A study published in March 2022 made some truly shocking findings regarding metformin.
It revealed that men who took metformin before conception increased the risk of their baby having birth defects by 40%.
These findings could pave the way to further research and, perhaps, encourage doctors to reconsider the decision to prescribe metformin to men who plan to have a family. Read on to learn more.
What is metformin?
Metformin is a first-line medication to treat high blood sugar levels caused by type 2 diabetes. It belongs to a class of drugs called biguanides. Metformin works to reduce the amount of glucose the body absorbs from food or is produced by the liver.
The drug was first discovered in 1922, but human studies began in the 1950s. Metformin was introduced as a medication in France back in 1957. In the United States, metformin use started in 1995, when the FDA approved it.
Metformin is one of the most widely prescribed medications for diabetes mellitus. In 2019, metformin was the fourth most commonly prescribed medication in the United States.
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What are the side effects of metformin?
Most people experience some side effects of metformin when they first start using the drug as their body adjusts to it.
The most common adverse reactions to metformin include:
- Nausea and/or vomiting
- Bloating and gas
- Stomach pain
- Metallic taste in the mouth
- Weight loss
However, metformin can cause more serious side effects too. These are:
- Anemia – metformin can reduce levels of vitamin B12. Anemia manifests itself through dizziness, lightheadedness, and tiredness.
- Lactic acidosis – a rare but serious disease resulting from the accumulation of metformin in the body. The buildup of metformin disrupts pH balance. Lactic acidosis is a medical emergency, and it’s indicated through symptoms such as weakness and extreme tiredness, nausea and vomiting, decreased appetite, dizziness and lightheadedness, trouble breathing, fast or slow heart rate, and others.
- Hypoglycemia – while metformin doesn’t usually cause low blood sugar or hypoglycemia, in rare cases, it can happen if you combine the drug with an unhealthy diet, strenuous exercise, other diabetes medications, and alcohol.
Can men taking metformin lead to an increase in birth defects?
As mentioned at the beginning of this post, one study found that men’s use of metformin increases the risk of birth defects.
The study was carried out by scientists from the University of Southern Denmark and Stanford University School of Medicine.
The main objective of the study
Diabetes mellitus decreases semen quality, while medications that treat this condition exhibit glucose-independent effects on the male reproductive system. However, it’s not entirely clear whether these medications impact offspring.
For that reason, the main objective of this study was to evaluate whether pharmacologic treatment of a father’s diabetes increases the risk for birth defects in offspring.
This nationwide study was set in Denmark from 1997 to 2016. Scientists used national registries to follow births and compare the risk of major birth defects in babies that were exposed to diabetes drugs or not.
The study only included children born to men under 40 and women under 35. The analysis didn’t include babies born to mothers who already had diabetes.
Babies were considered exposed if their fathers filled at least one prescription for diabetes management during fertilizing sperm development.
Results of the study
Results of the study were published in the March 2022 issue of Annals of Internal Medicine.
The study included more than one million babies in total. Of these, 3.3% had one or more major birth defects.
Results showed 5298 babies were insulin-exposed while 1451 were exposed to metformin. Metformin-exposed babies had a higher birth defects rate.
Interestingly, there was no link between birth defects risk and the use of other diabetes medications. Metformin was the only drug linked with birth defects.
The father’s use of metformin before conception increased the risk of birth defects by 40%.
Scientists concluded the study by explaining that preconception paternal use of metformin is related to major birth defects, especially genital birth defects in males. That said, further research is necessary to clarify the link between a father’s metformin use and the baby’s risk of birth defects.
The term major birth defect or congenital anomaly refers to structural changes in one or more parts of the body. These birth defects have serious effects on a baby’s development, health, and functional ability.
Which birth defects were identified?
The only metformin birth defects identified in this study were genital birth defects. As mentioned above, this birth defect was only present in male babies.
Genital birth defects occur when something goes wrong in the development of the baby’s genital tract during pregnancy.
In boys, genital birth defects can affect the penis, scrotum, or testes. Boys can also develop genital birth defects of the urethral opening or they may have abnormally shaped penis. Some boys are born with undescended testis. The study, however, didn’t specify the exact type of genital birth defect in male offspring.
Cases when metformin didn’t increase the risk of birth defects
Another important finding from this study was that men who took metformin before or after the three-month maturation period didn’t have a high risk of having a baby with birth defects.
Additionally, unexposed siblings of babies with birth defects also didn’t have the risk of being born with congenital anomalies.
Why is metformin linked to birth defects?
While the connection between paternal use of metformin and birth defects exists, it’s not entirely clear why that happens.
One theory is that some oral diabetes pharmacologic agents such as metformin could have antiandrogenic activity and thereby alter testosterone levels. This could explain genital birth defects in babies. However, further research is necessary to elucidate mechanisms of action through which metformin increases the risk of birth defects.
Is diabetes actually to blame?
A previous study published in the Asian Pacific Journal of Reproduction found that diabetes can jeopardize sperm quality and thereby impair male fertility.
For that reason, scientists who worked on birth defect study also wanted to determine whether diabetes plays a role here. That’s why they also compared the rates of birth defects in babies whose fathers took insulin. Their analysis showed insulin wasn’t linked to a change in birth defect risk.
Limitations to the study
Even though the study made significant findings, it did have some limitations worth addressing.
For example, scientists didn’t have data on medication compliance, glycemic control, and other aspects of diabetes. They only evaluated information on when the subjects filled the prescriptions.
It’s also useful to remember that metformin-exposed infants generally had older parents. These parents also had a lower socioeconomic status. These factors are also important when evaluating health risks.
Is it safe to take metformin during pregnancy?
Metformin is considered safe during pregnancy. However, some concerns require further research on this subject.
The biggest concern regarding metformin use in pregnancy is the fact this diabetes drug crosses the placenta. Basically, when a pregnant woman takes metformin, so does the baby she carries.
A review published in the Human Reproduction Update revealed the rate of birth defects in the metformin exposure group wasn’t statistically increased compared to groups where women didn’t use metformin. Scientists concluded that there is no evidence metformin is linked with a higher risk of major birth defects.
Other studies have also shown that metformin use in pregnancy doesn’t increase congenital abnormalities, and it’s usually well-tolerated.
Journal Diabetologia published a paper questioning the claims that metformin is safe during pregnancy. The paper also outlines some uncertainties.
Studies on the safety of metformin in pregnancy usually had a small sample size and only evaluated short-term effects. Many of those studies had various limitations, and their quality is questionable.
A paper from Diabetologia suggests more research on this subject is necessary. Scientists emphasize the importance of studies with large sample sizes, and they should evaluate long-term effects too.
To sum up, while metformin is considered safe in pregnancy, some studies show this is not clear and emphasize the significance of further research.
What are the side effects of taking metformin while pregnant?
While metformin is usually safe during pregnancy, as seen above, some women may experience certain side effects. These side effects are usually mild and include vomiting, nausea, diarrhea, gas, heartburn, stomach pain, and gastrointestinal changes.
In other words, the side effects of metformin in pregnancy are the same as the general adverse reactions of this drug. However, these side effects could worsen morning sickness in pregnant women.
How does metformin affect the fetus?
Since metformin can cross the placenta, it’s impossible not to wonder how it affects the fetus inside the womb. The truth is that research on this subject is scarce, which is why it’s difficult to understand how metformin can affect the baby.
The BMJ published a study that found there is no evidence that maternal use of metformin in the first trimester causes non-genetic birth defects. However, the only significant finding was for pulmonary valve atresia, but scientists explain it could be accidental.
Pulmonary valve atresia is a birth defect of the heart where the valve that regulates blood flow to the lungs from the heart doesn’t develop at all.
Other studies showed that women who used metformin in the first trimester lost less weight after delivery, and their babies were born heavier than the control group. Evidence also showed that metformin-exposed babies had larger head circumference when they were observed at the age of one.
To sum up, while evidence is limited, some studies do show that maternal use of metformin can increase the risk of certain birth defects, and it also induces metabolic changes in children compared to controls.
For that reason, fetuses could weigh more. Also, the diabetes drug metformin could have anti-growth, energetically- and nutritionally-restrictive effects on some cell types in women, which could affect infants.
The role of the father’s use of metformin on fetus outcomes is insufficiently explored. What we do know is that the use of this drug can increase the risk of genital birth defects.
The latest study showed that paternal use of metformin increases the risk of birth defects by 40%. The study only detected genital birth defects.
It’s not clear why that happens, but the drug could have an impact on testosterone. A lot more research is necessary to evaluate all the ways through which metformin can affect fetuses. The label of metformin doesn’t have an indication of potential risks due to scarcity of evidence.