Follow-up studies from tens of thousands of pregnant women suggest that some drugs double the risk of malformations in babies

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Written by| Li Shanshan

A three-year follow-up survey of more than 17,000 pregnant women in 23 third-class hospitals in 12 provinces across the country found that the use of Chinese herbal medicines in the first trimester and first half of pregnancy increased the risk of congenital malformations.

In pregnancy or perinatalism, the safety and health of the baby is the primary concern of every expectant mother, however, the choice of medication often confuses them, after all, the story of fetal malformations caused by medication is not uncommon in history.

In the 50s of last century, thalidomide (reaction arrest) was widely used to treat morning sickness, but it was famous for causing congenital malformations such as seal limbs; Also in the late 40s and early 50s, diethylstilbestrol was considered a "fetal miracle drug", but later studies found that it could cause genital tract malformations, and the effects were not limited to pregnancy, but may affect three generations, until it was banned in 1971, and it is estimated that five million to ten million people in the United States alone were exposed to diethylstilbestrol, of which one million to two million were pregnant women.

Thalidomide stories have led to caution when choosing Western medicines, but contrary to caution when using Western medicines, in Asian regions, Chinese herbal medicine is often considered a safe option because people rarely associate it with side effects. This time, the latest research shows that Chinese herbal medicines may also cause harm to the fetus and even lead to congenital malformations.

As early as 2012, a team of researchers from the Chinese University in Hong Kong published an article in the journal Human Reproduction at the University of Oxford, reporting the results of feeding pregnant mice with 20 Chinese medicines. According to that study, 20 kinds of Chinese herbal medicines, including dodder seeds and yew trees, can cause a series of toxic reactions that affect fetal development, and even problems such as stillbirth, postpartum death, birth delay or teratogenicity.

However, the association between the use of Chinese herbal medicines during pregnancy and fetal outcomes has been seldom explored until recently, as larger study samples are needed for specific Chinese herbal medicines and adverse fetal outcomes, particularly congenital malformations, which are associated with lower incidence outcomes. On April 19, the journal of the Nordic Federation of Obstetrics and Gynecology (AOGS) published an article entitled "Maternal Chinese Medicine Exposure and the Risk of Congenital Malformations: A Multicenter Prospective Cohort Study", using real-world data to obtain the conclusions at the beginning of the article.

The study also found several TCM ingredients suspected of teratogenicity, which require further study. This means that "clinicians should exercise caution when recommending TCM to women who are planning to become pregnant or who are already pregnant, and further research into the teratogenicity of specific herbs, such as chicken blood vine, is warranted".

Certain Chinese medicines more than double the rate of congenital malformations in children

This is almost the first large-scale cohort study in the medical community on the relationship between exposure to traditional Chinese medicines and the risk of congenital malformations.

Wu Jiangnan, a doctor at the Obstetrics and Gynecology Hospital of Fudan University, explained to Intellectual: Prior to this, animal studies showed that some Chinese herbal medicines commonly used during pregnancy were associated with an increased risk of congenital malformations (such as skeletal system abnormalities), "However, these findings are limited to animal testing and are controversial, and because there are too few cases, the differences between animals and people, etc., it is impossible to make a clear judgment." ”

Previously, there have been some follow-up studies on the effects of traditional Chinese medicine on pregnancy outcomes such as miscarriage and preterm birth, however, there have been few studies on neonatal outcomes with lower incidence. This time, from August 2017 to August 2020, in the pregnant cohort recruited by 23 tertiary hospitals in 12 provinces, the researchers collected data on early pregnancy diseases and therapeutic drug use, including periconceptional and first trimester Chinese medicine use, before ultrasound screening for fetal malformations at 11-13 weeks of gestation. Subsequently, the investigators explored the effects of preconception and first trimester ultrasound screening and drug exposure on adverse fetal outcomes through follow-up for outcomes such as infant malformations. Of course, the impact of traditional Chinese medicine was not the main goal of this cohort study, which is a project that targets the value of ultrasound screening for fetal malformations in the first trimester. According to reports, before this paper on traditional Chinese medicine and fetal malformations, the research group has used the data of this cohort study to publish a related study on the relationship between fetal ultrasound soft indicators in early pregnancy and adverse pregnancy outcomes, and the research group is also studying the relationship between other exposure factors and malformations.

In the study, more than 17,000 pregnant women were divided into three groups: no drugs, only Western medicines, and treatments containing traditional Chinese medicine. The survey data showed that excluding 962 pregnant women who lost to follow-up in the later stage, a total of 273 infants had at least one congenital malformation among more than 16,000 pregnant women, and the overall prevalence of congenital malformations was 1.63%, that is, 16.3 cases per 1,000 infants, of which the incidence of congenital malformations in the group that did not use drugs was 1.46%, the incidence of fetal malformations in the group using therapeutic western drugs (excluding preventive supplements such as folic acid and vitamins) was 2.01%, and the incidence of congenital malformations in children in pregnant women in the group containing traditional Chinese medicine was 3.46%.

Compared with pregnant women who did not use drugs, the incidence of congenital malformations in children was increased by 1.1 times in pregnant women who used traditional Chinese medicine, and the difference was statistically significant. Subsequent subgroup analysis showed that the teratogenic risk of traditional Chinese medicine use was cumulative, and the more traditional Chinese medicine used, the higher the risk of fetal malformation.

Thankfully, the study found that of the 4,417 respondents who had used drugs, only 289 (6.5%) had used traditional Chinese medicines. However, Wu Jiangnan explained that this situation may be related to the strict standards for the use of traditional Chinese medicines in the study, for example, "women who need to have received at least one course of traditional Chinese medicine treatment between six months before and during pregnancy, or who have explicitly used traditional Chinese medicine in the first trimester" will be defined as traditional Chinese medicine exposure. Those who had used Chinese medicine before pregnancy but "did not complete a complete course of treatment", or who used drugs containing Chinese herbal ingredients in the first trimester but did not know it, were not counted.

However, is the increase in infant malformations related to the mother's age factor, or are the pre-existing conditions that increase the infant's abnormalities?

Wu Jiangnan said that when they conducted statistical analysis, they have incorporated age into the model, and the current results have controlled the influence of age factors. For those diseases that caused the mother to use traditional Chinese medicine, on the one hand, the research group conducted a stratified analysis to exclude the impact of the disease itself; On the other hand, compared with the use data of traditional Chinese medicine and western medicine, compared with pregnant women who did not use drugs, the incidence of maternal and infant malformations using traditional Chinese medicines was still significantly increased, and the incidence of maternal fetal malformations treated with western medicines was also increased (22%), but there was no statistical significance.

Although there are some shortcomings in the study, there are strong data to prove whether traditional Chinese medicine has an impact on the rate of infant malformations, however, what researchers want to know more is: which traditional Chinese medicine ingredients cause children's malformations? "We are more concerned about the safety of the drug than on evaluating the efficacy. We hope to find the harmful ingredients of Chinese medicine and keep the essence and remove the bad, so that we can fundamentally promote and develop the cause of Chinese medicine. ”

Dangerous Chinese medicine: chicken blood vine

Analyzing and tracking the traditional Chinese medicines used by 10 mothers of malformed children who reported exposure to traditional Chinese medicine, Wu Jiangnan found two suspected teratogenic traditional Chinese medicines.

Among the 10 pregnant women, 2 mothers used Chinese medicine before pregnancy and 8 used Chinese medicine in the first trimester. Four out of eight reported using bushelan for colds, pharyngitis, etc. It contains four ingredients: purple flower, skullcap, fussoe match, and banlan root, among which skullcap has attracted the attention of researchers.

For the relationship between skullcap and fetal skeletal malformations, there have been early animal experimental data. A 2009 study of mice by Hong Kong Baptist University showed that intake of scutellaria baicalensis root aqueous extract below this value did not cause obvious external fetal or skeletal malformations at 32 g/kg/day, but once above this value, it showed potential maternal toxicity. In 2010, a study from South Korea showed that high-dose skullcap exposure could cause fetal lumbar malformations.

Regarding the relationship between scutellaria baicalensis and infant malformations found in this study, Wu Jiangnan explained, "Due to some shortcomings in the study, such as the inability to directly analyze the association between the use of drug ingredients and fetal malformations, we can only look at which traditional Chinese medicines have been used in these cases, hoping to find suspicious ingredients." However, due to the small number of malformations, larger samples or more direct correlated data are required to assert them."

At the end of 2018, the State Food and Drug Administration issued an announcement revising the adverse reactions, contraindications and precautions on the instructions of Pudilan oral liquid as "not yet clear", adding "caution for pregnant women" and "caution for those with allergies".

If the discovery of teratogenicity in scutellaria baicalensis only provides new evidence for the known facts, the increase in the rate of infant heart malformations caused by the use of chicken blood vine before pregnancy suggests that the use of traditional Chinese medicine before pregnancy may also affect fetal growth and development, and this situation has not been paid attention to before.

Of the 10 children with congenital malformations, 3 were diagnosed with congenital heart malformations, and two of them reported using Chinese medicine before pregnancy – almost the first clear data that preconception use of Chinese medicine also had teratogenic effects. The two mothers' use of traditional Chinese medicine has a common ingredient - chicken blood vine that caught the researchers' attention.

Chicken blood vine is a common herb that has been widely used to treat menstruation-related conditions such as irregular menstruation, dysmenorrhea, and amenorrhea, and infertility. According to analysis, the effect of chicken blood vine mainly comes from a flavonoid component it contains, which can help regulate blood and blood vessel function, improve hematopoietic function, anti-platelet aggregation and angiogenesis.

However, studies have shown that prolonged periconceptional exposure to chicken blood vine may interfere with the subsequent steps of fetal cardiac organogenesis, leading to an increased risk of congenital heart defects. Of course, some researchers speculate that the effects of chicken blood vine "may also be partly due to exposure to contaminants during cultivation, production or processing."

Regarding the relationship between traditional Chinese medicine and infant heart malformations, Li Qingchen, a pediatric surgeon and author of "Extracardiac Legends", told Intellectual: It is true that the pediatric surgery textbooks and congenital heart disease surgery textbooks do not mention the risks of traditional Chinese medicine, but at least we know very well that there is no situation where it is necessary to take traditional Chinese medicine, whether it is during pregnancy or pregnancy."

But in any case, this cohort study showed a strong association between infant heart malformations and the use of chicken blood vine before pregnancy. "Safety should always be a priority principle for drug use, and now we have found a suspected "mine" and hope to promote the industry's subsequent "demining" work." Demining is certainly very difficult, but only by avoiding these mines can Chinese medicine embark on a healthy road and continue to develop healthily," Wu Jiangnan told Intellectual.

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1, Maternal traditional Chinese medicine exposure and risk of congenital malformations: a multicenter prospective cohort study，Ting Peng, etc. Acta Obstetricia et Gynecologica Scandinavica, 2023;

2, Safety evaluation of commonly used Chinese herbal medicines during pregnancy in mice, Chi Chiu Wang etc. Human Reproduction, 2012

3, Traditional Chinese medicine，Jin-Ling Tang, etc. Lancet, 2008