Perinatal Infections

Infections have plagued humankind since the beginning of recorded history. Obstetricians who deal with both the mother and fetus are faced with balancing the health of both. Many infections may have mild, if any, effects on the mother but cause devastating damage to the fetus, especially if they occur in early pregnancy. In addition to the difficulties in diagnosis because of the frequent lack of symptoms, the problem is compounded by the fact that most of these infections are viral, with no specific therapy. Other organisms infect the fetus during the birth process, resulting in serious and sometimes lethal neonatal illness. More recent evidence seems to point to an infectious etiology to premature labor and possibly even to cerebral palsy. The clinician faces serious dilemmas in caring for patients who may be at risk for an adverse outcome. Should there be screening for all pregnant women? If the tests are positive, how can the results be interpreted? How should we advise patients who test positive or those who are carriers for organisms that may impact on pregnancy outcome? Most of these questions cannot be answered, but it is hoped that further clinical investigations may provide some future clarification of these issues.

Toxoplasmosis, other (syphilis, hepatitis, zoster), rubella, cytomegalovirus, and herpes simplex, or TORCH infections, are a group of maternal infections that have few maternal symptoms, lack effective therapy and can have major consequences for the fetus. Prenatal diagnosis of these infections is generally inconclusive, and routine screening is not currently recommended, except for rubella.

Toxoplasmosis

The incidence of congenital toxoplasmosis has been reported to be anywhere from 1 in 1000 to 1 in 10,000 births.¹ Universal screening in Massachusetts and New Hampshire reported a rate of 0.82 confirmed cases per 10,000 births.²  The rate of congenital infection is about 15% in the first trimester, 25% in the second trimester, and 60% in the third trimester.³ The severity of congenital infection, however, increases with gestational age. Spiramycin has been reported to decrease the rate of fetal infection by 60%.⁴

Toxoplasmosis is caused by Toxoplasma gondii, a protozoan parasite. The organism is carried by wild rodents and cats and in its oocyst form can persist for extended periods in soil. The prevalence of toxoplasmosis in the United States is 20–50%, as determined by serologic screening of adults.⁵ Much higher rates occur in Europe and Africa. Most adults with positive serologic tests are unaware that they have had the disease because 80% of acutely infected patients are asymptomatic. Even when symptoms do occur, they are nonspecific, or appear as a viral syndrome, suggesting mononucleosis.⁶ A single, enlarged cervical lymph node is the most common clinical presentation among women who exhibit symptoms.⁷ Negative test results for mononucleosis⁵ should lead to suspicion of toxoplasmosis or cytomegalovirus (CMV) infection. The disease is acquired from oocysts in the feces of an infected cat or from eating or handling (hand-to-mouth contact) raw or undercooked meat. Cats that are confined indoors to avoid wild rodents and those that are fed only cooked food present no threat. Careful handling of the cat litter affords added protection.

The perinatal risk of toxoplasmosis occurs only when the infection happens just before or during pregnancy.^{8, 9} As is true of most of the perinatal infections, the risk is greatest when it occurs in the early weeks. Fortunately, the organism is somewhat less likely to cross the placenta in the first trimester than it is later in the pregnancy. The rate of perinatal transmission increases with gestational age secondary to the well developed placental blood flow. About 50% of women infected at any time during pregnancy will give birth to infected children if they are not treated.⁵ With first-trimester transmission, spontaneous abortion is common, but if the fetus is affected and survives, the consequences can be devastating. The syndrome of congenital toxoplasmosis is characteristic, and its manifestations include growth restriction, chorioretinitis, microcephaly, convulsions, skin rash, hepatosplenomegaly, pneumonitis, jaundice, and fever. Intracranial calcifications result from the destruction of neural tissue. Anemia and thrombocytopenia can occur, but the spinal fluid findings may be nonspecific. Many of these infants (85%) die; however, those who survive are seriously disabled, especially neurologically: 80% have seizures, 60% are spastic, 50% are visually impaired, and 28% have hydrocephalus or microcephaly.

Most commonly, the diagnosis is not made in the mother until abnormalities are seen on ultrasound or an affected child is born. Occasionally, suspicion is engendered by a mononucleosis-like syndrome, especially if the circumstances suggest it (ingestion of raw meat or contact with cats). The diagnosis is made serologically using the Sabin–Feldman dye test or an indirect immunofluorescent antibody test.¹⁰ The former is more specific but less widely used. In both instances, one must demonstrate a conversion from negative to positive or a rising titer to establish a diagnosis.

The problem in diagnosis is to differentiate acute infection from a residual titer representing a past infection. Immunoglobulin M (IgM) antibodies to T. gondii may persist for years in healthy individuals. Positive IgG and IgM titers do not necessarily indicate a recent infection. There is a specific IgM test that is helpful,¹¹ and more recently, attention has been focused on detecting subsets of IgG antibodies that are formed only in the early stages of infection. A differential agglutination test¹² and immunoblot and enzyme-linked immunosorbent assay (ELISA) tests for IgG subclasses¹³ are available. In 1996, the United States Food and Drug Administration (FDA) and Centers for Disease Control (CDC) conducted an extensive evaluation of the six most commonly used commercial IgM kits in the United States. The sensitivity ranged from 93.3 to 100%. The specificity ranged from 77.5 to 99%.¹⁴ In 1997, the FDA issued an advisory to physicians informing them of the limitations associated with serologic testing.¹⁵ A positive result in any IgM test should be confirmed at a toxoplasmosis reference laboratory, such as the Toxoplasmosis Serology Laboratory at the Palto Alto Medical Foundation (http:www.pamf.org/serology). When the diagnosis of acute infection is made during pregnancy, it is important to determine whether fetal infection has occurred because the responses, abortion, or treatment with potentially toxic drugs cannot be justified if the fetus is not infected. Chorionic villus sampling, amniocentesis,¹⁶ and cordocentesis¹⁷ with analysis of fetal blood have all been used. A number of techniques have been used to evaluate these specimens, including IgM testing, tissue culture, and mouse inoculation. More recently, a polymerase chain reaction (PCR) method has proved both accurate and rapid.¹⁸ Ultrasound findings of hydrocephaly, intracranial calcifications, or hydrops may provide indirect evidence of congenital Toxoplasma infection.¹⁹

If the diagnosis is suspected at delivery, it can be confirmed by histologic evaluation of the placenta, which must be promptly fixed in formalin. Rarely, the diagnosis is made by lymph node biopsy.²⁰

The diagnosis in the newborn is suspected on the basis of clinical findings or from a diagnosis established in the mother. It is confirmed by a positive specific IgM test or a persistent or rising IgG titer, indicating it is of neonatal and not maternal origin.

Therapy is generally not required for the mother because most adults, if immunologically intact, recover spontaneously.

Clinicians should be particularly alert to the coexistence of toxoplasmosis and acquired immune deficiency syndrome (AIDS), in which case the manifestations of toxoplasmosis are likely to be far more severe. When the diagnosis of acute Toxoplasma infection is established during pregnancy and ideally confirmed in the fetus, there are two management options. Because the fetal consequences are severe, especially if infection occurs in the first trimester, pregnancy termination should be offered. A second option is to treat the mother in an effort to reduce the fetal effects. There is evidence from European trials that the severity of congenital infection can be reduced by such an approach.²¹

The regimen available in the United States includes sulfadiazine, 1 g orally four times a day, and pyrimethamine, 25 mg orally four times a day, both for 28 days.²² Sever et al.²² suggest that folinic acid, 6 mg intramuscularly (IM) or orally three times a week, be given to lessen the hematologic effects of the pyrimethamine, a folic acid antagonist. It is preferable to avoid the use of pyrimethamine in the first trimester and sulfadiazine close to term. Spiramycin has been used effectively in Europe but is not available in the United States. However, it is available for the treatment of pregnant women from the Division of Special Pathogens and Immunologic Drug products at the US Food and Drug Administration (301–827–2127). It should be emphasized that such therapy does not guarantee a newborn free of the effects of toxoplasmosis. Subsequent pregnancies are rarely affected.

Therapy for the symptomatic newborn is accomplished with the same drugs; however, several courses are often necessary. Infants with no symptoms should be treated only if the specific IgM test is positive or if IgG is stable or rising. Isolation is not necessary.

The obvious means of prevention of congenital toxoplasmosis are preventing infection during pregnancy and detecting infection during pregnancy to provide early treatment. Important infection avoidance measures include not eating raw or undercooked meat, carefully washing fruits and vegetables, and wearing gloves while gardening and handling cat litter. It is best that litter be changed frequently to avoid drying with resultant aerosol spread. Cats that are confined house pets and eat only pasteurized and thoroughly cooked food are not a risk. Attempts at early detection of infection during pregnancy are much more difficult than prevention. Only 10% of immunocompetent women with acute infection have symptoms, and maternal symptoms do not correlate with fetal infection. Consequently, the only way to accomplish this purpose is by systematic screening. This requires identifying women at risk (those who are seronegative before pregnancy) and periodic testing during pregnancy. Such programs have been effective in France and Austria but have not yet been evaluated in the United States. In the United States, routine screening for toxoplasmosis is not currently recommended during pregnancy; however, screening is recommended for women who are HIV positive.

Rubella

The prototype of the perinatal infections was first recognized by the Australian ophthalmologist Gregg in 1941 during a rubella epidemic.²³ Although large numbers of cases occur in epidemics, the sporadic incidence is low. Eighty to 90% of the adult population is immune, and with the use of rubella vaccine, the susceptible population can be further reduced. Nonetheless, sporadic cases do occur, posing a serious threat to the pregnant woman and her fetus. Although the incidence of rubella reached an all-time reported low in 1988, there has been a distinct increase in the incidence since then, reaching the highest level since 1982 during 1990. Distinct outbreaks seemed to occur in two settings: (1) in locations in which unvaccinated adults congregate, such as workplaces, colleges, and prisons, and (2) among children in religious communities with low levels of vaccination.²⁴ There also has been an increase in the reported cases of congenital rubella syndrome, but the absolute numbers are quite small.

If rubella occurs in the first trimester, the virus is severely cytopathic and the most common result is spontaneous abortion. If the early pregnancy survives, the incidence of some effect in the fetus is high (up to 70%).²⁵ The full-blown clinical picture, the “expanded rubella syndrome,” is not readily distinguished from congenital toxoplasmosis or CMV infection, at least not without the aid of laboratory tests. Typically, there are growth restriction, cataracts, pneumonitis, deafness, heart disease, jaundice, hepatosplenomegaly, and decreased platelets. The mortality is high (up to 33%). When rubella occurs in the second trimester, the effects are less severe; if it occurs in the third trimester, there may be no obvious effects, except for a positive IgM antibody test in the cord blood. Unfortunately, however, the viral genome tends to remain latent in neural tissue. Children born with minimal or no effects may fall victim to the activation of the rubella virus in the second decade of life, in the form of a fulminant panencephalitis.²² The newborn with congenital rubella sheds virus for up to 1 year and consequently is an infectious hazard to healthcare personnel. The placenta is also a source of virus.

The most common problem the clinician faces with regard to rubella is exposure of the pregnant woman to an infected child. Confirmation of the diagnosis by a pediatrician is most helpful. Although the clinical diagnosis is usually not difficult, similar pictures can be seen with enteroviral infections, mild measles, and human parvovirus B19. Consequently, serologic confirmation is essential, considering the pregnancy implications. If the pregnant woman is known to be immune by prior testing, only reassurance is needed. If her status is not known, an immediate hemagglutination inhibition (HI) titer should be done and a portion of the serum preserved by freezing.²⁶ This should be done within 10 days of exposure because later testing will be less discriminating. If this initial test shows detectable antibody, the patient can be reassured that she is immune from a prior exposure or vaccination. Some repeat this test in 4 weeks for reassurance. If the initial test shows no detectable antibody, the patient should be observed for the development of clinical illness and repeat titers should be done at 2 and 4 weeks. Up to one-third of adults who contract rubella have no signs or symptoms. All samples should be saved by freezing and tested simultaneously in the same laboratory to avoid the problems of variation in technique. Conversion from negative and a fourfold rise in titer indicate acute infection, and the patient should be counseled accordingly. If no antibody develops and no clinical infection appears, the patient can be reassured. If, for any reason, there is a delay in evaluating the patient after exposure, the HI titer may already be positive and therefore not helpful in confirming the diagnosis. The detection of rubella-specific IgM within 28 days of the clinical syndrome is diagnostic. There have been some reports of cross-reactions between rubella and human parvovirus infections in IgM tests. Therefore, caution should be exercised in interpreting low or equivocal values of rubella-specific IgM values.²⁷

Treatment of the mother who has rubella is limited to symptomatic measures because the illness is not a serious one. The use of gamma globulin is not advised because it may well modify the clinical illness without preventing the fetal effects. Should the patient be unable to consider termination under any circumstances, gamma globulin might be considered if all concerned accept the fact that there is no evidence that it will prevent fetal effects. Essentially, then, appropriate management for the gravida with rubella is to provide the information necessary for her to make a considered decision regarding the continuation of the pregnancy.

With the development of rubella vaccine, there is now at least the theoretical possibility for preventing congenital rubella. Because natural immunity protects 80–90% of women in the reproductive age group, the remainder might be covered by childhood immunization. Unfortunately, this strategy has not proved effective because a significant number of those immunized lose detectable antibody in 5–10 years. Although it is still recommended that all children be immunized (at about 15 months of age), women must be retested when they reach childbearing age and vaccinated again if antibody is not detected. This must be done when the woman is not pregnant and will not conceive for three cycles. Although the fetal risks of the vaccine virus appear to be considerably less than those of the wild virus,²⁸ the vaccine virus does gain access to the products of conception, and there is at least one case of suspected eye damage resulting from infection of the fetus with vaccine virus.

Since 1979, with the introduction of the RA 27/3 rubella vaccine, a registry of administrations during pregnancy has been maintained, and there is no evidence of congenital rubella syndrome among 272 susceptible, 32 immune, and 379 women of unknown immune status. Prior reviews of women vaccinated during pregnancy with the Cendehill or HPV-77 vaccines also failed to show evidence of congenital rubella syndrome.²⁹ Based on this information, there is no reason to recommend pregnancy termination for women inadvertently vaccinated during pregnancy. An alternative time for the vaccination of susceptible women is immediately postpartum, when conception is less likely. Breastfeeding is not contraindicated for the vaccinated mother. Patients should be tested for immunity before vaccination, and because there is a 5% failure to develop antibody, follow-up titers should be done in 6–12 weeks. Revaccination is indicated if no titer has developed. Complications are not common, the most frequent being a transient arthralgia. There continues to be a search for more potent vaccines that might provide more complete protection.

Cytomegalovirus

Cytomegalovirus is the most frequent of the TORCH infections affecting the newborn.  It is the most common cause of congenital hearing loss and neurological impairment.³⁰ It is a double stranded DNA virus that is part of the human herpesvirus family. As with other members of this family, it has the ability to establish latency and reactivate at a later time. CMV is acquired by 1–2% of all newborns, and approximately 10% of these newborns show some evidence of damage if they are carefully followed. This makes the incidence of significant neonatal infection 1 in 500 to 1000 births. Congenital transmission of CMV can occur with primary infection, reactivation or recurrent maternal infection during pregnancy, although the risk of congenital infection is much higher with primary infection (30–40% with primary infection versus less than 1% with recurrent infection). Maternal recurrent CMV occurs more frequently than primary infection (1–14% vs. 0.7–4%).³¹ There is a steady acquisition of CMV from birth to the reproductive age, by which time 50% of women have serologic evidence of prior infection.¹² CMV is transmitted by contact with infected blood, saliva, urine or by sexual contact. CMV is isolated from the endocervix of 3–5% of sexually active women. This provides for additional exposure during the birth process.

In healthy adults, transmission requires prolonged or repeated intimate contact. The incubation period is 30–60 days. CMV is usually asymptomatic in adults with intact host defenses. If symptoms occur, they typically include malaise, fever, headache, and myalgia. Laboratory findings may consist of relative lymphocytosis and thrombocytopenia. Moderate elevation in liver enzymes may also occur. Most infections resolve in 2–6 weeks. CMV is endemic and serious among those immunocompromised patients with organ transplants or those receiving cancer chemotherapy. These patients are a hazard to pregnant healthcare personnel. CMV can also be spread by blood transfusion, usually resulting in an enigmatic fever in a recently transfused patient.²⁵ Most often, however, the diagnosis is unsuspected until the birth of an affected infant. Confirmation of the diagnosis is not simple.³² Serologic testing is complicated by the large number of patients who have antibodies from prior exposure. Even sophisticated techniques such as ELISA and neutralizing antibody test do not necessarily clarify the situation. Rapidly rising titers and a specific IgM are good indicators but can take time. Virus isolation is the most reliable diagnostic method, but the process may take as long as 6 weeks.

As is true of the other TORCH infections, the fetus can be affected at any stage of pregnancy, but the effects are most severe when it occurs early.³³ More severe sequelae are seen in children of mothers with primary infection. Ten to fifteen per cent of infants with congenital CMV infection are symptomatic at birth. Maternal infection in the first trimester can result in a full-blown syndrome similar to that seen with toxoplasmosis and rubella. Manifestations include growth restriction, microcephaly, intracranial calcifications, chorioretinitis, hepatosplenomegaly, and disseminated intravascular coagulation. The mortality rate among symptomatic infants is 20–30%. Ninety per cent of those who survive have serious neurological sequelae.³⁴ Clinical manifestations include mental retardation, seizures, hearing loss, visual problems, and developmental delay. Asymptomatic infants are also at risk, for 5–15% of them are found to have neurological sequelae, especially sensorineural hearing loss.³⁵ Differentiation from other TORCH infections generally requires laboratory assistance. With infection later in pregnancy, the fetal effects are less serious, and in the third trimester the only apparent result may be a positive specific IgM or viral isolation. The question of long-term effects is not completely settled.³⁶ Some have reported a definite association with deafness, but the relationship to learning disabilities, for example, is less clear. There are isolated reports of fetal infection as the result of intrauterine transfusion. Neonatal infection can occur from multiple sources, including breast milk, and is characterized by pneumonia and hepatosplenomegaly.

Currently, there is no effective therapy for CMV infection during pregnancy. Ganciclovir is used to treat CMV in immunocompromised patients. It has hematologic toxicity. Treatment with ganciclovir during pregnancy has not been shown to prevent congenital CMV infection.³⁷ The diagnosis is rarely established during pregnancy, but this presents the only opportunity for intervention. The pregnant woman who presents with a mononucleosis-like syndrome should be carefully evaluated for CMV infection. If the diagnosis is confirmed, she can be offered counseling with regard to the prognosis and the possibility of termination.³⁸ As with other perinatal infections, there are increasing numbers of reports of confirmation of the diagnosis of CMV in the fetus. Viral isolation from amniotic fluid, cordocentesis with serologic testing, and viral culture have been reported.^{39, 40} Reports suggest that PCR done on amniotic fluid samples obtained after 21 weeks' gestational age appears to be a reliable method of detecting CMV infection, even after a 7-week interval.⁴¹ There may be a relationship between the quantity of CMV detected in the amniotic fluid and the presence of fetal abnormalities. Higher quantities of viral DNA were identified in the amniotic fluid of symptomatic fetuses and newborns compared to those without symptoms.⁴² Prenatal detection of intracranial calcifications has also been reported, but this usually occurs too late in gestation to provide useful options.⁴³

Recent studies by Nigro and colleagues have shown a significant reduction in both the incidence and severity of congenital CMV with the use of passive immunization with hyperimmune globulin (CMV HIG).^{44, 45} Likewise, there is no specific therapy for the affected newborn though neonatal treatment with ganciclovir showed prevention of hearing loss progression.⁴⁶ Isolation is indicated, however, because both the infant and the placenta are infectious. Subsequent pregnancies are rarely affected.

There is considerable effort underway to develop a CMV vaccine.⁴⁷ This is primarily directed toward patients who will undergo organ transplantation. The work has been hampered by the fact that the virus does not always express its genome completely in tissue culture. There is also the concern that the vaccine strain may  reactivate and shed from the cervix and into the breastmilk. There is even a concern about oncogenicity. For these reasons, the application of the vaccine in preventing perinatal infection is not imminent. Women of childbearing age should be educated about CMV infection and transmission. They should be cautioned about the careful handling of soiled diapers. Effective handwashing is critical in the presence of young children and immunocompromised individuals.

Herpesvirus

Most (85%) genital infections are caused by Herpesvirus hominis (HSV) type II, with the major perinatal concern being infection acquired by the infant during the birth process.⁴⁸ Such infections are infrequent (1 in 5000–20,000), but the morbidity and mortality are high. In contrast, the frequency of maternal infection is relatively high. When prenatal patients are screened by both endocervical culture and observation for lesions, the rate is 0.5–1.0%. The comparison of these rates would indicate a relatively low attack rate, although some authors have suggested that the risk of neonatal infection is as high as 50% when vaginal delivery occurs through an infected birth canal. The factors that determine whether a fetus exposed to HSV becomes infected and whether the infection will be systemic or localized are not well understood. Some have suggested that the presence of humoral antibody is critical; however, neonatal infection has been reported in the presence of both maternal and passively acquired fetal antibodies. The present state of knowledge does not permit decisions concerning the route of delivery based on the patient's immune status.

The clinical diagnosis of genital HSV is simple when there are characteristic lesions; however, surveys indicate that as many as 40% of infections in pregnant women are asymptomatic and 20–30% of lesions atypical. Primary HSV infection is relatively uncommon in pregnancy. In this situation, the patient lacks antibody to both HSV I and HSV II and becomes systemically ill, the result of viremia, with fever and malaise. Multiple lesions are the rule, with severe pain and tender inguinal lymph nodes. Urinary retention is a common symptom secondary to vulvar lesions, which are sensitive to contact with urine, and also to a degree of neurogenic bladder dysfunction resulting from the virus in the dorsal nerve roots. The lesions begin as vesicles, which unroof to become wet ulcers and subsequently form a dry crust. Viral shedding from lesions continues until they dry, most often for 7–10 days, but can occur for as long as 30 days. Some patients continue to shed virus from the endocervix after vulvar or vaginal lesions heal. Disseminated HSV infection is rare in the adult but may be lethal.⁴⁹ A more common complication is meningitis, and patients should be observed for the occurrence of headaches, stiff neck, photophobia, and other signs of meningeal irritation.

Because recurrent infection is common (up to 50% of patients), patients should be counseled about that possibility. Recurrences generally occur within 6 months and average three or four per year for the next few years. It has been suggested that HSV is more likely to recur during pregnancy. After primary infection, the virus is presumed to migrate along the sensory nerve and remain latent in the dorsal nerve root. The activating factors may be obvious, such as a menstrual period, or unknown, but in either case the virus travels down the same sensory nerve, producing a lesion in the same area as the primary one. Because there are circulating antibodies, there is protection against viremia and the clinical illness is milder and of shorter duration. Viral shedding occurs for a shorter time.

The diagnosis of HSV infection is best established by viral isolation.⁵⁰ HSV must be grown in tissue culture but is relatively easy to isolate, and positive cultures can usually be reported in 24–48 hours. Samples are best obtained from a wet ulcer or by unroofing a vesicle and scraping the base. Material should be placed in a commercial transport medium, which may be frozen if it cannot be processed promptly. Cytologic methods are an alternative. Smears can be stained by a variety of techniques, including Papanicolaou (Pap). The findings include multinucleated giant cells with viral inclusions, and in good hands the method is 80–85% accurate, with the major problem being false-negative results. The diagnosis can also be made by the viral type specific DNA PCR method, which is more sensitive than viral cultures.^{51, 52}  Immunofluorescent monoclonal antibody techniques may provide for easier screening. Detection of HSV antigens by ELISA immunofluorescence is another diagnostic method that has been developed. Although this approach has the advantage of being rapid, it is not as sensitive as viral culture.

Serologic testing is of limited value because many patients have type I antibodies and 30–60% have type II antibodies from prior exposure. The antibodies are cross-reactive in preventing viremia but can be separated in the laboratory by relatively complex procedures. The importance of serologic testing is the differentiation between primary and recurrent HSV infections; however, because antibody does not provide complete protection for the neonate, the information is of limited application. A specific IgM test is diagnostic for recent infection, but the test is not widely available.

Neonatal infection may be systemic or localized to the skin, eyes, or mouth. Systemic disease has multiple system involvement, including the central nervous system, with a very high mortality (over 50%). Because of this, aggressive antiviral therapy with potentially toxic agents is justified. Survivors commonly have serious residua, and there are even sequelae with localized disease. When primary infection occurs antepartum, the results vary with the time of occurrence. In the first trimester, the cytopathic virus most often leads to spontaneous abortion, although rarely, congenital infection similar to the other TORCH infections occur. Primary infection in the late second and early third trimester increases the risk of premature labor. Because the potential consequences are so severe, it is appropriate to counsel the patient with first or second trimester primary infection about termination options. If abortion is not an acceptable option, acyclovir therapy might be considered. To date there is no evidence of teratogenicity or other adverse effects of acyclovir in pregnancy.⁵³

Sexual contact with potentially infected partners should be avoided. If primary infection occurs in the first trimester, there is little experience on which to base a logical therapeutic approach. If spontaneous abortion does not occur, the patient should be advised of the risks; however, the magnitude of the risk is not known. Amniocentesis with attempts at viral isolation from the fluid has been suggested as an approach to deciding the route of delivery.⁵⁴ The suggestion is that a positive culture obviates cesarean delivery, the fetus already being infected. There is, however, no evidence to support this theory.

The problem more often faced, however, is the patient in whom a nonprimary first episode genital infection (previous type I, nongenital infection with circulating antibody) or a recurrent genital infection develops, or the patient who is at risk for either of these (prior infection). Available evidence suggests that there is no greater risk to mother or fetus in the patient with a nonprimary first episode infection than in the patient with recurrent infection. Such patients should be followed by regular careful examinations of the genital area for the presence of lesions. Special attention should be given to the site of prior lesion because recurrences will occur in the same dermatome. Blind cultures have not proved helpful and are not recommended unless lesions are present. If lesions are present at the onset of labor, or when the membranes rupture, delivery should be by cesarean section. If no lesions are present, in the absence of prodromal symptoms, vaginal delivery is acceptable. Cultures of the mother and infant should be obtained to give a time advantage to the pediatricians should an infection develop.⁵⁵ Antiviral prophylaxis should be considered at 36 weeks in women with the first episode occurring during the current pregnancy and women at risk for recurrent outbreaks.⁵⁶

Available studies indicate that if the membranes have been ruptured for more than 4 hours, the probability is that ascending infection may already have occurred and cesarean delivery will not be helpful.⁵³ Although this is a general principle to guide therapy, it should not be applied rigidly. There is no evidence that there is a duration of premature rupture of membranes beyond which the fetus does not benefit from cesarean section.⁵⁷ 

The problem for the future in the management of HSV in pregnancy is the identification of those women who have unrecognized asymptomatic infection. Evidence indicates that most cases of neonatal HSV infection occur in neonates born to women without lesions and not known to be asymptomatically infected. Rapid, accurate HSV testing and the possibility of screening large populations may provide an answer to that problem. After delivery, the patient must be instructed about precautions to be taken in dealing with the infant. Although isolation may be ideal, it is not practical. Hand washing and the use of occlusive dressings and gloves will prevent contact. It must be noted that an oral HSV lesion in the mother may provide an even greater risk than a genital lesion.

The newborn of a mother with active HSV should be isolated from other newborns and observed for lesions for 2 weeks. If none occur by that time, the risks have passed. If lesions or positive cultures occur, the newborn should be treated with antiviral agents. Breastfeeding is not contraindicated unless breast lesions are present.

Parvovirus 

Human parvovirus B19 was first identified in 1975 by Cossart and colleagues.⁵⁸ Infection peaks in the winter and spring months. It is a nonenveloped single-stranded DNA virus that causes erythema infectiosum (fifth disease) in children. In adults, the presentation may consist of flu-like symptoms including low grade fever, malaise, and headache. Arthralgia may also occur. Approximately 25% of infected adults are asymptomatic. Immunocompromised adults, however, may develop chronic parvovirus B19 infection with anemia and aplastic crisis.

The annual incidence of acute parvovirus infection during pregnancy is 1 in 400 pregnancies. The seroconversion rate is approximately 16%. The risk of acute infection is highest for susceptible pregnant women with school age children and those who are teachers. The risk of vertical transmission to the fetus is 33%.⁵⁹ Parvovirus has a predisposition for fetal erythroid progenitor cells. It induces cell cycle arrest at the G1 and G2 phases.⁶⁰ Damage to red blood cell precursors leads to severe anemia. Severe anemia and tissue hypoxia can lead to high output cardiac failure and fetal hydrops. Myocarditis may be another pathway to fetal cardiac failure. Parvovirus can also attack the fetal platelets and liver. Nonimmune hydrops occur in approximately 3% of infected fetuses.⁶¹ Fetal infection may also result in spontaneous abortion and stillbirth.⁵⁹

Unfortunately, methods to limit exposure to parvovirus have been ineffective. The phase of viral replication and shedding occurs prior to the development of symptoms. By the time the host is symptomatic, she is no longer infectious. A high index of suspicion is necessary to diagnose infection during pregnancy. It should be entertained when there is a known contact with an infected host and during the evaluation of a pregnancy complicated by nonimmune hydrops. Maternal infection is diagnosed by serologic testing detecting specific IgM antibodies. Negative IgM and IgG titers indicate a nonimmune or window status. Paired sera samples should be repeated in 3–4 weeks to rule out seroconversion. Positive IgG and negative IgM titers indicate prior infection and immune status. There is no risk of fetal infection. Positive IgM with or without positive IgG titers indicates acute infection. The fetus is thus at risk of infection and hydrops. Amniocentesis, with PCR to detect parvovirus DNA, can be used to diagnose fetal infection. Fetal death following infection has been reported from 4 to 12 weeks. Fetal surveillance is thus recommended up to 12 weeks after infection. In the late second and third trimesters, this includes weekly ultrasound examinations to search for evidence of hydrops and to evaluate the middle cerebral artery Doppler evaluation can be used  to identify fetal anemia from velocimetry of the middle cerebral artery.⁵⁹ Peak systolic velocity (PSV) is inversely proportional to the fetal hemoglobin level. Middle cerebral artery PSV greater than 1.5 MoM for gestational age or an increased trend is associated with severe fetal anemia.⁵⁹ The sensitivity of PSV in detecting fetal anemia is 94%.⁵⁹ Fetal anemia is confirmed by umbilical cord blood sampling. Severe fetal anemia remote from term can be managed with intrauterine blood transfusion.  Spontaneous resolution of nonimmune hydrops without transfusion has been reported.^{62, 63, 64}

Acquired immunodeficiency syndrome (AIDS)

The human immunodeficiency virus (HIV) epidemic is now over 30 years old. The number of cases of people living with HIV/AIDS globally rose from 29 million in 2001 to 33.2 million in 2007.⁶⁵ Since the first cases of HIV disease, diagnosed June of 1981, there have been tremendous advances in the understanding of the pathophysiology, diagnosis, and management. Advances in treatment, particularly with highly active antiretroviral therapy (HAART), have dramatically reduced the mortality and morbidity. We now are faced with the challenge of managing pregnancies of women who have acquired HIV via perinatal vertical transmission.⁶⁶ HIV infection is still a leading public health problem in the United States, and a major perinatal infection, particularly in urban areas. It is currently the leading cause of death among young adults 25–44 years of age. The incidence of AIDS is increasing faster among women than among men. In 2008, there were an estimated 1.2 million people living with HIV/AIDS in the United States.⁶⁷ The CDC estimates that 40,000 persons in the United States are infected with HIV each year.^{68, 69} In 2006, blacks accounted for 49% of the  AIDs cases diagnosed and Hispanics accounted for 19%.⁶⁷ Black and Hispanic women consistently account for approximately three-quarters of HIV and AIDS cases in women. The etiology is a retrovirus, HIV, which was first isolated in 1983.⁷⁰ Although the epidemic appears to have slowed among gay males because of behavior modification, the same cannot be said for the drug-abusing population. Among women with AIDS in New York City, 61% are drug users and 25% are sexual partners of drug users. Seroprevalence in obstetric patients varies widely with a high of 12% in Zambia. In New York City, the rate was 1 in 77 in 1987.⁷¹ Because of the association between poverty and substance abuse, as well as secondary heterosexual spread, HIV disproportionately affects inner city blacks and Hispanics. In New York City, 59% of males, 85% of women, and 90% of children with HIV are minorities. Cocaine use, lack of prenatal care, syphilis, and HIV all are more common in this population.

The diagnosis of HIV in the adult is made by detecting antibodies to HIV, usually with ELISA and confirmed by a western blot analysis. The sensitivity and specificity are high; however, in low-prevalence populations, there is an increase in false-positive results. A disproportionate amount of HIV-infected women receive no prenatal care.⁷² Rapid HIV testing can be used to identify women with HIV infection who present in labor without a documented HIV status. There are several rapid tests available. The OraQuick, OraSure, and Reveal are FDA approved and available. The diagnosis in the newborn is more difficult because of passive transmission of maternal IgG antibodies. These may take 15–18 months to clear. Many approaches have been suggested to overcome the problem. Viral culture is useful but time consuming and expensive. Measuring IgA antibodies and the use of PCR studies to detect portions of the viral genome are the most promising. Although they identify only a small portion of infected newborns in the first month of life, these methods can identify almost all by 6 months.^{73, 74, 75}

The key role for the obstetrician–gynecologist with regard to HIV and pregnancy is counseling and testing, because under most circumstances, once identified, the infected patient can be referred or at least co-managed with someone specifically expert in HIV. HIV testing has been the subject of considerable debate. Offering testing based on high-risk behavior fails to identify up to 40% of infected individuals who do not admit such behavior.⁷⁶ There are variations of two prenatal HIV testing strategies that are most commonly practiced in the United States. The opt-in approach requires specific informed consent. This strategy is the foundation for most state laws and regulations in effect today.⁷⁷ The op-out approach is when universal HIV testing, with patient notification, is a component of routine prenatal care. This approach is associated with higher rates of testing and is endorsed by the American College of Obstetricians.⁷⁷

There are differing views on the impact of pregnancy on the course of HIV infection. Early anecdotal reports suggested an acceleration of the clinical course, and follow-up of asymptomatic women who gave birth to children in whom AIDS developed suggested the same. It is possible, however, that these women were more prone to both perinatal transmission and disease progression. Finally, when HIV-positive pregnant women are monitored with CD4 counts, those with low counts (below 300) are more prone to opportunistic infection.

Studies concerning the impact of HIV infection on the course of pregnancy are also somewhat confusing. Although some show no impact on parameters such as low birth weight and prematurity, others are in disagreement. There are, of course, confounding variables such as the stage of HIV disease, poor nutrition, poverty, and drug use. Determination of the rate of prenatal transmission has been hampered by the difficulties in newborn testing already described. Best estimates now indicate that the transmission rate is in the range of 20–35%.⁷⁸ In New York City, 86% of pediatric AIDS cases are the result of perinatal transmission, the bulk associated with drug abuse. Interestingly, only 11% of the prenatal cases were born to symptomatic parents.

Counseling is the first critical step in managing the HIV-infected gravida. This should be done as early as possible in pregnancy to provide the patient with all her options. Counseling should include a discussion of the manifestations of AIDS, its prognosis, and advice concerning behavior that could result in infecting others. Patients should be urged to share the diagnosis with other healthcare providers and partners, and they should be made aware of the risks of perinatal transmission.⁷⁹ The potential risks and benefits of antiretroviral therapy, especially during the first trimester, should be discussed. In addition to counseling and psychosocial support, management must involve screening for other infections and vaccination against pneumococcal pneumonia and hepatitis B and C. Monitoring the CD4 counts and viral load can help identify patients at risk for opportunistic infection and disease progression. It may be difficult to evaluate HIV-infected patients' symptoms during pregnancy because some symptoms, such as fatigue and modest weight loss, may be dismissed as pregnancy related. The management of HIV-infected pregnant women requires consultation with an infectious disease specialist. Pregnancy should not significantly alter the management of this disease. The criteria used to guide the use of antiretroviral therapy are generally unchanged. As in the nonpregnant patient, antiretroviral therapy is given when the CD4 count is less than 350 or viral load greater than 100,000 copies. A HAART regimen should be used. One should avoid drugs that are associated with teratogenic effects. Patients who require antiretroviral therapy should continue with their regimen throughout the first trimester. Zidovudine (ZDV) should be included in the regimen when possible. Patients with CD4 counts less than 200 cells/mm³ are at risk for opportunistic infections and require prophylaxis. Pneumocystis carinii pneumonia (PCP) prophylaxis is provided when the CD4 count is less than 200 cells/mm³ (Bactrim-DS daily). Prophylaxis against Mycobacterium avium complex (MAC) is initiated when the CD4 count is 50 cells/mm³  or less (azithromycin (AZT) 1200 mg/week). 

As a result of the AIDS Clinical Trials Group (ACTG) Protocol 076, the US Public Health Service published recommendations for the use of ZDV or AZT to reduce the risk of HIV transmission from infected women to their infants.⁸⁰ These recommendations are as follows:

  Antepartum: ZDV, 100 mg orally five times per day, starting at 14–34 weeks
  Intrapartum: ZDV, 2 mg/kg intravenously (IV), loading dose, given over 1 hour, followed by 1 mg/kg/hr IV until delivery
  Newborn: ZDV syrup 2 mg/kg orally every 6 hours, beginning 8–12 hours after birth for the first 6 weeks of life

ZDV, as part of the ACTG Protocol 076, has been estimated to reduce the rate of perinatal transmission from 25.5 to 8.3%.⁸¹ It is now recommended that combination therapy during the antepartum period (CDC) be used for vertical transmission prevention. This risk may be further reduced to approximately 2% if a scheduled cesarean section is performed.^{82, 83} It is not yet known if there is a significant benefit from cesarean delivery in patients who have viral loads of less than 1000 copies/ml who are on HAART. Maternal morbidity is greater with cesarean delivery, particularly in those women with low CD4 cell counts. Therefore, women who are HIV positive must be counseled about the maternal risks and potential benefits of both ZDV prophylaxis and cesarean delivery so that they can make informed choices. If cesarean delivery is chosen, it should be performed electively at 38 weeks of gestation. ZDV should begin 3 hours prior to delivery. It is important to use perioperative prophylactic antibiotics to reduce maternal infectious morbidity. The management of labor (if the patient chooses this option) should include avoidance of scalp electrodes and scalp sampling. Research is needed to determine the appropriate management of HIV-infected women who present with rupture of membranes and who have an undetected viral load.

The newborn should be carefully cleaned of maternal blood and secretions, especially when drawing blood. There is no evidence that the postpartum course is altered. The virus has been isolated from breast milk, and although the risk of transfer is not known, breastfeeding is not recommended when there is a suitable alternative, as exists in the developed world.^{84, 85} A final step in the case of the HIV-infected patient is to see that the patient receives ongoing care. Even if she is asymptomatic after delivery, she will require support and surveillance for disease progression. Current guidelines for the management of HIV disease can be found on the AIDSinfo website, http://AIDSinfo.nih.gov.

Varicella zoster virus

The varicella zoster virus (VZV) is a member of the herpesvirus group but is not as well known for its perinatal impact. This is in part due to the fact that infection is rare in pregnancy (90% of adults are immune). It can remain latent and when activated results in zoster (shingles). If VZV occurs in early pregnancy, it can result in congenital infection not dissimilar to other TORCH infections except for the additional manifestations of skin scarring, muscle atrophy, hypoplastic extremities, and club feet.⁸⁶ Microphthalmia has also been reported. There are insufficient data to determine an exact risk, but it appears to be low. What does seem clear, however, is that congenital malformations are limited to those situations in which VZV occurred before 20 weeks' gestation.⁸⁷ Antenatal diagnosis is not currently available, although ultrasound may be able to detect some of the aforementioned defects.

There is also a risk when VZV occurs in late pregnancy, especially within 3–5 days of delivery, when there is not time for antibody synthesis in the mother and transfer to the fetus.⁸⁸ Under these circumstances, a fulminant disseminated infection may develop in the infant, with its onset at 5–10 days of age, pneumonia, and a mortality rate of up to 30%. If the infection occurs more than 5 days but less than 3 weeks before delivery, VZV may develop in the infant, but of a considerably milder form.⁸⁹ No deaths have been reported. Although there are sporadic reports of malformations following zoster during pregnancy, there are insufficient data on which to determine a risk. The information that is available, however, suggests a low risk.

The diagnosis in the mother is generally made clinically. It can be confirmed by viral cultures from the vesicles; however, the serologic diagnosis is complex. Because of the possibility of pneumonia complicating VZV in the pregnant adult, many suggest that a chest film should be part of the evaluation. In the newborn, the diagnosis is further complicated by the fact that lesions acquired from early pregnancy infection are no longer culture positive at delivery.

Treatment of the mother is symptomatic unless pneumonia develops,⁹⁰ which is a serious problem requiring reverse isolation, aggressive antibiotic treatment of secondary infection, and respiratory support. The antiviral agent acyclovir should be used in patients with VZV pneumonia and in all immunocompromised patients. Acyclovir is not useful in treating varicella encephalitis.⁹¹ There is no specific treatment for the newborn except when VZV developed in the mother within 4 days of delivery. These infants should receive varicella zoster immune globulin (VZIG) within 72 hours of birth, in an effort to prevent or modify the disseminated disease in the newborn.

Although experience is limited, modification rather than prevention is the more likely outcome. Because VZV is extremely contagious, isolation is essential. The main mode of infection is contact, except in patients with pneumonia, in whom there is the potential for aerosol spread. There is varicella vaccine available. All varicella susceptible women should be offered the vaccine after delivery.

Hepatitis

Hepatitis A is caused by a small RNA virus and is spread by the fecal–oral route. It is not known to cause any fetal or neonatal disease but is, nonetheless, a serious illness. Anyone, pregnant or not, who is exposed by contact or travel in endemic areas should receive immune serum globulin (0.02–0.05 mL/kg). If exposure is prolonged and close, the higher dose should be used and repeated every 4–6 months.³⁸

Hepatitis B virus (HBV) is caused by a DNA virus. This organism is the major cause of acute and chronic hepatitis, posthepatitis cirrhosis, and primary hepatoma. There is no specific therapy for active infection, but both passive immunization and active immunization are available and effective. Although there are a number of antigens and antibodies that can be identified in patients with hepatitis B, the simplest and most reliable test of infectivity is the presence of the surface antigen. Transmission is almost exclusively by contact with blood or semen. This helps to identify those at greatest risk: IV drug users; sexual partners of infected individuals; recent immigrants from countries with a high prevalence of hepatitis B chronic infection; healthcare workers; and, most important to obstetricians, infants born to mothers with circulating HBV. These infants, if chronically infected, are at high long-term risk for hepatic cancer. Because of this and because it is possible to prevent perinatal transmission, particularly if infection occurs in late pregnancy, testing for HBV surface antigen is recommended as a part of routine prenatal testing.⁹² Infants born to HBV-positive mothers should receive 0.5 mL of hepatitis B immune globulin within 12 hours of birth and simultaneously receive the first dose of HBV vaccine (half the adult dose). The remaining doses should follow the adult schedule. There is no reason to modify the obstetric management because cesarean delivery will not modify the risk. The HBV vaccine now in use is a recombinant product, poses no infectious risk, and can be used in pregnancy for women at risk. Complete immunization requires the initial dose with repeated doses at 1 and 6 months. Healthcare workers should know their HBV immune status and, if susceptible, should be vaccinated.

Non-A, non-B hepatitis has been known since the 1980s to be caused by the hepatitis C virus (HCV).⁹³ The incidence of HCV in pregnant women appears to be similar to that of the general population. Most patients are asymptomatic; there are no reports of teratogenic syndromes associated with HCV at present.

Vertical perinatal transmission of hepatitis C is proportional to the maternal RNA viral titer.^{94, 95} The transmission rate is approximately 7–8%.^{94, 96} Vertical transmission is increased in women who are also infected with HIV.⁹⁷ Invasive procedures should be avoided during the intrapartum period. At present, no vaccine is available for HCV, and there are insufficient data to recommend pregnancy termination. The management of the pregnant woman infected with HCV must be individualized until further evidence is available to make reasonable recommendations.

Influenza

Influenza is one of the more common viral infections to which pregnant women are exposed. When epidemics occur, the problem is magnified because of the patient's susceptibility to a new strain. In addition to the risks of seasonal influenza, pregnant women have experienced excess mortality during the influenza pandemics of 1918–19, 1957–58, and, most recently, the 2009 H1N1 pandemic.⁹⁸ Although transplacental passage of the influenza virus has been documented, teratogenesis has not, despite suggestions of central nervous system effects.⁹⁹ Premature delivery may occur, as in any febrile maternal illness, increasing the perinatal morbidity and mortality. The clinical syndrome in the mother is usually self-limited unless pneumonia supervenes and in the newborn manifests as any form of sepsis. Management of the mother is symptomatic unless pneumonia develops, in which case very aggressive therapy is indicated. Recent evidence suggests that the antiviral agent amantadine may be useful, but it has not been evaluated in pregnancy and consequently should be limited to life-threatening situations. Most vaccines are prepared from inactivated virus and consequently are safe from that perspective.

The 2009 H1N1 pandemic was particularly hazardous to pregnant women, with increased hospitalizations, ICU admissions and deaths. Prompt empiric treatment with appropriate neuramidase inhibitors (oseltamivir and zanamivir) appeared to decrease the risk of severe disease.¹⁰⁰ Preterm delivery and cesarean delivery were commonly associated with maternal illness with preterm birth rates as high as 30% and cesarean section rates of nearly double the current national baseline.¹⁰⁰

Influenza vaccination is now an important component of antenatal care. The CDC recommends that women who will be pregnant during the flu season (October through mid May) be vaccinated.¹⁰¹ Vaccination may be performed in all three trimesters. Specific vaccines prepared for epidemic strains are more effective than the polyantigenic preparations. Complications of vaccination are generally mild, except for Guillain-Barré syndrome. This is characterized by progressive ascending paralysis but fortunately is usually self-limited and reversible. Evidence from the swine flu epidemic of 1976 suggests that the incidence is approximately 1 in 100,000 vaccinations. The frequency of complications does not appear to be altered by pregnancy. The theoretical risks of vaccination are outweighed by its benefits.

Mumps

Mumps is a rare complication of pregnancy, with estimates of incidence varying from 0.8 to 10 cases per 10,000. The severity of the disease is not greater in pregnancy, and 30% of infections are asymptomatic. There does appear to be a modest increase in spontaneous abortion when mumps occurs in the first trimester but no increase in prematurity.¹⁰² Mumps has not been shown to cause fetal malformations.¹⁰³ The proposed association with endocardial fibroelastosis remains controversial and unestablished.

Genital condylomata

Human papillomavirus (HPV) infections of the genital tract are among the most common sexually transmitted diseases in the United States. Although the exact prevalence is not known, new techniques, especially DNA sequencing, provide evidence of the ubiquity of this infection. Although the major concern about HPV in women is its role in genital dysplasia and neoplasia, the other concern in pregnancy is fetal/neonatal infection. Although genital infection can occur in the newborn, the serious concern is the development of juvenile laryngeal papillomatosis. Although rare, this can be an intractable recurrent and devastating disease. There is a great deal that is unknown, however, about maternal–fetal/newborn transmission. It is not known whether the rate of transmission is related to the volume of maternal disease or to viral load. It is also not known for certain whether infection occurs during passage through the infected birth canal, antepartum, or even postpartum. When this is coupled with the multifocal nature of the infection and our inability to eradicate the virus with available treatment methods, there is no solid basis for management strategies. When a patient has extensive lesions during pregnancy with bleeding and pain, there is little difficulty in deciding that treatment is indicated. In fact, occasionally lesions are so extensive that the risk of evulsion and hemorrhage with delivery necessitates treatment. The real challenge is in the patient with lesser lesions, for whom the major concern is the reduction of perinatal transmission. Although there are estimates that the risk is in the range of 1 in 1000,¹⁰⁴ more data are needed. If a patient is treated for low-volume symptomatic disease based on physician or patient concerns, it is imperative to know that there is no hard evidence that such treatment can prevent, or even reduce, transmission.⁸⁸ When treating the pregnant patient with HPV infection, the treatment should be timed in such a way as to have maximal effect at term. There is almost never a reason to perform a cesarean section for condylomata if the patient is seen sufficiently early in pregnancy to accomplish treatment. A variety of treatment methods are available, but pregnancy limits the choices. Podophyllin is potentially teratogenic and has unacceptable maternal and fetal side effects.^{105, 106} Treatment with 5-fluorocytosine is effective but is not approved for use in pregnancy. Trichloroacetic acid is the best choice for isolated or small-volume genital disease.⁹³

The treatment of choice for large-volume and symptomatic disease is the carbon dioxide (CO₂) laser,¹⁰⁷ and it is suggested that treatment with it be carried out in the third trimester to reduce the chances of recurrence from latent HPV infection at the time of delivery. Interferons have been used successfully¹⁰⁸ but are not yet approved for clinical use.

Group B streptococci

Group B streptococci (GBS) have emerged as an important neonatal pathogen as well as a common cause of puerperal endometritis. The diagnosis in most clinical laboratories is made presumptively rather than by specific serotyping. Commonly, reports will state “β-hemolytic Streptococcus, not group A or D,” and such a designation is quite adequate for clinical purposes. Recovery may be enhanced by the use of selective media,¹⁰⁹ an important consideration because false-negative cultures otherwise occur at a relatively high rate and make screening less practical. There are five subtypes, 1a, 1b, 1c, 2, and 3, which can be separated serologically.¹¹⁰ The major concern is that subtype 3 has a predilection for neural tissue and predominates when there is meningitis. Colonization rates vary widely, in part because of real population differences but also because of laboratory technique. In the nonpregnant population, rates are highest in the young sexually active woman who uses an intrauterine device.¹¹¹ There is sexual transmission, and partners will have positive urethral cultures in 50–60% of cases. The rate of colonization is higher in pregnancy and rises steadily toward term, when it may be as high as 30%.¹¹² The sites include the vagina (especially the lower third), the anorectal canal, the pharynx, and the urinary tract. Neonatal colonization occurs primarily during the birth process but also from nosocomial and, later, community sources. Newborn colonization rates increase steadily from birth and tend to reach levels similar to those in the mother by the time of hospital discharge.

Despite the high colonization rate of GBS, the attack rate is quite low. Early-onset infection occurs at a rate of 3–4 per 1000 live births and is manifest within the first 5–7 days of life, usually within 48 hours.¹¹³ Affected infants are often premature or growth restricted and are the product of a complicated pregnancy or labor. The initial presentation is most commonly a bout of apnea; the course is fulminant, often with septic shock and death despite heroic therapy. Mortality rates exceed 50%. All serotypes are involved except when there is meningitis, in which case subtype 3 is predominant. Infection is presumed to occur by way of the ascending route after rupture of the membranes or during the birth process. Organisms enter through the respiratory epithelium, abetted by intrauterine respiratory efforts and perhaps by resuscitation efforts after delivery. The clinical picture is quite similar to respiratory distress syndrome, including the radiographic findings.

Late-onset GBS infection occurs after the first week of life, and the onset may be as late as 4 months. The infants are most often normal, healthy newborns who have gone home from the hospital. The frequency is even less than that of early-onset GBS, estimated to be 0.5–1 per 1000 for term infants.¹¹⁴

Late-onset disease also occurs in premature infants, and in that population the attack rate is higher. Occasionally, there may be localized infection, but late-onset disease almost always takes the form of meningitis. If the organism is acquired at birth, it must remain latent for a time. Alternatively, colonization may occur from family or community sources after discharge from the nursery. Most cases are caused by subtype 3, which has a special predilection for neural tissue. There has been a characteristic lack of antibody to subtype 3 in infants with meningitis and in their mothers as well. This finding has raised the possibility of developing a vaccine to protect against GBS infection, especially late-onset disease. The mortality is somewhat lower in late-onset disease (up to 40%), but neurologic residua are common in survivors.

The drug of choice for the newborn is penicillin; however, even with early and aggressive use it often fails. This has led to the development of a variety of schemes to try to prevent early-onset disease. The most direct of these approaches is to screen all women in late pregnancy and to treat the carriers to eliminate the presence of the organism at the time of birth. Although this has theoretical appeal, it is fraught with numerous problems. The screening test, the culture, has a significant false-negative rate. The organism is sexually transmitted, necessitating the treatment of sexual partners. Treatment does not eradicate GBS in all cases, and therefore follow-up cultures must be done. All these problems make routine screening impractical. Alternatives include selective screening of patients at risk by virtue of past pregnancy performance (e.g., prematurity or premature rupture of the membranes) or current pregnancy complications (e.g., threatened premature labor).

The risk-based approach fails to identify approximately 50% of infants with GBS sepsis.¹¹⁵ The results of a multistate retrospective cohort study of live births, the Active Bacterial Core Surveillance/Emerging Infections Program network, concluded that the culture-based approach is superior to the risk based approach.¹¹⁶ The CDC recommends that providers adopt a culture-based approach for the prevention of early-onset GBS disease in the newborn.¹¹⁷  These recommendations were updated by the CDC in November 2010.¹¹⁸ 

Rectovaginal GBS screening cultures should be performed in all pregnant women at 35–37 weeks of gestation. Patients with positive GBS cultures will require intrapartum antibiotic prophylaxis (IAP). GBS culture should not be performed if the patient has had GBS bacteruria during the current pregnancy or a previous infant with invasive GBS disease. These patients require intrapartum antibiotic prophylaxis. Patients with GBS bacteruria of a concentration of 10⁴ or greater also require antibiotic therapy at the time of diagnosis. In patients with an unknown GBS status, the presence of risk factors should guide therapy. Intrapartum antibiotic prophylaxis is required for delivery less than 37 weeks, rupture of membranes for 18 hours or more, or intrapartum temperature of 100.4F (38°C) or higher. Antibiotics for GBS are not recommended for patients undergoing planned cesarean delivery in the absence of labor or rupture of membranes regardless of GBS culture status.

As stated earlier, penicillin is the drug of choice for GBS treatment and prophylaxis. Ampicillin is an acceptable alternative. Penicillin is preferred due to its narrow spectrum of activity. Five million units of penicillin G is given as the loading dose. This is followed with 2.5–3.0 million units every 4 hours until delivery. The dose of ampicillin is 2 g loading followed by 1 g every 4 hours. Increased resistance of GBS isolates to second-line therapies has been noted. Susceptibility testing should be ordered in patients who are allergic to penicillin. Cefazolin is recommended for patients that are not at high risk for anaphylaxis. Two grams are given intravenously followed by 1 g every 8 hours. If the patient is a high risk of anaphylaxis, treatment would depend on the susceptibility of the isolate. Clindamycin (900 mg IV every 8 hours). Erthromycin is no longer an acceptable alternative for penicillin allergic women at high risk for anaphylaxis. Patients at high risk of anaphylaxis with unknown susceptibility or resistance to clindamycin, should be treated with vancomycin.¹¹⁸ The dose of vancomycin is 1 g every 12 hours until delivery. It must be emphasized that vancomycin is reserved for patients at high risk for anaphylaxis. A carrier identified by selective screening could be treated at the time, but as previously noted, there is the risk of recurrent colonization or failure to eradicate. If treatment is deferred until the onset of labor, it is effective unless delivery is precipitous.

Women with intact membranes who present with threatened preterm delivery and unknown GBS status should receive IAP until GBS culture results are available. If GBS is negative, or the patient is not in true labor, IAP may be discontinued and re-screening should be done at 35–37 weeks.¹¹⁸

The availability of a rapid, reliable, and inexpensive test to identify the colonized patient would seem to be the ideal solution, permitting the screening of all patients at the onset of labor. The use of a vaginal Gram stain has proved to be insufficiently sensitive or specific to be useful.¹¹⁹

Immunoassays have been developed that appear to be sensitive and specific in detecting heavy vaginal colonization.¹²⁰ Unfortunately, these assays do not detect light colonization, which can be associated with a risk of neonatal infection.¹²¹

The experience at Mount Sinai Medical Center in New York¹²² with routine penicillin prophylaxis for all newborns has led to studies of this approach. The observation that GBS infection was rarely a problem when penicillin was given routinely has been tested in other studies. Results of prospective studies indicate a reduction, but not elimination, of GBS infection,¹²³ but there is concern that the overall rate of neonatal infection remains the same, indicating an increase in infections due to other organisms. This could be due to the development of resistant strains as a result of the extensive antibiotic exposure. Work continues toward the development of a vaccine to protect women and their newborns against GBS infection. It has been shown that mothers of newborns with type III GBS infection have low or nonprotective levels of antibody to the type III polysaccharide. Vaccination of the pregnant women has been shown to produce antibody, which is transferred to the fetus and persists for 2 months in 72% of infants.¹²⁴

Listeriosis

Listeria monocytogenes is a Gram-positive bacillus that is microaerophilic. Although the organism is recognized as a cause of neonatal sepsis and meningitis,¹²⁵ there is very little known about its ecology, colonization rates, or attack rates. There are several reasons for this lack of information, including the difficulties in culturing the organism in the laboratory and its morphologic similarity to diphtheroids.

Listeria is one of several organisms the presence of which in the genital tract has been associated with recurrent abortion, but a causal relationship has not been established. The fetus may acquire the organism as the result of listerial sepsis in the mother; however, the clinical syndrome in the mother is often mild, self-limited, and nonspecific (flu-like), and the problem goes unrecognized until the birth of a stillborn or septic neonate. The mother may be completely asymptomatic, but there is a progressive involvement of the uterus, placenta, and fetus.

The Listeria organism may also be acquired during the birth process and, in the fashion of GBS, produces either early-onset or late-onset infection. The former is a multisystem process caused by subtypes Ia and IVb in newborns of complicated pregnancies, especially those complicated by chorioamnionitis and urinary tract infection. Perinatal mortality is extremely high despite therapy, and, for reasons as yet unknown, this infection is more common in Europe than in the United States. Late-onset infection is quite like GBS, occurring in infants born of uneventful pregnancy, having been discharged from the hospital, and almost exclusively presenting with meningitis. The subtype is IVb, and the mortality is high (40–50%), although less than in early-onset disease. Residua in survivors are frequent, especially hydrocephalus and mental retardation.

Ampicillin is the treatment of choice, although Listeria is also sensitive to tetracycline and chloramphenicol. Some recommend coupling ampicillin with an aminoglycoside.¹²⁶ The antibiotic sensitivities of this organism are, however, inconsistent, and therefore sensitivity testing is important.

The current state of knowledge of Listeria does not permit reasoned plans for prevention. Sexual transmission may occur but has not been established. It may be that patients with recurrent reproductive wastage should be screened for this organism, but this is not supported by hard data.

There is a case report in which the diagnosis of maternal infection with chorioamnionitis was made in the first trimester and after intensive antibiotic therapy the pregnancy was carried to term with a successful outcome.¹²⁷ In another report, amniocentesis was useful in confirming the diagnosis of listerial infection in a gravida with obscure fever, leading to prompt delivery also with good neonatal outcome.¹²⁸ Although these are anecdotal reports, they might provide some guidance in this relatively rare clinical problem.

Tuberculosis

Tuberculosis (TB) has been known to us since antiquity. During the 19th and early 20th centuries, it was the subject of many novels and dramatic operas. The advent of chemotherapeutic agents radically changed the attitudes toward and management of this dreaded disease. However, since the onset of the HIV epidemic, we have seen a resurgence of TB, as well as the development of drug-resistant organisms. Despite these setbacks, the standard treatment of tuberculosis remains effective in most cases when correctly applied. The effects of TB on pregnancy and of pregnancy on the disease have been extensively studied. At present, there is no evidence that TB is worsened by pregnancy.¹²⁹ The development of effective treatment has essentially reduced the possibility of this disease having any substantial effects on pregnancy.¹³⁰ There may be an increase in disease activity in the postpartum period, but since the advent of effective therapy this has little clinical significance.

Screening for TB is easily performed with a purified protein derivative (PPD) skin test. All pregnant women at risk for TB should be screened on first visit. Risk factors include HIV infection, contact with infected persons, birth in a country with a high prevalence, and alcohol and drug addiction. In endemic urban areas, universal screening may be warranted.

Women with a positive skin test must be evaluated for active TB. A chest radiograph may be safely performed with an abdominal shield. If possible, one may delay evaluation until after the first trimester. Most patients are symptomatic. Symptoms may include cough, weight loss, malaise, fever, and hemoptysis.

Treatment depends on the presence or absence of active disease because the risk of progression is highest in the first 2 years after PPD conversion. Therefore, recent converters should be treated with isoniazid, 300 mg/day, starting after the first trimester and continuing for 6–9 months. Women younger than 35 years of age with a positive PPD of unknown duration should receive isoniazid, 300 mg/day, for 6 months after delivery. Prophylaxis is not recommended for women older than 35 years of age in the absence of active disease because of concern about hepatotoxicity.

Patients with active disease should be started on treatment immediately on diagnosis, with dual-agent therapy for 9 months. Isoniazid 300 mg/day, combined with rifampin, 600 mg/day, is the standard. Ethambutol, 2.5 g/day, may be substituted in case of resistance. Pyridoxine (vitamin B₆) supplementation, 50 mg/day, is essential for all patients receiving isoniazid. None of these medications are known to have adverse effects in pregnancy. Breastfeeding is considered safe during maternal treatment as long as the infant is not receiving antituberculous therapy. Infants born to women with active tuberculosis should receive isoniazid prophylaxis (10 mg/kg/day) until maternal disease has been inactive for 3 months.¹³¹

Syphilis

Syphilis tends to be under-reported in adults and overdiagnosed in newborns because of passively acquired maternal antibodies. Treponema pallidum can cross the placenta at any gestational age, and the determining factor for fetal infection is the degree of spirochetemia in the mother. The incidence of syphilis in adults has risen dramatically in the past few years, particularly in endemic urban areas. Congenital syphilis is also seen with increasing frequency in these same areas. The population at risk is heavily involved with drug use, particularly crack cocaine, and also has a much increased seroprevalence for HIV.¹³²

Although it is possible to establish the diagnosis by dark-field examination of material from primary or secondary lesions, this is quite uncommon in obstetric practice, where one must most often deal with serologic testing. Serologic testing is required in many states, and usually a reagin-type antibody test is used. These tests are nonspecific, and the common ones used are the rapid plasma reagin (RPR) and the Venereal Disease Research Library (VDRL) tests. The specific study is the fluorescent treponemal antibody absorption test (FTA-ABS). False-positive results are uncommon and generally of low titer; consequently, a positive FTA-ABS result is generally regarded as an indication for treatment. Once a patient has been infected with syphilis, FTA remains positive for life, and evidence of response to treatment or reinfection can only be followed with serologic titers. Biologic false-positive test results may result from pregnancy, but the most significant cause is a collagen vascular disease, such as lupus erythematosus. Because of this association, long-term follow-up is indicated in patients with biologic false-positive serologies.

False-negative results of screening tests can occur when a patient is tested long after treatment, following the late latent phase, or after the prozone phenomenon. The latter occurs when there is an excess of antibodies preventing a positive flocculation reaction. This can be overcome by diluting the sample, which should be done when there are negative test results in women from high prevalence areas.¹³³ When a diagnosis of latent syphilis is made during pregnancy, a spinal fluid serology is advised. If this is not done, neurosyphilis must be assumed and the treatment extended accordingly.

Clinicians should be aware that the Jarisch–Herxheimer reaction occurs in pregnant women with a frequency similar to that in nonpregnant patients.¹³⁴ In a patient with a severely affected fetus with congenital syphilis, there may be preterm labor, preterm delivery, or even fetal death as a consequence.

Treatment is indicated for the symptomatic newborn; however, the more common problem is an asymptomatic infant with a positive serology. The question is whether this is a passively acquired antibody or an indication of active disease. The specific IgM FTA-ABS is not yet clinically applicable, but a positive spinal fluid serology in the newborn dictates treatment. If the spinal fluid is negative, the serum VDRL should gradually fall and disappear in 3–4 months. Treatment is not necessary in such cases. If the VDRL titer is higher in the newborn than in the mother, treatment is indicated. If there is any doubt, it is best to treat the newborn.

Therapy is indicated in the gravida with a positive FTA-ABS of recent onset, and the drug of choice is penicillin.¹³⁵ The regimen recommended is the same as in the nonpregnant woman. For early syphilis, a single dose of 2.4 million units of benzathine penicillin G is recommended. Some recommend a follow-up dose 1 week later, particularly in the third trimester. For late-stage syphilis (more than 1 year of duration), three doses are recommended. For the patient allergic to penicillin, treatment with penicillin after oral desensitization is recommended. This should be done in a facility that has appropriate provisions for resuscitation, if needed.¹³⁶

Gonorrhea

Because gonorrhea is one of the most common communicable diseases, its association with pregnancy is also frequent. Maternal infection most often is asymptomatic, and in some populations the rate of endocervical colonization exceeds 5%. Salpingitis rarely occurs in the first trimester, and with PROM, cervical colonization can lead to chorioamnionitis in late pregnancy.¹³⁷ Disseminated gonorrhea occurs in pregnancy;¹³⁸ gonococcal arthritis has a special propensity for pregnancy, with 40% of cases occurring in gravidas.¹³⁹

The major perinatal concern with gonorrhea is ophthalmic infection in the newborn,¹⁴⁰ but disseminated infection and arthritis also occur occasionally.

The diagnosis must be established by culture on specific media (such as Thayer–Martin). Gram-stained smears are helpful, but not specific, in women. Because of the increasing frequency of resistant organisms, current recommendations include one of the following regimens:

• Ceftriaxone, 125 mg IM, single dose
  
• Cefixime, 400 mg orally, single dose
  
• Spectinomycin, 2 g IM, single dose (for patients who cannot tolerate a cephalosporin).
  

In addition, treatment for Chlamydia should be administered because of the likelihood of coinfection.¹⁴¹ Disseminated infection in the newborn requires high-dose treatment, and ophthalmic infection should be treated both locally and systemically. Prevention of perinatal infection is best accomplished by careful maternal screening and treatment.

Mycoplasmas

The mycoplasmas are the smallest order of organisms capable of extracellular growth. Mycoplasma hominis and Ureaplasma urealyticum are the clinically important strains, and they have been associated with a variety of obstetric problems, including abortion,¹⁴² low birth weight,¹⁴³ chorioamnionitis,¹⁴³ and neonatal¹⁴⁴ and postpartum infection. These associations have not been conclusively established, and, consequently, treatment should be used only if there is reasonable evidence for causality in a given situation.

Diagnosis is based on laboratory isolation, which is not available in all clinical laboratories.

The treatment for the pregnant woman and the neonate is clindamycin for Mycoplasma hominis and erythromycin for M. pneumoniae and Ureaplasma urealyticum.

Chlamydia

The Chlamydia organism is an obligate intracellular parasite, and there are two species with significance in human disease. Chlamydia psittaci causes psittacosis, whereas C. trachomatis has a variety of manifestations, including lymphogranuloma venereum, trachoma, salpingitis, and nongonococcal urethritis. The implications for the newborn are conjunctivitis and pneumonia.

The ecology of the Chlamydia organism is poorly understood, largely because of the relative unavailability of diagnostic studies. The most accurate study is isolation in a tissue culture system.

Serologic studies are fraught with the usual problems in acute versus chronic titer and cross-reactivity of strains. A cytologic technique using monoclonal antibody with fluorescent labeling is now commercially available and reasonably sensitive and specific. This may well be the most practical approach in the average hospital laboratory.

The rate of asymptomatic cervical infection in obstetric populations is high (5–10%), as is urethral infection in the male (sexual transmission occurs). Newborns acquire the organism at birth in significant numbers, and conjunctivitis is common.¹⁴⁵Chlamydia is the leading cause of pneumonia in young infants.¹⁴⁶

The drug of choice is tetracycline, which cannot be used in pregnancy. Recommended treatment for pregnancy includes the following¹⁴⁷:

• Erythromycin base, 500 mg, or erythromycin ethylsuccinate, 800 mg orally four times daily for 7 days
  
• Amoxicillin, 500 mg orally three times daily for 7 days
  
• Azithromycin, 1 g orally as a single dose
  

Inclusion conjunctivitis can be treated with topical erythromycin or sulfonamides, but silver nitrate is not effective. It should be noted that local treatment of conjunctivitis does not eliminate the organism or the threat of subsequent pneumonia. The question of maternal screening and prophylactic treatment to prevent neonatal infection is unsettled. As diagnostic studies have become more readily available, screening has become more practical. The decision to routinely screen a prenatal population should probably be based on a determination of the specific population prevalence.

Salmonella

Typhoid fever is currently a rare disease in the United States. When the disease does occur in pregnancy, it may, like any serious febrile illness, result in spontaneous abortion or premature labor. In those cases in which the exposure of the fetus to maternal disease has been less than 2–3 weeks, the organism has not been recovered from aborted fetuses. With longer exposure, fetal colonization and infection may occur. Despite the fact that Salmonella typhi can be recovered from the alimentary tract of such neonates, the children are most often asymptomatic and have a good prognosis. Widal's reaction (contingent on IgM antibodies) is positive in these children, confirming intrauterine exposure.

Maternal disease is characterized by initial intestinal infection that is self-limited and may have minimal manifestations. This is followed by lymphatic invasion, involvement of the reticuloendothelial system, and bacteremia. Systemic symptoms accompany this phase, and there may be a skin rash.

Organisms reappear in the stool, and diarrhea may appear. The liver and spleen are enlarged, and rarely ileal perforation may occur. A small number of patients become chronic carriers, usually in association with intrinsic gallbladder disease. For those chronic carriers with cholelithiasis and cholecystitis, removal of the gallbladder may be required to eliminate the carrier rate. Treatment is chloramphenicol, despite the existence of some resistant strains. Alternate antibiotics are ampicillin or amoxicillin and the combination of trimethoprim and sulfamethoxazole. The latter is useful for resistant strains but should be avoided in pregnancy if possible. Aspirin should be avoided because patients with typhoid are extremely sensitive and severe hypothermia may result.

A far more common problem is nontyphoidal salmonellosis,¹⁴⁸ causing enterocolitis. This may appear sporadically or in the form of localized outbreaks due to contaminated food or water. Animals (food source), insects, and rodents may be a source, as can be convalescent patients who may excrete the organism for weeks or even months. The incidence of fecal carriers in the United States has been estimated to be from 2 to 50 per 1000 (normal population) and is higher in food handlers. The usual course is fever, abdominal pain and nausea, vomiting, and diarrhea that lasts 3–5 days. The incubation period is 8–24 hours, which is somewhat longer than that for staphylococcal food poisoning. The illness usually subsides spontaneously in 5 days but occasionally persists for up to 2 weeks. Organisms may persist in the stool for up to 3–4 weeks, and a very small number remain positive longer. Occasionally, an illness with all the manifestations of typhoid fever (paratyphoid) or bacteremia develops, but this is uncommon. The diagnosis of Salmonella enterocolitis is confirmed by stool culture. Antibiotic therapy does not alter the course of Salmonella enterocolitis, and the cornerstone of therapy is the correction of dehydration and electrolyte imbalance. Agents that slow peristalsis should be used sparingly because they may prolong the disease and fecal carriage. Either paratyphoid fever or bacteremia is cause for therapy with chloramphenicol. The prognosis with enterocolitis is excellent for most patients; however, serious illness may result in infants, the elderly, and those debilitated by underlying disease. Pregnant women do not appear to be at increased risk unless they are affected by intercurrent disease. Prevention is best accomplished by sanitation and hygienic processes and the control of faulty food processing.

Trichomonas vaginalis

Trichomonas vaginalis is likely the most common parasite to infect women. Newborns can be infected at birth; however, the manifestations are generally benign, in the form of vulvovaginitis, malodorous discharge, dysuria, and enuresis.³ Because of evidence of a possible relationship between vaginal trichomoniasis and adverse pregnancy outcomes, metronidazole, 2 g orally as a single dose, can be given after the first trimester.

Malaria

Malaria is not a common problem for obstetric practice in the United States, but in endemic areas it is a serious concern and a leading cause of anemia in pregnancy. Perhaps the most likely consideration is a pregnant woman who must travel to an endemic area.³ Chloroquine phosphate, 500 mg once a week starting 1 week before the trip and continuing for 6 weeks after, is the recommendation. This can be safely given to pregnant women.

Candidiasis

Vaginitis caused by Candida albicans is very common during pregnancy. The major perinatal impact is oropharyngeal infection (thrush), which is very common in newborns of women who are vaginal carriers of the fungus. Rarely, a life-threatening systemic infection occurs in the newborn.¹⁴⁹ These infants are most often immunologically compromised or debilitated, and the mortality is high.

Coccidioidomycosis

Coccidioides immitis most often produces a rather benign and self-limited respiratory infection. It is endemic in the Southwestern United States and in 10% of cases progresses to disseminated infection. If the latter occurs in pregnancy, the placenta may be involved; however, there are no documented cases of congenital infection.¹⁵⁰

Preterm birth is the leading cause of neonatal mortality in the United States and is associated with 50% of  long-term neurological impairments in children. Despite efforts at treatment and prevention, the preterm birth rate has not changed significantly over the past 30 years. Births occurring prior to 34 weeks are much more frequently accompanied by clinical or subclinical intra-amniotic infection compared to births after 34 weeks.¹⁵¹  Infection and its inflammatory response has been linked to a increased risk for cerebral palsy.¹⁵² The frequency of positive amniotic fluid cultures is inversely related to the gestational age at spontaneous delivery.  There is ever-increasing evidence for an infectious cause for preterm delivery with or without PROM. The evidence takes two forms: the associations with specific organisms and the occurrence of infectious morbidity in prematurely born infants and their mothers. The earliest evidence is in the form of associations such as the increased rate of GBS colonization in patients with PROM and preterm delivery.¹⁵³ Anaerobes, especially Bacteroides species, and a diagnosis of bacterial vaginosis have also been associated with prematurity.

The anaerobes produce phospholipase A₂, an enzyme necessary for prostaglandin synthesis.¹⁵⁴Neisseria gonorrhoeae,¹³⁷Chlamydia, and the mycoplasmas have also been studied with inconsistent results. There is also circumstantial evidence for an infectious etiology for prematurity in the rates of infection in premature newborns. Sepsis is several-fold more common in premature infants. Although it could be related to incompletely developed host defenses, there is also evidence that such infection begins before delivery and even before rupture of the membranes. Postpartum maternal infection is also more common in women who deliver prematurely with or without PROM, and is dependent on whether the delivery is by cesarean section or vaginal. To complete the circle, it is necessary to involve a theoretical mechanism whereby infectious agents precipitate preterm delivery. Microorganisms, by locally infecting the membranes, might weaken them and lead to rupture. Those organisms that produce phospholipase A₂ might initiate prostaglandin synthesis from precursors (phosphatidyl-ethanolamine) that are found in large quantities in the membrane.

A number of studies, including a large collaborative one, have been undertaken in an attempt to clarify these issues. There is as yet no clear-cut evidence of causality; however, associations have been strengthened. Treatment trials have produced inconsistent results. A fair summary at this point would be that some significant portion of premature labor is related to infectious agents. If these patients can be identified, eradication of the offending organisms might assist in the prevention and treatment of preterm labor.

Periodontal disease is one of the most common chronic infectious disease known in humans. Over the past decade, there have been emerging data linking it to systemic health conditions such as diabetes, cardiovascular, neurological, and pulmonary disease. There are now data linking it to adverse perinatal outcomes such as spontaneous abortion and preeclampsia.¹⁵⁵ In a meta-analysis  by Xiong et al., periodontal disease was found to be a risk factor for preterm low birth weight, low birth weight, preterm birth, preeclampsia, decreased birth rate, spontaneous abortion, and stillbirth in 18 of the 25 studies included.¹⁵⁵ There was, however, considerable variability in the definition and severity of disease, definition of adverse pregnancy outcomes, and the confounding variables controlled for. Periodontal disease is a Gram-negative anaerobic infection that results in destruction of the tooth supporting structure. This destruction results from direct damage by bacterial products and indirect damage from the hosts inflammatory and immune response. Gram-negative bacteria produce lipopolysaccharide (LPS), an endotoxin, which initiates the release of cytokines and matrix metalloproteinases. There is subsequent destruction of the extracellular matrix and recruitment of additional cytokines. Some individuals are predisposed to a hyperinflammatory response. This local inflammatory response may become systemic leading to the above disorders.

Some of the organisms commonly found in the amniotic fluid or placenta of women who deliver prematurely are also found in the oral flora. Fusobacterium nucleatum is the most frequently isolated species from amniotic fluid cultures in women who deliver prematurely with intact membranes.¹⁵⁶ The species and subspecies of fusobacteria identified from the amniotic fluid most closely match those found at the subgingival sites rather than strains from the lower genital tract.¹⁵⁶ It has been proposed that Gram-negative bacteria initiate the production of inflammatory mediators including prostaglandin E₂ (PGE₂) and cytokines locally. This results in an increase in systemic inflammatory mediators that are involved in the pathogenesis of preterm labor. Gingival crevicular fluid levels of PGE₂ were found to be significantly higher in women who delivered preterm low birth weight infants compared to controls.¹⁵⁷ Maternal and fetal humoral response may also play a role in the pathogenesis of preterm labor. A lack of maternal IgG to oral pathogens was associated with an increased risk of preterm birth. The highest rate of preterm birth was found in mothers without protective IgG to oral pathogens who delivered infants that demonstrated an IgM response.¹⁵⁸ It is still unclear if the treatment of periodontal disease during pregnancy will significantly reduce the rate of preterm birth.