks' gestation to inform decisions about mode of delivery19,46 (more frequent monitoring, i.e., every 1–2 months, with risk for loss of viral suppression, e.g., poor adherence)
  • hepatitis panel to assess for any hepatic disease should be performed before starting antiretroviral therapy44
  • renal and liver function testing, that should be checked weekly near the beginning of the antiretroviral therapy and every 3 months if the initial analysis results are stable
  • standard glucose screening at 24–28 weeks’ gestation
  • other laboratory tests to assess HIV disease status

DTG, dolutegravir; NTDs, neural tube defects.

*This decision was based on the recent data that show a very small increase in risk of neural tube defects associated with the use of dolutegravir compared to several advantages (i.e., once-daily dosing, generally well tolerated, producing rapid and durable viral load suppression).

In all HIV-infected pregnant women in antiretroviral therapy, the standard antenatal assessment is recommended in conjunction with a specific assessment of HIV disease status and HIV-related medical care in pregnancy:

  • Prior and current laboratory tests:
    • CD4 cell counts, that should be monitored:
      • at the initial antenatal visit,
      • every 3 months if the duration of antiviral therapy <2 years and/or CD4 counts <300 cells/mm3 and/or detectable viral loads and/or poor adherence (in all other cases, no other monitoring during pregnancy is recommended),19
      • at delivery;45,46
    • Plasma HIV RNA levels, that should be monitored:
      • at the initial antenatal visit,
      • 2–4 weeks after initiating/changing antiretroviral therapy,
      • every month until undetectable HIV RNA levels,
      • at least every 3 months during pregnancy,
      • at 34–36 weeks' gestation to inform decisions about mode of delivery19,46 (more frequent monitoring, i.e., every 1–2 months, with risk for loss of viral suppression, e.g., poor adherence);
    • Complete blood cell count, that should be monitored monthly;45,46 
    • Standard glucose screening at 24–28 weeks’ gestation;
    • Renal and liver function testing, that should be checked weekly near the beginning of the antiretroviral therapy and every 3 months if the initial analysis results are stable;
  • Review of prior and current:
    • Antiretroviral therapy use,
    • Antiretroviral drug-resistance tests,
    • Adherence to antiretroviral therapies,
    • Toxicities/adverse effects caused by previous antiretroviral therapies,
    • HIV-related illnesses;
  • Screening for:
    • Viral hepatitis,
    • Sexual health and STI,
    • Opportunistic infections,
    • Depression and anxiety,
    • Intimate partner violence,
    • HIV status of sexual partner;
  • Assessment of the need for:
    • Treatment/prophylaxis for diseases and other infections,
    • Supportive care,
    • Other interventions.

All women should be counseled regarding the importance of daily adherence to antiretroviral therapy to minimize the development of antiretroviral drug-resistance and maximize effectiveness of viral suppression: women with poor adherence during pregnancy are more likely to have detectable viral loads at delivery and antiretroviral drugs resistance.

Prevention and treatment during labor and delivery

During labor or before scheduled cesarean delivery, HIV-infected women should continue their prescribed antiretroviral therapy on schedule.19

Any pregnant women who present to care in labor or delivery and who have unknown or undocumented HIV status urgently require rapid HIV testing (an initial positive antigen/antibody combination immunoassay) at the time of admission or as soon as possible.48 In case of positive result, (1) additional confirmatory testing should be performed with an HIV-1/2 differentiation assay and an HIV RNA level, and (2) women should be assumed to have HIV infection, therefore they should immediately receive intrapartum antiretroviral prophylaxis and newborns should receive an antiretroviral regimen appropriate for infants at higher risk of perinatal HIV transmission as early as possible, pending results of supplemental HIV testing. Starting antiretroviral treatment during labor and delivery, or even providing it to the newborn within a few hours after birth can reduce mother-to-child transmission by half.49

Women with a plasma viral load of <50 HIV RNA copies/mL at 34–36 weeks’ gestation (or 4–6 weeks before delivery) and in the absence of obstetric contraindications, can have a normal vaginal delivery. In these circumstances, premature rupture of membranes is not an indication for cesarean delivery (Table 1).19

In women with a plasma viral load of ≥50 and ≤1000 HIV RNA copies/mL at 34–36 weeks’ gestation (or 4–6 weeks before delivery), cesarean delivery is not recommended because this viral load level is associated with a low rate of vertical HIV transmission (Table 1).19

The guidelines of the British HIV Association (BHIVA) indicate that in case of viral load of ≥50 and ≤399 HIV RNA copies/mL at 34–36 weeks’ gestation, a scheduled cesarean delivery (i.e., pre-labor cesarean) should be considered, “taking into account the actual viral load, the trajectory of the viral load, length of time on treatment, adherence issues, obstetric factors and the woman’s views.”.45

In case of lack of virologic suppression, a regimen change is generally indicated, but when this lack is detected late in pregnancy (i.e., near the date of birth through plasma HIV RNA >1000 copies/mL19 or ≥400 HIV RNA copies/mL44 from 34 to 36 weeks’ gestation or 4–6 weeks before delivery) women need to deliver through a cesarean section at 38 weeks’ gestation to reduce the risk of perinatal transmission of HIV avoiding the potential risk of spontaneous labor and rupture of membranes. Elective cesarean section should be planned after woman's counseling on indications for it.50,51,52 In these pregnant women undergoing elective cesarean delivery, zidovudine should be administered intravenously and initiated 3 hours before the surgery using a 1-hour loading dose of zidovudine at 2 mg/kg dose for 1-hour followed by a continuous infusion of 1 mg/kg for at least 2 hours.19 The use of intrapartum intravenous zidovudine is also recommended in women with documented zidovudine resistance. Elective cesarean delivery and intrapartum antiretroviral medication substantially reduce vertical HIV transmission risk.53 If a woman originally scheduled for cesarean delivery (because of HIV RNA >1000 copies/mL), arrives at the maternity unit in labor or following rupture of membranes, an individualized plan should be developed because evidence does not clearly demonstrate the effectiveness of cesarean delivery in reducing the risk of vertical HIV transmission in these circumstances (Table 1).19

An intrapartum intravenous zidovudine prophylaxis is also indicated in women with (1) antiretroviral therapy adherence concerns, (2) not having received antiretroviral therapy, (3) HIV diagnosis in labor.19 However, evidence is insufficient to determine whether cesarean delivery reduces the risk of vertical HIV transmission for these women.19 Therefore, the decision about the mode of delivery must be individualized: the involvement of the woman herself and an expert in perinatal HIV is essential in these circumstances (Table 1).

1

Intrapartum management for HIV-infected pregnant women in resource-rich settings.19


Women (1) having received antepartum ART, (2) having an undetectable VL (HIV RNA <50 copies/mL) at ≥34–36 weeks’ gestation (or 4–6 weeks before delivery), (3) being adherent to their antiretroviral therapy

Women having received antepartum ART and having a detectable VL (HIV RNA ≥50 and ≤1000 copies/mL) at ≥34–36 weeks’ gestation (or 4–6 weeks before delivery)

Women having a higher level of detectable VL (HIV RNA >1000 copies/mL) at ≥34–36 weeks’ gestation (or 4–6 weeks before delivery)

Women not having received antepartum ART or Women non-adherent to ART or Women with HIV diagnosis in labor

Level of transmission risk

Lowest risk

Low–moderate risk


High risk

High/unknown risk

Intrapartum antiretrovirals

Continue usual ART

Intrapartum intravenous zidovudine is not recommended

Continue usual ART and take into account intrapartum intravenous zidovudine.* Clinicians may reasonably add intrapartum zidovudine, especially in case of concerns about adherence to ART during pregnancy

Continue usual ART and administer intrapartum intravenous zidovudine*

Administer intrapartum intravenous zidovudine*

Delivery mode

Choose between cesarean delivery or vaginal delivery depending on obstetric indications

Vaginal delivery (cesarean delivery is not recommended)

Schedule cesarean delivery at 38 weeks’ gestation

Mode of delivery personalized. In these cases, the role of cesarean delivery in decreasing vertical HIV transmission is unclear


ART, antiretroviral therapy; VL, viral load.

*Intrapartum intravenous zidovudine: a 1-hour loading dose of zidovudine at 2 mg/kg dose for 1-hour followed by a continuous infusion of 1 mg/kg for at least 2 hours.

Operative delivery with forceps or a vacuum extractor and fetal scalp monitoring should be avoided in HIV-infected women or women are presumed HIV. Even artificial rupture of membranes is not recommended particularly when maternal viral load is not suppressed (≥50 copies/mL) or is unknown.19

In HIV-infected women with postpartum bleeding caused by uterine atony, an assessment of the appropriateness of methergine use must be undertaken because of the risk of drug interactions with some antiretroviral drugs.

Prevention and treatment during postpartum

Women are more susceptible to HIV infection during early postpartum period19 and in turn, acute or recent HIV infection during breastfeeding is associated with an increased risk of perinatal HIV transmission.

Postpartum women who have not previously had HIV screening require rapid HIV testing as soon as possible. If the rapid test is positive, supplemental HIV testing should be performed and women pending results of supplemental HIV testing must be advised to cease breastfeeding immediately until HIV infection is confirmed or excluded unless they live in resource-limited settings.54 Women should be counseled against breastfeeding and about the possibility to express breast milk while HIV diagnostic testing is completed. In addition, women must immediately initiate antiretroviral prophylaxis and newborns must receive an antiretroviral regimen for infants at higher risk of HIV transmission as early as possible (ideally ≤6 hours after birth), pending results of supplemental HIV testing. If supplemental test results are negative (acute HIV infection is excluded) and there is no ongoing risk, breastfeeding can be resumed (if they live in resource-rich settings) and infant antiretroviral therapy discontinued. If supplemental test results are positive, women should not resume breastfeeding and should continue the antiretroviral therapy which can be adapted (see Box 1 for antiretroviral therapy).

Women who are already taking antepartum antiretroviral therapy, should generally continue with the same antiretroviral therapy regimen during postpartum. However, antiretroviral therapy initiated during pregnancy can be modified after delivery especially because some simplified regimens (that could not be used during pregnancy due to safety, and/or insufficient pharmacokinetic data) may be used in postpartum with positive impact on long-term adherence.19 In any case, the choice must be carefully documented, shared with the woman and evaluated by her HIV care provider. If a woman decides to stop antiretroviral therapy, a further resistance test is recommended to ensure that mutations are not missed with reversion during the off-treatment period.45

Breastfeeding in HIV-infected women requires further consideration, in fact, the risk of vertical HIV transmission related to breastfeeding is not completely eliminated through antiretroviral therapy or prophylaxis of the mother and infant55 and it is cumulative: the additional risk of transmission through breastfeeding increases with the amount of breastfeeding duration.56 As a result, in resource-rich settings where formula and clean drinking water are available, HIV-infected women are advised not to breastfeed, since HIV can be transmitted through breastfeeding even in the case of maternal use of antiretroviral therapy and the availability of affordable and safe alternatives.19 In resource-limited settings where there is a limited access to formula and clean drinking water, HIV-infected women can breastfeed, since, in this situation, morbidity and mortality are significantly higher in infants who are fed on formula and lower in infants who are breastfed.57,58 In resource-poor settings in which women breastfeed for prolonged periods, postpartum transmission accounts for about 44% of infant cases.59 Unfortunately, breastfeeding women who acquire HIV in this period (acute HIV infection) have a greater risk of transmitting HIV to their infant than women who became infected with HIV before pregnancy.20

Postnatal depression should be routinely assessed in the short and medium term (e.g., 4–6 weeks and 3–4 months postpartum).45

Refer to the Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection for recommendations and information about the prevention and treatment of HIV infection in infants and children, and the managing adverse events of antiretroviral drugs in children.35 These guidelines are developed for the United States and may not be applicable in other countries. Refer to World Health Organization guidelines for resource-limited settings.37

DIAGNOSIS

HIV is classified as a member of the family Retroviridae and genus Lentivirus. HIV infections are difficult to measure since they can initially be asymptomatic or have non-specific symptoms. As a result, few newly infected patients go for HIV testing and most are diagnosed months or years after infection. Furthermore, there is a 1–3 months window period during which antibody tests cannot detect the HIV infections meaning early infections can be missed especially for people with very recent infections.60 Instead, early diagnosis would be important in order to prevent further transmission of HIV and improve the patient's quality of life beginning antiretroviral therapy in time.

All sexually active or pregnant women or women who are planning to get pregnant and their partners should be screened for HIV as soon as possible for an early diagnosis of HIV in order to begin antiretroviral immediately or as early as possible. HIV testing should be offered during each pregnancy.

In the third trimester HIV testing should be repeated before 37 weeks for pregnant women with negative initial HIV antibody tests (1) who are at increased risk of acquiring HIV or (2) those who reside in states that require third trimester testing or (3) those who reside in settings with elevated HIV incidence or (4) those having signs or symptoms of acute HIV.19

In addition, HIV testing should be repeated at other times during pregnancy when a woman presents with symptoms that are consistent with acute HIV infection, a confirmed sexually transmitted infection diagnosis, or symptoms that are suggestive of a sexually transmitted infection diagnosis.

Any woman with unknown or undocumented HIV status who presents to care in labor should receive expedited HIV testing as soon as possible during labor, delivery or during the immediate postpartum period61,62 (the antigen/antibody combination immunoassay with results available in less than 1 hour is recommended).19

The antigen/antibody combination immunoassay, that is capable of detecting HIV-1 antibodies, HIV-2 antibodies, and HIV-1 p24 antigen, should be the initial testing.19 If the antigen/antibody combination immunoassay is not available, the most sensitive expedited test available should be used as initial testing. Supplemental testing, an HIV-1/HIV-2 antibody differentiation assay, should be performed in case of a reactive antigen/antibody combination immunoassay. A plasma HIV RNA assay should be performed in case of a reactive antigen/antibody combination immunoassay (i.e., initial testing) and a nonreactive differentiation test (i.e., supplemental testing), in order to make a diagnosis of acute HIV infection.19,63

The HIV RNA assay is a virologic test and can detect the presence of HIV as early as 10 days post-infection, the combined antigen/antibody immunoassay within approximately 15 days of acquisition and other assays 29 days. Therefore, in acute infection there may be two possible test combinations: (1) a negative antigen/antibody combination immunoassay and positive HIV RNA assay (prior to HIV seroconversion); (2) a positive antigen/antibody combination immunoassay, negative HIV-1/HIV-2 antibody differentiation assay, and positive HIV RNA assay.

CDC recommends testing all pregnant women for HIV regardless of their reported risk behaviors using an opt-out approach (i.e., HIV screening is conducted after women are notified that testing will be performed unless they explicitly decline to be tested and a separate written consent for HIV testing should not be required considering general consent for medical care as sufficient).64 The opt-out approach is associated with higher testing rates than opt-in approach,65 but it is not allowed in all jurisdictions.

If during pregnancy, labor/delivery, or breastfeeding, an acute HIV infection is suspected, a plasma HIV RNA test should be performed in conjunction with the antigen/antibody combination immunoassay, because HIV RNA test can detect the presence of HIV approximately 5 days earlier than the initial testing.19

Refer to the Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection for recommendations and information about the diagnosis of HIV infection in infants and children (these guidelines are developed for the United States and may not be applicable in other countries). Refer to World Health Organization guidelines for resource-limited settings.37

CONCLUSION

In conclusion, the combination of maternal antepartum, intrapartum, postpartum prophylaxis and infant prophylaxis is recommended to prevent perinatal transmission. All HIV-infected pregnant women should receive combination antiretroviral therapy to reduce maternal viral load below the limit of detection and to decrease the risk of transmission.

The information cited cannot be considered exhaustive, because this is a very complex subject. Consequently, for a more detailed description of the management of HIV-infected pregnant women, it is advisable to consult the following guidelines that are relevant to resource-rich settings: (1) guidelines of the Department of Health and Human Services in the United States;19 (2) guidelines of the American College of Obstetrician and Gynecologists;66 (3) guidelines of the British HIV Association (BHIVA);45 (4) guidelines of the European AIDS Clinical Society;67 (5) position statement of Canadian Paediatric Society (and guidelines of several Canadian societies).68,69

PRACTICE RECOMMENDATIONS

  • All women who are planning to get pregnant and their partners should be screened for HIV as soon as possible for an early diagnosis of HIV in order to begin antiretroviral immediately or as early as possible.
  • All pregnant women should be screened for HIV as soon as possible for an early diagnosis of HIV in order to begin antiretroviral immediately or as early as possible. HIV testing should be offered during each pregnancy.
  • All HIV-infected pregnant women should receive combination antiretroviral therapy, regardless of CD4 cell count or plasma HIV RNA copy number, in order to reduce maternal viral load below the limit of detection and to decrease the risk of transmission.
  • A complete blood count should be monitored monthly and a CD4 cell count should be performed every 3 months and at delivery.
  • The use of maternal antepartum and intrapartum antiretroviral therapy as well as infant antiretroviral prophylaxis decreases the risk of HIV acquisition.
  • The risk of vertical HIV transmission related to breastfeeding is not completely eliminated through antiretroviral prophylaxis and therapy of the mother and infant.

CONFLICTS OF INTEREST

The authors of this chapter declare that they have no interests that conflict with the contents of the chapter.


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