Janice I. French

Antenatal microbiologic and maternal risk factors associated with prematurity.

In a prospective study of 202 women (gestational age 24 +/- 4 weeks), we evaluated possible influences of lower genital tract infection or bacterial conditions on obstetric outcomes, including preterm labor, preterm premature rupture of membranes, and preterm birth. The presence of bacterial vaginosis (18.7%) was associated with an increased risk of preterm labor (relative risk, 2.6; 95% confidence interval, 1.08 to 6.46). For women with bacterial vaginosis who also had Mobiluncus species morphotypes identified on Gram stain, the relative risk of preterm labor was 3.8 (95% confidence interval, 1.32 to 11.5). Presence of vaginal Mycoplasma hominis (10.8% of patients) was associated with both preterm labor (relative risk, 1.8; 95% confidence interval, 0.77 to 4.4) and preterm birth (relative risk, 5.1; 95% confidence interval, 1.45 to 17.9). Recovery of Staphylococcus aureus (3.0%) was associated with preterm labor (relative risk, 3.1; 95% confidence interval 1.12 to 8.7). Identification of two or more bacterial-linked abnormalities was also associated with preterm labor (relative risk, 3.3; 95% confidence interval, 1.44 to 7.58). An increased level of vaginal wash protease (greater than or equal to 10 trypsin units) (16%) was associated with preterm labor and was noted in 50% of women with preterm premature rupture of membranes. A history of prior preterm birth was the single best historical predictor of both preterm labor (relative risk, 3.6; 95% confidence interval, 1.92 to 6.83) and preterm birth (relative risk, 6.7; 95% confidence interval, 2.2 to 20.4). History of three or more abortions, antenatal urinary tract infection, and occurrence of medical complications during pregnancy also correlated with increased risk of preterm labor. These findings affirm and refine associations of various maternal reproductive tract infections with preterm labor, premature rupture of membranes, and birth, allowing for controlled treatment trials aimed at prevention of preterm birth.

Adjunctive erythromycin treatment for idiopathic preterm labor: results of a randomized, double-blinded, placebo-controlled trial.

Pathogenesis and optimal treatment and prevention of preterm labor remain incompletely understood. Entry of cervical/vaginal microorganisms into lower uterine tissues has been implicated in preterm labor and may be amenable to specific therapy. Fifty-eight women with less than 34 completed weeks of gestation and without other obstetric complications, who were receiving intravenous tocolytics because of uterine contractions and who had cervical alteration (less than 5 cm dilated), were enrolled in a prospective randomized, double-blinded evaluation of 7 days of adjunctive therapy with enteric-coated erythromycin base (333 mg three times daily by mouth) versus placebo. Microbiologic examination included cultures for Neisseria gonorrhoeae, Chlamydia trachomatis, and group B streptococcus. Fifty-eight women with singleton pregnancies (29 erythromycin; 29 placebo) completed the protocol. Among women with cervical dilatation greater than or equal to 1 cm at the beginning of treatment, mean time until delivery was 32.5 days with erythromycin and 22.4 days with placebo treatment (p = 0.027). Of the erythromycin-treated women, seven of eight were delivered at greater than or equal to 37 weeks and only three of nine placebo-treated women were delivered at greater than or equal to 37 weeks (p = 0.035). Orally administered enteric-coated erythromycin as adjunctive treatment of pregnant women in labor less than or equal to 34 weeks is well tolerated. Adjunctive erythromycin given to women treated for preterm labor less than or equal to 34 weeks is associated with prolongation of pregnancy and delivery at 37 weeks only in women with cervical dilatation at the beginning of treatment.

The pathobiology of premature rupture of membranes

Premature rupture of membranes arises from what are likely multifaceted and multistep pathogenic pathways. Pathophysiological processes may involve both endogenous and exogenous fetal and maternal factors. This article reviews and analyzes information regarding, first, the form and function of fetal membranes; second, how membranes physically fail (rupture) at term and preterm gestations; and third, evaluates if we can reduce risks of rupture using physiological understanding and evidence-based clinical studies.

Chlamydia trachomatis infection during pregnancy

Although transmission of Chlamydia trachomatis to infants during vaginal birth can result in conjunctivitis and pneumonitis, there is uncertainty about other adverse effects of chlamydial infection during pregnancy. There is some evidence that it may contribute to adverse complications such as premature rupture of membranes, preterm labor and birth, low birth weight, and still birth. Infection with C. trachomatis is also implicated in postabortal, postcesarean section, and postpartum maternal infections. Treatment of chlamydial infection during pregnancy has proved beneficial in the prevention of neonatal morbidity and is now recommended by the Centers for Disease Control.

The Omega-3 Story:: Nutritional Prevention of Preterm Birth and Other Adverse Pregnancy Outcomes

Healthy intrauterine growth and development, appropriately timed parturition, and safe birth continue to be critical determinants of each child’s chances of achieving their full biological potential. Essential fatty acids (EFAs) and their metabolites are involved in the synthesis of eicosanoids that play essential and multifaceted roles in human reproduction, especially during pregnancy, parturition, and lactation. Fatty acid-derived prostaglandins (PGs), hydroxyeicosatetraenoic molecules (HETE), leukotrienes (LTs), thromboxanes (TXs), and prostacyclins (PIs) play well-documented “final common pathway” molecular roles in both normal term labor as well as in preterm parturition (1). Abnormalities of thromboxane and prostacyclin physiology also occur with preeclampsia, eclampsia, and pregnancy-induced hypertension (PIH), which often require preterm delivery (2). Docosahexaenoic acid (22: 6v-3, DHA) and other EFA derivatives are important components of the rapidly growing brain and retinal tissues of the perinate (3). DHA, a long-chain omega-3 (v-3) fatty acid (LCPUFA) is expressed in breast milk, and breast-fed and DHA-nutritionally supplemented children demonstrate improved performance on various tests of brain and vision functioning (4). Ensuring maternal and perinatal nutritional sufficiency during pregnancy and lactation is investigated increasingly as an effective and inexpensive strategy for optimizing pregnancy and lactational outcome (5). Informed families and providers are invested both in preventing the occurrence and consequences of prematurity and inadequate uterine growth (6). Families and providers are similarly interested in optimizing healthy growth and development of the fetus’ developing organs, especially brain, retina, and the cardiovascular system (7). Preterm birth continues to cause neonatal morbidity and life time disabilities (8). Preterm birth is associated with potentially immense direct and indirect costs, as well as liabilities for care providers. Preterm birth is best understood as a syndrome caused by numerous diseases such as intrauterine infection and inflammation, uterine over-distention or intrauterine bleeding. Such causes of prematurity are best considered as “complex diseases.” Complex diseases involve interactions between multiple bodily systems or parameters including nutrition, immunity, coagulation, and the endocrine system. For example, the fetus depends on maternal nutrients, such as EFAs, for multiple bodily functions including eicosanoid metabolism as well as brain growth and retinal development. Thus, if the mother is deficient in certain fatty acids, this deficiency tends to be compounded in the fetus (9). Such complex disease processes are best dealt with using primary prevention techniques—such as ensuring nutritional sufficiency, particularlyv-3 LCPUFA sufficiency, during pregnancy and lactation.

Association of cervicovaginal infections with increased vaginal fluid phospholipase A2 activity

Abstract OBJECTIVE: The purpose of this study was to determine if phospholipase A 2 was detectable within vaginal fluid and to correlate its presence with the presence of common lower genital tract infection or microbial conditions. STUDY DESIGN: Pregnant women were examined at the first prenatal visit with standard clinical evaluations and microbiologic cultures or tests. Vaginal fluid samples were evaluated for phospholipase A 2 activity by means of a standardized enzyme fluorometric assay. Data were stratified to control for coexisting infections. RESULTS: Phospholipase A 2 activity was detected among 29.8% of women and was independently associated with the presence of bacterial vaginosis ( p p Chlamydia trachomatis ( p 2 activity and the level of activity was increased in the presence of more than one infection. CONCLUSIONS: Elevated reproductive tract phospholipase A 2 concentrations among pregnant women may play roles in the pathogenesis of preterm labor and birth. Identification of pregnant women with increased concentrations in vaginal fluid may allow for development of effective intervention strategies to reduce the risk of preterm birth. (AM J OBSTET GYNECOL 1992;167:1588-94.)

Single-dose cefotetan versus multidose cefoxitin for prophylaxis in cesarean section in high-risk patients.

A prospective, randomized, open trial of a single intravenous dose of a new broad-spectrum and long-acting cephalosporin was compared with the effect of three doses of cefoxitin in a group of 70 women undergoing cesarean section who were at high risk for postoperative endomyometritis and wound infection. All patients either had ruptured membranes or were in active labor, or both, without clinically detectable chorioamnionitis at the time of prophylaxis. Forty-six women received a single 2 gm dose of cefotetan and 24 received 2 gm of cefoxitin every 4 hours to complete a three-dose regimen. Outcomes of infectious febrile morbidity due to endomyometritis (15% versus 8%), wound erythema (4% versus 12%), and other parameters were similar for cefotetan and cefoxitin, respectively. Both agents were well tolerated in this high-risk population. Within the limits of this study, single-dose cefotetan chemoprophylaxis appears to be comparable to multidose cefoxitin administration in reducing morbidity in operative site infections after cesarean section.

A new proline aminopeptidase assay for diagnosis of bacterial vaginosis

Bacterial vaginosis is one of the most common occurring vaginal conditions among women of reproductive age. A rapid and reliable laboratory test for diagnosis of bacterial vaginosis would be helpful in the clinical detection of this disease. Elevated proline aminopeptidase activity has been identified as a reliable marker enzyme for bacterial vaginosis. A proline aminopeptidase assay has been shown to predict accurately women with a clinical diagnosis of bacterial vaginosis. However, this assay has significant practical disadvantages, the most notable of which is the production of a carcinogenic end product, alpha-naphthylamine. We have developed a modified assay for this bacterial vaginosis marker enzyme with L-proline p-nitroanilide, a substrate that does not yield a carcinogenic end-product. The new proline aminopeptidase assay is a one-step test that is analyzed colorimetrically with microsomal leucine aminopeptidase used as a standard enzyme (linear from 3 to 125 mU per well). We have determined the activity of proline aminopeptidase in vaginal wet preparations from 57 patients with both assay methods. In addition, vaginal smears were examined with Grams stain and analyzed for bacterial vaginosis with the Spiegel method. When compared with the Spiegel method, the two proline aminopeptidase assay methods were similar with respect to assay sensitivity (93%), specificity (91% to 93%), and the predictive value of a positive result (78% to 82%) or a negative result (97% to 98%). Vaginal wash samples also were assessed for proline aminopeptidase activity. Values for samples identified as bacterial vaginosis positive were significantly different (p less than 0.0001) from those that were negative according to the Spiegel analysis of Grams stain: negative results, 66 +/- 41 mU/ml; positive results, 704 +/- 145 mU/ml. These findings indicate that this improved proline aminopeptidase assay will offer a rapid, sensitive, and objective laboratory method for the diagnosis of bacterial vaginosis.

Trichomonas vaginalis Weakens Human Amniochorion in an In Vitro Model of Premature Membrane Rupture

Objective: Trichomonas vaginalis (TV) infection is associated with preterm rupture of membranes (PROM) and preterm birth. We evaluated the effects of TV growth and metabolism on preparations of human amniochorion to understand and characterize how TV may impair fetal-membrane integrity and predispose to PROM and preterm birth. Methods: Term fetal membranes were evaluated using an established in vitro fetal-membrane model. Fresh TV clinical isolates were obtained from pregnant women. The protozoa (5.0×105 to 1.5×106/ml) were incubated with fetal membranes in modified Diamonds medium for 20 h at 37°C in 5% CO2.The effects of fetal-membrane strength (bursting tension, work to rupture, and elasticity) were measured using a calibrated Wheatstone-bridge dynamometer. Tests were also performed to evaluate the effects of 1) inoculum size; 2) metronidazole (50 μg/ml); and 3) cell-free filtrate. Results: The TV-induced membrane effects were 1) isolate variable; 2) inoculum dependent; 3) incompletely protected by metronidazole; and 4) mediated by both live organisms as well as protozoan-free culture filtrates. Six of 9 isolates significantly reduced the calculated work to rupture (P ≤ 0.02); 7 of 9 reduced bursting tension; and 1 of 9 reduced elasticity. One isolate significantly increased the work to rupture and bursting tension (P ≤ 0.002). Conclusions: In vitro incubation of fetal membranes with TV can significantly impair the measures of fetal-membrane strength. This model may be used to delineate the mechanisms of TV-induced membrane damage. This study suggests that there are enzyme-specific effects as well as pH effects.

Evidence-based Prevention of Preterm Birth and Rupture of Membranes: Infection and Inflammation

Abstract Prevention of preterm birth and subsequent newborn immaturity is a primary goal of health care in Canada and throughout North America. Much accumulated evidence shows that (I) as many as 30 to 50 percent of preterm births are caused by common genital tract infections and subsequent maternal/fetal inflammatory responses; (2) microbial and maternal host factors (phospholipases, proteases) play roles in preterm labour and preterm premature rupture of membranes (pPROM); (3) identification and systemic treatment of common genitourinary infections, most importantly bacterial vaginosis (BV), reduces risks of preterm delivery and PROM; and, (4) antimicrobial treatment with erythromycin, clindamycin or other antibiotics can significantly delay delivery and reduce the risks of maternal and neonatal morbidity as well as reduce the risk of early onset group B streptococcal sepsis in women with pPROM or preterm labour prior to 34 completed weeks gestation. Diagnosis of EV can be made inexpensively and accurately by using Amsel’s clinical criteria: homogeneous discharge, pH ≥4.5, positive amine test, and “clue” cell identification (3 of 4). Optimal treatment for BV during pregnancy is either prompt administration of oral metronidazole or clindamycin followed by a “test of cure” evaluation and retreatment as necessary. Screening and treatment for BV and other prevalent reproductive tract infections and bacteriuria are most easily and effectively performed during the initial antepartum visit. Screening and treatment can be repeated at 20 or 28 weeks gestation in patients judged at risk for repeated infection. Partners of women with sexually transmitted diseases should be treated; both patients and partners should have “tests of cure.” Both asymptomatic and symptomatic infections should be treated. Potentially powerful interactions of reproductive tract infection and inflammation with other obstetric factors, including a prior history of preterm birth, first trimester bleeding, and possibly, short cervix and multiple gestation can be mitigated by effective treatment of reproductive tract infections. Medical care providers now have the opportunity and the obligation to reduce infection-mediated preterm birth by expeditiously identifying and treating prevalent reproductive tract infections in their pregnant patients.