Acquired immunodeficiency syndrome AIDS
American College of Obstetricians and Gynecologists ACOG
Chemokine receptor type 5 CCR5
Centers for Disease Control and Prevention CDC
Central nervous system CNS
Combination antiretroviral therapy cART
Congenital rubella syndrome CRS
Congenital varicella syndrome CVS
C-X-C chemokine receptor type 4 CXCR4
Deoxyribonucleic acid DNA
Disseminated intravascular coagulopathy DIC
Enzyme-linked immunosorbent assay ELISA
Epstein-Barr virus EBV
Erythema infectiosum EI
Fixed-dose combination FDC
Hemagglutinin HA or H
Hepatitis A virus HAV
Hepatitis B core antigen HBcAg
Hepatitis B early antigen HBeAg
Hepatitis B immune globulin HBIG
Hepatitis B surface antigen HBsAg
Hepatitis B virus HBV
Hepatitis C virus HCV
Hepatitis delta antigen HDAg
Hepatitis delta virus HDV
Herpes simplex virus HSV
Human immunodeficiency virus HIV
Human papillomavirus HPV
Immune reconstitution inflammatory syndrome IRIS
Integrase strand transfer inhibitor INSTI
Intrauterine growth restriction IUGR
Long terminal repeat LTR
Measles, mumps, rubella MMR
Mother-to-child transmission MTCT
Mycobacterium avium complex MAC
Neuraminidase N or NA
Nonnucleoside reverse transcriptase inhibitor NNRTI
Nucleic acid test NAT
Nucleic acid sequence-based amplification NASBA
Nucleoside reverse transcriptase inhibitor NRTI
Opportunistic infections OI
Papanicolaou smear PAP smear
Pediatric AIDS Clinical Trials Group PACTG
Polymerase chain reaction PCR
Preexposure prophylaxis PrEP
Protease inhibitor PI
Rapid influenza diagnostic test RIDT
Reverse transcriptase RT
Ribonucleic acid RNA
Sexually transmitted disease STD
Spontaneous rupture of membranes SROM
Subacute sclerosing panencephalitis SSPE
Purified protein derivative PPD
Varicella zoster immune globulin VZIG
Varicella zoster virus VZV
World Health Organization WHO
Viruses have been identified in virtually all organisms. They are among the simplest of living organisms, yet they have significantly influenced history and are an important causative factor for infectious disease. Viruses are obligate intracellular parasites that utilize the host cell’s structural and functional components while exhibiting remarkably diverse strategies for gene expression and replication. Viral infection ranges from asymptomatic or subclinical to overwhelming and highly lethal, with findings such as meningoencephalitis or hemorrhagic fever with shock. Viral infection is highly variable; many viruses are limited to acute, time-limited infection. However, some viruses establish long-lasting infection. Latent viruses have the capacity to reactivate gene expression many years after acute infection, retroviruses integrate into the host cell genome, and multiple viruses have oncogenic potential.
Virus particles contain nucleic acid and structural proteins, which together are referred to as a nucleocapsid. Viral nucleic acid is composed of either DNA or RNA, which may be single or double stranded. Viral genomes can be linear or circular and can exist in multiple segments or as a single segment. Viral genome size ranges from two genes in parvovirus B19 to over 200 genes in cytomegalovirus (CMV). Some viruses have lipid bilayer envelopes external to the nucleocapsid; these envelopes are derived from the host cell and contain viral proteins. Herpes viruses have an additional layer, called a tegument, between the nucleocapsid and envelope. Viruses are classified by the International Committee on Taxonomy into orders, families, subfamilies, genera, and species. Classification is based on morphology, nucleic acid type, the presence or absence of an envelope, genome replication strategy, and homology to other viruses.
Infection is typically initiated by the virus binding to a specific host cell receptor. Receptors are normally functional host cell membrane proteins but are also recognized by a viral protein ligand within the viral envelope or nucleocapsid. The viral protein and cellular receptor interaction defines, in part, the host range of the virus, which limits infection to cells that display the appropriate receptor. Virus enters the host cell via translocation of the virion across the plasma membrane; this involves endocytosis or fusion of the viral envelope with the cell membrane. The virus then uncoats its nucleic acid for replication, ultimately leading to viral gene expression and replication. This may occur in either the cytoplasm or nucleus of the cell and may involve integration into the host genome, as in the case of retroviruses. Intracellular assembly of progeny virions occurs followed by release of newly formed virions by cell lysis or by budding from the cell surface, as in the case of most enveloped viruses.
Despite their inability to replicate independently, viruses play a central role in infectious disease, altering the structure and/or the function of the host cell. For productive infection to occur, viruses must enter cells, replicate their genome, and release infectious virions. The inability of a virus to complete any of these required steps results in a “nonproductive infection.” Viral pathogenesis occurs via several mechanisms and does not require productive infection. These include direct effects on infected host cells, which may result in cell death via lysis or apoptosis. Infected cells can also be killed by antiviral antibody and complement or by cell-mediated immune mechanisms. In addition, some viral genomes encode oncogenes, which can mediate transformation of infected host cells. Viral proteins can also impact the function of uninfected cells, including those of the immune system. Finally, the host immune response to viral infection encompasses both local and systemic effects via activation of immune cells, the induction of an adaptive immune response, and the release of cytokines, chemokines, and antibodies. Thus the immune response contributes to or causes the signs and symptoms associated with viral infections, which includes fever, rash, arthralgias, and myalgias. The outcome of viral infection is dependent on host factors such as immune status, age, nutritional status, and genetic background. Genetic factors can alter susceptibility to viral infection, the immune response generated following infection, and the long-term consequences of viral infection.
This chapter discusses many of the viral infections relevant to pregnancy that have significant impact on maternal health and/or pregnancy outcome. The virology, epidemiology, diagnosis, clinical manifestations, management during pregnancy, and impact on the fetus/neonate are reviewed for the viruses listed in Table 53-1 .
|HIV||Opportunistic infection||Perinatal infection||Immunoassay||PCR||cART||cART to reduce perinatal transmission|
|Influenza||Pneumonia, increased maternal mortality||NA||RT-PCR or immunofluorescence, RIDT for screening||NA||Oseltamivir prophylaxis and treatment, supportive care, vaccinate annually||Maternal vaccination to protect the neonate|
|Parvovirus B19||Rare||Anemia, hydrops, death||PCR or antibody detection||PCR, ultrasound for anemia||Supportive care||Intrauterine transfusion for severe anemia|
|Rubeola (measles)||Otitis media, pneumonia, encephalitis||Abortion, preterm delivery||RT-PCR or antibody detection||NA||Supportive care, vaccinate prior to pregnancy||NA|
|Rubella||Rare||Congenital infection||Antibody detection or RT-PCR||RT-PCR, ultrasound for congenital rubella syndrome||Supportive care, vaccinate prior to pregnancy||Consider pregnancy termination for fetus with CRS|
|CMV||Chorioretinitis||Congenital infection||PCR||PCR, ultrasound for detection of sequelae||Ganciclovir for severe infection||Consider pregnancy termination for infected fetus with primary maternal infection|
|HSV||Disseminated infection, primarily in immunocompromised patients||Neonatal infection, intrauterine infection is extremely rare||Examination, PCR, antibody detection||Examination, PCR, antibody detection||Antiviral Tx for infection and prophylaxis to reduce recurrences||Cesarean delivery when mother has active genital lesions|
|Varicella||Pneumonia, encephalitis, zoster||Congenital or perinatal infection||History, PCR, antibody detection||Ultrasound||VZIG, antivirals for prophylaxis and/or treatment||VZIG, antivirals for prophylaxis and/or treatment|
|Hepatitis A||Rare||None||RT-PCR or antibody detection||NA||Supportive care, vaccination||IG to neonate if mother acutely infected at delivery|
|Hepatitis B||Chronic liver disease||Perinatal infection||HBsAg detection, HBV PCR||NA||Supportive care, vaccination; HBIG for exposed, unvaccinated individuals||HBIG and HBV vaccine immediately following delivery. Consider antepartum tenofovir to further reduce transmission|
|Hepatitis C||Chronic liver disease||Perinatal infection||HCV antibody screen, NAT confirmation||NA||Supportive care, consider antiviral Tx||Maternal treatment may reduce transmission|
|Hepatitis D||Chronic liver disease||Perinatal infection||Antigen and antibody detection||NA||Supportive care||HBIG and HBV vaccine immediately following delivery|
|Hepatitis E||Increased mortality||Neonatal infection||RT-PCR, antibody detection||NA||Supportive care||None|
Human Immunodeficiency Virus
Human immunodeficiency virus (HIV) is a member of the Retroviridae family, characterized by spherical, enveloped viruses. The virus envelope surrounds an icosahedral capsid that contains the viral genome and consists of two identical pieces of positive-sense, single-stranded RNA about 9.2 kb long. HIV has a total of nine genes that include 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) 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, which has made 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 + 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 CXCR4 and CCR5. New infections almost always occur with an HIV strain that utilizes the CCR5 coreceptor, which potentially reflects 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 disease progression of HIV in perinatally infected children and adults.
The Centers for Disease Control and Prevention (CDC) estimates that over 1.2 million people in the United States are infected with HIV, and 14% of infected individuals are undiagnosed or unaware of their infection. Most HIV-infected individuals reside outside the United States. Global HIV burden is estimated at 37 million individuals; moreover, women account for more than half of all people living with HIV. In contrast, approximately 50,000 Americans are diagnosed with HIV infection annually; women account for 20% of new HIV infections and 23% of existing infections. Women typically acquire HIV infection by heterosexual contact, and about 65% of new infections occur in black Americans. White women have the highest percentage of HIV infections attributable to injection drug use (25%), whereas injection drug use accounts for only 14% of HIV infections in Hispanic women and only 11% in black women. Factors associated with an increased prevalence of HIV infection and transmission risk include a high number of sexual contacts, high-risk sexual exposure, receptive anal intercourse, sexual contact with an uncircumcised male, IV drug and/or crack cocaine use, residing in the “inner city,” and the presence of other sexually transmitted diseases (STDs), particularly those that cause genital ulcers (herpes, syphilis, chancroid).
HIV infection is limited to humans and chimpanzees, and most infections in the United States are caused by HIV-1, which is divided into three groups: M, N, and O. Over 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, whereas 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 a lower vertical transmission rate compared with HIV-1. Much less is known about the treatment of these related viruses given their prevalence in areas of the world where treatment with antiretroviral (ARV) agents is not readily available.
Historically, HIV infection was diagnosed via virus-specific antibody detection; initial serologic screen was via enzyme-linked immunosorbent assay (ELISA) and either Western blot (WB) or immunofluorescent antibody assay was performed for confirmation. The Western blot identifies antibodies and recognizes specific viral antigens, and it is considered positive when any two of the following three antigens are identified: p24 (capsid), gp41 (envelope), and gp120/160 (envelope). Several salivary and/or rapid blood tests are available with efficacy comparable to ELISA. These tests have a limited ability to diagnose early HIV and HIV-2 infection because they detect HIV-specific immunoglobulin (Ig) G antibodies. Current recommendations are to screen with an HIV-1/2 antigen/antibody combination immunoassay, or “combo assay,” with confirmation of infection with an HIV-1/HIV-2 antibody differentiation immunoassay and HIV-1 nucleic acid test (NAT; Fig. 53-1 ). This strategy enables diagnosis of acute HIV-1 infection, detection of HIV-2 infection, and faster turnaround time. Enhancements of the combo assay include more accurate HIV-2 diagnosis, p24 antigen assessment (measurable 15 days postinfection), and detection of IgM antibodies (measurable 3 to 5 days after p24 antigen positivity), which enables confirmation of HIV infection days to weeks before the HIV WB becomes positive. Combined with an HIV-1 NAT, this narrows the window between the time of infection and immunoassay reactivity and enables the diagnosis of acute HIV-1 infection, which was not possible using ELISA/WB assessment. Because the risk of HIV transmission from persons with acute and early infection is increased, this strategy may reduce perinatal HIV transmission.
Given the increasing prevalence of HIV infection and studies that demonstrate that identification of HIV-infected pregnant women and early antiretroviral therapy (ART) most effectively prevents perinatal HIV transmission , both the American College of Obstetricians and Gynecologists (ACOG) and the CDC recommend an “opt out” approach to ensure routine HIV screening for all pregnant women, ideally performed at the first prenatal visit. The CDC also advocates for repeat testing in the third trimester, citing its cost effectiveness even in areas of low prevalence. A second HIV test in the third trimester is recommended for women at increased risk of HIV infection and those living in areas of elevated HIV incidence, which includes residents of Alabama, Connecticut, Delaware, the District of Columbia, Florida, Georgia, Illinois, Louisiana, Maryland, Massachusetts, Mississippi, Nevada, New Jersey, New York, North Carolina, Pennsylvania, Puerto Rico, Rhode Island, South Carolina, Tennessee, Texas, and Virginia as well as women who receive health care in facilities at which prenatal screening identifies at least one HIV-infected pregnant woman per 1000 women screened.
Clinical Manifestations and Staging
The clinical presentation of HIV infection and/or acquired immunodeficiency syndrome (AIDS) depends on when infection occurred and whether immunodeficiency resulted. Following exposure and primary infection, 50% to 70% of individuals infected with HIV develop the acute retroviral syndrome. At this time patients may have “mononucleosis-like” symptoms that include fever, rigors, pharyngitis, arthralgias, myalgias, maculopapular rash, urticaria, abdominal cramps, diarrhea, headache, and lymphocytic meningitis. The acute phase of infection usually occurs 4 to 6 weeks following HIV exposure and can last several weeks. However, it is uncommon for individuals to be diagnosed during acute infection. Following acute HIV infection, patients enter latent-phase infection, which can last approximately 5 to 10 years in untreated patients and comprises stage 1 and 2 of infection ( Table 53-2 ). During this asymptomatic phase of infection, in the absence of ART, chronic immune activation and progressive destruction of lymphatic tissue ensues. If untreated, most patients will develop stage 3 infection, AIDS, which typically includes one or more of the conditions listed in Box 53-1 .
|CDC STAGE||CD4+ T-LYMPHOCYTE COUNT AND PERCENTAGES|
|Stage 1 (HIV infection)||CD4+ T-lymphocyte count ≥500 cells/µL or ≥ 29%|
|Stage 2 (HIV infection)||CD4+ T-lymphocyte count 200 to 499 cells/µL or 14% to 29%|
|Stage 3 (AIDS)||CD4+ T-lymphocyte count <200 cells/µL or <14%|
Candidiasis of bronchi, trachea, or lungs
Candidiasis of esophagus *
* Condition that might be presumptively diagnosed.
Cervical cancer, invasive †
† Only among adults and adolescents aged at least 13 years.
Coccidioidomycosis, disseminated or extrapulmonary
Cryptosporidiosis, chronic intestinal (>1 month duration)
Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age >1 month
Cytomegalovirus retinitis (with loss of vision) †
Encephalopathy, HIV related
Herpes simplex: Chronic ulcers (>1 month duration) or bronchitis, pneumonitis, or esophagitis (onset at age >1 month)
Histoplasmosis, disseminated or extrapulmonary
Isosporiasis, chronic intestinal (>1 month duration)
Kaposi sarcoma *
Lymphoid interstitial pneumonia or pulmonary lymphoid hyperplasia complex †
Lymphoma, Burkitt (or equivalent term)
Lymphoma, immunoblastic (or equivalent term)
Lymphoma, primary, of brain
Mycobacterium avium complex or M. kansasii, disseminated or extrapulmonary *
Pneumocystis jiroveci pneumonia *
Progressive multifocal leukoencephalopathy
Salmonella septicemia, recurrent
Toxoplasmosis of brain, onset at age >1 month *
Wasting syndrome attributed to HIV
AIDS, acquired immune deficiency syndrome; HIV, human immunodeficiency virus.
Evolution of Human Immunodeficiency Virus Infection and Treatment
The diagnosis, treatment, and prognosis of HIV infection has improved considerably over the past 30 years. Subsequent to the availability of effective ARVs with fewer adverse effects, HIV infection has evolved from a terminal diagnosis to a chronic but treatable life-long disease. Treatment objectives for all infected individuals are to maximally and durably suppress viral load. Effective treatment prevents HIV disease progression and transmission, including perinatal transmission. As treatment has progressed to preserve immunologic function, reducing HIV-related morbidity, and prolonging the duration and quality of life for infected individuals, management recommendations have changed to focus on tolerability, toxicity, and prevention of resistance. Historically, Pediatric AIDS Clinical Trial Group (PACTG) 076 was the first study to show that ART reduces perinatal HIV transmission. This randomized, placebo-controlled study comprised treatment-naïve HIV-infected women beyond the fist trimester of pregnancy with a CD4 count above 200/mm 3 . Treatment included prenatal oral zidovudine (ZDV) and intrapartum intravenous (IV) ZDV, and infants received oral ZDV for 6 weeks following delivery; randomization was ethical because the safety within pregnancy and efficacy of ZDV at the time the study was initiated was unknown. Secondary to reduced HIV transmission, ZDV became the backbone of perinatal HIV treatment for over 20 years. Conversely, updated guidelines limit the recommended use of this drug secondary to toxicity (bone marrow suppression; gastrointestinal [GI] and mitochondrial toxicities such as lipoatrophy, lactic acidosis, and hepatic steatosis; skeletal muscle myopathy; and cardiomyopathy) and the availability of highly effective, well-tolerated therapies with fewer toxic side effects. Moreover, combination antiretroviral therapy (cART) has been shown to more effectively limit perinatal HIV transmission.
Pregnant patients should be offered ART based on the same principles used for nonpregnant individuals, taking into account pregnancy-specific maternal or fetal safety issues. When caring for HIV-infected pregnant women, two separate but related goals emerge: (1) treatment of maternal infection and (2) chemoprophylaxis to reduce the risk of perinatal HIV transmission. Providers who care for HIV-infected women may encounter patients who decline to start or continue ART. For guidance, the author supports the recommendations of the Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. In summary, the provider is responsible for providing information to enable the woman to make an informed choice regarding this and other medical recommendations, including elective cesarean delivery. Coercive and punitive policies undermine trust and the provider-patient relationships. Results can include prenatal care discontinuation or failure to disclose her HIV status to other health care providers, preventing the adoption of behaviors to enhance maternal and fetal well-being. Respecting patient autonomy, we consider it unethical to consider punitive actions against a patient secondary to her decisions regarding her HIV treatment or disclosure of her HIV status. Moreover, disclosure carries risks that range from discrimination to intimate partner violence, making it critical to respect the patient’s decision. Clinicians should be aware of local legal requirements in regard to confidentiality and disclosure of HIV-related health information.
Management During Pregnancy
Beyond the standard initial antenatal assessment for all pregnant women, including a first-trimester ultrasound to confirm gestational age, evaluation of an HIV-infected pregnant woman should include status assessment as described in Box 53-2 . Plasma HIV RNA (viral load) is determined using reverse transcriptase–polymerase chain reaction (RT-PCR) technology. If the patient’s HIV viral load is undetectable in the absence of treatment, retesting and/or using an alternative assay is recommended (bDNA signal amplification or nucleic acid sequence-based amplification [NASBA] technique). Some patients may have an undetectable viral load; however, the patient could be infected with a non–clade B HIV-1 isolate or HIV-2. None of the above-mentioned assays detect HIV-2 plasma RNA. Consultation with an infectious disease physician with experience in the management of HIV disease can be helpful in these cases or when the woman’s genotype and phenotype assay demonstrate significant resistance to ART. Following complete evaluation, recommendations for a plan of HIV-related medical care that includes antepartum, intrapartum, and postpartum care should be provided, taking into account issues described in the following sections.
HIV History Review
HIV infection duration, transmission route (if known), prior HIV-related illnesses and hospitalizations
Prior and ongoing ARV drug use, duration, whether treatment was for maternal benefit and/or to prevent perinatal HIV transmission, adherence and tolerance issues
Outcome of HIV-impacted pregnancies
CD4 cell counts and HIV viral loads (plasma HIV RNA copies/mL of plasma) and their relationship to ARV, results of prior HIV ARV drug-resistance studies
Assess need for opportunistic infection prophylaxis
Immunization/infection/serology status with attention to HAV, HBV, HCV, tuberculosis, pneumococcus, and Tdap
CD4 count and HIV viral load
ARV drug-resistance studies (genotype preferred) prior to starting or modifying ARV regimens in patients with HIV RNA levels above the threshold for resistance testing (e.g., >500 to 1000 copies/mL)
Baseline complete blood cell count with platelets and renal and liver function testing
Serologic assessment as required by history and CD4 count (for CD4 <200 cells/mm 3 , serology for cytomegalovirus and Toxoplasma gondii is indicated)
HLA-B*5701 testing, if abacavir use is anticipated
In PPD-positive patients, chest x-ray to rule out active pulmonary disease
If abnormal PAP smear, HPV testing and colposcopy as indicated
ARV, antiretroviral; HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HLA, human leukocyte antigen; HPV, human papillomavirus; PAP, Papanicolaou; PPD, purified protein derivative; Tdap, tetanus, diphtheria, and pertussis (vaccine).
Combination care with at least three drugs from at least two classes of ARVs is standard care for HIV infection in the United States. Patients who enter pregnancy on ART with complete viral suppression should continue their current therapy; if a component of their regimen is contraindicated in pregnancy, the regimen should be altered without therapy interruption. If pregnancy-associated vomiting interferes with ongoing adherence to therapy, antiemetics should be aggressively used prior to discontinuing therapy. Treatment recommendations for ARV-naïve pregnant women are delineated in Table 53-3 , and the most commonly used ARTs in pregnancy are described in Table 53-4 . Commonly used drug classes include nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs). Fusion inhibitors (FIs), CCR5 antagonists, and integrase strand transfer inhibitors (INSTIs) have been less commonly used in pregnancy; however, the number of INSTI-treated women who become pregnant will increase because most recommended treatment regimens for nonpregnant adults are INSTI based. Therapeutic considerations include timing of therapy initiation, dosing changes secondary to pregnancy-associated physiologic changes, side effects, drug interactions, teratogenicity, comorbidities, convenience and adherence potential, viral resistance, and the pharmacokinetics and toxicity of transplacentally transferred drugs.
|PREFERRED BACKBONES AND REGIMENS||COMMENT|
|TDF/FTC or TDF/3TC||Truvada |
200 mg FTC+ 300 mg TDF tablet
|The recommended NRTI backbone for nonpregnant adults; can be administered once daily. TDF has potential renal toxicity and should be used with caution in patients with renal insufficiency.|
300 mg 3TC + 600 mg ABC tablet
|Can be administered once daily; ABC is associated with HSRs and should not be used in HLA-B*5701–positive patients; it may be less efficacious than TDF/FTC in patients with HIV RNA level >100,000.|
150 mg 3TC + 200 mg ZDV tablet
|Backbone with the most experience in pregnancy, disadvantages include twice-daily administration and increased toxicity; not a preferred backbone in nonpregnant adults.|
|ATV/r + two-NRTI backbone||Once-daily administration of ATV/r; no longer preferred in nonpregnant adults secondary to increased toxicity-related discontinuation compared with DRV- and RAL-based regimens.|
|DRV/r + two-NRTI backbone||Twice-daily administration of DRV/r in pregnancy; preferred PI in nonpregnant adults, increasing experience with use in pregnancy.|
|EFV + two-NRTI backbone||Atripla |
200 mg FTC + 300 mg TDF + 600 mg EFV tablet
|Atripla enables once daily administration of a single tablet regimen; concern due to observed birth defects in primates, although human risk is unconfirmed; postpartum contraception must be ensured; preferred regimen in women who require coadministration of drugs with significant PI interactions.|
|RAL + two-NRTI backbone||Twice-daily administration of RAL; preferred NRTI regimen in nonpregnant adults, increasing experience and established PK in pregnancy. Rapid viral load reduction; however, twice daily dosing required.|
|RPV/TDF/FTC||Available in coformulated single-pill, once-daily regimen with PK pregnancy data. However, relatively little clinical experience in pregnancy and not recommended for pretreatment HIV RNA >100,000 or CD4 count <200 cells/mm 3 .|
|LPV/r + two-NRTI backbone||Twice-daily administration; once-daily LPV/r is not recommended for use in pregnant women; not a preferred PI in adults secondary to higher rates of GI side effects, hyperlipidemia, and insulin resistance.|
|No Longer Recommended|
|SQV/r + two-NRTI backbone||Not recommended based on potential toxicity and dosing disadvantages. Baseline ECG recommended before initiation secondary to potential PR and QT prolongation; contraindicated with preexisting cardiac conduction system disease; large pill burden.|
|NVP + two-NRTI backbone||No longer recommended secondary to higher adverse event potential, complex lead-in dosing and low resistance barrier. NVP is administered twice daily; caution should be used when initiating ART in women with CD4 count >250 cells/mm 3 . Use NVP and ABC together with caution; both can cause HSRs within the first few weeks after initiation.|
|DRUG DOSAGE||FDA PREGNANCY CATEGORY||PHARMACOKINETICS IN PREGNANCY||PREGNANCY CONCERNS AND RECOMMENDATIONS|
|Tenofovir disoproxil fumarate (TDF; Viread), 300 mg QD||B||AUC lower in third trimester than postpartum with adequate trough levels in the majority of women. Placental transfer is high.||Twofold increase in birth defects ruled out, 2.2% birth defect prevalence (47 of 2141 births); clinical studies in humans (particularly children) show reversible bone demineralization with chronic use; with HBV coinfection, possible HBV flare when drug is stopped; monitor renal function secondary to potential toxicity.|
|Lamivudine (3TC; Epivir), 150 mg BID or 300 mg QD||C||PKs are not significantly altered in pregnancy; no change in dose is indicated. Placental transfer is high.||A 1.5-fold increase in birth defects ruled out, with a 3.2% birth defect prevalence (137 of 4418 births). Short-term safety demonstrated for mother and infant; 3TC has antiviral activity against HBV; if coinfected, HBV flare is possible if drug is stopped postpartum.|
|Emtricitabine (FTC; Emtriva), biologically active form of 3TC, 200 mg QD||B||PK study shows slightly lower levels in third trimester compared with postpartum; no need to increase dose. Placental transfer is high.||Twofold increase in birth defects ruled out, 2.3% birth defect prevalence; antiviral activity against HBV; if coinfected, HBV flare is possible if drug is stopped postpartum.|
|Abacavir (ABC; Ziagen), 300 mg BID or 600 mg QD||C||PKs are not significantly altered in pregnancy; no change in dose is indicated. Placental transfer is high.||Twofold increase in birth defects ruled out, 3.0% birth defect prevalence (27 of 805 births); hypersensitivity reactions occur in ~5% to 8% of nonpregnant persons; a much smaller percentage are fatal, usually associated with rechallenge. Patients should be educated regarding symptoms, and HLA-B*5701 testing identifies patients at risk.|
|Zidovudine (ZDV; Retrovir), 300 mg BID||C||PKs are not significantly altered in pregnancy; no dose change is indicated. Placental transfer is high.||1.5-fold increase in birth defects ruled out, 3.2% birth defect prevalence (129 of 4034 births). Short-term safety demonstrated for mother and infant. ZDV is associated with macrocytic anemia.|
|Didanosine (ddI; Videx), ≥60 kg: 400 mg QD, with TDF 250 mg QD; <60 kg: 250 mg QD, with TDF 200 mg QD||B||PKs are not significantly altered in pregnancy; no change in dose is indicated. Placental transfer is moderate.||Human birth defect rate was 4.8% (20 of 418), compared with 2.7% in the general population; no pattern of defects was discovered. Cases of lactic acidosis, some fatal, have been reported in pregnant women receiving ddI and d4T together; only use if no other alternative is available.|
|Stavudine (d4T; Zerit), ≥60 kg: 40 mg BID; <60 kg: 30 mg BID||C||PKs are not significantly altered in pregnancy; no change in dose is indicated. Placental transfer is high.||Twofold increase in birth defects ruled out, 2.6% prevalence in birth defects (21 of 809 births); antagonistic with ZDV; cases of fatal lactic acidosis have been reported in pregnant women receiving ddI and d4T together.|
|Efavirenz (EFV; Sustiva), 600 mg QD at or before bedtime||D||AUC decreased during third trimester, compared with postpartum, but nearly all third-trimester subjects exceeded target exposure; no dosage change is indicated. Placental transfer is moderate.||Antiretroviral Pregnancy Registry (prospective) documented birth defects in 20 of 852 live births (2.3%) following first-trimester EFV exposure, including a single NTD with fetal alcohol syndrome and a single case of bilateral facial clefts, anophthalmia, and amniotic band (2.3% birth defect prevalence, twofold increase in overall birth defects ruled out). Retrospective data include six case reports of CNS defects following EFV exposure; however, a meta-analysis of more than 2000 first-trimester EFV-exposed live births showed no increase in overall birth defects (2.0%) and a single NTD (overall incidence 0.07%).|
|Nevirapine (NVP; Viramune), 200 mg QD for 14 days, then 200 mg BID||C||PKs are not significantly altered in pregnancy; no dose change is indicated. Placental transfer is high.||Twofold increase in birth defects ruled out, 2.9% birth defect prevalence (31 of 1068 births); increased risk of symptomatic, rash-associated, potentially fatal liver toxicity in women with CD4 + counts >250/mm 3 when initiating therapy; pregnancy does not increase this risk. Women who become pregnant while taking NVP-containing regimens but are tolerating them well should continue therapy independent of CD4 + count.|
|Etravirine (ETR; Intelence), 200 mg BID||B||PK data suggest increased exposure in pregnancy of 1.2-1.6 fold. Limited data suggest high placental transfer.||Fewer than 200 first-trimester exposures reported to the Antiretroviral Pregnancy Registry, precluding conclusions regarding birth defect risk.|
|Rilpivirine (RPV; Edurant), 25 mg QD||Limited PK studies suggest 20% reduced AUC in second trimester and 30% reduction in the third trimester. Placental transfer is unknown.||The limited number of first-trimester exposures reported to the Antiretroviral Pregnancy Registry precludes conclusions regarding birth defect risk.|
|Atazanavir (ATV; Reyataz), PK enhancement required (low-dose RTV), ATV 300 mg + RTV 100 mg QD (increase ATV dose to 400 mg for TDV, EFV, or H2 blocker)||B||PK studies with RTV boosting during pregnancy suggests that standard dosing yields decreased AUC; however, for most pregnant women, no dose adjustment was needed. TDF reduces ATV AUC in all patients by 25%. Placental transfer is low.||Twofold birth defect increase ruled out, 2.2% birth defect prevalence (16 of 922 births). Neurodevelopmental delays have been reported in two studies. ATV-treated adults often have elevated indirect bilirubin levels; increased bilirubin was reported in some infants born to mothers receiving ATV, associated with UGT1A1 genotypes linked to decreased UGT function. Neonatal hypoglycemia has been reported in 3 of 38 ATV-exposed infants.|
|Lopinavir/ritonavir (LPV/r; Kaletra), built in low-dose RTV boosting 400/100 mg BID |
In second and third trimesters, 600/150 mg BID
|C||Once-daily dosing is not recommended in pregnancy. AUC is decreased in second and third trimesters with standard dosing. LPV/r 600 mg/150 mg BID resulted in AUC similar to that of nonpregnant adults receiving LPV/r 400 mg/100 mg. Alternative strategy adds a pediatric LPV/r tablet (100/25 mg) to the standard adult dose. Placental transfer is low.||Twofold increase in birth defect ruled out, 2.2% birth defect prevalence (26 of 1174). Well-tolerated, short-term safety has been demonstrated in Phase I and II studies.|
|Ritonavir (RTV; Norvir), 100 mg to 400 mg in one or two divided doses as PK enhancer||B||RTV levels are reduced in pregnancy, including low-dose RTV PK enhancement to boost the concentrations of other PIs. Minimal placental transfer to fetus.||Limited experience at full dose in human pregnancy; this agent is currently used as low-dose RTV boosting with other PIs. No evidence of human teratogenicity (twofold increase in birth defects ruled out).|
|Saquinavir HGC (SQV; Invirase), use with PK enhancement (low-dose RTV), SQV 1000 mg + RTV 100 mg BID||B||PK data suggest that 1000 mg SQV HGC/100 mg RTV twice daily achieves adequate SQV drug levels in pregnant women. Placental transfer to fetus is minimal.||Well-tolerated, short-term safety has been demonstrated for mother and infant for SQV in combination with low-dose RTV boosting. Baseline ECG is recommended before starting because PR and/or QT interval prolongations have been observed.|
|Indinavir (IDV; Crixivan), prescribe with low-dose RTV boosting (IDV 800 mg + RTV 100 mg) BID||C||Studies using IDV alone showed markedly lower pregnancy levels, compared with postpartum, although HIV RNA suppression was seen. Use only with RTV PK enhancement. Placental transfer to the fetus is minimal.||Twofold increase in birth defect ruled out, 2.4% birth defect prevalence (7/289). |
Pill burden and renal stone potential are concerns. In rhesus monkeys, neonatal IDV exacerbated transient physiologic hyperbilirubinemia; this was not seen following in utero exposure. Given limited data regarding dosing, trough drug levels should be monitored.
|Nelfinavir (NFV; Viracept), 1250 mg BID||B||Using 625-mg tablets, lower AUC and peak levels were seen in the third trimester versus postpartum; however, viral load was suppressed in most women. Placental transfer is minimal.||Twofold increase in overall birth defects ruled out; well-tolerated, short-term safety demonstrated for mother and infant; consider in special circumstances when alternative agents are not tolerated given extensive experience in pregnancy.|
|Darunavir (DRV; Prezista), PK enhancement required; ARV exp with mutations or pregnancy (DRV 600 mg + RTV 100 mg) BID||C||Used in pregnancy with low-dose RTV boosting; reduced third-trimester plasma concentrations have been observed. Placental transfer is low to moderate.||Experience in human pregnancy is limited with 2.3% (6 of 258 births) birth defect prevalence. Once-daily dosing is not recommended in pregnancy, although 800 mg plus RTV 100 mg twice daily is being investigated.|
|Fosamprenavir (FPV; Lexiva) |
Amprenavir prodrug; must use low-dose RTV boosting (FPV 700 mg + RTV 100 mg) BID
|C||With RTV boosting, AUC is reduced in the third trimester; however, trough levels appear adequate for patients without PI resistance mutations. Placental transfer is low.||Data are insufficient to assess human teratogenicity. Unboosted FPV and once-daily dosing are not recommended in pregnancy.|
|Tipranavir (TPV; Aptivus), low-dose RTV PK enhancement required (TPV 500 mg + RTV 200 mg) BID||C||Unknown rate of placental transfer to fetus. Safety and PK data in pregnancy are insufficient to recommend use.||Exposures are insufficient to establish birth defect prevalence.|
|Raltegravir ( RAL; Isentress), 400 mg BID||C||PKs are variable in pregnancy; however, there is no clear relationship between raltegravir concentration and virologic effect in nonpregnant adults. Placental transfer is high.||Severe, potentially life-threatening and fatal skin and hypersensitivity reactions have been reported in nonpregnant adults. One case of markedly elevated liver transaminases was reported with use in late pregnancy. This agent rapidly suppresses viral load, but experience in pregnancy is limited.|
|Dolutegravir (DTG; Tivicay), 50 mg QD for INSTI-naïve patients||B||No studies of DTG use in pregnancy have been reported; placental transfer occurs in animals.||Exposures are insufficient to establish birth defect prevalence.|
|Elvitegravir (EVG; Stribild, which includes COBI/TDF/FTC), 1 tablet daily||B||No studies of EVG use in pregnancy have been reported; breast milk secretion in animals has been reported.||Exposures are insufficient to establish birth defect prevalence.|
The ideal regimen demonstrates durable virologic suppression with immunologic and clinical improvement, is well tolerated with a simple dosage regimen, and has been shown to be effective in pregnancy in terms of reducing perinatal HIV transmission. ARV drug regimens used today are more convenient and better tolerated than previously utilized regimens, and this has resulted in greater efficacy and improved adherence. At least one NRTI with high placental transfer should be included within the ART regimen if possible; consultation with HIV medicine specialists is advised for women with previous ARV use for maternal indications who demonstrate significant ARV resistance upon testing or when there is a suboptimal response to ART. Up-to-date U.S. treatment recommendations, including a comprehensive review of drug interactions within the adult treatment guidelines, are available online at www.AIDSinfo.nih.gov , and the National Perinatal HIV Hotline (888-448-8765) provides free clinical consultation on all aspects of perinatal HIV care.
Maternal cART should be started as soon as possible and should not be delayed for resistance testing results. Resistance testing should still be performed because it provides important information for ongoing patient care, and results can be used to modify treatment if needed. Early initiation of therapy is based on the knowledge that comprehensive regimens that comprise antepartum and intrapartum maternal treatment and postpartum infant treatment provide the best protection against perinatal HIV transmission. Additionally, the European National Study of HIV in Pregnancy and Childhood demonstrated that with longer duration of antenatal ARV prophylaxis, starting prior to 28 weeks’ gestation, each additional week of therapy corresponds to a 10% reduced risk of HIV transmission after adjusting for viral load, mode of delivery, and sex of the infant. Moreover, expanding infant postexposure prophylaxis does not fully substitute for the protective effect of increased maternal ART duration, which also supports early effective maternal treatment. Women with undetectable viral loads should also receive cART because their risk of perinatal transmission is 9.8% if untreated.
Nucleoside/Nucleotide Reverse Transcriptase Inhibitors
Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) are used within combination regimens that usually include two NRTIs with either an NNRTI, INSTI, or a PI. Tenofovir (TDF)–emtricitabine (FTC) is the preferred NRTI backbone in treatment-naïve nonpregnant adults, and Table 53-3 shows recommended NRTI backbones for ARV-naïve pregnant women. FTC is the biologically active form of lamivudine (3TC), thus these drugs can be used interchangeably, and there is no benefit to using FTC and 3TC together. Abacavir (ABC) is associated with hypersensitivity reactions. Human leukocyte antigen B (HLA-B) *5701 testing identifies patients at risk; testing should be performed and documented prior to initiating this therapy, and NRTIs are described in Table 53-4 . ZDV and 3TC remain a preferred treatment option for treatment-naive pregnant women, despite their toxicity, secondary to extensive experience. All NRTIs bind to mitochondrial γ-DNA polymerase , potentially causing dysfunction that manifests as clinically significant myopathy, cardiomyopathy, neuropathy, lactic acidosis, or fatty liver—which resembles hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. Lactic acidosis and hepatic failure have been noted with long-term combined stavudine and didanosine use, linked to a genetic defect in mitochondrial fatty acid metabolism; therefore this regimen should not be used in pregnancy. Mitochondrial toxicity has been observed in children born to HIV-infected mothers treated with NRTIs, although no increase in mortality was observed.
Nonnucleoside Reverse Transcriptase Inhibitors
Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are typically used with two NRTIs. Efavirenz (EFV) remains the preferred NNRTI in pregnancy; however, tolerability concerns and potential suicidality association led to reclassification to an alternative regimen in nonpregnant adults. EFV is associated with a 2.3% birth defect incidence following first-trimester exposure ; however, EFV remains classified as U.S. Food and Drug Administration (FDA) pregnancy category D based on retrospective studies that have reported central nervous system (CNS) defects. Current perinatal HIV treatment guidelines support initiation of EFV after the first 8 weeks of pregnancy. Continuing EFV in virologically suppressed women who present for care in the first trimester is also endorsed because the potential neural tube defect risk is restricted to the first 5 to 6 weeks of pregnancy. This recommendation considers the low likelihood of early pregnancy diagnosis, potential loss of viral control if ARV drugs are changed, and the increased perinatal HIV transmission risk associated with therapy interruption in the first trimester (4.8%). Nevirapine (NVP) is no longer recommended based on its low resistance barrier, high potential for adverse events, and complex lead-in dosing. NVP should not be used for initial treatment in ART-naïve pregnant women with CD4 + cell counts greater than 250 cells/mm 3 ; however, it is safe to continue this drug in women who become pregnant while taking NVP-containing regimens.
Protease inhibitors (PIs) are characterized by minimal transplacental passage and few adverse side effects, and they are typically paired with two NRTIs. These drugs are ideal for patients who require therapy initiation prior to receiving genotyping results because PI-resistant viruses in ARV-naïve patients are uncommon. And because their short half-life protects against the emergence of resistance with therapy discontinuation, PIs are also a good choice for women who may discontinue therapy postpartum; however, these agents are associated with hyperglycemia in adults, although pregnancy does not seem to increase hyperglycemia. An early glucose challenge test followed by repeat testing after 28 weeks is reasonable in high-risk patients. Conflicting data exist regarding preterm delivery in women who receive PIs. During pregnancy, lower serum concentrations of lopinavir/ritonavir (LPV/r), atazanavir (ATV), and nelfinavir (NFV) have been reported; pregnancy-adjusted dosage regimens are detailed in Table 53-4 . Pharmacokinetic (PK) enhancers or boosters—cobicistat (COBI) or low-dose ritonavir, as well as the INSTI elvitegravir (EVG)—improve the PK profiles of several of these drugs via cytochrome (CY) P3A4 inhibition. Although more experience has been reported in pregnancy using ritonavir PK enhancement, multiple fixed-dose combination (FDC) products that incorporate cobicistat are available. Thus providers are likely to encounter women entering pregnancy using cobicistat-containing regimens.
Integrase Strand Transfer Inhibitors
INSTIs are a recently developed class of ARV drugs inhibiting HIV integrase, the enzyme catalyzing insertion of HIV DNA into the human cell genome. Integration is required for replication and stable maintenance of the viral genome, also enabling the establishment of persistent infection. Enzymatic activity consists of two steps: a preparatory step excising two nucleotides from one strand at both ends of the HIV DNA and a final “strand transfer” step inserting viral DNA into an exposed region of cellular DNA. Current integrase inhibitor drugs target the second integration step, strand transfer. Because HIV integrase represents a distinct therapeutic target, integrase inhibitors are expected to maintain activity against HIV that is resistant to other classes of ARV drugs. INSTIs are characterized by their ability to rapidly reduce HIV viral load. Raltegravir (Isentress, RAL) is FDA pregnancy category C and a component of the preferred INSTI regimen in pregnancy.
All HIV-infected women should be screened for hepatitis B virus (HBV) and hepatitis C virus (HCV) unless they are already known to be infected. Recommended screening is via antibody detection, and for HIV-infected women, HBV screening should include hepatitis B surface antigen (HBsAg), anti-HBs, and anti-HBc (hepatitis B core). Women with negative screens should receive the HBV vaccine series. Women found to be HBV coinfected should receive ART that uses an NRTI backbone with two drugs active against HIV and HBV; TDF/3TC and TDF/FTC are the preferred NRTI backbones for HIV/HBV coinfected pregnant women. Women with HBV coinfection should have transaminase testing 1 month after initiating ARV and every 3 months thereafter. Differentiating among an HBV flare, immune reconstitution, and drug toxicity can be challenging, and consultation with an expert in HIV and HBV coinfection is recommended. For prophylaxis, the infant should receive HBV immune globulin and the first dose of the HBV vaccine series within 12 hours of birth. HCV therapy is rapidly evolving, and some regimens are safe in pregnancy; therefore HCV coinfected women should be referred to a hepatologist for treatment evaluation. For coinfected patients, delivery planning should be solely based on standard obstetric and HIV-related indications. Coinfected patients should be screened for hepatitis A virus (HAV); and women who are negative for HAV IgG should receive the HAV vaccine series.
Opportunistic Infection Prophylaxis
Patients with a CD4 count below 200 cells/mm 3 should also receive prophylaxis against opportunistic infections (OIs). Transient CD4 count decreases may occur secondary to pregnancy-associated hemodilution; in these cases, the relative percent of CD4+ cells (see Table 53-2 ) can be used to guide decisions regarding OI prophylaxis. Prophylaxis regimens for Pneumocystis jiroveci pneumonia (PJP), toxoplasmosis, tuberculosis (TB), Mycobacterium avium complex (MAC), and cryptococcosis are listed in Table 53-5 ; additional prophylaxis is listed in the Guidelines for the Prevention and Treatment of Opportunistic Infection in HIV-Infected Adults and Adolescents. Prophylactic pyridoxine is increased to 50 mg/day in pregnancy to prevent maternal and fetal neurotoxicity. When untreated HIV patients are diagnosed with a treatable OI—including TB, MAC, PJP, toxoplasmosis, histoplasmosis, HBV, cytomegalovirus (CMV), varicella zoster virus (VZV), or cryptococcal meningitis—providers should be aware of the potential for immune reconstitution inflammatory syndrome (IRIS) when ART is started. In short, IRIS may be observed when the immune system begins to recover and responds to the previously acquired OI with an exaggerated inflammatory response. However, given the goal of reducing perinatal HIV transmission, ART should be started prior to or concurrent with OI treatment.
|CONDITION||INDICATION FOR PROPHYLAXIS||ANTIBIOTIC REGIMEN|
|Pneumocystis jiroveci pneumonia||Prior infection or CD4 <200/mm 3||TMP-SMX 1 DS tablet QD indefinitely|
|Toxoplasma gondii encephalitis||CD4 <100/mm 3 , Toxoplasma IgG+||TMP-SMX 1 DS tablet QD indefinitely|
|Mycobacterium tuberculosis infection (i.e., treatment of latent infection)||+PPD >5 mm |
No active disease on chest radiograph
|300 mg INH and 50 mg pyridoxine QD for 9 months|
|Disseminated Mycobacterium avium complex disease||CD4 <50/mm 3||1200 mg azithromycin weekly|
|Cryptococcosis||CD4 <50/mm 3||Prophylaxis is not recommended in the absence of documented infection; patients treated for acute cryptococcal infection should receive 200 mg fluconazole QD indefinitely.|
In addition to routine prenatal care and evaluation, viral load should be performed monthly when starting a new medication regimen or when a change in viral load is detected. Patients on stable ART regimens and with suppressed viremia can have viral loads checked each trimester. CD4 counts can be performed every 3 to 6 months. Vaccinations for pneumococcus and influenza should be given as needed. Coordination of services among prenatal care providers, primary care and HIV specialty care providers, mental health and drug abuse treatment services, and public assistance programs are essential to ensure that infected women remain active participants in their care and that they adhere to their ARV drug regimens.
Factors That Influence Transmission
Perinatal HIV transmission risk is associated with cigarette smoking, illicit drug use, genital tract infections, and unprotected sexual intercourse with multiple partners during pregnancy. Elimination of modifiable risk factors reduces perinatal HIV transmission and improves maternal health. Key factors that influence perinatal HIV transmission are listed in Box 53-3 . Most perinatal HIV transmission occurs within the intrapartum period; thus effective cART or scheduled cesarean delivery in patients without viral suppression substantially reduces transmission. A minority of infected infants acquire HIV in utero, as characterized by an infant who is positive by polymerase chain reaction (PCR) testing at birth. Most studies were not designed or powered to prevent in utero HIV transmission, however data suggest that early, sustained control of viral replication prevents in utero HIV transmission. The study evaluated perinatal transmission risk factors in women with HIV RNA of fewer than 500 copies/mL at delivery; the overall HIV transmission rate was 0.5% in this population. HIV transmitters were less likely to have received ARV drugs at the time of conception than nontransmitters. Moreover, HIV transmitters were less likely to have HIV RNA of fewer than 500 copies/mL at 14, 28, and 32 weeks of gestation. Among women starting ARV during pregnancy, viral load decreased earlier in nontransmitting women, and both groups initiated therapy at the same time (30 weeks’ gestation). This suggests that early and sustained control of viral replication is associated with decreased HIV transmission, which supports cART initiation as early in pregnancy as possible for all women not treated preconceptionally.