Cleft lip and palate develop when tissues in a baby’s face don’t fully close during the first weeks of pregnancy. In the United States, about 1 in 1,000 babies is born with a cleft lip (with or without a cleft palate), and roughly 1 in 1,687 is born with a cleft palate alone. The causes are rarely a single factor. Most cases result from a combination of genetic susceptibility and environmental exposures during a narrow window of early development.
How Clefts Form During Pregnancy
The lip forms between the fourth and seventh weeks of pregnancy. The roof of the mouth, or palate, forms between the sixth and ninth weeks. During these periods, separate plates of tissue on each side of the face grow toward the midline and fuse together. A cleft happens when that fusion is incomplete, leaving a gap in the lip, the palate, or both.
Because the lip and palate develop on slightly different timelines, it’s possible to have a cleft lip without a cleft palate, a cleft palate without a cleft lip, or both together. Whatever disrupts normal tissue growth or fusion during those critical early weeks, whether genetic or environmental, can produce a cleft. Most women don’t even know they’re pregnant during this window, which is why preconception health matters so much.
Genetics and Family History
About 70% of cleft lip and palate cases are classified as nonsyndromic, meaning the cleft occurs on its own without other birth defects. These cases typically involve multiple genes, each contributing a small amount of risk. No single “cleft gene” has been identified for most nonsyndromic clefts. Instead, a child may inherit several genetic variants that, together, make the facial tissues more vulnerable to incomplete fusion. Having a first-degree relative with a cleft significantly raises the likelihood, though most babies with clefts are born into families with no history of the condition.
The remaining 30% of cases are syndromic, meaning the cleft appears alongside other abnormalities involving the heart, kidneys, nervous system, or skeleton. The most common syndrome linked to clefting is Van der Woude syndrome, which accounts for a large share of syndromic cases and is caused by a mutation in a single gene. Other associated conditions include 22q11.2 deletion syndrome, Patau syndrome, Stickler syndrome, Treacher Collins syndrome, and Goldenhar syndrome, among others. Syndromic clefts are more likely to be identified through genetic testing, and they often require a broader treatment plan beyond cleft repair.
Smoking During Pregnancy
Maternal cigarette smoking is one of the best-established environmental risk factors. Women who smoke during pregnancy face a 34% increased risk of having a baby with cleft lip or palate compared to nonsmokers. The relationship is dose-dependent: smoking 1 to 10 cigarettes per day raises the risk by about 32%, while smoking more than 20 cigarettes per day pushes the risk up by 69%. Secondhand smoke exposure has also been flagged as a potential contributor, though the evidence is less precise. The chemicals in tobacco are thought to interfere with cell growth and signaling during the weeks when the lip and palate are forming.
Maternal Health: Obesity and Diabetes
A mother’s weight before pregnancy plays a measurable role. A large meta-analysis found that maternal obesity (a BMI of 30 or higher before pregnancy) increases the risk of orofacial clefts by about 18% overall. When broken down further, obesity raises the risk of cleft lip with or without cleft palate by 13% and cleft palate alone by 22%. These aren’t dramatic numbers on an individual level, but across a population they account for a meaningful share of cases.
Pre-existing diabetes, particularly type 2 diabetes, adds further risk. Poorly controlled blood sugar in early pregnancy can disrupt normal embryonic development across several organ systems, including the face. Obesity and diabetes often co-occur, and their combined effects on fertility and pregnancy outcomes compound the concern. Managing blood sugar levels before conception appears to reduce these risks.
Medications Linked to Clefts
Several medications taken during early pregnancy have been associated with cleft formation. Anti-seizure drugs carry some of the strongest evidence. Valproic acid and phenytoin have both been linked to cleft lip and palate in multiple studies. Lamotrigine, another seizure medication, has shown an elevated rate of cleft palate specifically, with roughly 17 cases per 10,000 exposed pregnancies compared to background rates.
Other medications flagged in research include certain pain relievers like naproxen, some blood pressure medications, and the fertility drug clomiphene, which showed roughly double the expected rate of cleft palate in registry data. These associations don’t mean every exposed pregnancy will be affected. Risk depends on timing, dosage, genetic susceptibility, and other factors. For women who need these medications, the decision involves weighing the treatment benefit against reproductive risk, ideally before conception.
Pesticides and Environmental Chemicals
Animal studies have consistently shown that certain pesticides can cause cleft lip and palate in developing embryos. Organophosphates, some herbicides, and dioxin (a toxic byproduct in the manufacture of some pesticides) have all produced clefts in laboratory animals at sufficient doses. Dioxin exposure in pregnant mice, for example, causes clefts in a dose-dependent pattern: higher exposure, more clefts.
The picture in humans is less clear. Epidemiological studies have found increased rates of clefts among children whose mothers lived near agricultural areas or had occupational pesticide exposure during pregnancy, but results across studies remain inconsistent. The challenge is that people are exposed to mixtures of chemicals at varying doses, making it difficult to isolate the effect of any single substance. Still, the animal evidence is strong enough that minimizing pesticide exposure during pregnancy is a reasonable precaution.
Folic Acid and Prevention
Folic acid, the synthetic form of folate (a B vitamin), is well known for preventing neural tube defects like spina bifida, but it also reduces the risk of cleft lip. Women are recommended to take 400 micrograms of folic acid daily starting at least four weeks before conception and continuing through at least the eighth week of pregnancy. This timing matters because it covers the critical window when the lip and palate are forming.
Most women don’t get enough folate from food alone to reach protective levels, which is why supplementation is important. Many countries have also added folic acid to flour and grain products to boost population-wide intake. The protective effect appears strongest for nonsyndromic cleft lip with or without cleft palate. For women with a family history of clefts, or those on medications that interfere with folate metabolism, higher doses may be appropriate.
Why Most Cases Have No Single Cause
For the majority of cleft lip and palate cases, no single factor is responsible. A baby may carry genetic variants that make facial development slightly more vulnerable, and then an environmental trigger during weeks four through nine tips the balance. Two pregnancies with the same genetic background can have different outcomes depending on nutrition, medication use, smoking status, or chemical exposures during that narrow developmental window. This is why clefts can appear in families with no history and skip generations in families where they’re known. The interplay between genes and environment makes predicting individual cases nearly impossible, but it also means that modifiable risk factors like smoking, folate intake, and blood sugar control offer real opportunities to lower the odds.