James H. Harger

Etiology of Recurrent Pregnancy Losses and Outcome of Subsequent Pregnancies

Prospective evaluation of 155 couples with two or more consecutive pregnancy losses disclosed uterine morphologic abnormalities in 27%, chromosomal abnormalities in 21 individuals (7.7%, or 15.4% of the couples), and at least one abnormal diagnostic test suggestive of a cause for recurrent pregnancy losses in 106 (68%). A positive test for antinuclear antibody was found in 7.5% of the women, whereas the expected rate in a population of this age is less than 2%. Cervical cultures for Ureaplasma urealyticum (T-strain my-coplasma) were positive in 48% of the women, and 28% of these women had a genetic or uterine abnormality to explain their pregnancy losses. Thyroid function profiles and cervical cultures for Mycoplasma hominis provided no significant information in the evaluation in these couples. With the exception of women with a positive antinuclear antibody, the overall prognosis for later pregnancies was quite good whether the diagnostic evaluation of the couple was normal (77% subsequent live births) or abnormal (71% subsequent live births). The significance of the positive antinuclear antibody in these women is unclear, but further studies and long-term evaluation are necessary to determine the relationship between recurrent pregnancy losses and later development of collagen-vascular diseases.

Risk Factors and Outcome of Varicella-Zoster Virus Pneumonia in Pregnant Women

To determine the factors associated with an increased risk of developing varicella-zoster virus (VZV) pneumonia during pregnancy, a case-control analysis was done in which 18 pregnant women with VZV pneumonia were compared with 72 matched control subjects. VZV infection was identified clinically, and VZV pneumonia was diagnosed by dyspnea and findings on chest radiographs. Of 347 pregnant women with VZV infection, 18 (5.2%) had pneumonia treated with acyclovir, and none died. Mean gestational age at rash onset was 25.8 plus minus 8.8 weeks for patients with pneumonia and 17.7 +/- 10.3 weeks for control subjects, which was not significant in the multivariable model. Women with VZV pneumonia were significantly more likely to be current smokers (odds ratio [OR], 5.1; 95% confidence interval [CI], 1.6-16.7) and to have > or = 100 skin lesions (OR, 15.9; 95% CI, 1.9-130.2). Pregnant women with VZV infection may be more likely to develop varicella pneumonia if they are smokers or manifest > or = 100 skin lesions.

Prospective evaluation of 618 pregnant women exposed to parvovirus B19: Risks and symptoms

Objective To assess the risk of maternal parvovirus B19 infection from exposure to various sources and the fetal morbidity of those infections. Methods We obtained demographic and occupational information about pregnant women exposed to sources of B19 and about the nature and duration of the exposures. We performed serologic testing 10–14 days after exposure using an indirect capture enzyme-linked immunosorbent assay. Women with immunoglobulin (Ig) M were examined with weekly ultrasound until 12 weeks after exposure, and the outcome of the pregnancy was ascertained from interviews with patients and their obstetricians. Logistic regression analysis was used to determine risk factors for maternal immunity and infection by B19. Results Of 618 pregnant women exposed, 307 (49.7%) were immune to B19, 259 remained susceptible after exposure, and 52 (16.7% of all susceptibles) contracted B19 infection. None of the 52 fetuses of infected women developed nonimmune hydrops, and there were no fetal deaths attributable to B19 in this group. The relative risk of maternal B19 infection was 2.8 if the source was a related child living in the household (95% confidence interval 1.7, 4.6; P < .001). No significant differences were found for maternal B19 infection in eight categories of maternal occupation. Maternal symptoms of polyarthralgia (46%), fever (19%), and nonspecific rash (38%) were significantly more common (P < .001) in IgM-positive patients than in noninfected women (4.1%, 2.8%, and 5.7%, respectively). Only 17 (33%) of the IgM-positive women were entirely asymptomatic. Conclusion The risk of maternal B19 infection in pregnancy could not be predicted by a gravidas occupation, but it was significantly higher when the source of exposure was her own child. The fetal risk of nonimmune hydrops after maternal B19 infection must be very low. As a consequence, exclusion of pregnant women from the workplace during endemic periods with seasonal clusters of cases is not justified. Weekly fetal ultrasound evaluation in these cases carried a low Yield.

Cerclage and cervical insufficiency: An evidence-based analysis

Since the cervical cerclage was introduced to clinical practice 50 years ago, the efficacy of the operation has not been established by evidence-based standards for many indications. Serious flaws in the methods employed to study the safety and efficacy of cerclage have led to confusion and misuse of the operation, although some investigators maintain that current standards make randomized clinical trials of this traditional surgery unethical. At present, five randomized clinical trials have offered significant information about elective cerclages performed for historical indications, and the expected neonatal survival rate with properly selected elective cerclages is around 87%. Transvaginal ultrasound studies have revealed new paradigms regarding normal cervical function in pregnancy and further understanding about the significance and predictive value of cervical changes at gestational ages between 20-37 weeks. Only two randomized clinical trials have been conducted regarding cerclage in women with decreasing cervical length or with cervical funneling. One of these two failed to demonstrate any resulting improvement in neonatal survival, and the other was too small to be conclusive. To date, no randomized clinical trials have been conducted to demonstrate the efficacy or safety of emergency cerclages performed for advanced cervical dilatation. The many retrospective case series regarding emergency cerclage have failed to provide an evidence-based solution to the management of this problem. Before this traditional surgery continues extensive use in clinical practice, it should be assessed rigorously with randomized clinical trials of sufficient statistical power and external validity to establish the appropriate indications for the operation. In addition, a more thorough understanding of cervical function and molecular biology is essential.

HLA sharing and spontaneous abortion in humans

Twenty-one Caucasian couples with two or more idiopathic fetal losses and with either no live-born children or with only one live-born child were typed for HLA-A, B, and DR antigens, and mixed lymphocyte responses of the maternal lymphocytes to stimulation by paternal lymphocytes were studied. The mixed lymphocyte response results showed that women who experienced habitual fetal loss had normal immune responses, thereby lending less credence to the idea that a defective immunologic response is involved in problem pregnancies. The data were pooled and analyzed with those of similar reports, and there was a strong indication that aborting couples shared a greater portion of the chromosome that contains the major histocompatibility complex (MHC) than would be expected in random matings.

Frequency of congenital varicella syndrome in a prospective cohort of 347 pregnant women

OBJECTIVE To estimate the rate of congenital varicella zoster virus syndrome in neonates born to women developing varicella zoster virus infections during pregnancy. METHODS Pregnant women with clinical varicella zoster virus infection were enrolled at ten perinatal centers. Maternal and fetal immunoglobulin (Ig) G and IgM by fluorescent antibody confirmed 74.3% of cases. Specialists examined neonates at 0–6 months, 7–18 months, and 19–30 months after delivery to detect abnormalities of their eyes, hearing, and physical and developmental features. A hierarchical set of criteria was used to define congenital varicella syndrome. A jury of four investigators assigned the classification of all findings. RESULTS In 362 women enrolled from 1993 to 1996, 15 had herpes zoster, and 347 had primary varicella zoster virus infection. Varicella zoster virus affected 140 women (38.7%) in the first trimester, 122 (33.7%) in the second trimester, and 100 (27.6%) in the third trimester. Five twin pairs were included. Only one case (0.4%) of definite congenital varicella syndrome was found, a 3360‐g female infant having a left retinal macular lesion with typical skin scars after maternal varicella at 24 weeks. The maternal blood sample at birth was negative for IgG antibodies to toxoplasmosis and cytomegalovirus. Two cases involved fetal death at 20 weeks and fetal hydrops at 17 weeks after maternal varicella at 11 and 5 weeks, respectively. We found no cases of limb hypoplasia, microcephalus, or cataract. CONCLUSION The frequency of congenital varicella syndrome is very low (0.4%) in a prospectively studied cohort. Eye examinations of exposed infants had a low yield.

Serologic and virologic evidence for frequent intrauterine transmission of human parvovirus B19 with a primary maternal infection during pregnancy.

OBJECTIVE To define the intrauterine viral transmission rate during primary maternal parvovirus B19 infection and identify factors that may influence this rate. METHODS Forty-three pregnant women at two medical centers were identified with a primary B19 infection and followed to delivery. At delivery maternal and infant (umbilical cord) blood was obtained for B19 serologic and virologic PCR testing. RESULTS All of the women delivered healthy infants at term and none was hydropic. Overall 22 (51%) of the 43 infants had some evidence of a congenital B19 infection. B19-specific IgM was detected in 11 infants at delivery, B19 IgA was detected in 10 and B19 DNA was detectable by PCR in 11 infants. One infant was negative at birth but became positive for IgM, IgA and PCR at 6 weeks of age. No association was found between the likelihood of intrauterine infection and: maternal age; symptomatic maternal infection; method of delivery; maternal IgG titer at delivery; maternal IgG avidity at delivery; or maternal viremia at delivery. Intrauterine infection was associated with maternal IgM positivity at delivery; this association may have been a result of maternal infection occurring later in gestation. CONCLUSION Although the incidence of intrauterine hydrops and fetal demise after maternal infection is low, there is a high rate of intrauterine viral infection that occurs throughout gestation and yields newborns who, although infected in utero, are asymptomatic at birth.

Selection of patients for antibiotic prophylaxis in cesarean sections

We conducted a prospective, double-blind, randomized, placebo-controlled study of cefoxitin perioperative prophylaxis in 386 women having cesarean sections after labor or rupture of membranes. Private patients constituted 70% of subjects. Cefoxitin was chosen for its low toxicity and its broad spectrum against common obstetric pathogens including Bacteroides fragilis. Cefoxitin-treated women received 2 mg of drug intravenously at umbilical cord clamping and at 6 and 12 hours after surgery. Demographic and obstetric variables did not differ between the 190 placebo-treated women and the 196 cefoxitin-treated women. The morbidity rate from infection was significantly reduced by cefoxitin prophylaxis. Seven factors were significantly correlated with increased risk of infection after cesarean section: maternal age, socioeconomic status, race, gestational age, duration of internal fetal monitoring, use of intrauterine pressure catheter, and obesity. Cefoxitin prophylaxis resulted in significant decreases in infection incidence in women with one, two, and three risk factors, respectively, but the reduction was not significant in women with no risk factors. Length of hospital stay was not significantly reduced by cefoxitin prophylaxis but antibiotic use was decreased 24%.

Management of pelvic endometriosis with low-dose danazol*†

Thirty-eight women with pelvic endometriosis diagnosed by laparotomy or laparoscopy were enrolled in a double-blind study utilizing danazol. Danazol was administered for 6 months in four doses schedules: 600, 400, 200, and 100 mg/day. At the completion of 6 months of therapy, repeat laparoscopy was performed and 71% of the women were found to have improvement of pelvic endometriosis. Minimal and moderate pelvic endometriosis appeared to respond well to doses of danazol of less than 400 mg/day, whereas severe endometriosis appeared to be best treated with danazol doses of greater than 400 mg/day. Symptomatic relief of pain, dysmenorrhea, and dyspareunia occurred in 89% of the women. The over-all pregnancy rate in women attempting conception was 28% (8 of 28). Fifty-four per cent of the women had recurrence of symptoms within 1 year of discontinuation of danazol.

Intrauterine parvovirus B19 infection may cause an asymptomatic or recurrent postnatal infection

Although infection with parvovirus B19 (B19) during pregnancy may cause fetal demise, the true incidence of intrauterine infection is unknown. For 19 women with serologically confirmed B19 infections between 4 and 38 weeks of gestation, we performed follow-up examinations of their infants. Serial sonograms of the 19 fetuses showed that none developed hydrops. All 19 women delivered healthy term infants. Cord sera of four infants were tested for IgM to B19 and three were positive. Between 3 and 21 months of age, all 19 infants had normal physical examinations, developmental evaluations and hematocrits; and 16 lacked IgG to B19. One infant who was IgM-positive to B19 at birth was IgM-positive at age 7 months when he also had an IgG titer to B19 of 1:500,000 (mothers concurrent titer, 1:10,000), and had B19 DNA in serum detected by polymerase chain reaction. The other two infants who were IgM-positive at birth were IgM- and IgG-negative by 11 and 16 months of age. These results suggest that intrauterine B19 infection may be frequent and occasionally cause an asymptomatic postnatal infection.