Fetal testing for prediction of low birth weight

Details Fetal testing for prediction of low birth weight Fetal testing for prediction of low birth weight

2000-10-20

2004-05-11

Myers, Carla J. (Department: 1634)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving nucleic acid

C435S091200, C536S023500, C536S024310, C536S024330

Reexamination Certificate

active

06733967

ABSTRACT:

1 BACKGROUND OF THE INVENTION
1.1 Field of the Invention
The present invention relates to a genetic association between interleukins and low birth weight. Particularly, the invention relates to using fetal tissue to predict low birth weight delivery. The invention also provided kits for determination of susceptibility to low birth weight deliveries.
1.2 Brief Description of the Prior Art
In the United States there are about 250,000 spontaneous preterm births each year, occurring at less than 37 weeks gestation, resulting in birth weights under 2500 g or 5½ pounds. This obstetric problem accounts for about two-thirds of all neonatal mortality and over 5 billion dollars in ICU hospital costs each year. Furthermore, permanent disability among survivors is high, especially for respiratory and neurological disorders. Despite increased attention to maternal prenatal care over the last forty years and advances in medical care, most of the advances in infant mortality have been gained through improved capacity to improve the survival of the very low birth weight infants (i.e., those infants having a birth weight of <1500 g). Unfortunately, the incidence of spontaneous preterm births (SPB) has not significantly changed over the last decade. This has been attributed to the recognition that there is currently little understanding of the antecedent risk factors associated with spontaneous preterm births. Furthermore, there are currently no tests for identify mothers or fetuses at high risk. Recent data suggest that as much as 60% of the observed SPB has no suspected etiology. Maternal systemic infections and especially bacterial vaginosis have been shown to be an important source of preterm deliveries and histologic chorioamnionitis, which is highly correlated with SPB. However, other infectious or inflammatory processes may also be involved in SPB. Especially, since intraamniotic increases in PGE
2
, IL-1 and TNF are consistently found in SPB, even in the absence of detectable infection.
Bacterial infections are associated with premature low birth weight (PLBW). Bacterial infections in the genitourinary tract have been reported to be a major risk factor for preterm delivery (1-4). In the largest study conducted to date by Hillier et al. (2) the relationship between bacterial vaginosis, preterm delivery and low birth weight was explored. In the study Hillier and her colleagues followed more than 10,000 women, from seven medical centers, from 23-26 weeks gestation through delivery. Vaginal cultures were taken to ascertain if bacterial vaginosis was present. Of the 10,397 women, 4.8% delivered PLBW infants. During this study it was also suggested that women who had urinary tract infections or used antibiotics prior to enrollment in the study were also more likely to deliver a PLBW infant. The data from this study demonstrated that 16% of the study population had bacterial vaginosis (BV) and that those 16% were 40% more likely to give birth prematurely than women without BV. The study also determined that bacterial vaginosis was associated with the preterm delivery of low birth weight infants independently of other recognized risk factors.
In other studies conducted by McGregor et al. (4) and Gravett et al. (5) it was postulated that the presence of bacterial vaginosis is associated with subclinical amniotic fluid infection in women with intact fetal membranes; an increased risk of abortion at less than 22 weeks; premature rupture of membranes (PROM), and preterm birth. Other studies have also shown the association between bacterial vaginosis and amniotic fluid infection, histological and clinical chorioamnionitis, placental infection, PROM, premature labor, preterm delivery and a higher maternal infectious morbidity postpartum (5-20). Thus, it appears likely that the genitourinary tract represents a major source of potential infectious challenge that contributes to PLBW.
Recently, a more distant chronic bacterial infection in the oral cavity, periodontitis, has, in certain aspects, been associated with PLBW deliveries. Offenbacher et al. (21) conducted a case control study on 124 pregnant or post-partum women. PLBW cases were defined as a mother with a birth weight of less than 2500 grams and one or more of the following: gestational age <37 weeks, preterm labor (PTL), or preterm premature rupture of membranes (PPROM). Controls were all normal birth weight infants (NBW). Certain types of severe periodontal disease was associated with an increased risk of PLBW (adjusted odds ratio of 7) after controlling for known obstetric PLBW risk factors such as smoking, race, alcohol usage, age, nutrition and genitourinary tract infection.
The primary bacteria involved in the genitourinary and periodontal infections are Gram-negative and are known to release the endotoxin lipopolysaccharide (LPS) into the tissue environment. There is substantial evidence that LPS is associated with pregnancy complications in animals. Endotoxins from enteric bacteria are capable of inducing placental necrosis, spontaneous abortions, fetal organ damage, fetal death and malformations (22).
When challenged with
E. coli
LPS, Lanning et al. (23) found that the embryological development of the golden hamster was affected, resulting in malformations, spontaneous abortions and low fetal weight. These series of experiments clearly demonstrated that infections in pregnant animals could elicit many pregnancy complications including spontaneous abortion, preterm labor, low birth weight, fetal growth restriction and skeletal anomalies. These experiments also supported the hypothesis that the bacteria associated with bacterial vaginosis, pelvic inflammatory disease and other sexually transmitted diseases have the potential to induce alterations that become evident at the outcomes of pregnancy.
In addition, recent studies (24, 25) involving the bacteria that are involved in periodontitis further suggest that chronic, non-disseminating infections, including those at distant sites, may strongly influence fetal outcomes. Of critical importance to these early experiments was the demonstration that these low-grade infections with low numbers of oral pathogens were not of sufficient magnitude to induce maternal malaise or fever. There was, however, a measurable local increase in PGE and TNF&agr;, as well as a 15-18% decrease in fetal weight (26). Furthermore, the magnitude of the PGE
2
and TNF&agr; response was inversely related to the weight of the fetuses, mimicking the intraamniotic changes seen in humans with PLBW (26). LPS dosing experiments demonstrated that higher levels of LPS could induce fever and weight loss in pregnant animals and resulted in more severe pregnancy outcomes including spontaneous abortions and malformations. These more dramatic outcomes were not seen in the low challenge-oral infection models, but rather resulted in a consistent decrease in fetal weight, and previous sensitizations or exposures to these pathogens prior to pregnancy enhanced the severity of the fetal growth restriction when a secondary exposure occurred during pregnancy (24, 25).
Inflammatory mediators such as prostaglandin E
2
(PGE
2
) and interleukin-1 (IL-1) are present not only in all immuno-inflammatory processes, but also regulate the normal physiologic process of parturition, as well as pathologic prematurity. Amniotic fluid levels of PGE
2
rise steadily throughout pregnancy until a critical threshold level is reached to induce labor, cervical dilation and delivery.
The role of prostaglandins in regulating the normal physiology of pregnancy has been well documented. Gibbs et al. (27) summarized the evidence supporting the role of prostaglandins in human labor. Treatment with prostaglandin inhibitors delays the process of mid-trimester abortion and the onset of labor and can arrest preterm labor. Parturition at term is associated with elevated amniotic fluid and maternal plasma concentrations of prostaglandins.
The association between preterm labor and changes in amniotic fluid concentrations of PGE
2
and prostaglandin F2&a

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