What is the strongest risk factor for preterm labor?

Low DHA and EPA a ‘strong risk factor’ for preterm birth: Danish data

Pregnant women with low plasma levels of long chain omega-3 fatty acids in their first and second trimesters may be at a significantly higher risk of early preterm birth, new research suggests.

The data, published in EBioMedicine, suggests that that low blood concentrations of certain long chain fatty acids — specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) — may be a ‘strong risk factor’ for preterm birth.

Preterm birth is a major cause of neonatal death and is linked to a raft of health issues during development and later life including cognitive deficiencies and cardiometabolic problems.

The team, led by Sjurdur Olsen from Harvard Chan School and Statens Serum Institut in Copenhagen, noted that for decades it has been suggested that higher intakes of EPA and DHA, can reduce the risk of preterm birth. But, while some studies have supported this theory, research findings have been inconsistent.

The new study is the first study to examine whether low plasma concentrations of long chain omega-3 fatty acids in early and mid-pregnancy is associated with increased risk of subsequent early preterm birth.

“Our findings of a relatively strong association between plasma concentrations of total EPA and DHA in pregnancy and risk of early spontaneous preterm birth may suggest that that body levels of these fatty acids are causally implicated in the physiologic processes leading up to premature labour and delivery,” said the authors.

The findings also suggest that plasma measurements of EPA and DHA in pregnancy could be used to identify women at risk of early preterm birth, they concluded.

«At a time when many pregnant women are hearing messages encouraging them to avoid intake of fish altogether due to mercury content, our results support the importance of ensuring adequate intake of long chain omega-3 fatty acids in pregnancy,” said Olsen.

Olsen and her team looked at data from the Danish National Birth Cohort, a nationwide study that follows 96,000 children in Denmark through questionnaires and registry linkages.

In a case-controlled study they analysed blood samples from 376 women who gave birth very prematurely (prior to 34 weeks of gestation) between 1996 and 2003 and 348 women who had a full-term birth. All women had given blood samples during their first and second trimesters of pregnancy.

Analysis of the blood samples showed that women with the lowest levels of EPA+DHA (with EPA+DHA levels of 1.6% or less) had a 10 times higher risk of early preterm birth when compared with women in the three highest groups (with EPA+DHA levels of 1.8% or higher).

When the team further split up the data and looked just at women who had been consistently in the lowest group for DHA and EPA concentration in both the first and second trimester, the team found that those women were associated with 48 times more risk of early preterm birth than those in the higher groups.

Analysis also showed a threshold effect for EPA+DHA concentrations somewhere between 2.0% and 2.5%, said Olsen and colleagues — who noted a ‘sharp increase’ in risk at low levels which then flattens rapidly out at higher levels.

The authors said that their findings suggest that for pregnant women with low levels of EPA+DHA, eating more fish or taking a fish oil supplement could potentially lower the risk of preterm birth.

«Early preterm birth has immense health, economic, and emotional costs,” said study co-author Andrew Thorne-Lyman. “Our findings are consistent with the results of most randomised trials of long chain omega-3 fatty acid supplements in pregnancy and support the importance of ensuring adequate intake of these nutrients during pregnancy, either through fish intake or supplements, to help prevent early preterm birth.»

“Extending pregnancy even by a few days could be of significant clinical value in foetuses in danger of being delivered prior to 34 weeks,” the team noted.

However, the team cautioned that broad generalisations about the findings may be limited due to the fact that it was conducted in Denmark, where preterm birth rates are low.

As such, the study needs to be replicated in other populations, they added.

«An effect of this magnitude is rare, but the precision of the estimate is tight, which supports the reliability these findings,” commented co-author Jeremy Furtado, senior research scientist at Harvard Chan School. “It will be important to replicate these findings in other populations, but the results of this study certainly suggest that assessment of plasma EPA+DHA status in women has the potential to be used in the future to help predict women’s risk.»

Preterm birth

Preterm is defined as babies born alive before 37 weeks of pregnancy are completed. There are sub-categories of preterm birth, based on gestational age:

• extremely preterm (less than 28 weeks)
• very preterm (28 to 32 weeks)
• moderate to late preterm (32 to 37 weeks).

Babies may be born preterm because of spontaneous preterm labour or because there is a medical indication to plan an induction of labour or caesarean birth early.

An estimated 15 million babies are born too early every year. That is more than 1 in 10 babies. Approximately 1 million children die each year due to complications of preterm birth (1). Many survivors face a lifetime of disability, including learning disabilities and visual and hearing problems.

Globally, prematurity is the leading cause of death in children under the age of 5 years. Inequalities in survival rates around the world are stark. In low-income settings, half of the babies born at or below 32 weeks (2 months early) die due to a lack of feasible, cost-effective care such as warmth, breastfeeding support and basic care for infections and breathing difficulties. In high-income countries, almost all these babies survive. Suboptimal use of technology in middle-income settings is causing an increased burden of disability among preterm babies who survive the neonatal period.

Why does preterm birth happen?

Preterm birth occurs for a variety of reasons. Most preterm births happen spontaneously, but some are due to medical reasons such as infections, or other pregnancy complications that require early induction of labour or caesarean birth.

More research is needed to determine the causes and mechanisms of preterm birth. Causes include multiple pregnancies, infections and chronic conditions such as diabetes and high blood pressure; however, often no cause is identified. There could also be a genetic influence.

Where and when does preterm birth happen?

The majority of preterm births occur in Africa and southern Asia, but preterm birth is truly a global problem. There is a dramatic difference in survival of premature babies depending on where they are born. For example, more than 90% of extremely preterm babies (less than 28 weeks) born in low-income countries die within the first few days of life, yet less than 10% of extremely preterm babies die in high-income settings.

The solution

Preventing deaths and complications from preterm birth starts with a healthy pregnancy. WHO’s antenatal care guidelines include key interventions to help prevent preterm birth, such as counselling on healthy diet, optimal nutrition, and tobacco and substance use; fetal measurements including use of early ultrasound to help determine gestational age and detect multiple pregnancies; and a minimum of 8 contacts with health professionals throughout pregnancy – starting before 12 weeks – to identify and manage risk factors such as infections.

If a woman experiences preterm labour or is at risk of preterm childbirth, treatments are available to help protect the preterm baby from future neurological impairment as well as difficulties with breathing and infection. These include antenatal steroids and tocolytic treatments to delay labour.

In 2022, WHO also published new recommendations on the care of the preterm infant. These reflect new evidence that simple interventions such as kangaroo mother care immediately after birth, early initiation of breastfeeding, use of continuous positive airway pressure (CPAP) and medicines such as caffeine for breathing problems can substantially reduce mortality in preterm and low birthweight babies.

WHO guidance stresses the need to ensure the mother and family take the pivotal role in their baby’s care. Mothers and newborns should remain together from birth and not be separated unless the baby is critically ill. The recommendations further call for improvements in family support including education and counselling, peer support and home visits by trained health workers.

WHO response

WHO is committed to reducing the health problems and lives lost as a result of preterm birth, including working with Member States and partners to implement Every newborn: an action plan to end preventable deaths, adopted in May 2014 in the framework of the UN Secretary-General’s Global strategy for women’s and children’s health; and strengthening the availability and quality of data on preterm births.

WHO regularly updates clinical guidelines for the management of pregnancy and mothers with preterm labour or at risk of preterm birth, and guidelines on the care of preterm and low birth weight babies.

WHO also supports countries to implement WHO’s guidelines, aimed at reducing the risk of negative pregnancy outcomes, including preterm births, and ensuring a positive pregnancy and postnatal experience for all women and their infants. This includes developing and updating tools to improve health workers’ skills and assess the quality of care provided to mothers at risk of preterm delivery and preterm babies.

WHO also undertakes research to improve care for women and preterm newborns in low- and middle-income countries, including the WHO ACTION Trials (Antenatal Corticosteroids for Improving Outcomes in preterm Newborns); the nutritional management of growth faltering in early infancy trial; and an implementation research trial to scale-up immediate kangaroo mother care (KMC). WHO works with partners around the world to conduct research into the causes of preterm birth and provides updated analyses of global preterm birth levels and trends every 3 to 5 years.

References

1. Perin J, Mulick A, Yeung D, Villavicencio F, Lopez G, Strong KL, et al. Global, regional, and national causes of under-5 mortality in 2000-19: an updated systematic analysis with implications for the Sustainable Development Goals. Lancet Child Adolesc Health. 2022;6(2):106-15. doi:10.1016/S2352-4642(21)00311-4

2. Blencowe H, Cousens S, Oestergaard M, Chou D, Moller AB, Narwal R, Adler A, Garcia CV, Rohde S, Say L, Lawn JE. National, regional and worldwide estimates of preterm birth. The Lancet, June 2012. 9;379(9832):2162-72. Estimates from 2010.

WHO recommendations

• Launch of the WHO recommendations for care of the preterm or low birth weight infant
• WHO recommendations on antenatal corticosteroids for improving preterm birth outcomes , 2022
• WHO recommendation on tocolytic therapy for improving preterm birth outcomes , 2022
• WHO recommendations on interventions to improve preterm birth outcomes , 2015

Data and evidence

• UNICEF-WHOLow birthweight estimates
• Born too soon: the global action report on preterm birth
• Evidence for Global Health Care Interventions for Preterm or Low Birth Weight Infants
• A population-based, multifaceted strategy to implement antenatal corticosteroid treatment versus standard care for the reduction of neonatal mortality due to preterm birth in low-income and middle-income countries: the ACT cluster-randomised trial
• The World Health Organization ACTION-I (Antenatal CorTicosteroids for Improving Outcomes in preterm Newborns) Trial
• Immediate “Kangaroo Mother Care” and Survival of Infants with Low Birth Weight | NEJM
• Scaling up Kangaroo Mother Care in Ethiopia and India: a multi-site implementation research study (bmj.com)

Causes and Risk Factors of Cerebral Palsy

Cerebral palsy (CP) is caused by abnormal development of the brain or damage to the developing brain that affects a child’s ability to control his or her muscles. There are several possible causes of the abnormal development or damage. People used to think that CP was mainly caused by lack of oxygen during the birth process. Now, scientists think that this causes only a small number of CP cases.

The abnormal development of the brain or damage that leads to CP can happen before birth, during birth, within a month after birth, or during the first years of a child’s life, while the brain is still developing.

Congenital CP

CP related to abnormal development of the brain or damage that happened before or during birth is called congenital CP. The majority of CP (85%–90%) is congenital. In many cases, the specific cause is not known.

Risk Factors for Congenital CP

Some things increase the chance that a child will have CP. These are called risk factors. It is important to remember that having a risk factor does not mean that a child will have CP. Some of the risk factors for congenital CP are:

• Low birthweight―Children who weigh less than 5 1/2 pounds (2,500 grams) at birth, and especially those who weigh less than 3 pounds, 5 ounces (1,500 grams) have a greater chance of having CP. Read article external icon
• Premature birth―Children who were born before the 37th week of pregnancy, especially if they were born before the 32nd week of pregnancy, have a greater chance of having CP. Intensive care for premature infants has improved a lot over the past several decades. Babies born very early are more likely to live now, but many have medical problems that can put them at risk for CP. Read article external icon
• Multiple births―Twins, triplets, and other multiple births have a higher risk for CP, especially if a baby’s twin or triplet dies before birth or shortly after birth. Some, but not all of this increased risk is due to the fact that children born from multiple pregnancies often are born early or with low birthweight, or both. Read summary external icon
• Assisted reproductive technology (ART) infertility treatments―Children born from pregnancies resulting from the use of some infertility treatments have a greater chance of having CP. Most of the increased risk is explained by preterm delivery or multiple births, or both; both preterm delivery and multiple births are increased among children conceived with ART infertility treatments. Read article external icon , Read summary external icon
• Infections during pregnancy―Infections can lead to increases in certain proteins called cytokines that circulate in the brain and blood of the baby during pregnancy. Cytokines cause inflammation, which can lead to brain damage in the baby. Fever in the mother during pregnancy or delivery also can cause this problem. Some types of infection that have been linked with CP include viruses such as chickenpox, rubella (german measles), and cytomegalovirus (CMV), and bacterial infections such as infections of the placenta or fetal membranes, or maternal pelvic infections. Read summary external icon , Read article external icon
• Jaundice and kernicterus― Jaundice is the yellow color seen in the skin of many newborns. Jaundice happens when a chemical called bilirubin builds up in the baby’s blood. When too much bilirubin builds up in a new baby’s body, the skin and whites of the eyes might look yellow. This yellow coloring is called jaundice. When severe jaundice goes untreated for too long, it can cause a condition called kernicterus. This can cause CP and other conditions. Sometimes, kernicterus results from ABO or Rh blood type difference between the mother and baby. This causes the red blood cells in the baby to break down too fast, resulting in severe jaundice.
• Medical conditions of the mother―Mothers with thyroid problems, intellectual disability, or seizures have a slightly higher risk of having a child with CP. Read summary external icon
• Birth complications―Detachment of the placenta, uterine rupture, or problems with the umbilical cord during birth can disrupt oxygen supply to the baby and result in CP. Read summary external icon

Preventing CP

In many cases, the cause or causes of congenital CP aren’t fully known, which means that currently little can be done to prevent it. CP related to genetics is not preventable. However, there are actions people can take before and during pregnancy, as well as after birth that might help reduce the risk of developmental problems, including CP.

Taking steps to help ensure a healthy pregnancy can help prevent developmental problems, including CP. Acquired CP often is related to an infection or injury, and some of these cases can be prevented.

Before Pregnancy

• Be as healthy as possible before pregnancy. Make sure that any infections in the mother are treated and health conditions are in control, ideally before pregnancy occurs.
• Get vaccinated for certain diseases (such as chickenpox and rubella) that could harm a developing baby. It is important to have many of these vaccinations before becoming pregnant.
• If assistive reproductive technology (ART) infertility treatments are used to get pregnant, consider ways to reduce the chance of a multiple pregnancy (twins, triplets, or more), such as transferring only one embryo at a time.

During Pregnancy

• Learn how to have a healthy pregnancy.
• Get early and regular prenatal care, both for your health and for that of your developing baby.
• Wash your hands often with soap and water to help reduce the risk of infections that might harm your developing baby.
• Contact your health care provider if you get sick, have a fever, or have other signs of infection during pregnancy.
• A flu shot is your best protection against serious illness from the flu. A flu shot can protect pregnant women and their unborn babies, both before and after birth. Flu shots have not been shown to cause harm to pregnant women or their babies.
• If there is a difference in the blood type or Rh incompatibility between mother and baby it can cause Jaundice and kernicterus. Women should know their blood type and talk to their doctor about ways to prevent problems. Doctors can treat the mother with Rh immune globulin (“Rhogam”) when she is 28 weeks pregnant and again shortly after giving birth to prevent kernicterus from occurring.
• Talk to your doctor about ways to prevent problems if you are at risk for preterm delivery. Research has shown that taking magnesium sulfate before anticipated early preterm birth reduces the risk of CP among surviving infants. (1,2,3,4)

After the Baby is Born

• Learn how to help keep your baby healthy and safe after birth.
• Any baby can get jaundice. Severe jaundice that is not treated can cause brain damage, called kernicterus. Kernicterus is a cause of CP that potentially can be prevented. Your baby should be checked for jaundice in the hospital and again within 48 hours after leaving the hospital. Ask your doctor or nurse about a jaundice bilirubin test. In addition, steps can be taken to prevent kernicterus that is caused by Rh blood type incompatibility between the mother and baby.
• Make sure your child is vaccinated against infections that can cause meningitis and encephalitis, including Haemophilusinfluenzae type B (HiB vaccine) and Streptococcuspneumoniae (pneumococcal vaccine).
• Take steps to prevent injuries:
  • Buckle your child in the car using an infant or child car seat, booster seat, or seat belt (according to the child’s height, weight, and age).
  • Make living areas safer for children by using window guards to keep young children from falling out of open windows and using safety gates at the top and bottom of stairs.
  • Make sure the surface on your child’s playground is made of a shock-absorbing material, such as hardwood mulch or sand.
  • Carefully watch young children at all times around bathtubs, swimming or wading pools, and natural bodies of water. Adults watching kids near water should avoid distracting activities like using a computer or handheld device, reading, or talking on the phone.
  • Make sure your child wears a helmet for activities like riding a bike.
  • Never hit, throw, shake, or hurt a child.

  For More Information

  • American Academy of Pediatrics Healthy Children / Cerebral Palsy external icon
  • National Institute of Neurological Disorders and Stroke (NINDS) Cerebral Palsy Information external icon

  References

  1. Doyle LW, Crowther CA, Middleton P, Marret S. Antenatal magnesium sulfate and neurologic outcome in preterm infants: a systematic review. Obstet Gynecol. 2009 Jun;113(6):1327-33.
  2. Magnesium sulfate before anticipated preterm birth for neuroprotection. Committee Opinion No. 455. American College of Obstetricians and Gynecologists. Obstet Gynecol 2010;115:669–71.
  3. Crowther CA, Middleton PF, Voysey M, et al (2017). Assessing the neuroprotective benefits for babies of antenatal magnesium sulphate: An individual participant meta-analysis. PLoS Med, 14(10):e1002398.
  4. Magnesium sulfate use in obstetrics. Committee Opinion No. 652. American College of Obstetricians and Gynecologists. Obstet Gynecol 2016;127(1):e52-3.