Читать книгу Genetic Disorders and the Fetus - Группа авторов - Страница 114

Some drugs, such as meperidine, cross the placenta and accumulate in AF, but the direct action of the drug on the fetus is not well understood. The amount of free methadone is 4–5 times that in the maternal plasma, but the active metabolite normeperidine is absent.⁴⁶⁶ There is evidence of an increased risk of certain heart defects when the fetus is exposed to opioid analgesics early in pregnancy.⁴⁶⁷ It is exceedingly difficult to tease apart the causation of relatively small effects such as poor school performance when drug abuse, other prenatal exposures, lack of adequate parenting, and exposure to violence coexist.

Blocking factors in the fetus might alter the action of antibodies to acetylcholine receptor at the neuromuscular junction, thus preventing transient or neonatal myasthenia gravis until after birth.¹⁹⁷ Fetal hydantoin syndrome is observed in infants of epileptic mothers receiving certain anticonvulsant drugs during pregnancy. Although the exact risk of fetal demise is unknown, it is believed that these mothers have a two‐ to threefold increased risk of giving birth to an infant with mental retardation, cleft lip and/or palate, heart defect, and minor skeletal anomalies. Anticonvulsants are metabolized by a variety of enzymatic reactions, the cytochrome P450 superfamily almost certainly having a key role in determining fast and slow catabolizers.⁴⁶⁸

An accumulation of nicotine and its metabolites was reported³⁰³ in midtrimester AF samples of self‐reported smokers and in fetal arterial blood samples obtained at delivery. Cotinine accumulation in the fetus was noted as early as 7 weeks of gestation in both active and passive smokers.⁴⁶⁹ Milunsky et al. documented a tobacco‐specific carcinogen in midtrimester AF of smoking mothers (Table 3.5).⁴⁹⁸ Tobacco smoke is considered the most extreme example of a systemic human mutagen.⁴⁹⁹

Table 3.5 Examples of environmental drugs and chemicals in the fetal environment

Chemical class	Chemical	Matrix measured	Selected references
Pharmaceuticals	Anesthetics	Meconium	471, 472
Analgesics	Meconium	471, 472
Antihistamines	Meconium	471, 472
Adrenergics	Meconium	471, 472
Expectorants	Meconium	471, 472
Antidepressants	Meconium	471, 472
Anticonvulsants	Meconium	471, 472
Herbicides	–	AF	473
Illicit drugs	Cocaine	Meconium	471, 472
Opiates	Meconium	472
Cannabinoid	Meconium	472
Morphine	Meconium	472
Methadone	Meconium	472
Stimulants	Meconium	472
Alcohol	Fatty acid ethyl esters	Meconium	474
Tobacco	Cotinine/nicotine	Meconium	475
Trace elements/metals	Arsenic	Meconium	476
Bromine	Cord blood	477
Cadmium	Meconium/cord blood	476, 478
Cesium	Cord blood	479
Copper	Cord blood/meconium	480, 481
Iron	Cord blood	480, 481
Lead	Meconium	476, 478
Manganese	Cord blood	482
Magnesium	Cord blood	483
Mercury	Meconium	476
Methylmercury	Cord blood	484
Potassium/calcium	Cord blood	477
Rubidium	Cord blood	477
Selenium	Cord blood/meconium	485
Strontium	Cord blood	483
Zinc	Cord blood/meconium	477, 478
Pesticides	Bisphenol A	AF	486, 487
Chlordane	Meconium	476
Chlorpyrifos	Meconium/cord blood	476, 488
Diazinon	Cord blood	476
Organophosphorus metabolites	AF, meconium	489, 490
Bendiocarb	Cord blood	491
Pesticide metabolites, chlorinated phenols	AF	473, 492
DDT	Meconium	476, 488
DDE	Cord blood	471
Hexachlorobenzene	Cord blood	471
Lindane	Meconium	476
Malathion	Meconium	476, 488
Parathion	Meconium	476, 488
Pentachlorphenol	Meconium, cord blood	476
Polychlorinated biphenyls (PCBs) (includes dioxin)	PCBs	Cord blood	473, 492
Polybrominated diphenyl ethers (PBDEs)	PBDE	Cord blood	493
Perchlorate		AF	489
Phytoestrogens	Daidzein	AF	494
	Genistein	Cord blood	495
Phthalates	Phthalates esters	AF	496, 497
Tobacco carcinogen	Methylnitrosamino pyridyl butanol	AF	498

Source: Modified from Barr et al. 2007. ⁴⁷⁰

Accurate bioanalytical methods facilitate discovery of drugs of abuse, such as cocaine, in AF. This is important given that, in one study, some 17 percent of mothers denying cocaine use had a positive maternal or newborn specimen.⁵⁰⁰ These methods enable monitoring of drugs of abuse not only in AF, but also in vernix caseosa, cord blood or tissue, meconium, urine, hair, nails, sweat, and saliva.⁵⁰¹

An improved method to measure cocaine and norcocaine was developed and employed to show a significant correlation between the presence of cocaine metabolites in neonates' urine and symptoms of acute cocaine intoxication.^{502, 503} Multiple studies^504–506 have shown no evidence of teratogenicity, although increased risk of placental abruption and premature rupture of membranes was observed.⁵⁰⁶ A 2011 meta‐analysis found association between cocaine exposure and preterm birth, low birthweight, and small for gestational age infants.⁵⁰⁷

In women treated during pregnancy with fluvoxamine, sertraline, and venlafaxine, antidepressant and metabolite concentrations were detectable in the AF.^{508, 509} No adverse effects of the medication were reported. The presence of these antidepressants in AF suggests that fetal exposure is continual and may occur via placental passage, fetal swallowing, and fetal lung absorption.

Omtzigt et al.⁵¹⁰ report on three women with epilepsy who were taking long‐term valproate. They measured the concentrations of the parent compound and 13 of its metabolites in AF, maternal serum, and 24‐hour maternal urine samples. AF concentrations of valproate and its metabolites correlated with, but were much lower than, total valproate concentrations as well as with unbound valproate concentrations in maternal serum. The AF may act as a deep compartment, with slow appearance and disappearance of valproate and its main metabolites. In pregnancies associated with fetal NTDs (n = 55) significantly higher daily doses of valproate were used and higher levels of valproate were found in maternal serum. However, the metabolite patterns in maternal serum, 24‐hour urine samples, and AF did not show significant differences in pregnancies with NTDs.

Ethanol, a well known teratogen, causes fetal alcohol spectrum disorders in up to 5 percent of children in the United States and Europe.⁵¹¹ Ethanol enters the fetal compartment freely but is eliminated very slowly: “While the fetus has the ability to metabolize some ethanol, removal from the fetal‐maternal unit relies primarily on maternal metabolic capacity. The alcohol elimination rate from the fetal compartment is approximately 3% to 4% of the maternal rate.”⁵¹²

The vast majority of human cancers are thought to have environmental origins, whereas about 60 percent of congenital malformations have unrecognized causes. Since carcinogenesis and teratogenesis may share common pathways involved in cellular growth proliferation, migration, and differentiation, it is worrisome that many toxicants found in AF, meconium, or cord blood must reflect their entry into the fetal environment⁴⁷¹ (see Tables 3.5 and 3.6). For example, bisphenol A (BPA), an estrogenic endocrine‐disrupting chemical used in the plastics industry, is found in AF.⁵¹⁴ BPA reportedly affects preimplantation and alters postnatal development,⁵¹⁵ and experimental evidence in rats suggests BPA interferes with amelogenesis.⁵¹⁶ Given the importance of thyroid hormone in brain development, the realization that BPA acts as a thyroid hormone receptor antagonist⁵¹⁷ evokes concern.

Table 3.6 Examples of toxicants reported in amniotic fluid

Toxicant	References
Pesticides	473, 490
Dioxin	513
Organophosphates	489
Polychlorinated biphenyls	513
Herbicides	473
Chlorinated phenolic compounds	473
Perchlorate	489
Phthalates	496
Bisphenol A	486, 487
Phytoestrogens	494

Not only have all the toxicants shown in Table 3.5 been found in AF, but organophosphates have been reported in postpartum meconium.⁵¹⁸ Fetal exposure to certain phthalates may result in adult infertility, as shown in rats.⁵¹⁹ We all have grave concerns about our toxic environment, but which government will act to safeguard fetal futures?