N-acetyl cysteine treatment in recurrent unexplained pregnancy loss
By: Alec Hampton, M.S.
Executive Director’s Note: This week, we feature a research review summarized by Alec Hampton, a medical student and former FACTS elective participant. Previous studies have identified a link between oxidative stress and miscarriage, which prompts the question of the role of antioxidants in healthy, full-term pregnancy. This study explores a well-researched antioxidant supplement, N-acetyl cysteine (NAC), as a preventative intervention in the setting of recurrent pregnancy loss.
Although recurrent pregnancy loss (RPL) remains a common diagnosis, a definitive cause is known in only 50% of cases. Early pregnancy loss (prior to 20 weeks of gestation) is even more common, and most clinicians do not evaluate for hidden causes until two or three miscarriages. Research suggests that oxidative stress may contribute to RPL. Notably, pregnancy itself is a natural state of oxidative stress, especially in the first trimester when the placenta is becoming established and the increased mitochondrial activity produces reactive oxygen species. It is hypothesized that some RPL is due to a deficiency in antioxidant defense mechanisms. N-acetyl cysteine (NAC) is a medication known for its antioxidant properties and benign safety profile. Previous studies demonstrate NAC is well tolerated; no fetal or maternal risks were found. This 2008 study by Amin et al aims to assess the use of N-acetyl cysteine for the prevention of miscarriage in pregnant women with a history of recurrent pregnancy loss.
“Research suggests that oxidative stress may contribute to recurrent pregnancy loss.”
This hospital-based prospective controlled study recruited 168 participants from 2005 to 2007. The women, aged 20-35, were menstruating regularly, and each of them had a history of RPL with the same partner. Exclusion criteria included women with irregular menstruation or endocrine abnormalities, abnormal uterine anatomy or positive antiphospholipid antibodies. Group 1 was given NAC 0.6 g plus folic acid 500 µg daily, and Group 2 was only given 500 µg of folic acid daily. Treatment began as soon as pregnancy was confirmed. Participants were followed every two weeks with ultrasound up until 20 weeks of gestation for a primary outcome of a viable pregnancy beyond 20 weeks of gestation. Secondary outcomes included side effects, rate of fetal growth, malformations, amniotic fluid volume, and take-home baby rate. Analysis of data was conducted by a two-sided chi-squared test.
Analysis of the two groups found no statistically significant difference in the participants’ age, previous obstetric history or the percentage lost to follow-up. Yet, Group 1 had a significantly higher rate of the primary outcome of pregnancy continuation with a relative risk of 2.90 (95% CI 1.5-5.6, p-value 0.002). This means women taking both NAC and folic acid were 2.9 times more likely to continue pregnancy past 20 weeks’ gestation compared to Group 2 with folic acid alone. Group 1 also had a higher take-home baby rate with a risk ratio of 1.98 (95% CI 1.3-4.0, p <0.047), meaning that women taking NAC and folic acid were 1.98 times more likely to bring their babies home compared to women taking only folic acid. Furthermore, the study found that women in Group 2, who only took folic acid, had a statistically significant increased risk of a discontinued pregnancy compared to women taking NAC and folic acid (p<0.0004).
“Women taking both NAC and folic acid were 2.9 times more likely to continue pregnancy past 20 weeks’ gestation compared to Group 2 with folic acid alone.”
This study examined the use of N-acetyl cysteine during pregnancy to decrease the risk of recurrent pregnancy loss. The total study population consisted of 168 participants, which is a considerable sample size for a study in a pregnant population with a known history of recurrent miscarriage. The study suggests NAC can be a promising medication to offer to women with a history of RPL. According to the study, pregnant women taking NAC will have an increased rate of pregnancy continuation, a higher take-home baby rate, and a lower risk of pregnancy discontinuation.
A notable benefit of this study is its support of the previously reported favorable safety profile of N-acetyl cysteine when used during pregnancy. There were no statistically significant adverse effects of the medication in the mother or fetus. This is encouraging, as it may ease the minds of patients and medical professionals considering the use of NAC in pregnant patients. A potential limitation of this study is that treatment did not commence until after pregnancy was confirmed, which typically may not occur until at least 4 weeks estimated gestational age. The question remains, would treatment prior to implementation lead to a further increase in pregnancy continuation rates?
Women who utilize fertility awareness-based methods (FABMs) are much more in tune with their ovulatory cycles. As such, they may be able to detect the possibility of pregnancy earlier, leading to more prompt treatment. Training in FABMs also enables physicians and other medical professionals to assess the quality of the different phases of a woman’s cycle, which aids in the diagnosis of otherwise hidden problems that impact fertility. Given NAC’s thinning of mucus,  some clinicians prescribe it to help augment the presence of cervical mucus. Patients who take NAC can be assured the medication is safe and might even aid in preventing a miscarriage. Given its safety, minimal side effects, and its role as a potential treatment in the setting of recurrent pregnancy loss, N-acetyl cysteine could become a routinely prescribed medication for all pregnant patients and those trying to conceive, or at least for those with reasonable concern for miscarriage.
“Given its safety, minimal side effects, and its role as a potential treatment in the setting of recurrent pregnancy loss, N-acetyl cysteine could become a routinely prescribed medication for all pregnant patients.”
 Practice Committee of the American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril. 2012;98(5):1103-1111. doi:10.1016/j.fertnstert.2012.06.048.
 Amin AF, Shaaban OM, Bediawy MA. N-acetyl cysteine for treatment of recurrent unexplained pregnancy loss. Reprod Biomed Online. 2008;17(5):722-726. doi:10.1016/s1472-6483(10)60322-7.
 Banerjee S, McCormack S. Acetylcysteine for Patients Requiring Mucous Secretion Clearance: A Review of Clinical Effectiveness and Safety [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2019 Jun 14.
ABOUT THE AUTHOR
Alec Hampton, MS is a fourth-year medical student at Kansas City University College of Medicine. He earned a Master’s degree in Biomedical Sciences at Kansas City University College of Biosciences, and completed his undergraduate education at Newman University in Wichita, KS. He plans to pursue residency in family medicine and is interested in obstetrics and fertility medicine. He participated in the FABM electives in medical school and plans to pursue further training on the subject. His wife is a family medicine resident with similar interests. After residency, they plan to practice full-spectrum family medicine in rural Kansas, helping women and couples to understand their fertility better so they may grow their families and plan their futures.