1.Introduction
Gastrointestinal diseases are common, and due to special physiological changes during pregnancy, pregnant women often have various digestive symptoms or some combined digestive diseases, such as varying degrees of nausea, vomiting, heartburn, epigastric discomfort, constipation, etc., which may affect pregnancy in severe cases. Clinicians should have clear indications when applying medication to pregnant women, avoid unnecessary medication in the early stages of pregnancy, and choose medications with reference to the 5 categories of drug risk to pregnancy grading standards A, B, C, D, X issued by the U.S. Food and Drug Administration, with increasing risk, and choose the drug with the least impact on the fetus.
2. Antacids and peptic ulcer treatment drugs
Research shows that the rate of gastroesophageal reflux and “heartburn” during pregnancy is 45-85%, and the main reason for its occurrence is related to the increase of estrogen and progesterone during pregnancy and the low function of the pyloric sphincter. The quality of life of pregnant women with severe symptoms will be affected. Once the decision is made, the first-line drugs of choice are antacids and aluminum thioglycollate.
Long-term studies have shown that their effects on the fetus are minimal, if any, and not teratogenic; H2 receptor blockers (e.g., ranitidine, cimetidine) or pro-gastric drugs (metoclopramide, cisapride) can be used as second-line drugs for patients with slightly more severe symptoms (nizatidine should be avoided if possible); as for proton pump inhibitors, they are generally not recommended unless used in patients with severe GERD or as preanesthetic As for proton pump inhibitors, they are generally not recommended in pregnancy unless used in patients with severe GERD or as pre-anesthesia medication, and the results of studies on this subject show that lansoprazole is the best choice. The following are some of the commonly used drugs.
2.1 Aluminum thioglycollate
Also known as gastric ulcerin, Dixian, Shukefi, Gastric Smile, classified as Class B by FDA. Basic function: It binds to pepsin and inhibits the enzyme from decomposing protein, and decomposes aluminum hydroxide and sucrose sulfate complex under the action of gastric acid, which can polymerize into insoluble negatively charged colloid and form protective film on gastric mucosa, which is conducive to regeneration of mucosa and healing of ulcer.
According to the data of the U.S. Michigan Drug Use Monitoring Study from 1985 to 1992, 183 pregnant women who used this product in the first 3 months of pregnancy had 5 cases of severe malformation in their newborns, which was lower than the expected number of 8 cases, suggesting that this product has no teratogenic effect on the fetus.
2.2 Cimetidine
It is also known as Tegetimex and Mecamylamine, classified as Class B by FDA.
Basic action: It is H2 receptor blocking drug, competitively inhibits the action of histamine at H2 receptor, inhibits the secretion of gastric acid caused by basal gastric acid and various stimuli, and can reduce the secretion of gastric juice and the secretion of pepsin. It also has an anti-androgenic effect.
It is used for the treatment of gastroduodenal ulcers. VKOREN et al. studied 23 pregnant women who used cimetidine in early pregnancy. 2 cases of spontaneous abortion, 2 cases of pre-eclampsia, 18 cases of normal newborns and 1 case of hemangioma on the right upper eyelid were safely removed, so the authors concluded that cimetidine is not teratogenic in humans.
Data from the 1985-1992 Michigan Drug Use Monitoring Study in the United States showed no teratogenic effect on the fetus. Currently cimetidine is widely used in clinical practice and is often applied when women are not found to be pregnant, and no adverse effects on the fetus have been found.
2.3 Ranitidine
It is also known as Zanogastride and Furanilamide, classified as Class B by FDA.
Basic action: Ranitidine is an H2 receptor blocking drug, the effect is 4-6 times stronger than cimetidine, this product has no anti-androgenic effect. No teratogenic effects were found in animal experiments. 1985-1992 Michigan Drug Use Monitoring study data from the United States showed that 516 newborns whose mothers applied this drug in early pregnancy were studied and the results showed no teratogenic effects.
Ruigoemz et al. studied cimetidine, ranitidine and omeprazole in pregnant women in the United Kingdom (1179 cases – and 1057 cases in Italy) during 1991-1996. 20 of these cases were stillbirths and 100 of the 2261 surviving children had congenital malformations, with an overall malformation rate of 4.4%. The risk of non-inherited congenital malformations associated with cimetidine, ranitidine and omeprazole application was 1.2 [95% confidence interval (CI): 0.6-2.3], 0.9 (95% CI: 0,3-2.2), 1.4 (95% CI; 0.8-2.4), respectively, with no statistical difference compared to pregnant women who were not exposed to the drugs during pregnancy, and did not increase the preterm birth and fetal The incidence of intrauterine growth retardation was not increased.
2.4 Famotidine
It is also known as Gastrodin, Kamat, Rifabutin, and Cinfadin, which is classified as Class B by FDA.
Basic action: Famotidine is an H2 receptor blocker, about 20 times stronger than cimetidine and about 7.5 times stronger than ranitidine.
It is able to pass through the placenta. In order to study the long-term safety of Famotidine, Japanese and American researchers have given oral and intravenous Famotidine to rats, rabbits and dogs, and the maximum dose observed was up to 4000mg/d.kg for 105 weeks (2000mg/d>kg), and no teratogenic, mutagenic or carcinogenic effects were found. There are no adequate and available controlled studies to report whether this product has teratogenic effects on humans.
2.5 Omeprazole
Also known as Loxacor and Oxycodone, classified as Class C by FDA.
Basic action: The drug acts specifically on gastric mucosal wall cells to inhibit hydrogen ion-potassium ion-triphosphate adenosine enzyme, thereby inhibiting H+ secretion, and has a significant inhibitory effect on all forms of stressful gastric acid secretion.
Omeprazole can pass through the placenta. The teratogenic effect of omeprazole was not found in animal studies. 955 infants whose mothers had applied omeprazole during pregnancy, registered in the Swedish Medical Birth Registry from 1995 to 1999, were studied by Hallen. 824 cases were applied in early gestation, 92 cases in middle and late gestation, and 32 cases in both early and late gestation, resulting in 5 stillbirths and a slight increase in the incidence of congenital heart disease. There was a slight increase in the odds, but it was not statistically significant.
Lalkin conducted a multicenter, prospective, controlled study to investigate whether the application of omeprazole during pregnancy increased the incidence of congenital malformations, spontaneous abortions, low birth weight babies, or perinatal complications. 113 pregnant women who applied omeprazole during pregnancy had a 4% rate of severe fetal malformations, which was not statistically significant compared to the 2% rate in the control group. statistically significant difference
The birth weight of newborns, maternal gestational weeks of delivery, preterm delivery and incidence of neonatal complications were similar between the two groups (P=0.68). CONCLUSION: The application of omeprazole during the organogenesis phase did not increase the incidence of severe malformations, and the application of omeprazole during pregnancy did not increase the incidence of spontaneous abortion, low birth weight infants, or perinatal complications. Although the teratogenic effect of this drug cannot be completely ruled out, it can be considered that the individual risk of applying this drug in early pregnancy is low.
2.6 Mesalazine
Also known as 5-aminosalicylic acid, enteritis complex, classified as Class B by FDA.
Basic action: Mesalachin, the active ingredient of salazosulfapyridine, has a significant anti-inflammatory effect on inflammation of the intestinal wall, and is particularly effective in inflamed connective tissue of the intestinal wall. It is often used as a suppository or suspension for the treatment of ulcerative colitis, rectosigmoiditis and proctitis. Less than 20% of the drug is absorbed by the colon and excreted in the urine through acetylation when the drug is administered by enema.
In a study conducted by Marlean on 123 pregnant women with colitis in 3 gastroenterology centers in France, Mesalachin was used in 69 cases in early pregnancy, 48 cases in mid pregnancy and 6 cases in late pregnancy at a mean daily dosage of (2.1±0.8) g. The mean daily dosage was less than 3 g/d in the low dose group in 86 cases, and 37 cases in the low dose group. The number of abnormalities in the low-dose and high-dose groups were: ectopic pregnancy (1, 0), spontaneous abortion (1, 1), stillbirth (0, 1), preterm delivery (3, 5), and congenital malformation (3, 1). The authors concluded that it is safe to take mesalamine equal to or less than 2 g/d during pregnancy.
No teratogenic or toxic effects on the fetus have been observed with the application of this product during pregnancy. Studies on the safety of this product for the fetus during pregnancy are still very inadequate.
3.Antiemetic and Gastric stimulant drugs
Pregnancy vomiting is one of the most common gastrointestinal symptoms during pregnancy. Since pregnancy vomiting is self-limiting and the symptoms are not serious, most people do not need to apply anti-vomiting drugs. Patients can improve their symptoms by eating less and more meals, increasing carbohydrates, reducing fat intake and avoiding contact with foods and smells that bother pregnant women. It is safer to apply appropriate amount of vitamin B6 during pregnancy, but its effect on pregnancy vomiting is not yet certain. For severe vomiting that cannot be improved by any of the above measures, with the consent of the pregnant woman, the
Clinically, drugs that have less effect on the pregnant woman and the fetus can be used. Current data indicate that meclozine, seclizine, and metoclopramide are among the antiemetic drugs with low teratogenic risk.
3.1 Meclozine
Also known as chlorpheniramine, meclizine and meclizine, classified as Class B by FDA.
Basic effect: It is a piperazine antihistamine, and its effect can be maintained for 12-24 hours. It is used for nausea and vomiting caused by pregnancy, radiation therapy and motion sickness. Application of high doses of this product to pregnant rats (25 times-30 times the human dosage) can cause cleft palate in fetuses. Numerous epidemiological studies have shown no teratogenic effects of meclozine in humans. According to data from the National Perinatal Collaborative Program study, no increase in malformation rates was seen in 1014 newborns whose mothers applied this product early in pregnancy. The FDA concluded that there is no need to restrict the use of meclozine in pregnancy or to warn about its use during pregnancy.
As with other antihistamines, application of this product within 2 weeks prenatally may increase the chance of posterior lens fibrous tissue formation in newborns.
3.2 Seclorizine
Also known as benzosin, classified as Class B by the FDA.
Basic action: Piperazine antihistamine with antihistamine, antiemetic and anti-dizziness effects.
Animal experiments have found that cyclozine has teratogenic effects. However, in humans, miklovich’s study showed that the incidence of serious congenital anomalies and perinatal mortality in live-born neonates treated with cyclozine for pregnancy vomiting during the 12th week of gestation was not statistically different compared to untreated controls. This suggests that cyclozine has no teratogenic effect. The relationship between the application of antihistamines during pregnancy and the occurrence of cleft lip malformation has been investigated. It was found that the incidence of cleft lip malformation in newborns was not increased in the group of pregnant women who were administered cyclozine.
3.3 Metoclopramide
Also known as gastroflucan and methotrexate, classified as Class B by FDA.
Basic action: It acts on the emetic chemoreceptor area of the delayed brain by blocking dopamine receptors and has a powerful central antiemetic effect. It is used for the prevention and treatment of motion sickness, and also for the treatment of pregnancy vomiting.
Metoclopramide can pass through the placenta. In recent years, metoclopramide has been gradually used
In an analysis of 39 pregnant women who received metoclopramide during pregnancy, there were no statistical differences in fetal malformation rate, fetal weight, preterm delivery and stillbirth when compared with 13327 pregnant women who did not receive the drug, sorenscn (2000). CONCLUSION: Treatment with metoclopramide during pregnancy cannot be considered to be associated with the development of abnormal pregnancy outcomes. In another study, a retrospective analysis of 646 pregnant women who were treated with outpatient application of metoclopramide for severe pregnancy vomiting, comparing several indicators such as maternal weight, symptoms, fetal abnormalities and adverse effects before and after treatment, showed that outpatient application of metoclopramide for severe pregnancy vomiting was safe and effective without teratogenic effects.
3.4 Isoprostanes
Also known as fenagan, antiamine nettle, pramipexole hydrochloride, FDA classified as Class C.
Basic action: phenothiazine antihistamines with powerful central cholinergic blocking activity and central tranquilizing effect.
It is used in obstetrics and gynecology clinics for the treatment of pregnancy vomiting and analgesia during labor and delivery. It is generally believed that its application to pregnant women does not increase the rate of fetal malformations. However, in a study of 1197 newborns whose mothers used this product in early pregnancy, it was found that the incidence of cardiovascular malformations was slightly higher than that of the control group. Although this cannot be ruled out as being related to the mother’s disease or the concomitant use of other drugs, caution should be exercised in early pregnancy.
In late pregnancy, the drug concentration in the umbilical cord blood is almost the same as that in the mother’s blood 15 minutes after intravenous administration because of the rapid passage of promethazine through the placenta, and it is maintained for at least 4 hours. It has been reported that the application of this drug during labor may cause respiratory depression in the newborn, therefore, this drug should be used with caution for labor analgesia.
3.5 Ondansetron
Also known as pivoxanine, pivodan, endanserone, ondanserone, classified as Class B by FDA.
It is a highly selective 5-hydroxytryptamine 3 receptor (5-HT3) blocker, mainly used for the treatment of nausea and vomiting caused by chemotherapy and radiation therapy.
No teratogenic effects have been found in animal studies. In humans, it has been reported to be used for the treatment of severe vomiting in pregnancy that is difficult to be controlled by other drugs, with definite antiemetic effect, but there are no sufficient and controllable studies on the teratogenic effect of this product, so its clinical application is limited to after 12 weeks of pregnancy.
3.6 Cisapride
Also known as Prevacid, classified as Class C by FDA.
Basic action: It is a gastroprokinetic agent that selectively promotes the release of acetylcholine at the postganglionic area of the muscular plexus of the intestine, significantly increasing the contraction of the gastric body and sinus region, increasing gastric tone and accelerating the emptying of the gastrointestinal tract. It does not affect dopamine receptors.
No teratogenic effects were found in experiments with rats and rabbits, but embryotoxic and fetotoxic effects could be produced at extremely high doses (14 and 16 times the human dosage, respectively). In a multicenter study of 129 cases of cisapride application during pregnancy (88 of which were applied during fetal organogenesis), pregnant women with comparable disease type, age, smoking and alcohol intake were selected as controls, and there were no statistical differences between the two groups in terms of medical history, birth weight, gestational age at delivery, live birth rate, spontaneous and pre-eclampsia abortion rate, incidence of intrauterine distress, and incidence of severe and minor malformations. There were no statistical differences. The results suggest that the use of cisapride during pregnancy does not increase the incidence of malformations, spontaneous abortions, or low birth weight babies. Due to the lack of adequate and available controlled studies, it should not be used in pregnant women.
3.7 Domperidone
Also known as morpholine, gastrodex, perphenazine, no FDA classification reported yet.
Basic action: Peripheral dopamine receptor blocker, acts directly on the gastrointestinal wall, enhances gastric motility, promotes gastric emptying, and effectively prevents bile reflux. It can increase the plasma level of prolactin. There are no adequate and controlled studies on the safety of this product for the fetus in pregnant women, so pregnant women should use it with caution.
4. Laxatives and antidiarrheal drugs
During pregnancy, due to the action of a large amount of estrogen and progesterone, the smooth muscle relaxation, gastrointestinal tract tension is reduced, peristalsis is slowed down, and due to the mechanical compression of the pregnant uterus, constipation occurs in about 30% of pregnant women. Laxatives basically have no teratogenic effect, but stronger laxatives should not be used for pregnant women if they are not specifically needed. When functional constipation exists in pregnant women, it is appropriate to use laxatives and laxatives.
4.1 Lactulose
Also known as Dulcolax, FDA classified as Class B.
Basic action: Lactulose is a synthetic disaccharide that is converted into lactic and acetic acid by bacterial action in the colon to acidify feces. Lactulose is rarely absorbed in the small intestine, so it is not harmful to the fetus. For example, lactulose is mainly used in obstetric clinics to treat common constipation during pregnancy. The results of a multicenter study showed that after 1 week of application of lactulose, the number and character of stools of patients with habitual constipation improved significantly, and after 2 weeks, the stool habit could be restored to normal without significant adverse effects.
4.2 Phenolphthalein
Also known as fruit guide, classified as Class C by FDA.
Basic action: Stimulating laxative, forming soluble sodium salts after taking, stimulating colonic mucosa, prompting its peristalsis and preventing intestinal fluid absorption. About 15% of phenolphthalein is absorbed after oral administration, and most of it is excreted by urine. If the urine is alkaline, it will be pink in color.
The molecular weight of this product is small and it is presumed to pass through the placenta. It has no teratogenic effect on the fetus when used during pregnancy.
4.3 Liquid paraffin
FDA classified as Class C.
Basic action: It is a lubricating light laxative. It is basically not absorbed by the gastrointestinal tract after oral administration.
It is safe for pregnant women and fetus when applied according to the recommended dose. Long-term use of this product may interfere with the absorption of fat-soluble vitamins.
4.4 Loperamide
Also known as loperamide, chlorphenesinamide, emmenagogue, classified as Class B by FDA.
Basic action: It is a non-specific antidiarrheal drug. It can act directly on the smooth muscle of gastrointestinal tract, inhibit its peristaltic hyperactivity, prolong the residence time of the contents in the small intestine, promote the absorption of water, electrolytes and glucose, and have a significant inhibitory effect on diarrhea caused by intestinal overproduction. This product does not affect the central nervous system.
Application during pregnancy: In animal experiments, no teratogenic effect of this product has been found. Data on human studies are more limited. One study followed 105 women from 5 teratogenic research centers who applied loperamide during pregnancy (89 of them in early pregnancy) and used women who were similar in age, smoking, and alcohol intake but not exposed to loperamide as control group, and their fetal malformation rate, spontaneous abortion, preterm abortion and preterm birth rate, and mean birth weight The results showed that the fetal malformation rate, spontaneous abortion, preterm abortion and preterm birth rate, and mean birth weight were observed between the study and control groups.
The results showed no statistical difference between the study group and the control group, however, the weight of the newborns of the 21 pregnant women who were exposed to loperamide throughout pregnancy was 200 g lower than that of the control group.Conclusion: The use of loperamide during pregnancy does not increase the incidence of serious fetal malformations, but its effect on fetal weight needs to be further studied.
4.5 Simethicone
Also known as double octahedral montelukast, no FDA classification report is available.
Basic action: The drug has a laminar structure and non-uniform charge distribution. It has an extremely strong fixing and inhibiting effect on viruses and bacteria in the digestive tract and the toxins they produce. It has a strong covering ability on the mucosa of the digestive tract and improves the defense ability of the mucosal barrier against attack factors. It does not enter the blood circulation and does not alter the normal intestinal motility.
Application during pregnancy: It is safe for pregnant women and fetus when applied in recommended doses. The dosage should be reduced if constipation occurs in a few patients when applied.
5.Cholestatic drugs
5.1 Ursodeoxycholic acid
Also known as deoxycholic acid, Ursodeoxycholic acid, FDA classified as Class B.
Basic action: Oral administration of this product can promote the secretion of bile acids and cause changes in the composition of bile acids. It is a drug of hepatic-intestinal circulation. After oral administration, it is mainly absorbed by ileum, combined with glycine or taurine in the liver, discharged from the bile into the small intestine and involved in hepatic-intestinal circulation, and only a small amount enters the large circulation. It is mainly used for cholesterol type stones or primary biliary cirrhosis, and during pregnancy it is mainly used for the treatment of intrahepatic cholestasis during pregnancy.
Animal experiments have not found teratogenic effects of this product, but it has mild embryotoxic effects. In humans, it has been gradually applied in recent years at home and abroad for the treatment of intrahepatic cholestasis in pregnancy with relatively satisfactory results, and most of the results show that it can effectively improve the prognosis of mother and child. Current studies have not found any teratogenic effects or adverse effects on the fetus and newborn.
5.2 Adenosylmethionine
Also known as Simethicone, no FDA classification report is available.
Basic action: It is a physiologically active molecule present in all tissues and body fluids of the human body. In the liver, it regulates the fluidity of hepatic cell membranes by methylation of plasma membrane phospholipids, promotes the synthesis of sulfide products in the detoxification process through the transsulfuration reaction, and helps prevent bile accumulation in the liver. No teratogenic effects have been found in animal studies, but some studies have shown that it can cause fetal growth retardation.
In humans, a small sample of studies using this product for the treatment of intrahepatic cholestasis during pregnancy did not reveal adverse effects on the fetus and newborn. However, the studies are inadequate and need to be further investigated in depth.