Maternal and Perinatal Infection in Pregnancy: Viral

Virology

Human immunodeficiency virus (HIV) is a member of the Retroviridae family, characterized by spherical, enveloped viruses. The virus envelope surrounds an icosahedral capsid containing the viral genome, consisting of two identical pieces of positive-sense, single-stranded RNA approximately 9.2 kb long. HIV has a total of nine genes including three main genes: gag, pol, and env, which are surrounded by long terminal repeat (LTR) regions. The gag gene encodes the precursor for the virion capsid proteins, which include the full-length p55 polyprotein precursor and its cleavage products: p17 matrix, p24 capsid, p9 nucleocapsid, and p7. The pol gene encodes the precursor polyprotein for several viral enzymes including protease, reverse transcriptase, RNase H, and integrase. The env gene encodes the envelope glycoprotein (gp160), which is cleaved to the surface unit (gp120) and the transmembrane protein (gp41) that is necessary for fusion. Retroviruses are unique because the viral genome is transcribed into DNA via the viral enzyme reverse transcriptase, followed by integration into the host cell genome via the viral enzyme integrase. HIV also has the capacity to become latent within quiescent infected cells, making eradication of the virus thus far impossible.

The HIV envelope glycoprotein (gp120) is a ligand for CD4, the cellular HIV receptor; thus HIV predominantly infects CD4-expressing cells, including T cells, monocytes, and macrophages. Coreceptors required for viral entry and infection have been identified. The two primary HIV coreceptors are the chemokine receptors C-X-C chemokine receptor type 4 (CXCR4) and CC-chemokine receptor type 5 (CCR5). New infections almost always occur with an HIV strain utilizing the CCR5 coreceptor, potentially reflecting viral fitness. Individuals homozygous for a 32-base pair deletion within the CCR5 gene are much less likely to become HIV infected, even following significant exposure; moreover, some CCR5 polymorphisms correlate with HIV disease progression.

Epidemiology

The Centers for Disease Control and Prevention (CDC) estimates that more than 1.2 million people in the United States are infected with HIV, with 11% of infected women undiagnosed (or unaware of their infection). Approximately 40,000 Americans are diagnosed with HIV infection annually; women account for 19% of new HIV infections and 23% of existing infections. Women typically acquire HIV infection by heterosexual contact (85%), with 61% of HIV diagnoses occurring in African American women. HIV prevalence and transmission risk are associated with multiple factors, including women who are unaware of their partner's HIV risk factors (intravenous [IV] drug use or having sex with men), receptive anal intercourse, sexual contact with an uncircumcised male, a high number of sexual contacts, and sexually transmitted infections (STIs). Women with a history of sexual abuse may be more likely to engage in high-risk sexual behaviors, including exchanging sex for drugs, having multiple sex partners, or having sex without a condom. It is important to note that among women living with HIV, just under two-thirds have received some HIV care, with about half retained in care, and half are virally suppressed. Thus obstetric providers should anticipate that a significant proportion of HIV-infected patients may not be receiving antiretroviral therapy (ART) prior to the initiation of prenatal care . Approximately 5000 women living with HIV give birth annually in the United States.

HIV infection is limited to humans and chimpanzees. Most infections in the United States are caused by HIV-1, which is divided into three groups: M, N, and O. More than 95% of HIV-1 infections are caused by group M, which is divided into subtypes (or clades) A through K. The predominant type of HIV within the United States is clade B, while other clades predominate in other regions of the world. HIV-2, a related strain of HIV, is endemic in Africa, Portugal, and France and appears to have lower perinatal transmission compared to HIV-1. Much less is known about the treatment of these related viruses given their prevalence in areas of the world where antiretroviral (ARV) treatment is not readily available.

Clinical Manifestations

Primary HIV infection presents with acute retroviral syndrome, occurring 4 to 6 weeks postexposure, in 50% to 70% of individuals. “Mononucleosis-like” symptoms, which can last several weeks, include fever, rigors, pharyngitis, arthralgias, myalgias, maculopapular rash, urticaria, abdominal cramps, diarrhea, headache, and lymphocytic meningitis. Following acute HIV infection, patients enter an asymptomatic, latent phase of infection, lasting 5 to 10 years. Without ART, most patients will develop acquired immunodeficiency syndrome (AIDS); however, progression to AIDS has been virtually eliminated secondary to widely available, effective ART.

Diagnosis

Historically, HIV infection was diagnosed via enzyme-linked immunosorbent assay (ELISA) screening, followed by Western blot confirmation. However, these virus-specific antibody tests had a limited ability to diagnose HIV-2 or acute HIV-1 infection. Current recommendations are to screen with the fourth-generation HIV-1/2 combination antigen/antibody immunoassay (“combo assay”), with confirmation via HIV-1/HIV-2 antibody differentiation immunoassay and HIV-1 nucleic acid testing (NAT) ( Fig. 57.1 ). The combo assay detects antibodies to both HIV-1 and HIV-2, including immunoglobulin (Ig)M, which becomes measurable 3 to 5 days after p24 antigen positivity, and p24 viral antigen (measurable 15 days postinfection), enhancing our ability to diagnose HIV-2 infection and HIV-1 infection prior to antibody development. Combined with reflex HIV-1 NAT, this strategy enables diagnosis of acute HIV-1 infection, which was not possible via ELISA/Western blot. This testing algorithm provides faster, more accurate diagnosis of HIV-1 and HIV-2 infection. For patients at highest risk for acute HIV infection, an HIV RNA test should also be ordered because NAT can detect the presence of HIV 5 days earlier than the combination assay. As HIV transmission risk is increased in undiagnosed, acutely infected individuals, this diagnostic strategy may lead to a reduction in perinatal HIV transmission.

Given the prevalence of undiagnosed HIV infection and studies demonstrating that early initiation of therapy benefits HIV-infected individuals, while reducing sexual and perinatal HIV transmission , both American College of Obstetricians and Gynecologists (ACOG) and the CDC recommend early prenatal HIV screening using an “opt out” approach, ideally performed at the initial prenatal visit. A second HIV test in the third trimester, preferably before 36 weeks of gestation, is recommended for pregnant women with initial negative HIV tests who are at increased risk for HIV acquisition, such as women receiving care in facilities that have an HIV incidence in pregnant women of at least 1 per 1000 per year or residing in jurisdictions with elevated HIV incidence, or incarcerated women. Some states require third trimester testing. If at any time during pregnancy a clinician suspects a pregnant woman may be in the “window” period of seroconversion (i.e., has signs or symptoms consistent with acute HIV infection), then a plasma HIV RNA test should be used in conjunction with the HIV antigen/antibody fourth-generation test. Plasma HIV RNA will be positive a few days before the antigen/antibody combination immunoassay. If the plasma HIV RNA is negative, it should be repeated in 2 weeks. Most perinatal HIV transmission in the United States occurs in women who are not known to be HIV infected prior to the birth of their child. Therefore it remains critical to emphasize the importance of prenatal care, universal HIV testing, and strategies to diagnose acute HIV infection in late pregnancy and prior to delivery and breastfeeding.

Ethics and Evolution of HIV Infection and Treatment

ART has improved steadily since its inception, transforming HIV infection from a terminal diagnosis to a treatable, chronic condition. Treatment objectives for all infected individuals are to maximally and durably suppress HIV RNA levels (viral load) because effective treatment prevents HIV transmission and disease progression. Treatment has progressed to preserve immunologic function, reducing HIV-related morbidity and prolonging the duration and quality of life for infected individuals. As such, management recommendations have been refined to focus on tolerability, toxicity, and prevention of resistance. Current HIV treatment guidelines provide healthcare providers with information to discuss with HIV-infected women, enabling collaborative, informed decision making regarding current and future pregnancies. The intent is that pregnant women should be offered ART similar to nonpregnant individuals, accounting for pregnancy-specific maternal or fetal safety issues. When caring for HIV-infected pregnant women, there are two separate but related goals: (1) treatment of maternal infection and (2) chemoprophylaxis to reduce perinatal HIV transmission risk.

Providers caring for HIV-infected women may encounter patients who decline to start or continue ART. Professional responsibilities include providing complete and accurate information and enabling women to make an informed personal choice regarding ART and other clinical recommendations including scheduled cesarean delivery. Coercive policies undermine trust and impair the provider/patient relationship. This can lead to ART and prenatal care discontinuation, reluctance or refusal to disclose their HIV status with healthcare providers and intimate partners, and may prevent the adoption of behaviors enhancing maternal and fetal well-being. Respecting patient autonomy, it is unethical to consider, threaten, or implement punitive actions against an individual with regard to her choices about HIV treatment, HIV status disclosure, delivery management, or infant feeding. Furthermore, the scope of disclosure risks encompasses discrimination and intimate partner violence, making it critical to respect the patient's decision.

Preconception Counseling

Healthcare providers have a responsibility to provide preconception counseling and to discuss reproductive desires with all women of childbearing age. For both HIV-infected and exposed women, HIV prevention or risk reduction should be discussed using a straightforward, nonjudgmental approach. Ongoing risk identification should be performed, including sexual behaviors, IV drug use, sexually transmitted infections, and untreated psychiatric issues that may potentially increase a person's likelihood of engaging in risky behaviors. Behavioral interventions, treatment, and avoidance of risk factors should be discussed, emphasizing the importance of consistent condom use and consideration of ARV preexposure prophylaxis (PrEP) for serodiscordant relationships where the HIV-infected partner is not virologically suppressed.

HIV-infected women should be informed that there is no major effect of HIV on pregnancy outcome, nor does pregnancy influence HIV infection. In addition, providers should discuss the safety of ART during pregnancy and the importance of strict adherence to the patient's treatment regimen. Finally, providers should discuss safe sexual practices to minimize the risk of infection with more virulent or resistant HIV strains or other STIs, and appropriate contraceptive choices to reduce the likelihood of unintended pregnancy because ART (predominantly nonnucleoside reverse transcriptase inhibitors [NNRTIs]) reduces hormonal contraceptive efficacy. The perinatal treatment guidelines contain detailed, specific information regarding interactions between ARV drugs and hormonal contraceptives.

Preconceptual evaluation should include HIV disease status assessment, hepatitis B and C virus (HBV and HCV) status assessment, and evaluation and potential refinement of therapy based on the effectiveness of the ARV regimen and pregnancy considerations (see Treatment section). Elimination of alcohol, tobacco, and other drugs of abuse should be recommended. Preconception consultation should also include screening and treatment of genitourinary tract infections in both partners because inflammation is associated with viral shedding and increased transmission risk. HIV-infected women should attain a stable, maximally suppressed viral load prior to conception (ideally with two HIV RNA assessments below the limits of detection at least 3 months apart) because early and sustained control of HIV replication is the most effective means of reducing perinatal and sexual HIV transmission risk. Women contemplating pregnancy are recommended to take a daily multivitamin including 400 mg of folic acid to help prevent birth defects.

Serodiscordant couples also benefit from preconceptual counseling. Before attempting conception, the HIV-infected partner should begin or continue ART to maximally suppress viral load; this reduces sexual HIV transmission by as much as 96%. For couples with discordant HIV statuses, when the partner living with HIV is ART treated and has achieved sustained viral suppression, sexual intercourse without a condom limited to the 2 to 3 days before and the day of ovulation (peak fertility) is an approach to conception with “effectively no risk” of sexual HIV transmission to the partner without HIV. For couples with discordant HIV status who attempt conception via sexual intercourse without a condom when the partner living with HIV has not been able to achieve viral suppression or when the viral suppression status is not known, administration of PrEP to the partner without HIV is recommended to reduce the risk of sexual HIV transmission. Combination TDV/emtricitabine (FTC) regimens (300 mg/200 mg daily, coformulated as Truvada) is currently recommended for both men and women at risk of HIV acquisition. PrEP is not contraindicated during pregnancy. To minimize HIV exposure, discordant couples are counseled to limit sex without condoms to the period of peak fertility; use of an ovulation kit is the optimal method to identify the most fertile time.

For couples with discordant HIV statuses attempting conception when the partner living with HIV has achieved viral suppression, it is unclear whether administering PrEP to the partner without HIV further reduces the risk of sexual transmission. To completely eliminate the risk of HIV transmission to a seronegative male partner, the safest method is artificial insemination performed in the periovulatory period at home with a syringe. When the male partner is living with HIV, the safest option is to use donor sperm from an uninfected male.

Management During Pregnancy

Intrapartum Therapy

Women should continue taking their ART on schedule as much as possible during labor and before scheduled cesarean delivery. Intrapartum IV ZDV is no longer required for HIV-infected women receiving ART regimens with HIV RNA ≤50 copies/mL during late pregnancy near delivery without adherence concerns. These updated recommendations are based on multiple studies demonstrating extremely limited perinatal HIV transmission in women with HIV RNA less than 1000 copies/mL who did not receive intrapartum ZDV. On a case-by-case basis, based on a woman's recent adherence, her preferences, and expert consultation if needed, IV ZDV prophylaxis may be considered for women with HIV RNA between 50 and 999 copies/mL. This recommendation was made because there is inadequate data to determine whether administration of IV ZDV to women with low but detectable viremia provides any additional protection against perinatal HIV transmission.

For intrapartum patients with recent HIV RNA greater than 1000, women living with HIV with unknown HIV RNA levels, or women who have not received antepartum ARV drugs, IV ZDV should be given as a loading dose of 2 mg/kg administered over 1 hour, followed by a maintenance dose of 1 mg/kg/h. Other ART should be taken with a sip of water, except stavudine, which is antagonistic to ZDV and should be withheld. ZDV should be given independent of maternal resistance because it crosses the placenta readily and is metabolized to the active triphosphate form within the placenta, providing both pre- and postexposure prophylaxis to the infant. When delivery is indicated for obstetric reasons, delivery must not be delayed for ZDV administration. Maternal single-dose NVP is not recommended because there is no added efficacy and a high likelihood of maternal harm, specifically the emergence of resistance. If expanded intrapartum maternal therapy is considered, INSTIs and NNRTIs have better transplacental passage than PIs and therapy should be continued postpartum for maternal benefit. Women should be referred for HIV care postpartum prior to discharge. Notifying the pediatric provider on admission is critical because the safest, most effective option to reduce perinatal HIV transmission in this setting is expanded infant prophylaxis.

Intrapartum Management

In women on ART with HIV RNA ≤1000 copies/mL, duration of ruptured membranes is not associated with an increased risk of perinatal transmission, and vaginal delivery is recommended. Moreover, artificial ROM can be performed for standard obstetric indications in virologically suppressed women receiving ART as delineated in Box 57.3 . The following procedures should generally be deferred in the absence of clear obstetric indications because of a potential increased risk of HIV perinatal transmission: artificial ROM in the setting of viremia, routine use of fetal scalp electrodes for fetal monitoring, and episiotomy. Deferral of nonessential operative delivery is recommended; however, a recent cohort study including 249 operative deliveries reported a single case of vertical HIV transmission in a patient with multiple complicating factors, concluding that operative delivery is a safe option for virologically suppressed women. Our personal experience additionally supports the safety of operative delivery in carefully selected patients. In cases of uterine atony, methergine should be avoided if possible. PIs are CYP3A4 inhibitors and concomitant ergotamine use is associated with exaggerated vasoconstrictive responses. NNRTIs are CUP3A4 inducers, with potential decreased methergine levels and inadequate treatment effect.

Postpartum Care of the Human Immunodeficiency Virus Infected Woman

The postpartum period poses unique challenges secondary to the demands of caring for a newborn. This is a challenging time for women, in terms of ART adherence and maintaining their own health, and studies have shown decreased ART adherence postpartum. ART is recommended for all individuals with HIV, regardless of CD4 T cell count, to reduce the morbidity and mortality associated with HIV infection and to prevent HIV transmission. It is critical to transition women to ongoing primary/HIV care; ideally, women will establish a relationship with an HIV-medicine provider during the latter part of pregnancy to facilitate transition into ongoing care postdelivery. Decisions regarding modifying ART after delivery should be made in consultation with the woman and her HIV care provider, preferably prior to delivery, taking into consideration the preferred regimens for nonpregnant adults versus those for pregnant adults.

Factors to consider regarding postpartum therapy include CD4 cell counts and trajectory, HIV RNA levels, adherence issues, partner HIV status, future childbearing plans, contraception, and patient preference. Postpartum simplification to once-daily coformulated ART regimens (preferred initial regimens for nonpregnant adults) could promote adherence during this challenging time. Women with perinatally acquired HIV warrant enhanced focus on adherence interventions after delivery. Contraceptive counseling is another critical aspect of postpartum care. Women should be offered highly effective contraceptives, including long-term reversible methods, implants, injectables, and intrauterine devices to be used in conjunction with condoms, to prevent unintended pregnancy. Based on ACOG and HIV treatment guidelines, women with HIV should have a follow-up appointment within 2 to 4 weeks of postpartum discharge, either with an obstetric or HIV healthcare provider.

Infant Feeding

Infant and/or maternal postpartum ARV prophylaxis dramatically reduces, but does not eliminate, the risk of breast milk-mediated postnatal HIV transmission. To date, in the United States breastfeeding avoidance in the setting of maternal HIV infection has been a strong and standard recommendation, given the ready availability of safe infant feeding alternatives . This is in contrast to the World Health Organization's (WHO) recommendation to exclusively breastfeed with ongoing ART. A recently published randomized controlled trial comparing postpartum maternal ART to infant nevirapine prophylaxis demonstrated an extremely low incidence of postpartum HIV-1 transmission at 6, 9, and 12 months of 0.3% (95% confidence interval [CI], 0.1 to 0.6), 0.5% (95% CI, 0.2 to 0.8), and 0.6% (95% CI, 0.4 to 1.1) with greater than 97% HIV-1-free survival at 24 months. This outcome is noteworthy secondary to the lower-than-expected HIV MTCT and the extraordinary infant survival in the resource-limited settings of this trial. Extrapolating from this highly reassuring safety data is also likely to overestimate HIV transmission risk in high-income settings.

A recent provider-perspective survey on infant feeding in the setting of maternal HIV infection documented that the majority of providers had encountered patients wishing to breastfeed and 29% reported caring for a patient who breastfed despite their recommendations. Considering this controverted issue, providers should recognize that women may face environmental, social, familial, and personal pressures to consider breastfeeding. Women from a country or cultural background where breastfeeding is the norm may have genuine concern that bottlefeeding will effectively disclose their HIV status. Women may also have successfully breastfed an HIV-negative infant previously or plan to return to their country of origin following delivery. Breastfeeding also promotes infant bonding and women may prefer breastfeeding due to its well-established health benefits.

Based on the framework of respect for human rights, available data suggest the risk differential is insufficient to exclude breastfeeding as a reasonable (potentially marginally inferior) option for HIV-infected women. Moreover, when providers do not use a shared decision-making approach with women living with HIV regarding infant feeding, they may miss opportunities to educate the mother about the risks she may be taking if she chooses to breastfeed. Prior to delivery, women should receive patient-centered, evidence-based counseling regarding infant feeding options. A strongly paternalistic approach with hardline counseling against breastfeeding has the capacity to alienate your patient. This would result in a lost opportunity for optimizing care and outcome. For women electing to breastfeed, a harm reduction model can be helpful. Rapid weaning and mixed bottle- and breastfeeding increase MTCT and should be avoided. Women should be apprised of the HIV transmission risk secondary to premastication (prechewing or prewarming in the mother's mouth) of infant food . Learning about the context in which the patient will be feeding her infant, developing a monitoring plan, and agreeing on a shared care plan is important. Finally, educating the entire healthcare team regarding the shared care plan is critical to avoid disrespectful and potentially illegal escalations, such as reporting breastfeeding events to child protection agencies.

Infant Prophylaxis, Screening and Diagnosis

HIV-exposed infants should receive postpartum ARV to reduce the risk of perinatal HIV transmission. For infants at low risk of HIV acquisition, a 4-week AZT regimen is recommended. Combination infant prophylaxis is recommended for infants at higher risk of HIV acquisition. Prophylaxis should be initiated as close to the time of birth as possible, preferably within 6 to 12 hours of delivery. In terms of screening, serologic tests of the HIV-exposed neonate will almost always be positive because the fetus receives maternal IgG by transplacental passage. Thus virologic tests are required to diagnose HIV infection in infants aged less than 18 months. These tests should be performed at 14 to 21 days of life, at age 1 to 2 months, and again at 4 to 6 months. Two positive tests (on different specimens, excluding cord blood) are required to diagnose HIV infection; one positive test is a presumptive diagnosis. Similarly, two negative tests are required to exclude perinatal HIV infection; further details on case definitions for HIV infection are available from the CDC at www.cdc.gov .

Virology/Epidemiology

Influenza virus is part of the Orthomyxoviridae family. There are three relevant genera (or types) of influenza. Influenza A has the capacity to infect both mammalian and avian species, whereas influenza B and C are found almost exclusively in humans. Influenza has a negative-stranded, segmented RNA genome enabling the rearrangement of viral gene segments in cells infected with two different influenza viruses. This results in the rapid generation of new influenza virus strains (recombinants), which have been responsible for pandemic outbreaks, and is termed “antigenic shift.” Point mutations within the viral genome result in minor, gradual antigenic changes defined as “antigenic drift.” These genetic strategies, combined with a wide host range and our inability to generate a protective immune response against the entire genera, enable influenza virus to remain an important pathogen requiring annual vaccination. The WHO and US Public Health Service recommend strains to be included in the annual vaccine based on recent prevalence.

Influenza viruses are enveloped, hemagglutinin (H or HA) and neuraminidase (N or NA) viral glycoproteins are present on the surface, and the virus capsid proteins are M1 and M2. HA binds the cell surface receptor (neuraminic acid), is highly antigenic, and is the target of neutralizing antibodies protecting against infection. NA cleaves sialic acid from the infected cell surface, facilitating virus release (budding) from these cells, and may remove sialic acid from mucin, enabling cell-free virus to reach epithelial cells. NA does not induce neutralizing antibodies; however, antibodies recognizing NA are disease suppressive while permitting infection. Viral entry begins when HA binds the cell receptor, followed by endocytosis of the viral particle. Within the endocytic compartment, low pH triggers conformational changes in HA, which are required for fusion. Viral uncoating also requires M2, an ion channel protein permitting influx of H ⁺ ions into the virus particle, enabling the viral nucleoprotein to enter the cytoplasm.

Influenza strains are named according to their genus (type), the species from which the virus was isolated (omitted if human), and the H and N subtypes. H subtypes confer species specificity and there is only a single NA subtype for influenza B . Influenza is spread by respiratory droplets, is highly contagious, and occurs as an epidemic typically during the winter months. Approximately 50 million cases occur annually in the United States, and children younger than 2 years old and the elderly have the highest hospitalization rates. In 2009 a novel influenza A, H1N1, emerged secondary to complex genetic reassortment. A unique pandemic ensued; 90% of hospitalizations and 87% of deaths occurred in people less than 65 years old. A total of 788 pregnant women with confirmed or probable H1N1, resulting in 280 intensive care unit admissions and 56 deaths, were documented during this pandemic. The documented case reports potentially underreport infection and overestimate the prevalence of severe illness. The influence of this pandemic can be extrapolated from the mortality rate. Five percent of H1N1-related deaths occurred in pregnant women, which represented 1% of the US population, suggesting that pregnant women infected with influenza have an elevated risk of serious illness and death, in accordance with multiple published studies.

Clinical Manifestations

Influenza virus causes acute upper respiratory tract illness, characterized by the abrupt onset of fever, chills, headache, myalgias, malaise, a dry cough, and nasal discharge. GI manifestations and conjunctivitis can also be present. The incubation period ranges from 1 to 5 days. Most cases of influenza are self-limited. Complications include pneumonia, occurring in up to 12% of influenza-infected pregnant women, Reye syndrome, and disseminated intravascular coagulation. Physiologic changes in the cardiac and respiratory systems likely increase the risk of severe illness in pregnant women infected with influenza.

Diagnosis

Rapid influenza diagnostic tests (RIDTs) are immunoassays using nasal swabs to identify influenza A and B viral nucleoproteins in 15 minutes or less. RIDTs are very specific (90% to 95%), but the sensitivity is limited (10% to 70%), with the potential for false-negative results during periods of high influenza incidence. False-positive results occur when influenza is at low prevalence. Some RIDTs distinguish between influenza A and B, but they cannot determine viral subtype. The optimal time of specimen collection is within 48 to 72 hours of illness onset. Confirmation is via reverse transcriptase polymerase chain reaction (RT-PCR), culture, ELISA, or immunofluorescence of respiratory secretions; immunofluorescence and RT-PCR have the most rapid turnaround. Given the low sensitivity, these diagnostic tools should not be used to determine initial treatment.

Management of Influenza During Pregnancy

Pregnant women suspected to be infected with influenza should be treated immediately, independent of vaccination status, without waiting for diagnostic confirmation. The recommended treatment for both seasonal and pandemic influenza infection is oseltamivir or zanamivir ( Table 57.3 ); acetaminophen should be used as an antipyretic. Over-the-phone treatment for low-risk patients is preferred to reduce the potential spread of disease among other pregnant patients in the office. Guidance regarding the assessment and management of pregnant women with influenza-like illness is provided by ACOG and the Society for Maternal-Fetal Medicine's Seasonal Influenza Assessment and Treatment of Pregnant Women with Influenza-like Illness algorithm at www.acog.org/More-Info/FluVaccine . The preterm birth rate following pandemic H1N1 infection was 30%. Increased preterm parturition also occurs following seasonal influenza infection, so appropriate monitoring should be undertaken, particularly in women with respiratory compromise. Early antiviral treatment (within 48 hours) reduces the duration of the illness, secondary complications, and hospitalizations; treatment should not be withheld if the ideal window is missed. Alternative therapy for infection includes amantadine or rimantadine, which block M2 channel activity in influenza A; however, significant viral resistance to these drugs limits their effectiveness. The risk of severe illness and death is highest in the latter part of pregnancy, compared to the first trimester, and the pregnancy-associated risk of illness persists for 2 weeks postpartum. Other risk factors are described in Box 57.4 , Risk Factors for Severe Illness and Death in Influenza Virus-Infected Pregnant Women.

Chemoprophylaxis should be considered for pregnant women and women within 2 weeks of delivery who have had close contact with infected individuals (see Table 57.3 ). To prevent maternal influenza infection and associated perinatal morbidity and mortality, both ACOG and the CDC recommend that all women who are or will be pregnant during influenza season (October to May) receive the intramuscular inactivated vaccine as soon as it is available, ideally prior to November. Maternal vaccination also protects infants up to 6 months of age from influenza infection, has no adverse fetal effects and is safe in breastfeeding women. The intranasal vaccine contains live virus and should not be used during pregnancy. Vaccination is safe and effective at any time of the year or gestational age, and egg allergy is no longer a contraindication to vaccination. Given that vaccination prevalence in the United States remains at 50%, consideration should be given to the development of standing orders to administer the influenza vaccine during prenatal care visits.

Virology/Epidemiology

Parvoviruses are small, nonenveloped viruses, containing negative-stranded DNA encoding two major genes: the REP or NS gene encoding functions required for transcription and DNA replication, and the CAP or S gene encoding the coat proteins VP1 and VP2. Parvovirus B19 was identified in the 1970s in blood bank specimens and was first linked to sickle cell disease patients with transient aplastic crisis. Parvovirus B19 was then associated with fifth disease or erythema infectiosum (EI), and later linked to hydrops fetalis. Parvoviruses preferentially infect rapidly dividing cells, explaining the observed fetal and neonatal susceptibility. Parvovirus B19 infection is restricted to humans and the cellular receptor is erythrocyte P antigen, explaining the propensity of this virus to infect red blood cells and their precursors. P antigen is also expressed on megakaryocytes, endothelial cells, placenta, fetal liver, and fetal heart. Parvovirus B19 is spread via respiratory droplets, infected blood products, perinatally, and from hand-to-mouth contact. The incubation period ranges from 4 to 20 days following exposure. Seroprevalence increases with age, and 65% of pregnant women have evidence of prior infection and are immune. Conversely, susceptible women have approximately a 50% risk of seroconversion following exposure to parvovirus B19. Daycare workers, teachers, and parents have all shown to be at increased risk of seroconversion.

Clinical Manifestations

The most common presentation of parvovirus infection is EI, characterized by a facial rash consistent with a slapped cheek appearance and a reticulated or lacelike rash on the trunk and extremities ( Fig. 57.2 ). The rash is immune complex–mediated and may reappear secondary to temperature changes, sunlight exposure, and stress for several weeks. Infection can also be accompanied by fever, malaise, lymphadenopathy, and symmetrical peripheral arthropathy. The hands are most frequently affected, followed by the knees and wrists. Symptoms are typically self-limiting but may last for several months. Asymptomatic infection occurs 20% of the time. Persistent parvovirus infection is rare and presents as pure red cell aplasia in patients failing to mount a neutralizing antibody response. Fetal infection can be asymptomatic or characterized by aplastic anemia of varying severity. Severe anemia can lead to high-output congestive heart failure and nonimmune hydrops. Direct infection of the myocardium may also contribute to fetal heart failure.