Cleft lip forms when tissues in an embryo’s face don’t fully fuse during early pregnancy, typically between the fifth and sixth weeks of development. About 1 in every 1,000 babies in the United States is born with a cleft lip, with or without a cleft palate. The causes are rarely simple. Most cases result from a combination of genetic susceptibility and environmental exposures during a narrow window of fetal development.
How the Lip Forms (and What Goes Wrong)
The structures that make up the upper lip fuse during the fifth and sixth weeks after conception, roughly eight weeks after the last menstrual period. The palate fuses later, between weeks seven and ten. During this process, separate tissue shelves grow toward each other, make contact, and merge into a continuous structure. If anything disrupts the timing, growth rate, or signaling between these tissues, a gap remains.
This means the causes of cleft lip have their effect very early, often before many people even know they’re pregnant. By the time a pregnancy is confirmed with a home test, the lip may have already formed or failed to fuse properly.
Genetic Factors
Over 70% of cleft lip cases occur without any other abnormalities and are classified as non-syndromic, meaning genetics alone don’t tell the full story. Still, several genes play a role. Variants in genes involved in facial tissue signaling and growth have been linked to increased risk. These include genes that regulate how cells communicate during embryonic development and how tissue layers form and merge.
One well-studied gene, IRF6, is involved in a small percentage of non-syndromic cleft cases (roughly 0.5%). Other genes connected to clefting include those that influence growth factor signaling and cell adhesion during facial development. Having a family history of cleft lip increases your child’s risk, but most babies born with a cleft have no affected relatives. The genetic component is polygenic, meaning many small contributions from different genes add up rather than one single gene being responsible.
Syndromic Cleft Lip
About 30% of cleft lip cases occur as part of a broader syndrome. Van der Woude syndrome is the most common, accounting for roughly 2% of all orofacial clefts. It’s caused by mutations in the IRF6 gene and typically includes lower lip pits along with the cleft. Other syndromes associated with clefting include conditions that affect limb development, kidney function, or the central nervous system alongside facial structures.
Smoking and Alcohol During Pregnancy
Maternal smoking during pregnancy increases the risk of cleft lip by about 79%, based on adjusted analyses that account for other variables. The chemicals in tobacco interfere with oxygen delivery to developing tissues and can disrupt the molecular signals that guide facial fusion.
Alcohol consumption during pregnancy carries its own risks. Research has found that drinking is associated with more than double the risk of cleft palate specifically. The developing face is especially vulnerable to alcohol’s effects during the same early weeks when lip and palate fusion occurs. Because these structures form so early, even drinking before a pregnancy is recognized can matter.
Medications That Increase Risk
Certain medications taken during the first trimester are known to raise the likelihood of cleft lip. Topiramate, a drug used for epilepsy and migraines, has been studied extensively. Babies exposed to topiramate early in pregnancy develop oral clefts at a rate of about 4.1 per 1,000, compared to 1.1 per 1,000 in unexposed pregnancies. At higher doses (above 100 mg daily), the risk increases roughly fivefold.
Isotretinoin, a powerful acne medication, is a well-established cause of birth defects including cleft lip and is strictly contraindicated during pregnancy. Valproic acid, another antiseizure medication, also carries known risks for facial clefts. The common thread with these medications is that they interfere with cell growth and differentiation during the critical weeks of facial development.
Folic Acid and Nutritional Gaps
Folic acid deficiency was known to produce facial clefts in animal studies even before its more famous connection to spinal cord defects was established. A large population-based study found that women who took at least 400 micrograms of folic acid daily around the time of conception had a 39% lower risk of having a baby with cleft lip. This is the same dose recommended for preventing neural tube defects and is found in most prenatal vitamins.
The protection was specific to cleft lip. Folic acid supplementation did not reduce the risk of cleft palate alone, suggesting these two conditions, while related, have partially different underlying mechanisms. Folate plays a key role in DNA synthesis and cell division, both of which are happening rapidly during the weeks when the face is forming.
Maternal Diabetes and Obesity
Pre-existing diabetes (type 1 or type 2 diagnosed before pregnancy) roughly doubles the risk of cleft lip. The likely mechanisms involve abnormal blood sugar levels creating oxygen stress for the developing embryo and triggering DNA damage through a process related to chronic high glucose. Gestational diabetes, which develops later in pregnancy, does not appear to carry the same risk, likely because it typically emerges after facial structures have already formed.
Maternal obesity independently raises the risk as well, though more modestly. Obese women have about a 26% higher chance of having a baby with an orofacial cleft compared to women at a normal weight. For every 10-point increase in BMI, the risk of cleft lip rises by roughly 23%. Several mechanisms may explain this: chronic low-grade inflammation associated with excess body fat, disrupted hormone signaling, and the accumulation and release of environmental pollutants stored in fat tissue. Overweight women (not yet in the obese range) also showed elevated risk, with about a 30% increase for cleft lip specifically.
Why Most Cases Have No Single Cause
For the majority of babies born with a cleft lip, no single factor is responsible. The current understanding is that most non-syndromic cases arise from a “threshold model,” where a child inherits a combination of genetic variants that make facial fusion slightly more vulnerable, and then an environmental exposure during the critical developmental window pushes past the threshold. A mother who smokes and has a family history of clefting faces a higher combined risk than either factor alone.
This also explains why cleft lip can appear in families with no history of it. A new combination of common genetic variants, paired with an environmental trigger at the wrong moment, can produce a cleft in a family where none has occurred before. The five-to-six-week fusion window is remarkably narrow, which means both the timing and the type of exposure matter as much as the exposure itself.