To our knowledge, this is the first report of such high levels of Cr and Co during a human pregnancy. Implantation of metal-on-metal hip devices can lead to an increase in metal ion serum levels, especially if mechanical dysfunction occurs. Some studies report an increase of Cr and Co levels in patients with metal-on-metal hip implants. The postoperative metal ion values of our patient exceed the values reported by other investigators more than 100-fold (Table 3). Renal impairment might cause increased metal ion levels but was excluded for our patient.
For industrial exposure to Co and Cr, health effects include: (1) impairment of cardiac, renal, and the male reproductive systems; (2) greater incidence of inflammatory and other immune reactions; and (3) development of lung cancer after long-term exposure to Cr (VI) . Local inflammatory and other immunologic reactions in periprosthetic tissues also have been reported . Inflammatory and necrotic changes in addition to a presumed delayed hypersensitivity response to CoCr particles might lead to the formation of pseudotumors [30, 50]. However, there is less information regarding systemic effects and the long-term effects of elevated Cr and Co levels from surgical implants are unknown. At concentrations equivalent to those found in the blood of patients with well-functioning metal hip prostheses, DNA double-strand breaks were caused by Cr (VI) and nanoparticles of CoCr alloy, the latter ones also inducing chromosome aberrations , however, Cr (VI) is rapidly reduced to its trivalent form after cellular uptake  and, as reviewed by Afolaranmi et al., Cr- and Co-induced carcinogenesis remain theoretical as no data have been published to suggest any definite pathologic effects . In our patient, Cr and Co were determined using ICP-MS that quantifies the overall metal content, thus information regarding the oxidation state could not be obtained.
Acute or chronic poisoning can lead to numerous clinical symptoms such as visual loss, hearing disturbance, and lower limb hyposthenia as described in a female patient with a metallic hip prosthesis and raised concentrations of Cr and Co in blood, plasma, urine, and cerebrospinal fluid. Chelating treatment with edetic acid decreased metal ion concentrations, but neurologic symptoms improved only after resection arthroplasty . Other case reports describe hypothyroidism, peripheral neuropathy, cardiomyopathy , impairment of hearing and sight, numbness in the feet, and dermatitis on the head and neck, with improving clinical symptoms after revision surgery . Cardiovascular, neurologic, and endocrine problems also were observed in five patients owing to remarkably high Co concentrations attributable to their prosthetic hip [46, 47]. Occult or future toxic effects related to cobaltism for the mother and the infant in our study cannot completely be ruled out.
There is concern regarding potential effects on the unborn. However, reports of adverse effects of elevated metal ion levels in human pregnancies are limited. Ziaee et al.  verified that Cr and Co cross the placenta in pregnant women with metal-on-metal hip resurfacings and in the control group of pregnant women without any metal implants. In contrast to the control group in which the differences between the mean maternal and cord blood levels were marginal, in the study group, cord blood levels of Cr and Co were 29.4% and 60.4% of the maternal blood levels, respectively. This led to the suggestion that the placenta does not act as a total barrier, but rather exerts a modulatory effect on the transfer of these essential trace elements that also are required by the developing fetus. None of the children reported in the study by Ziaee et al. had congenital anomalies . Regarding our case, the contents of Cr and Co in the amniotic fluid and in the cord blood were much lower than that in the maternal blood corresponding to transplacental transfer rates of 10.5% for Cr and 52.4% for Co (Table 2), which is consistent with the observations of Ziaee et al.  and those of Rudge et al. , who estimated a transplacental transfer of 45% for Co in 62 paired samples of maternal and cord blood. Even in the presence of much higher maternal levels, as was the case for our patient, than that reported by Ziaee et al.  (mean maternal blood Cr 1.28 μg/L, mean maternal blood Co 1.39 μg/L), the threshold for the placental modulatory effects obviously is not exceeded. In a more recent study, teratogenic effects also were not observed in three pregnant patients with metal-on-metal hip resurfacings, although there was a transplacental passage of less than 25% Cr and approximately 50% Co . In yet another study of three pregnant women with metal-on-metal implants and slightly elevated serum levels, Cr and Co could not be detected in the umbilical cord sera . However, in that study, metal ions were determined using graphite furnace atomic absorption spectrometry, which is not as sensitive as high-resolution ICP-MS used by Ziaee et al.  and which might contribute to the different findings.
Because our patient showed no neurotoxic symptoms or other signs of intoxication and developmental toxicity has not yet been suspected in human pregnancies, we did not recommend chelating therapy. Moreover, efficacy of chelating therapy in patients with elevated metal ions resulting from surgical implants is unclear and deficiency of essential trace elements, especially copper and zinc, is possible. However, although the chelating agent 2,3-dimercaptopropane-1-sulfonate is reportedly not teratogenic in laboratory animal experiments , there are no data regarding possible adverse reproductive effects in human pregnancies. Thus, we do not recommend chelating therapy in general for pregnant women with increased metal ion levels because of prosthesis wear but such a choice would need to be individualized.
We cannot generalize from one patient, but given the lack of documented reports on pregnant women exposed to extremely elevated Cr and Co levels, the seemingly uneventful outcome of this pregnancy may reassure colleagues when counseling patients with high ion levels whether to carry a pregnancy to term.
We thank Ute Schäfer-Graf MD, PhD, and her team (Berlin, Germany) for obtaining blood samples and all the staff of the laboratory of Hans-Jakob Limbach MD, PhD, and colleagues (Heidelberg, Germany) for analytical work.
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