Gestation and Birth

gestation and type 1
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Is the Risk of Type 1 Diabetes Affected by Factors Even Before Birth?

Perhaps. There is some evidence that even the prenatal environment can affect the risk of type 1 diabetes development later in life (Stene and Gale, 2013). Certain immune system markers are sometimes already present at birth in people who go on to develop type 1 diabetes during childhood or even adolescence (Thorsen et al. 2016). A new study, the ENDIA study is now looking at environmental factors beginning in pregnancy that may be linked to type 1 diabetes development (Phillips et al. 2016).

The Antibodies That Precede Type 1 Diabetes Can Be Present at Birth

While generally, type 1 diabetes does not appear at birth, but develops later in life, the autoimmune antibodies that often precede type 1 development may already be present at birth or in very early life, implying that fetal or early life environmental exposures may determine the development of autoimmunity (Hummel and Zeigler, 2011).

Scandinavian studies have found that babies born with these antibodies are at an increased risk of developing type 1 diabetes later in life (Eising et al. 2011; Lundgren et al. 2014). In Sweden, children under 15 who developed type 1 diabetes had an increased prevalence of these antibodies in their umbilical cord blood. However, those who developed type 1 at older ages did not (Elfving et al. 2003).

However, the antibodies present in cord blood may be transferred by the mother to the fetus, and have been found to disappear by the time the baby is 1 year of age (Ludvigsson and Wahlberg, 2002). So it is not entirely clear how important these antibodies are.

Month of Birth

People with type 1 tend to be born more often during certain months-- for example, in the U.S., children born in the spring had a higher risk of type 1, especially in northern vs southern areas (Kahn et al. 2009). Sweden shows a similar pattern of spring birth for children with an increased risk of autoantibodies or type 1 diabetes (Lewy et al. 2008; Wahlberg et al. 2005). However other authors noted that this pattern held only in homogeneous populations, not heterogeneous populations (Laron et al. 2005).

Gestation and type 2/obesity
In fact, even type 2 diabetes may be "programmed" during the prenatal period. I didn't know this, but fingerprints are permanently fixed by the 19th week of gestation. A study of Dutch women found that markers of their offspring's fingerprints varied by the season in which they were conceived, implying that the prenatal environment may influence fingerprints (Kahn et al. 2008). These fingerprint markers, in turn, were associated with the offspring's development of diabetes as well as their beta cell function later in life Kahn et al. 2009, Kahn et al. 2010). However, the season of birth is not associated with type 2 diabetes development in Denmark (Jensen et al. 2015).

Maternal and Paternal Age

An analysis of the data from 30 studies found that on average, there is a 5% increased risk of type 1 diabetes for every 5 year increase in maternal age. That is, children of older mothers have a slightly increased risk of developing type 1 diabetes. Children of older fathers, on the other hand, do not appear to have an increased risk of type 1 diabetes. The authors argue that increasing maternal age can only explain a very small percentage ("hardly any") of the increasing incidence of type 1 diabetes in children. Why might a higher maternal age increase the risk of type 1? We do not know. The chromosomal changes that are more common in children of older mothers are not thought to be involved in the development of type 1 diabetes (Cardwell et al. 2010a).

Family Members With Type 1 Diabetes

As a mother with type 1 diabetes, who has a child with type 1 diabetes, I first have to mention that the fact that more people with type 1 diabetes are now having babies than before does NOT explain the increased incidence of type 1 diabetes (Atkinson et al. 2014). Thank you.

The risk of type 1 developing in offspring is higher if the father has type 1 than if the mother has type 1, especially if the father was diagnosed at a young age. If you want the numbers, in one study, 7.8% of the offspring of fathers with type 1 developed type 1 by age 20, and 5.3% of the women (both higher than the general population) (Harjutsalo et al. 2006). This study was from Finland, where type 1 rates are high, but the father vs. mother finding holds in other populations as well (Stene and Gale, 2013). This does not bode well for my future grandchildren.

If a child has type 1 diabetes, the risk of type 1 diabetes in a sibling is 4.1% by age 20, and 6.9% by age 50 (Harjutsalo et al. 2005). These numbers again are from Finland, and may be higher than found in other countries. However, in the U.S. (Colorado), the overall risk of type 1 by age 20 was 4.4% (and highest if the sibling was diagnosed early)-- so comparable to European rates (Steck et al. 2005).

If you have a mother AND a sibling with type 1 diabetes, as my oldest son does, well, I don't know what the risk is, but I keep my eye on him.

It is also worth noting that most people who develop type 1 diabetes have no family members with the disease. Even in Finland, of those diagnosed with type 1, only 24% had first- or second-degree relatives with type 1 diabetes (Parkkola et al. 2013). Why am I citing so many studies from Finland? Mainly because the disease is well studied there, and they have some of the best type 1 diabetes data in the world.

Genetics or Epigenetics?

If we have a parent with diabetes, we assume that the higher risk of diabetes is due to genetics. But environmental factors may also play a role, via epigenetic mechanisms. Via epigentics, the environment can affect genes, and these changes can even be passed down from one generation to the next. For example, researchers have found that if a father has pre-diabetes, he has changes in his sperm, which lead to an increased susceptibility to diabetes in his offspring. In fact, these epigenetic changes can affect the pancreatic islet cells for two generations (Wei et al. 2014). Epigenetic changes in mothers with diabetes may play a role as well (Ge et al. 2014). Maternal diabetes is associated with numerous epigenetic changes in the offspring-- even in subsequent generations-- and epigenetic mechanisms may underlie these effects (Ma et al. 2015).

Maternal Smoking During Pregnancy

Kristina Mattson

Kristina Mattsson found that if a mother smokes during pregnancy, her daughters were at increased risk of gestational diabetes and obesity (Mattsson et al. 2013).

As part of her PhD research, she found that when genetic background is taken into account, maternal smoking during pregnancy is associated with an increased risk of type 1 diabetes in her children (Mattson et al. 2015).

In 2011, the National Institutes of Environmental Health Sciences (NIEHS) convened an expert workshop to examine the role of environmental chemicals in the development of diabetes and obesity. One of the factors they evaluated was maternal smoking during pregnancy (cigarettes contain not only the chemical nicotine, but thousands of others as well). They concluded that, "Current epidemiological data support a positive association between maternal smoking and increased risk of obesity or overweight in offspring. The data strongly suggest a causal relation..." which is a pretty strong statement from a group of scientists. (Paternal smoking may also be a contributing factor). (Behl et al. 2013). In fact, even smoking by grandparents may affect the weight status of granddaughters, although in general the risk may largely not persist past the first generation, and be mostly due to maternal smoking (Dougan et al. 2016). 

So, smoking during pregnancy can increase a child's risk of obesity. What about diabetes? The evidence on type 2 diabetes was too limited to draw a conclusion, according to the NIEHS review. The evidence did not support an association between maternal smoking during pregnancy and later type 1 diabetes in the offspring-- some studies actually showed a decreased risk (or no association).

But newer data on type 1 has now been published. It found that maternal smoking during pregnancy was linked to an increased risk of type 1 diabetes in the offspring-- when genetic background was taken into account (Mattsson et al. 2015). The more cigarettes, the higher the risk. Previous studies did not take into account genetic risk, which could explain the differing findings. Newer studies have also found that maternal smoking during pregnancy was linked to an increased risk of type 2 diabetes in the offspring (La Merrill et al. 2015).

Alcohol, Caffeine, and More

Exposure to maternal substance abuse (alcohol, cocaine, and nicotine) may increase the offspring's later risk of type 2 diabetes as well as related conditions (Vaiserman 2015). In animals, even drinking alcohol only around the time of conception can increases the offspring's later risk of glucose intolerance and insulin resistance (Gårdebjer et al. 2015). Also in animals, maternal intake of caffeine impairs insulin secretion and increases the risk of diabetes in offspring (Sun et al. 2014).

Maternal Body Weight, Diabetes, and Weight Gain During Pregnancy

Gestational diabetes and high maternal weight both (individually and combined) increase the mother's later risk of developing diabetes, high blood pressure, and cardiovascular disease (Kaul et al. 2014).

What about her children? It is becoming more and more clear that the mother's body weight during pregnancy (as well as blood glucose levels, type 1 and 2 diabetes, and insulin resistance), can affect the risk of metabolic diseases in the offspring later in life (Barbour 2014). Even in animals, exposure to high blood glucose in the womb had effects on glucose tolerance and weight of the offspring later in life (Blue et al. 2014), and maternal diabetes affects the fatty tissue of offspring (Oliveira et al. 2015). In laboratory animals, flax oil during pregnancy protects the offspring from the negative effects of maternal diabetes and high blood sugar in the womb (Correia-Santos et al. 2014).

I was happy to learn that weight gain during pregnancy is not associated with the development of beta cell autoimmunity in the offspring (I gained a lot of weight while pregnant). The mother's BMI (body mass index) before pregnancy was not associated with beta cell autoimmunity in the offspring either (Arkkola et al. 2010). On the other hand, other studies found that a high BMI before pregnancy was associated with beta cell autoimmunity in the offspring (Rasmussen et al. 2009) and increased risk of insulin resistance in the offspring (Muftei et al. 2014). And in a very large study from Sweden, high maternal BMI in the first trimester was associated with an increased risk of type 1 diabetes in the offspring (the risk was increased if either parent had diabetes as well) (Hussen et al. 2015). Maternal obesity is associated with altered immune cells in the umbilical cord, implying that obesity affects the infant's immune system (Wilson et al. 2015).

A high BMI does have the potential to affect the offspring in a variety of ways, involving various mechanisms, from epigenetics to inflammation, that can influence the growth and development of the child, and even lead to later disease in adulthood (Tarantal and Berglund 2014). A long-term study from Finland found that maternal obesity increased the offspring's risk of death, cancer, coronary heart disease, stroke, and diabetes. The associations were strongest for cardiovascular disease and type 2 diabetes, and the association with type 2 diabetes was stronger in women (Eriksson et al. 2014). 

There is not only an increased risk of obesity in children if the mother gains too much weight while pregnant, but there is also an increased risk if the mother gains too little weight as well (Sridhar et al. 2014). A large U.S. study found that maternal diabetes and obesity were strongly associated with type 2 diabetes in their children (Dabelea et al. 2008). Another U.S. study found that if the mother had gestational diabetes or high blood glucose during pregnancy, her children had a higher risk of obesity, especially if the mother was overweight or obese (Kubo et al. 2014).

Interestingly, adequate weight gain during pregnancy may help protect the fetus from exposure to environmental chemicals. If a pregnant woman does not gain enough weight while pregnant, her body loses fat as the baby grows, releasing persistent organic pollutants (POPs) into her blood, which can then enter the fetus. The newborn babies of women who have gained adequate weight while pregnant have lower levels of POPs than babies of women who do not gain enough weight (Vizcaino et al. 2014). For an article about this study, see Weight gain during pregnancy may protect babies from chemicals, published by Environmental Health News.

If the mother has diabetes, their children have an increased rate of BMI growth in late childhood (ages 10-13), thus increasing their long term risk for obesity (Crume et al. 2011a). Another study by the same authors found that gestational diabetes in the mother was associated with later weight gain in the offspring at ages 6-13 (Crume et al. 2011b). And, they also found that breastfeeding in infancy reduced the subsequent risk of this later weight gain. The authors suggest that adequate breastfeeding protects against childhood weight gain, and reduces the excess weight gain associated with exposure to diabetes in utero (Crume et al. 2011c). Other studies have also found that higher glucose levels in pregnancy (from gestational diabetes) are associated with higher BMI in the children (at age 7) (Zhu et al. 2016). The good news is that higher maternal blood glucose during pregnancy (but not to the level of diabetes) is not associated with obesity in the offspring during childhood (Thaware et al. 2015).

Epigenetic mechanisms probably have something to do with these associations. Maternal gestational diabetes, for example, is associated with epigenetic changes in the umbilical cord blood and placenta (Finer et al. 2015).

So which is worse for the child, maternal diabetes or maternal obesity? Diabetes. If a mother has diabetes, the offspring have higher risks than if the mother is obese. Both together are worse than either alone, at least for pregnancy outcomes (Langer 2014). 

Laboratory Studies

Laboratory studies confirm that maternal obesity, with or without diabetes, or high birth weight increases the likelihood of later life obesity. The potential mechanisms include altered organ development, cellular signalling, and epigenetic changes (Desai et al. 2013). The offspring of mice who have high blood sugar (and high insulin levels) during pregnancy (as in type 2 diabetes) have an impaired pancreas with fewer beta cells and lower beta cell mass, higher blood sugar and insulin levels, low birth weight and rapid weight gain, in addition to other hormonal changes (Kahraman et al. 2014). In mice, the effects of maternal obesity on the offspring was greater than that of malnutrition. The pancreas and liver were the tissues most affected, and the mechanism appeared to involve oxidative stress (Saad et al. 2015).

"Two Old Grandpas"

Jerry Heindel and Philippe Grandjean

Dr. Jerry Heindel (NIEHS) and Dr. Philippe Grandjean (Harvard School of Public Health) have organized numerous scientific meetings on "Prenatal Programming and Toxicity." They are interested in how environmental chemical exposures during early life affect the later risk of diabetes, obesity, immune system changes, and other diseases (and they told me to call them "two old grandpas").

Pre-Eclampsia or High Blood Pressure

An analysis of pooled data on maternal pre-eclampsia (high blood pressure and protein in urine during pregnancy) found little evidence of increased risk of type 1 diabetes in the offspring (Henry et al. 2011).

However a long-term study from Finland found that exposure to a mother's hypertension (high blood pressure) in the womb was associated with an increased risk of type 2 diabetes as an adult (Kajantie et al. 2016).

Child Spacing and Birth Order

Children born less than 3 years apart have a lower risk of type 1 diabetes than those born more than 3 years apart (Cardwell et al. 2012).

Birth order has not been consistently associated with type 1 diabetes (Stene et al. 2004). That is, first born vs. later born children do not appear to have a higher or lower risk of disease. However, a newer meta-analysis of 31 separate studies found there was some evidence for a slightly lower risk of type 1 diabetes in later born children as compared to first born children, especially in children under 5 years of age. The association varied a lot between studies (Cardwell et al. 2011). A more recent study from Poland found that first born children did not have a higher risk of type 1 diabetes (unless they were diagnosed after age 18) (Żurawska-Kliś et al. 2015).

Prematurity

A systematic review and meta-analysis of 23 studies found that preterm birth was associated with an increased risk of both type 1 and type 2 diabetes later in life (Li et al. 2014). A large study from Sweden found that birth at between 33-38 weeks was associated with a slightly higher risk of type 1 diabetes, as was being small for gestational age (Khashan et al. 2015). Preterm birth has also been linked to insulin resistance in childhood and adulthood, perhaps leading to the increased risk of type 2 diabetes. Babies born premature have been found to have higher insulin levels, and these levels persisted into childhood. The earlier the birth, the higher the insulin levels (Wang et al. 2014). Mothers who give birth to babies prematurely also have an increased risk of metabolic syndrome up to 25 years later (Catov et al. 2016).

Birth Weight

An analysis of the data from 29 studies found that babies weighing over 7.7 lbs (3.5 kg) at birth have a 6% higher risk of type 1 diabetes, and those that weigh over 8.8 lbs (4 kg) at birth have a 10% higher risk of developing the disease. This study controlled for factors such as maternal diabetes, gestational age, and some other factors that might affect birth weight (Cardwell et al. 2010b). A German study found that children who later developed diabetes were more likely to have a higher birth weight than those who did not (Kuchlbauer et al. 2014). And, another analysis of data from multiple studies found that high birth weight was associated with an increased risk of type 1 diabetes (Harder et al. 2009). 

While higher birth weight appears to be associated with type 1 diabetes, lower birth weight (and fast growth in infancy or childhood) appears to be associated with later obesity, insulin resistance, and type 2 diabetes (Inadera 2013; Labayan et al. 2012; Labayan et al. 2008). In black U.S. women, those with very low birth weight had a 40% higher risk of type 2 diabetes than women with normal birth weight, and those with low birth weight had a 13% higher risk -- no matter the BMI of the women (Ruiz-Narváez et al. 2014). Interestingly, low birth weight is also associated with LADA (latent autoimmune diabetes in adults) (a form of adult-onset type 1 diabetes) just as strongly as it is with type 2 diabetes, in a population-based study from Sweden (Hjort et al. 2015).

However, a Danish study of identical twins with different birth weights found that low birth weight was not associated with glucose metabolism in adulthood, once genetics and the environment were controlled for (Frost et al. 2012). And a systematic review and meta-analysis of 20 studies actually found that high birth weight was associated with later obesity, but not low birth weight (Yu et al. 2011).

Weight Gain During Infancy

A study based on two large population-based datasets from Scandinavia found that babies who gained the most weight during their first year of life had an increased risk of type 1 diabetes during childhood. The effect was highest in the first 6 months of life. The average change in weight was over 13 lbs during the first 12 months of life. This study also found that birth weight was not associated with type 1 diabetes development, nor was height or height gain in infancy (Magnus et al. 2015). Other studies have also found this association, see the height and weight page for more info.

Beth has had type 1 diabetes since age 8. Today she is the mother of five healthy boys, and writes a blog on type 1 diabetes and natural childbirth.

C-Sections

An analysis of data from 20 studies found that Caesarean sections were associated with a 20% increased risk of type 1 diabetes in offspring. Why? The authors suggest that perhaps this association is due to the gut microbiota. The gut microbiota differ in children born by C-section compared with those born vaginally (Cardwell et al. 2008). Another hypothesis is that immune function differs in babies born by C-section vs. vaginally (Puff et al. 2015). More recent studies have also found an association between C-sections and type 1 diabetes (Phillips et al. 2012). 

However, findings from a Swedish study show that the situation may be more complex. The Swedish study there was an increased risk of type 1 diabetes in children born by C-section (as well as "instrumental vaginal delivery"), but only by elective, and not emergency C-section. On the other hand, the association disappeared when siblings were compared, implying that the association between C-sections and type 1 diabetes may be due to family and/or environmental factors instead (Khashan et al. 2014). Another (population-wide) Swedish study also found no association between C-sections and type 1 diabetes; it was maternal diabetes that most strongly influenced the risk of type 1 diabetes in the offspring (Samuelsson et al. 2015). A Danish study also found no association between prelabor C-sections and type 1 diabetes in the offspring; the results were explained by maternal type 1 diabetes (and paternal type 1 diabetes had an even stronger effect) (Clausen et al. 2016). 

One study has also found differences in the levels of immune system cells called cytokines in babies born vaginally as compared to those born by C-section. Vaginal birth may instigate a form of inflammation that activates the baby's (and mother's) immune systems in a beneficial manner (Malamitsi-Puchner et al. 2005). And, in a Denmark-wide study, birth by C-section was associated with several immune system disorders in children, although not type 1 diabetes (Sevelsted et al. 2014). 

A prospective U.S. study found that complicated deliveries (e.g., breech, forceps, vacuum extraction) was associated with increased risk of type 1 diabetes-related autoantibodies in children genetically at risk for type 1 diabetes. How complicated deliveries would influence the development of autoantibodies is not known. Unlike most of the above studies (which measured the development of type 1 diabetes), this study did not find that C-sections increased the risk of type 1-associated autoantibodies. The results of this study remained the same when women with gestational or type 1 diabetes were excluded from the analysis (Stene et al. 2004).

On a related note, a long-term nationwide study from Denmark found that broad-spectrum antibiotics during the first two years of life was associated with an increased risk of type 1 diabetes in the next 13 years of life, but only in children delivered by C-section (not in children delivered vaginally) (Clausen et al. 2016).

Obesity and Metabolic Syndrome

In UK children, C-sections are associated with an increased body mass in childhood and adolescence in the offspring from 6 weeks until 15 years of age, according to a long-term study. Again, the mechanism may involve the microbiome, but that remains to be seen (Blustein et al. 2013). Meanwhile a long-term German study shows different results. It found that children born by C-section were more likely to be obese at age 2, but not at ages 6 or 10 (Pei et al. 2014). A U.S. study found children who had been delivered by C-section were more likely to be obese at age 3 (Huh et al. 2012), and another U.S. study found that C-sections increased the risk of obesity by 46% by age 7 (Mueller et al. 2014).

A meta-analysis of 15 studies found that people born by C-section had a higher BMI and were more likely to be overweight or obese in adulthood, as compared to those born vaginally (Darmasseelane et al. 2014).

A U.K. study found that babies born by non-elective C-section were more likely to have metabolic syndrome as adults. Since the risk of metabolic syndrome in vaginal and elective C-section were similar to each other, the authors suggest that a different mechanism may be involved, e.g., fetal stress (Bouhanick et al. 2014).

Neonatal Jaundice

Neonatal jaundice has been associated with a small increased risk of type 1 diabetes (McNamee et al. 2012).

Assisted Reproductive Technologies

Children conceived by assisted reproductive technologies may be at increased predisposition for insulin resistance, obesity, and metabolic syndrome, according to a small study from Greece (Gkourogianni et al. 2014).

A Danish study using nation-wide data from 1987-2010 found no increased risk of type 1 diabetes in children born to women with fertility problems (Hargreave et al. 2016). A different Danish study using nation-wide data from 1995-2003 found no overall association between fertility treatments and type 1 diabetes in the offspring. However, the researchers did find an association between type 1 in the offspring and the use of ovulation induction or intrauterine insemination with follicle-stimulating hormone (Kettner et al. 2016). Hopefully we will see further studies on this topic to determine whether this is a chance finding or not.

Fetal Sex

Maybe irrelevant, but I thought it was interesting: a boy fetus (vs a girl) is associated with a higher risk of gestational diabetes in the mother, as well as worse beta cell function and higher blood sugar levels (Retnakaran et al. 2015). Huh. I'd like to see if this holds true in larger studies.
Factsheets from the National Institute of Environmental Health Sciences (NIEHS):

Child Development and Environmental Toxins 

Other Related Pages

Prenatal and childhood exposure to famine is associated with later diabetes in offspring; see the nutrition page for more on that topic.

A number of additional factors may influence the development of type 1 diabetes during gestation or in early life. For information on breastfeeding and type 1 diabetes, see the breastfeeding page. The nutrition and wheat and dairy pages contain information on type 1 diabetes and early infant feeding or maternal diet during pregnancy. The viruses page discusses congenital rubella. The height and weight page considers growth in early life and type 1 diabetes. Vitamin D deficiency has been associated with pre-eclampsia (Mulligan et al. 2010), as well as type 1 diabetes.

And, exposure to environmental chemicals is another important environmental factor to consider during gestation and early life, since many contaminants can cross the placenta. Chemicals that are toxic to the developing immune system are addressed on the autoimmunity page. These chemicals may affect the risk of type 1 diabetes in the child. Some chemicals have also been linked to the development of gestational diabetes in the mother, such as air pollution (Malmqvist et al. 2013) and pesticides (Saldana et al. 2007).

In fact, a relatively new area of research (begun in 2006 and expanding today) is the study of early-life exposure to environmental chemicals and the later development of diabetes and obesity (Haugen et al. 2014).

The Bottom Line

A number of environmental influences that occur during gestation and birth may be involved in the development of type 1 diabetes, although further studies would need to confirm these associations. How these factors affect disease development is also worthy of further consideration. The increasing use of medically unnecessary C-sections may be a concern.

References

To download or see the references cited on this page, as well as other references related to environmental exposures (e.g., nutrition, chemical exposures, vitamin D levels, etc.) from fetal development through childhood, see the collection Gestation, birth and early-life exposures and diabetes/obesity in PubMed.