1. Introduction
Antibacterial drugs are the most widely used drugs in clinical practice. In this paper, according to the five classes of drug risk to pregnancy issued by the US FDA (Class A, no adverse effects on the fetus, minimal risk; Class B, no harm to the fetus in animal experiments, but lack of clinical control studies on safety in humans, many clinical drugs belong to this category; Class C, adverse effects on the fetus in animal experiments, but lack of clinical control studies on safety in humans (Class C, which has adverse effects on fetus in animal experiments but lacks clinical control studies on safety in humans; Class D, which is harmful to fetus but is very necessary clinically and there is no alternative drug, should be used after fully weighing the pros and cons; Class X, which has been proved to have teratogenic effects in humans and is extremely harmful and prohibited), and discuss the rational application of antimicrobial drugs during pregnancy.
2. Rational application of antimicrobial drugs during pregnancy
2.1 Penicillins
The commonly used penicillin antibiotics include penicillin, ampicillin, amoxicillin, penicillin V, benzocillin, methicillin, cloxacillin, piperacillin, meloxicillin and aloxacillin.
Penicillin antibiotics are all listed in FDA classification category B and are safer to use during pregnancy. Given that the renal clearance of this drug increases with glomerular filtration rate during pregnancy, blood levels in pregnant women tend to be lower and appropriate dose increases may be considered.
Penicillin has been the most studied to date, and the drug has been used clinically since the 1940s. The results of retrospective studies on populations have shown that the use of penicillin in the first trimester of pregnancy has not been found to have adverse effects on the embryo or fetus. The use of penicillin in pregnancy combined with syphilis is effective in treating the mother and protecting the fetus.
In drug application monitoring studies, no increase in the rate of fetal malformation caused by ampicillin, amoxicillin, penicillin V and benzathine was found. Ampicillin, amoxicillin and methicillin have a low protein binding rate and easily pass through the placenta and reach 0.5-1 times the maternal plasma drug concentration in the amniotic fluid; 90 minutes after maternal injection of ampicillin, its blood concentration is equal to that of the fetus, because of immature fetal renal function. The half-life of the drug is longer, and 200-300 minutes later, the blood concentration in the fetus is 7 times greater than that in the mother. Ampicillin is used in obstetrics for premature rupture of membranes and prevention of intrauterine infection.
The use of cloxacillin has been reported to cause malformations in newborns delivered by pregnant women, but the correlation with the drug is uncertain and may be related to the disease suffered by its mother during pregnancy.
Piperacillin does not easily pass through the placenta. It and meloxicillin and alloxicillin have been on the market for a short time, and there is no sufficient information on their safety in pregnancy, so they are generally not recommended.
2.2 Cephalosporins
Most cephalosporins belong to category B, except for cephalosporin, which is listed in category C of FDA, and are safer to use in pregnancy, but cefoperazone, cefmetazole and cephalosporin contain methyl sulfotetrazole side chain, which can reduce thrombinogen, and have testicular toxicity in animal experiments, and should be used with caution.
Cephalosporins can generally pass through the placenta, but the concentration in the fetus is low, only a few tenths to a third of the maternal concentration, with the exception of ceftizoxime, which can reach twice the maternal concentration in the fetus of a pregnant woman using the drug. As with penicillins, because the renal clearance of these drugs increases with the glomerular filtration rate during pregnancy, the blood concentrations in pregnant women tend to be lower, and appropriate dose increases may be considered.
The commonly used first-generation cephalosporins are cefadroxil, cefazolin, cefalexin and cefradine.
Cefadroxil can pass through the placenta and is used orally in obstetrics for the treatment of urinary tract infections, and no teratogenic or other adverse effects on the fetus have been found. Cardiovascular malformations and cleft lip and palate were more frequent in the fetuses of women who used the drug in the first trimester, but this may be related to the illnesses suffered by the mother during pregnancy and the combined use of the drug.
Cefazolin can pass through the placenta into the fetal circulation and amniotic fluid, and some studies have reported that the drug concentration in fetal umbilical blood is about one-third of that in the mother one hour after intravenous administration of 1 g to women in late pregnancy.
Cefradine can rapidly pass through the placenta, and when administered intravenously in the middle and late stages of pregnancy, the peak drug concentration in the umbilical blood is reached at about 50 and has a therapeutic concentration.
The commonly used second-generation cephalosporins are cefuroxime, cefmetazole and cefaclor. The first two drugs used during pregnancy can rapidly pass through the placenta and reach therapeutic concentrations in the fetal circulation and amniotic fluid.
The commonly used third-generation cephalosporins are cefotaxime, ceftizoxime, ceftriaxone, ceftazidime, cefoperazone, cefixime, and cefbutene.
The development of cephalosporins has been very rapid, and there are fewer data regarding them in drug application monitoring studies. The use of cefadroxil during pregnancy has not been found to increase the rate of fetal malformation; the rate of neonatal malformation in pregnant women using cefradine, cefaclor and ceftriaxone is higher, but the correlation with the drug is uncertain and may be related to the disease suffered by pregnant women and the combined use of drugs, etc.: the safety of other cephalosporins on the fetus lacks research data, and should not be preferred without special circumstances.
2.3 β-lactamase inhibitors
Imipenem, aminotrans, etc. belong to class B of FDA classification, and there is no research data on the safety of fetus, so they should not be used without special circumstances.
Clavulanic acid, sulbactam, tazobactam and other β-lactamase inhibitors also belong to the FDA classification of class B. These drugs are rarely used alone, but are mostly used in combination with other antibiotics, and no teratogenic effects on fetuses have been found in animal experiments.
2.4 Aminoglycosides
Aminoglycosides have no teratogenic effect on the fetus, and the effect on the fetus is mainly on the eighth toxicity to brain nerves and nephrotoxicity. Except for gentamicin, which is classified as Class C by FDA, all others belong to Class D. Aminoglycosides can pass through the placenta and the fetal blood concentration is lower than that of the mother; the maternal blood concentration may be lower than normal during pregnancy and blood concentration monitoring should be performed.
Aminoglycosides can damage both cochlear and vestibular functions. Neomycin, kanamycin and amikacin mainly affect hearing, streptomycin and gentamicin mainly involve the vestibule, tobramycin damages cochlear and vestibular functions to approximately equal extent, and ethyl viologen has the least ototoxicity.
Aminoglycoside toxicity to the brain nerve can be mechanistically divided into two types, one is dose-dependent, and the occurrence of toxicity is related to the dose, method of administration, and course of treatment, and is more likely to occur in renal insufficiency, presumably because the drug concentration in the inner ear lymphatic fluid is persistently too high, damaging the inner and outer hair cells of the inner ear cortical apparatus, and the initial lesions may be reversible, but the damage becomes irreversible when it exceeds a certain level The initial lesions may be reversible, but beyond a certain point the damage becomes irreversible and permanent;
The other type is the genetic mutation type, in which the occurrence of toxicity is not significantly related to the blood concentration or the concentration of the drug in the lymphatic fluid of the inner ear, and occurs mainly in patients with genetic mutations, which have been identified to occur in the seventh chromosome pair, and the type of mutation is also ethnically related and is mainly inherited through the mother.
The main site of renal function impairment by aminoglycosides is in the proximal tubule of the kidney, but does not involve the glomerulus. Nephrotoxicity is in decreasing order of kanamycin, cisomicin, gentamicin, amikacin, tobramycin, and streptomycin.
2.5 Tetracyclines
It is FDA classified as Class D and is prohibited during pregnancy. The effects of tetracycline on mother and child are multifaceted. Animal experiments have shown that tetracycline has embryotoxic effects in early pregnancy, and it is controversial whether the fetus has finger malformations or congenital cataracts and other teratogenic effects, but the middle and late pregnancy is the time of fetal bone and tooth development, tetracycline into the fetus and calcium complex formation complex deposited in the bone and teeth, and calcium chelate, forming a tetracycline-orthophosphate calcium complex, the fetus and young children’s bone development is inhibited The risk of this effect is greatest from the third year of gestation;
The use of tetracycline during the middle 6 years of gestation can also cause fetal and young children’s enamel hypoplasia, brown pigmentation, yellowing of teeth, the degree of discoloration related to the total amount used, and can be aggravated by repeated use of the drug; tetracyclines can cause liver damage, the liver of pregnant women and fetuses also have toxic effects, pregnant women with pyelonephritis or renal insufficiency, especially prone to hepatotoxicity, there have been many cases of intravenous use of pregnant women There have been many reports of acute liver failure caused by intravenous use of tetracycline in pregnant women, so tetracycline is prohibited during pregnancy.
Studies on the use of doxycycline, oxytetracycline, minocycline, and memantine have shown that the rate of neonatal malformations is higher in mothers who have used these drugs during pregnancy, and they should generally not be used during pregnancy. Doxycycline and oxytetracycline cause less tooth discoloration than other tetracyclines.
2.6 Chloramphenicol
Chloramphenicol belongs to the amidol class FDA classification as class C. Chloramphenicol can pass through the placenta, and the drug concentration in the umbilical cord blood is 30-106% of that of the mother when the product is applied in late pregnancy, and has not been found to have teratogenic effects, but chloramphenicol inhibits bone marrow hematopoietic function and leads to neonatal gray baby syndrome or fetal death, so blood concentration monitoring should be performed when it must be used.
2.7 Macrolides
FDA classified as Class C, with erythromycin as the representative drug. It is generally believed that erythromycin is not teratogenic and no adverse effects on offspring have been found, but the drug rarely passes through the placenta and cannot exert therapeutic effects on the fetus; erythromycin is used to treat mycoplasma infections during pregnancy, which can reduce miscarriage and decrease the number of low birth weight infants. However, the hepatotoxicity of erythromycin ester is very high, and its use should be prohibited in pregnant women.
The safety of erythromycin drugs such as azithromycin, roxithromycin, clarithromycin, and madicamycin in pregnancy is not well documented. Spiramycin is widely used in Europe and no adverse effects on the fetus have been observed. Spiramycin or acetylspiramycin is the preferred treatment for pregnant women with Toxoplasma gondii infection.
2.8 Sulfasalazine
FDA classifies sulfadiazine as Class B. No teratogenic effect has been found, but it competes with bilirubin for protein binding sites and can cause neonatal jaundice, bilirubin encephalopathy and hyperbilirubinemia. It should not be used in late pregnancy, especially in the prodromal period.
Sulfamethoxazole (Synthroid) FDA classified as Class C. Animal experiments have found reports of teratogenicity in rats, no similar effects in rabbits, but can increase mortality in pregnant rabbits, and there is no adequate information in humans.
Methotrexate is classified as Class C by the FDA, interferes with folic acid metabolism, and has teratogenic effects in animals. Methotrexate and sulfamethoxazole form a compound sulfamethoxazole (cotrimoxazole), both of which can pass through the placenta and have concentrations in fetal blood close to maternal blood concentration levels. A study of 2,296 pregnant women who had used cotrimoxazole in the first three months of pregnancy showed that 126 newborns had large birth defects, suggesting that there may be a correlation between cotrimoxazole and high rates of neonatal malformations and that it should not be used during pregnancy.
2.9 Quinolones
Commonly used quinolones include norfloxacin, ciprofloxacin, ofloxacin, levofloxacin, enoxacin, lomefloxacin and sparfloxacin, which are classified as Class C by FDA. In animal experiments, the concentration of ciprofloxacin in osteoarticular cartilage was high, and the manifestation of cartilage tissue destruction was seen under light and electron microscopy, and it has not recovered after 2 weeks of drug withdrawal.
There is little information on the use of quinolones in human pregnancy. It has been reported that of 132 newborns born to pregnant women treated with ciprofloxacin, only 2 were born with defects, which is less than the expected 2-3% risk; ciprofloxacin can slowly pass through the placenta, and the drug concentration in the amniotic fluid after 12 hours of administration exceeds 10 times the maternal blood concentration. Another documented case, 35 pregnant women in the first 3 months of pregnancy had been treated with norfloxacin or ciprofloxacin for urinary tract infections, their birth infants were healthy and no deformities or joint abnormalities were found. In view of the above results of animal experiments, it is recommended that caution must be exercised when using quinolones antibacterial drugs on pregnant women.
2.10 Others
Vancomycin is classified as Class C by FDA and can pass through the placenta. Vancomycin applied in the middle of pregnancy to treat chorioamnionitis can reach therapeutic concentration and no teratogenic effect was found, but it can cause fetal ototoxicity and should be used with special caution.
Furantoin has no adverse effects on the fetus, because it can pass through the placenta, theoretically it may cause hemolytic anemia in fetuses with glucose-6-phosphate dehydrogenase deficiency, but it has not been reported clinically. The teratogenic effect of furazolidone on the fetus has not been reported. Glucose-6-phosphate dehydrogenase deficiency may produce hemolytic anemia after application of this product, and should be used with caution in late pregnancy.
Clindamycin is commonly used for the treatment of drug-resistant anaerobic bacterial infections during labor and delivery, especially in the amniotic fluid and after delivery, and can pass through the placenta and reach therapeutic concentrations in fetal tissues.
3.Summary
The above is a brief introduction to the safety of antimicrobial drugs used in pregnancy according to their classification. In clinical work, it must be kept in mind that pregnancy is a very special physiological period, and when using antimicrobial drugs, in addition to the effectiveness of the drugs against pathogenic bacteria, the safety of the drugs is very important, and the adverse effects of the drugs on the fetus should be avoided to the maximum extent possible to reduce birth defects.