Can Spinal Muscular Atrophy Be Detected During Pregnancy?

Spinal muscular atrophy can be detected during pregnancy, and there are several ways to do it depending on the stage of planning and what is already known about the parents’ genetics. The most common path starts with carrier screening of the mother (and then the father, if needed), followed by direct testing of the fetus through a tissue sample or, increasingly, through analysis of the mother’s blood. Because SMA is a recessive genetic condition, both parents must carry a faulty copy of a specific gene for a pregnancy to be at risk, so detection during pregnancy is really a two-step process: figuring out whether the parents are carriers, and then testing the fetus if they are.

How Carrier Screening Works

SMA is caused by a missing or nonfunctional copy of a gene called SMN1, which produces a protein that motor neurons need to survive. Everyone has a nearby backup gene called SMN2 that makes a smaller amount of the same protein, but SMN2 alone cannot fully compensate when SMN1 is gone. A person who carries one working copy of SMN1 and one deleted copy is a carrier: healthy, with no symptoms, but capable of passing the deletion to a child.¹

Carrier rates vary by ancestry. People of European descent carry the deletion at a rate of roughly 1 in 40 to 1 in 50, and similar rates are seen in South Asian and admixed American populations. East Asian carrier frequencies are somewhat lower, and sub-Saharan African populations have the lowest rates, around 1 in 200 in some studies.² ³ The American College of Obstetricians and Gynecologists recommends offering SMA carrier screening to all pregnant women or those planning a pregnancy, regardless of ethnicity.

The screening itself is a blood test. Labs typically use quantitative PCR or a technique called MLPA to count how many copies of SMN1 a person has. Two copies is normal; one copy means carrier status. A large Chinese screening study of nearly 40,000 women used quantitative PCR as the primary method and confirmed results with MLPA, illustrating how labs layer these techniques for accuracy.⁴ Long-read sequencing, a newer approach, is also being evaluated for its ability to resolve ambiguous cases that older methods struggle with.⁵

If the mother is identified as a carrier, the father is tested next. Only when both parents carry a single copy of SMN1 does the pregnancy face a one-in-four chance that the baby will inherit two deleted copies and develop SMA. In a screening study of pregnant Thai women, the carrier rate was about 1 in 45, and over 92% of participants said they would want fetal testing if the couple turned out to be at risk.⁶

Testing the Fetus Directly

When both parents are confirmed carriers, the next step is testing the fetus itself. The traditional options are chorionic villus sampling (CVS), performed around 10 to 13 weeks of pregnancy, and amniocentesis, performed around 15 to 20 weeks. Both involve collecting fetal cells, either from the placenta or the amniotic fluid, and then analyzing the DNA for SMN1 deletions. These are considered the diagnostic gold standard for prenatal SMA.⁷

Both procedures carry a small risk of miscarriage, which is why they are reserved for pregnancies already identified as high-risk rather than used as a first-line screen. The trade-off is certainty: CVS and amniocentesis give a definitive yes-or-no answer about whether the fetus has homozygous SMN1 deletion.

Non-Invasive Prenatal Testing From Maternal Blood

A newer and rapidly improving alternative skips the needle entirely. Small fragments of fetal DNA circulate in the mother’s bloodstream during pregnancy, and researchers have developed ways to analyze these fragments to determine whether the fetus has inherited two deleted copies of SMN1. The approach, broadly called non-invasive prenatal diagnosis (NIPD), uses sequencing of cell-free DNA from a maternal blood draw.

One method relies on haplotype-based analysis, where the lab maps genetic markers surrounding the SMN1 gene in both parents and then looks for those marker patterns in the fetal DNA floating in the mother’s plasma. A proof-of-concept study using targeted sequencing of maternal plasma correctly identified one affected fetus, two carriers, and two unaffected fetuses, all confirmed by standard MLPA testing afterward.⁸ A separate validation study using a related technique called relative haplotype dosage reported 100% sensitivity and specificity with no inconclusive results in the patients tested.⁹

These are still relatively new technologies. They require DNA samples from both parents (and ideally an affected sibling or relative) for haplotype construction, which means they work best in families with a known history of SMA. For couples identified as carriers through routine screening with no prior affected child, the setup can be more complex. But the field is moving fast, and reflex single-gene NIPT workflows are being developed that integrate carrier screening results with fetal testing from the same maternal blood draw, cutting costs and eliminating the need for separate paternal testing in many cases.¹⁰

Predicting Severity Before Birth

Detecting that a fetus has SMA is one question. Predicting how severe it will be is another, and it is partially answerable. SMA exists on a spectrum, from the most severe type 0 and type I, which appear at or before birth, to milder forms like type III, where children learn to walk independently. The biggest known modifier is how many copies of the SMN2 gene the fetus carries. SMN2 is nearly identical to SMN1 but produces a functional protein only about 10 to 15% of the time. More copies mean more functional protein and a milder disease course.

Research has consistently shown that patients with one or two copies of SMN2 tend to develop the severe type I form, while three or more copies are associated with milder disease, with the affected person expected to at least sit unaided and live past age two.¹¹ A Jordanian study confirmed that SMN2 copy numbers correlated with disease severity in the majority of diagnosed patients.¹² Methods for counting SMN2 copies from fetal DNA, including exome sequencing-based analysis, have shown strong accuracy in distinguishing copy number states.¹³

This information matters enormously for decision-making. A fetus with confirmed SMA and four copies of SMN2 is likely to develop a milder form of the disease, while a fetus with only one copy faces a far grimmer prognosis. SMN2 copy number testing can now be performed on CVS or amniocentesis samples alongside the SMN1 analysis, giving families and clinicians a clearer picture of what to expect.⁷ The prediction is not perfect, since other genetic and environmental modifiers play a role, but SMN2 copy number remains the strongest single predictor available.

What Ultrasound Can and Cannot Show

Standard prenatal ultrasound is not a reliable way to detect SMA. Most forms of the disease produce no visible abnormalities on ultrasound because the motor neuron degeneration that causes muscle weakness has not progressed far enough to affect fetal anatomy during the typical scanning windows. A study that evaluated fetal movements via ultrasound in pregnancies known to be at risk found no obvious limitation of movement in affected fetuses, even in cases that went on to develop severe neonatal SMA.¹⁴

The exception is the rarest and most severe form, type 0. In these cases, disease onset occurs before birth, and ultrasound findings may include increased nuchal translucency in the first trimester, congenital heart defects, decreased fetal movement in late pregnancy, excess amniotic fluid, and abnormal fetal positioning.¹⁵ Even then, these signs are not specific to SMA and could suggest many other conditions. A recent review argued that SMA type 0 should be added to the list of conditions considered when increased nuchal translucency is paired with fetal heart disease, which could prompt genetic testing if it has not already been performed.¹⁶ But for the vast majority of SMA cases, ultrasound will look entirely normal throughout pregnancy.

Blind Spots in Current Screening

No screening test catches every case. The standard carrier test counts SMN1 copies, and a result of one copy reliably flags a carrier. But there are two situations where the test can miss someone.

The first involves so-called “silent carriers,” people who have two copies of SMN1 but both copies sit on the same chromosome, with zero copies on the other. These individuals look normal on a copy number test (two copies detected) but are genuine carriers (one chromosome has no SMN1 at all). This pattern, called a 2+0 arrangement, is more common in people of African descent, which is one reason standard carrier screening has a higher miss rate in that population.¹⁷ ² Newer sequencing-based methods can detect this arrangement, but they are not yet part of routine clinical practice everywhere.

The second blind spot is de novo mutations. About 2% of SMA cases arise from a new deletion that occurred spontaneously during the formation of the parent’s sperm or egg, meaning neither parent would test as a carrier on standard screening. A study of 340 SMA families identified seven cases caused by de novo rearrangements, and in six of those seven, the new mutation had occurred during the father’s meiosis.¹⁸ For these families, there was no way to predict the risk beforehand. The 2% figure is small, but it means that even a completely normal carrier screen for both parents does not reduce the risk to absolute zero.

Additionally, current screening methods focus on whole-gene deletions and may miss rare intragenic point mutations within SMN1 that also cause SMA. These account for a small fraction of cases but represent yet another gap in standard copy-number-based screening.¹⁷

Preimplantation Genetic Testing as an Alternative Route

For couples who already know they are both carriers, whether through previous screening or because they have had an affected child, there is an option that avoids prenatal diagnosis altogether. Preimplantation genetic testing for monogenic diseases (PGT-M) is performed during in vitro fertilization. Embryos are biopsied at the blastocyst stage, tested for the SMN1 deletion, and only unaffected embryos are transferred to the uterus.

A case series using this approach resulted in 11 healthy live births from 12 families, with genetic testing of all newborns confirming that none had homozygous SMN1 deletion. All 11 infants were developing normally at two years of follow-up.¹⁹ A separate case report described the birth of a healthy girl after PGT-M confirmed that the transferred embryo had intact SMN1.²⁰

A cost-effectiveness analysis found that IVF with PGT-M was cost-effective compared to unassisted conception for carrier couples, supporting the case for insurance coverage of the procedure in this context.²¹ The trade-offs are the cost and physical demands of an IVF cycle, and some transferred embryos will still be carriers (one deleted copy), though carriers are clinically unaffected. For couples who want to avoid having to face a difficult decision mid-pregnancy, PGT-M can offer peace of mind before implantation occurs.

Why Prenatal Detection Has Become More Urgent

The stakes of early SMA detection have changed dramatically in the last decade. Three disease-modifying treatments now exist: nusinersen (an antisense oligonucleotide given by spinal injection), onasemnogene abeparvovec (a one-time gene therapy), and risdiplam (a daily oral medication). All three work better the earlier they are given, ideally before symptoms appear. A systematic review of pre-symptomatic treatment studies found that starting therapy before motor neuron loss begins leads to substantially better motor and functional outcomes than waiting until after symptoms develop.²² Separate research on pre-symptomatic gene therapy delivery confirmed these findings and emphasized the value of identifying affected babies as early as possible.²³

Newborn screening programs, which are already in place in many countries and U.S. states, catch affected babies in the first days of life. But prenatal detection through carrier screening allows families even more lead time. Parents who know before birth that their baby has SMA can arrange delivery at a specialized center, have a treatment plan in place from day one, and start therapy within the first week of life rather than waiting weeks or months for a newborn screen result to come back and be acted on. A survey of families affected by SMA found that while 70% supported newborn screening, most subgroups actually preferred pre-conception or prenatal screening over newborn screening.²⁴

The Cost Question

Universal prenatal SMA carrier screening involves testing a huge number of people to identify a relatively rare condition. An older cost-effectiveness analysis estimated that about 12,500 women would need to be screened to prevent one case of SMA, putting the cost at roughly $5 million per case averted, which the authors deemed not cost-effective at the time.²⁵ That analysis, though, was published before current SMA treatments existed, when the only outcome of a positive prenatal diagnosis was information for reproductive decision-making.

The economics look different now. With lifetime SMA treatment costs estimated at around $2.6 million per patient, and with newer screening workflows that combine carrier screening with reflex non-invasive fetal testing to reduce follow-up costs by over 60%, the cost per identified affected pregnancy has dropped substantially.¹⁰ The availability of treatments that work dramatically better when started early also changes the calculus: prenatal detection no longer just informs a decision about the pregnancy, it can set the stage for timely intervention that alters the child’s lifelong trajectory.

Experimental Fetal Gene Therapy

The most forward-looking research asks whether SMA could be treated before birth. In mouse models of severe SMA, researchers injected gene therapy vectors directly into the brains of fetal mice at a stage equivalent to mid-pregnancy in humans. The treated pups survived for a median of 105 days, compared to just 12 days for untreated animals, and showed rescue of muscle wasting and preservation of motor neurons in the spinal cord.²⁶

The results were encouraging but came with caveats. Only about 44% of injected fetuses survived to full-term birth, possibly due to an inflammatory response to the viral vector used to deliver the gene. Even in surviving animals, lifespan was still roughly half that of healthy mice, and abnormally high levels of the therapeutic protein in the brain raised concerns about long-term toxicity. No human trials of in utero SMA gene therapy have been conducted, and significant safety hurdles remain. Still, the research establishes that delivering therapy before birth can rescue motor neurons that would otherwise be lost by the time a baby is born and treated postnatally. If the safety challenges can be solved, prenatal diagnosis could eventually become the gateway not just to early postnatal treatment but to treatment in the womb itself.

1
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2
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3
PubMed Central. Genetics of low spinal muscular atrophy carrier frequency in sub-Saharan Africa
4
PubMed Central. Analysis of spinal muscular atrophy carrier screening results in 32,416 pregnant women and 7,231 prepregnant women
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PubMed Central. Evaluating the clinical efficacy of a long-read sequencing-based approach for carrier screening of spinal muscular atrophy
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PubMed Central. Prenatal carrier screening for spinal muscular atrophy among pregnant Thai women
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8
PubMed. Targeted sequencing of maternal plasma for haplotype-based non-invasive prenatal testing of spinal muscular atrophy
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11
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12
PubMed. Outcomes of genetic testing and prenatal diagnosis of spinal muscular atrophy in Jordan
13
PubMed. Survival Motor Neuron Gene Copy Number Analysis by Exome Sequencing: Assisting Spinal Muscular Atrophy Diagnosis and Carrier Screening
14
PubMed. Ultrasound evaluation of fetal movements in pregnancies at risk for severe spinal muscular atrophy
15
PubMed. Type 0 Spinal Muscular Atrophy: Further Delineation of Prenatal and Postnatal Features in 16 Patients
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PubMed Central. De novo rearrangements found in 2% of index patients with spinal muscular atrophy: mutational mechanisms, parental origin, mutation rate, and implications for genetic counseling
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PubMed Central. Preimplantation Genetic Testing for Monogenic Disease of Spinal Muscular Atrophy by Multiple Displacement Amplification: 11 unaffected livebirths
20
PubMed Central. Birth of spinal muscular atrophy unaffected baby from genetically at-risk parents following a pre-implantation genetic screening: A case report
21
PubMed Central. Cost-effectiveness of IVF with PGT-M/A to prevent transmission of spinal muscular atrophy in offspring of carrier couples
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