In the 1980s Ivermectin was proved to be highly effective against river blindness (onchocerciasis). River blindness is a distressing condition that is caused by a parasitic worm and spread by flies. Ivermectin is approved by the FDA (Food and Drug Administration) to treat many neglected tropical diseases such as onchocerciasis, scabies, and helminthiases. Usually, Ivermectin is well tolerated by patients when used for these indications.
Ivermectin And Pregnancy
When it comes to pregnancy, there are a lot of questions regarding which medications are safe to use during pregnancy and which are not. Food and Drug Administration has allotted the Ivermectin to FDA pregnancy category C.
Animal reproduction studies demonstrated an adverse effect on the fetus and no sufficient and well controlled studies in humans are available. Animal studies have discovered proof of teratogenicity but at doses that were also harmful to pregnant females. The manufacturer of Ivermectin considers the drug contradicted during pregnancy.
Let’s understand more about the use of Ivermectin during pregnancy.
Ivermectin Pregnancy Cautions
A few cases have been reported involving the use of Ivermectin during pregnancy. As per these reports the risk of fetal damage in pregnant women treated with Ivermectin was not bigger than the control.
The risk against advantage must be considered in pregnant women severely infected with parasites, particularly during mass drug administration campaigns of Ivermectin in endemic regions. The benefit of treatment may offset any potential risk to the infant.
Ivermectin Breastfeeding Cautions
Ivermectin is expelled into human milk in low concentrations. The manufacturer of Ivermectin recommends that Ivermectin treatment during nursing should only given if the risk of delayed treatment to the mother offsets the possible risk to the infant. One review article acclaims the Ivermectin use in lactating women after the infant is 7 days old.
Possible Serious Adverse Events of Oral Ivermectin
There may be some common and non-serious adverse events of this drug. As per the conducted studies the serious adverse events that may occur when Ivermectin is used during pregnancy. Reported adverse events include stillbirth, spontaneous abortions, and congenital anomalies.
Other severe adverse effects marked in the protocol were not explained in these studies and thus could not be included in the analysis. It is not clear whether Ivermectin exposure during pregnancy increases the chances of spontaneous abortions and stillbirths.
Treatment Of Pregnant Women With Ivermectin During Mass Drug Administration: Investigation Of Safety And Potential Benefits Of This Drug
Presently onchocerciasis elimination programs depend majorly on annual or bi-annual community-directed treatment with Ivermectin. The African program for onchocerciasis control has proven successful in eliminating onchocerciasis as a public health issue in several African countries.
To date, pregnant females are not included in programs delivering community-directed inadvertent treatment of Ivermectin (CDTI) for onchocerciasis and preventive chemotherapy for other helminthiases due to concerns over the safety of Ivermectin administration during pregnancy.
This systematic barring withstands an infection reservoir at the community level and divests vulnerable populations from known advantages. Treating O. volvulus-infected females may improve pregnancy outcomes and diminish the risk of developing onchocerciasis-related morbidities in their children.
Moreover, teratogenic effects are noticed in non-clinical studies at doses that far exceed those used in CDTI. Early, undeclared, and undetected pregnancies are being systematically subjected to Ivermectin in practice. Treating this population necessitates proper supporting evidence for which a three-pronged approach is proposed.
The first is to create a roadmap explaining the major steps required to obtain regulatory clearance for the harmless and effective use of Ivermectin in all pregnant females who require it. The second is to perform a randomized placebo-controlled double-blind clinical trial to assess the safety and benefits of Ivermectin treatment in pregnant women with O. volvulus infection.
The trial should assess the possible side effects of Ivermectin in decreasing adverse pregnancy outcomes and neonatal death as well as diminishing the episodes of onchocerciasis-related epilepsy. The third is to establish a pregnancy registry for women who unintentionally got Ivermectin during pregnancy.
Access to valued therapies is often restricted, delayed, or denied for pregnant females because of insufficient evidence. Worries over protecting vulnerable people may cause harm to them. There should be acceptable methods to develop robust evidence for providing crucial interventions during pregnancy.
Mass Drug Distribution
Onchocerciasis heavily impacts poor and vulnerable populations in remote regions of sub-Saharan Africa. This condition causes serious disability such as blindness and epilepsy that lead to major psycho-social and economic consequences.
Currently, pregnancy is considered as contra-indication for Ivermectin treatment during CDTI even while formal pregnancy testing is not carried out before the Ivermectin distribution. Women are just advised not to take Ivermectin if they can be pregnant depending on their last menstrual period.
Often women hesitate to disclose their pregnancy status to Ivermectin distributors because of the uncertainty, privacy considerations, and social risk. It mostly happens during the early stages of pregnancy, even at later stages in case of unwanted or unplanned pregnancies. Thus pregnant women have been possibly exposed to inadvertent Ivermectin treatment at scale.
Around 3.7 billion Ivermectin doses have been administered in mass treatment campaigns globally at 10-100 times higher than current human doses. In a study performed in Ghana, during an MDA of Ivermectin and Albendazole, 14.6 % of pregnant females were involuntarily treated.
It signified 1.7% of childbearing age (15-49 years). On an Estimate around 50% of females in the first trimester of pregnancy in onchocerciasis prevalent areas of Africa may have got Ivermectin. Moreover, The registries often fail to report any adverse events after Mass drug administration with Ivermectin including inadvertent exposure during pregnancy. Treatment campaigns should put additional efforts on preventing inadvertent treatment of pregnant women.
What Most People Know About Ivermectin Safety During Pregnancy?
Presently, Ivermectin is not indicated for use during pregnancy due to a lack of available data concerning its use during pregnancy in humans. The progressive toxicity of Ivermectin was examined in rats, mice, dogs, and rabbits.
The results showed that teratogenic effects were found only at doses that are the same as those causing severe maternal toxicity. The teratogenic effects included clubbed fore-feet without skeletal changes in rabbits and cleft palates in rats, mice, and rabbits.
No observed effect level or NOEL for teratogenicity among the most sensitive species and strain in the CF-1 mouse was 0.2 mg/kg body weight while the NOEL for maternal toxicity was 0.1 mg/kg body weight. A subpopulation of the CF-1 utilized in these studies was later observed to be deficient in P-glycoprotein expression which is an efflux pump with an essential role in preventing Ivermectin toxicity.
In animal studies, the teratogenicity of Ivermectin was noticed at cumulative doses ranging between 20 and 600 times the human single dose target of 150-200 μg/kg during CDTI. Ivermectin has been broadly used in veterinary medicine including sheep, dogs, horses, cattle, and pigs for many years. Even though the number of pregnant animals treated in this study is not known, the occurrence of adverse reproductive effects after Ivermectin treatment is really low in all species.
Recently a systematic review and meta-analysis was performed on the safety of Ivermectin Treatment in pregnant females. Identified 496 pregnant females (500 pregnancy outcomes) who received Ivermectin inadvertently during mass drug administration. 397 (300 pregnancy outcome) women were treated as part of an open-label randomized clinical trial performed in Masindi, Uganda who purposely received Ivermectin.
The researchers from the Barcelona Institute for Global Health conducted a systematic review and meta-analysis of studies that stated cases of accidental exposure to the medicine among pregnant women. The conclusions of this analysis published in The Lancet Global Health says that The data is not sufficient.
Referring to these studies, no statistically substantial difference in pregnancy outcomes between Ivermectin-targeted pregnant females and concurrent control groups was noticed. No study reported neonatal deaths, preterm births, maternal morbidity, low birth weight, or any other birth defects in infants.
In a Randomized Controlled Trial in Masindi, Uganda the efficiency of Ivermectin and Albendazole 400 mg alone or combined was compared for treatment of soil-transmitted helminth infections in the second trimester of pregnancy. The abortion rate here was lower than recorded in previous reports.
It might be attributed to the anti-parasitic influence of treatment or as suggested, the exclusion of females with a history of habitual abortion and registration of females in their second trimester as most abortions happen in the first trimester of pregnancy.
The conclusion is that insufficient safety data concerning the use of Ivermectin during pregnancy is observed however there is also no evidence stating that Ivermectin during pregnancy is teratogenic in humans. That is why looking at the potential advantages of ivermectin treatment for pregnant females this type of treatment needs to be considered despite the potential risks.
Next to this argument, the French National Reference Centre for teratogenic agents of France no longer suggests not including pregnant women with helminthiases from Ivermectin treatment. Thus there is a model for prescribing Ivermectin during pregnancy offering a suitable risk balance assessment.
What Do You Need To Know About The Negative Effect Of Onchocerciasis In Pregnancy?
O. volvulus can be spread in utero to the developing fetus and prime the immune response in newborns. The severity of onchocerciasis and associated itching is an independent predictor of a shorter lactation period.
An O. volvulus infection in pregnant women may be allied to an amplified risk of spontaneous abortions and with the previous and more severe O. volvulus infections in their offspring.
The Effect Of O. Volvulus Treatment With Ivermectin In Pregnant Women On Pregnancy Outcomes
Treating O. volvulus-infected pregnant women with Ivermectin may improve pregnancy outcomes. Certainly, a study performed in Ecuador demonstrated that Ivermectin treatment in an onchocerciasis-endemic region reduced the frequency of spontaneous abortions.
The study compared the incidence rates of spontaneous abortions between onchocerciasis-prevalent and non-endemic regions. Between the years 1982 and 1989, a clear lift in spontaneous abortions of 9.5/1000 maternal years at risk was noticed in the onchocerciasis prevalent region and was linked with an increase in community O. volvulus microfilariae load.
In the same period, the incidence rate of spontaneous abortions was 1.3/1000 maternal years at risk in non-endemic regions. An MDA with Ivermectin started in 1990 (every 6 months) in the hyperendemic region and 90-95% of eligible people were treated.
It led to a dramatic reduction in community microfilariae load by 1996. This massive decrease in community microfilariae load was followed by a reduction in spontaneous abortion rates. By 1992 they were almost equivalent to non-endemic regions.
Does O. Volvulus Infection In Pregnant Females Develop Parasite Tolerance In Their Children?
Possibly, O. volvulus treatment in pregnant females with Ivermectin may decrease the risk of their babies developing onchocerciasis-related-morbidities. It may happen due to parasite tolerance.
Certainly, intra-uterine exposure to filarial antigens decreases cellular responses to parasite antigens in their children and increases the chances of post-natal filarial infection. Maternal O. volvulus infection will sensitize in utero parasite-specific cellular immune responsiveness in neonates and activate O. volvulus Ag-specific production of several cytokines (Th1- and Th2- type).
Immune responses with a preferential Th2 pattern develop parasite tolerance in newborns and neonatally-developed specific immune responses will persist upon secondary antigen contact in later life.
An 18-year follow-up study included about 4000 families in West Africa. It showed that O. volvulus infection was linked with a four-fold increased risk of O. volvulus infection in children. In the same study, the children born to O. volvulus-infected women have an increased risk of becoming infected earlier in life and developing a higher persistent mf load. In two cohort studies performed in Cameroon, a high mf load is a risk factor for developing epilepsy.
In a current case-control study performed in northern Uganda, it was found that pre-term birth could be a risk factor for nodding syndrome. It is hypothesized that pre-term birth could be associated with an untreated O. volvulus infection during pregnancy.
In an onchocerciasis-endemic region in Cameroon, the presence of onchocerciasis antibodies was determined in 209 school-age children without epilepsy and evaluated their neurocognitive performance. Moreover, post-Ivermectin use was linked to increased neurocognitive scores.
These findings show that O. volvulus exposure may affect neurocognitive performance in children. Additionally, a study performed in Uganda suggested that nodding syndrome may be led by prodromal features such as excessive sleepiness and blank staring over a few weeks to 2 years.
In kids born to infected mothers, parasite tolerance has been detected with other filarial infections. However, a study performed in India demonstrated that a proportion of infected mothers had cleared their lymphatic filariasis infections because of ongoing Mass Drug administration. The children born to such females developed the infection at comparable rates to kids those are born to females who had cleared the infection.
A systematic Review and Meta-analysis to assess the safety of oral Ivermectin during pregnancy
In this analysis, they searched relevant databases and trial registry platforms for randomized controlled trials and observational studies that reported adverse effects in pregnant women. The outcomes on focus were stillbirths, spontaneous abortions, congenital anomalies, neonatal death, maternal morbidity, low birthweight and preterm births.
The decision in the early days of Ivermectin MDA programs depended on the large clinical experience of the campaigns in which inadvertent drug exposures in hundreds of pregnant women had no harmful effect. The decision was encouraged by evidence that P-glycoprotein in the placenta prevents Avermectins from penetrating the placenta. Expression of multidrug resistance P glycoprotein in the human placenta decreases with advancing gestation.
P-glycoprotein also reduces chemically induced birth defects in mammals by active efflux of drug at the blood-brain barrier, preventing entry into the Central Nervous System. However, P glycoprotein expression in human and rat placenta during gestation varies. Placental P-glycoprotein expression in humans wanes during the gestation period whereas it increases in rats.
Generally, the development of the human blood-brain barrier starts earlier in gestation and procedures rapidly as compared to rodents and the human blood-brain barrier P-glycoprotein is detectable as early as 8 weeks of gestation. In humans, the expression of blood-brain barrier P-glycoprotein becomes far higher in concentrations during gestation as compared to rats or mice.
The analysis aimed to review and sum up all available safety data controlled studies of the impact of Ivermectin exposure during pregnancy to accommodate programmatic decision-making and to better comprehend the implications of Ivermectin use in Pregnant women. Weighing the risks and advantages of ivermectin during pregnancy is vital for informed public health policy such as mass drug administration as well as for individual treatment decisions.
Can You Take Ivermectin While Pregnant?
So now coming to the main question and conclusions of all the studies and trials performed concerning the safety of Ivermectin during pregnancy. First of all, never take Ivermectin during pregnancy without consulting a healthcare practitioner. Always talk to a healthcare professional before taking this drug during pregnancy.
There is inadequate evidence to conclude the safety status of Ivermectin during pregnancy. Authors argue for the necessity of establishing an open data repository of inadvertent drug exposures during pregnancy to attain better safety data. Toxicological studies need to be conducted in animal models. In the meantime, Ivermectin treatment campaigns should focus additional efforts to prevent inadvertent treatment of pregnant females.
