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The Famine Ended 70 Years Ago, but Dutch Genes Still Bear Scars

By Carl Zimmer

• Jan. 31, 2018

In September 1944, trains in the Netherlands ground to a halt. Dutch railway workers were hoping that a strike could stop the transport of Nazi troops, helping the advancing Allied forces.

But the Allied campaign failed, and the Nazis punished the Netherlands by blocking food supplies, plunging much of the country into famine. By the time the Netherlands was liberated in May 1945, more than 20,000 people had died of starvation.

The Dutch Hunger Winter has proved unique in unexpected ways. Because it started and ended so abruptly, it has served as an unplanned experiment in human health. Pregnant women, it turns out, were uniquely vulnerable, and the children they gave birth to have been influenced by famine throughout their lives.

When they became adults, they ended up a few pounds heavier than average. In middle age, they had higher levels of triglycerides and LDL cholesterol. They also experienced higher rates of such conditions as obesity , diabetes and schizophrenia.

By the time they reached old age, those risks had taken a measurable toll, according to the research of L.H. Lumey, an epidemiologist at Columbia University. In 2013, he and his colleagues reviewed death records of hundreds of thousands of Dutch people born in the mid-1940s.

They found that the people who had been in utero during the famine — known as the Dutch Hunger Winter cohort — died at a higher rate than people born before or afterward . “We found a 10 percent increase in mortality after 68 years,” said Dr. Lumey.

The patterns that Dr. Lumey and his colleagues documented are not disputed, but scientists still are struggling to understand how they come about.

“How on earth can your body remember the environment it was exposed to in the womb — and remember that decades later?” wondered Bas Heijmans, a geneticist at Leiden University Medical Center in the Netherlands.

Dr. Heijmans, Dr. Lumey and their colleagues published a possible answer, or part of one, on Wednesday in the journal Science Advances. Their study suggests that the Dutch Hunger Winter silenced certain genes in unborn children — and that they’ve stayed quiet ever since.

While all cells in a person’s body share the same genes, different ones are active or silent in different cells. That program largely is locked in place before birth.

But scientists have learned that later experiences — say, exposure to a virus — can cause cells to quiet a gene or boost its activity, sometimes permanently.

The study of this long-term gene control is called epigenetics. Researchers have identified molecules that cells use to program DNA, but how those tools work isn’t entirely clear. One of the best studied is a molecular cap called a methyl group.

At millions of spots across our DNA, genes may carry a methyl group. They seem to silence genes — at least, researchers have found that silenced genes often have a collection of methyl groups lurking nearby.

Many researchers have speculated that prenatal conditions can influence people’s health across their lifetime, and some have speculated that methyl groups or other forms of epigenetics put this so-called fetal programming into action.

But it’s hard to put that idea to a firm test. The Dutch Hunger Winter might offer an opportunity, Dr. Heijmans and Dr. Lumey realized.

When Dr. Lumey first started studying the Dutch Hunger Winter cohort in the 1990s, he took blood samples from thousands of middle-aged subjects. He also took samples from their siblings, born before or after the famine.

Over a decade later, he and his colleagues were able to take advantage of powerful new technology for detecting methyl groups in blood cells. They retrieved DNA from the samples and placed it in a device able to find methyl groups at nearly 350,000 spots on the genome.

Next, the researchers looked for odd patterns. They searched for methyl groups that were common in the Dutch Hunger Winter cohort, for example, but missing from their siblings.

Then they turned their attention to the health of their subjects. They sorted people according to their body mass index, for example, and looked for methyl groups that were unusually common in overweight people.

Finally, the researchers merged the results — and found a few methyl groups that were linked both to the famine and to health conditions later in life. “We were able to connect the three dots,” said Dr. Lumey.

Dr. Lumey and his colleagues propose that these methyl groups disrupt how cells normally use genes. One methyl group that is linked to a higher body mass index may be able to quiet a gene called PIM3, which is involved in burning the body’s fuel.

So here’s the theory: Perhaps the Dutch Hunger Winter added a methyl group to fetuses born to starving mothers, which made the PIM3 gene less active — and continued to do so for life.

The result? “Maybe your metabolism is in a lower gear,” Dr. Heijmans said.

Dalton Conley, a biosociologist at Princeton University who was not involved in the new study, said that there might be other explanations for the results. Perhaps putting on extra weight as you age triggers an epigenetic change to PIM3, rather than the other way around.

And the Dutch famine probably led to many miscarriages and early deaths. It’s possible that the survivors had some genetic variant that made them resilient and gave them a distinctive epigenetic profile not captured in this study.

John M. Greally, the director of the Center for Epigenomics at Albert Einstein College of Medicine, noted that blood is made up of many different types of cells, each with its own epigenetic profile.

Maybe the Dutch famine made some types of cells more common, he said, rather than altering the epigenetics.

But Dr. Heijmans and his colleagues studied the same methyl groups in muscle cells, fat cells and other tissues they got from cadavers. In any given person, the pattern was roughly the same.

Still, Dr. Heijmans said that the new study would need to be followed up — for example, with carefully controlled experiments on animals that can shed more light on how a pregnant mother’s food supply affects the epigenetics of her offspring.

If scientists can solve the Dutch Hunger Winter’s lingering mysteries, they might also get some clues to how other kinds of stress can reprogram children’s health even before they’re born.

Dr. Lumey speculated that epigenetic profiles might someday allow doctors to detect changes that would lead to problems much later in life. “You don’t have to wait for sixty years,” he said.

Follow Carl Zimmer on Twitter @carlzimmer

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The Hunger Winter: the Dutch famine of 1944-45

A dark chapter in Dutch history

The Hunger Winter took place as World War II was in its final year. Following a German blockade, food supplies to the Netherlands dwindled, and people began to starve.

It was a rare instance of famine in a developed and wealthy country in recent history. Let’s talk about it.

Why was there a Hunger Winter?

If the Dutch had survived the war so far without running into food shortages, why was there a famine in the winter of 1944? There were a couple of reasons.

The obvious and literal cause of the famine was a German blockade enacted in retaliation to a Dutch railway strike that aimed to help the Allied invasion of the country.

The German army blocked water and road routes into the Netherlands and only lifted the water blockade when temperatures had already fallen too low to allow boats to operate in the icy conditions.

At this point in the war, Allied forces had liberated the south of the Netherlands. But as the forces pushed further north, the failure of Operation Market Garden impeded their progress.

READ MORE | The Hague in World War II: Paratroopers, V2 rockets and the British bombing the Bezuidenhout

The Allied forces failed to seize a bridge over the Rhine at Arnhem. They decided to focus on other parts of the liberation process first, including capturing the French ports of Calais, Boulogne and Dunkirk.

Their progress into Germany slowed down at the time because they couldn’t use the port of Antwerp.

How did people survive the Hunger Winter?

Between 18,000 and 22,000 people died during the Hunger Winter, most of whom were older men. When we talk about survival rates, it’s important to remember that it was not just the supply of food hampered by the blockade.

It was also the supply of heating fuel: coal.

So, not only was it a very hungry winter, but it was also a very cold winter for the Netherlands from 1944 to 1945.

READ MORE | The Dutch ship that disguised itself as an island during World War II

The starvation was particularly intense in cities — after all, in the countryside, most people lived around farms. That didn’t mean they didn’t experience food shortages, but the survival rates were much higher outside urban areas. For the Netherlands’ city-living population, times were hard.

So how much food did people consume during the Hunger Winter?

Rations decreased in calorie content over the long winter. In big cities like Amsterdam, adults had to contend with only 1000 calories of food by the end of November 1944 — but that dropped to 580 calories a day by February 1945. Even the black market was empty of food.

People walked long distances to farms to trade anything they had for extra calories. As the winter wore on, tens of thousands of children were sent from cities to the countryside so that they, at least, would get some food.

When it came to heating, people desperately burned furniture and dismantled whole houses to get fuel for their fires.

How did the Hunger Winter end?

The Hunger Winter came to a close in May 1945 when the Allies liberated the Netherlands . However, Allied efforts partially alleviated the starvation of the Dutch population.

Sweden shipped flour, and the Dutch made it into bread to feed the people. The Germans also allowed airdrops of food supplies from the end of April forward.

What were the effects of the Hunger Winter on the Netherlands in the long term?

The Hunger Winter had long-term effects on the health of the Dutch population. Even when the blockade ended and people returned to eating normally, starvation had long-lasting effects on the body.

The  Dutch Famine Birth Cohort Study revealed that the children of women who had starved during the Hunger Winter had health problems: including higher rates of diabetes, obesity, and cardiovascular disease. One study also showed that the grandchildren of women who had experienced famine were smaller than average at birth.

How is the Hunger Winter remembered in the Netherlands today?

The Hunger Winter is usually remembered in conjunction with the resistance movement during World War II. There is an exhibition on it at the Resistance Museum in Amsterdam , for example. There are also statues commemorating the Hunger Winter.

READ MORE | The 14-year-old assassin who lured Nazis and traitors to their deaths

The Hunger Winter wasn’t the first time people in the Netherlands had experienced starvation — the Siege of Leiden during the Eighty Years’ War was another occasion where food shortages affected the population.

Did we miss anything important about the Hunger Winter? Let us know in the comments below. Editor’s Note: This article was originally published in December 2019 and was fully updated in November 2023 for your reading pleasure. 

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My mother a widow in Halfweg drove on a bicycle with solid tyres kilometers with me a four year old along farms in the poulder to find food only to reach a farm where food was given out that day as she was told to meet a closed gate.I was lucky at to eat sugar beet while mum had to eat tulip bulbs.I learned from mum never to throw away any food.I still taste the swedish white bread and chocolate .

Great story Kees. I was born in Zwanenburg and heard many horrible stories from my father.

It has also been noted that children that were conceived and born around this time have greater difficulty with anxiety and stress that has had an effect on their entire lives.

Those were extreme difficult conditions for the dutch citizens – during the end of WWII – sugar beets seemed to be the only survival food. Many died of starvation – conditions were cruel and citizens paid a dear price as a result of the German invasion of their country.

My mother was one of six siblings and they all suffered ill health throughout their lives. All but one died in their sixties. I have always said that deprivation in the war was the cause of their ill health and early death.

My Oma was one of the hunger children mentioned in this article . Poor skinny thing was sent to a farm for a period where there was more food and milk . 25 years later she returned to the farm 250 pounds and almost 6 foot tall.

Apparently during that period, they also ate tulip bulbs

If they were lucky enough to get hold of any. I was only 6, but what I saw, straight after liberation, I will never forget. From South Limburg, we were liberated on 13 September 1944. My parents were in the avant Gaurd of the Dutch Resistance and I only had 2 brothers, 6 and 8 years older than me, regardless of age, we were all active members, one way or the other. I spoke an understandable English, learned from Churchill while listening to him on the clandestine radio under the roof, where there were always people hidden, I was born in 1937. I am writing my memoirs and having a big problem writing past 1943/1945. There are many pictures in my head that come alive when I look at them and the more I look, the more extensive the scene gets.Never left me, in particular in my old age, the more I write down, the more scenes come back to me. My initial intention was to just briefly mention it, more than ten years ago. The active group of this Resistance formed the first Dutch Batallion , trained in “The Harskamp”. All survivors of this batallion were at my wedding in 1958, same house, same street, right next to the most Southern big Railway Station, Wyck/Maastrocht

Ik ga nog over m”n nek als ik eraan denk

My mother, who was a teenager at that time, told me about the ”hongertochten” she made with her father. I learned from here to empty my dishes …

If I’m not mistaken, this gave way to extreme innovation in farming and agriculture, as the Dutch wanted to prevent being dependent on imports for survival for the generations to come. Today the Netherlands is second largest exporter of agricultural products in the world.

yes, my mother’s family suffered hunger and cold during this hunger winter in the Netherlands. My aunt ‘s digestion was never the same; she couldn’t really eat anything and died in her early 60s. My Mother suffered from malnutrition in her teeth, nails and bones all thru her life. When she came to the US in 1946, it took a long time for her to be able to eat anything but bits of food. But since living in the US, she lived a long time into her life, 88. Her middle sister was on a farm during the war so she had food but not alot of it. They ate the beets and tulip bulbs. we learn from their experiences.

I was born at the end of October 1944 in Amsterdam, the city hardest hit by the “hongerwinter.” My father was “ondergedoken” in our apartment from the Germans. My Mom, pregnant with me, would go out on her bike, either by herself or with her brother, and barter for food with the farmers. On one occasion my Father paid 100 guilders for a loaf of bread. Times were desperate but our family survived.

I’ve been researching for information about Catholic orphanages that were located in or near the Hauge in 1944. The stories I’ve read are heartbreaking. Thank you all for sharing.

I missed the part of children who wereld sent to the Northern provincies from the cities in the west. They were sent to farms to survive. My father was sent from the Hague to Friesland.

During that time, we ate soup from the ”gaar keuken,as I was told . soup was made from tulip bulbs, my dad and brother and sister went to Overijsel bij handcar,to pick up some potatoes,etc. we lived in Amersfoort,they walked for 60 km one way,on the way back the germans schot on many people who went that way to survive,and landed up side down in the ditch.some did not survive.wood was taken from near by plantsoen, to keep de kachel going.there is so much narigheden te vertellen.Many gave their lives for our freedom.good to read all the replies.

My grandmother – my grandparents lived in the Rivierenbuurt in Amsterdam during the war – told me how during the Hunger Winter with dollars they had at home, they bought food on the black market and everyday, she fed 20 boys from the streets with one warm meal a day. “Mijn jongens” she called them. During that same winter, my grandfather decided to get my great-grandmother from her home in Koog a/d Zaan, 30 km north of Amsterdam, because the old widow of 87 was starving. Since there were no trains, my grandfather of 54 got a sled which he pushed over the frozen canals in the horrible cold all the way to Koog a/d Zaan, put his mother onto that sled together with a mountain of blankets and her personal belongings, and pushed the sled all the way back to Amsterdam. My granddad’s health was never the same afterwards. But there are other stories, like that of a math teacher of mine, a German, who told me he was a soldier of the Amsterdam garrison during that winter. The soldiers were ordered by their officers NOT to give the starving people any food. But he an his comrades every morning put bread and sausage in their great-coats, and while they were walking guard, they secretly gave the food to the starving Dutch children. Three stories about the Hunger Winter I got first-hand and that I now have shared.

Actress Audrey Hepburn was famous for her tiny waist. But she said she got it because her digestion was destroyed by starvation as a youth in the Netherlands during the war. She had difficulty with her digestion her entire life.

i remember and lived in tHE hAGUE AND THE TIME at the time AND SURVIVED , DO NOT KNOW HOW, WAS SEND TO A FARM NEAR THE BELGIUM BORDER TO REGAIN MY HEALTH, I LEARNED HOW TO PRAY DURING THE LAUNCHING OF THE V2, MANY OF THEM WOULD FAIL THE LAUNCH AND CRASHED IN THE NEIGHBORHOODS KILLING MANY PEOPLE, BUT AT 88 I AM STILL HERE,MAYBY THE SUGAR BEES AND TULIP BULBS ARE GOOD FOR , tom YOUR HEALTH

I researched and wrote a book about the Hunger Winter. Hunger Winter: A WW2 Novel tells the true story of the final winter of the war in the form of historical fiction. Over sixty readers have given it a 5 star review and the Corrie ten Boom Foundation, whose museum commemorates WW2, said, “I would love to encourage everyone to read this book.” Hunger Winter: A WW2 Novel is available on Amazon and other sites where books are sold.

Is it in English?

How cold did it get that winter?

somehwere between 0 C and -18 C

Thank you fir this information. My late husband Henk Mulder often spoke about that time. His father Gerard, had been taken away by the Germans in about 1943 for forced/slave labour, I presume in Germany. Henk did not see his dad until after the war ended. Gerard got caught up with the Russian Army, on his way back home to Zeist. He never wanted to speak about it. They migrated to Australia in 1956 on the ship Johan Von Barneveldt. I have never been able to find out where in Germany he was sent, or how he journeyed back home.

The Dutch national archives opened sites where you can find out about your father

My mother was in Amsterdam. 16 years old when the war finished. Told me her mum made soup by boiling pieces of wood to give it flavour. She said there wasnt a rat, cat or dog left as they all got eaten. She was about 6 foot 2 and weighed less than 60 kg I think. Didn’t menstruate until she gained weight after the war. Was sent to Austria after the war to fatten her up. It didnt work. Her health was pretty bad overall (diabetes, heart disease, strokes and cancer 3 times) and she died at 69. I was the youngest of 6 kids and she also suffered 6 miscarriages. I think my old e siblings know more, but this is mostly what she told me.

I was born in 1940 and went through the hunger winter we were eating sugar beets and tulip bulbs to survive my older brother’s were away days on end to get food for their siblings

I have a copy of a 1955 Spiegel magazine in which there are photos of the hunger winter. Men removed railway sleepers for firewood.. A picture of a young man dead from hunger on the sidewalk.. columns of people walking from South Holland to get food in Friesland only to have it taken from them by German Soldiers. I was born 30th April 1945.The doctor that delivered me got for his payment a slice of bread with some sugar on it. Dad peddled a byci cal to drive a dynamo to produce power for a light so the Doctor could see. Unbelievable stories my parents could tell. No wonder we migrated to Australia after the war.

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The Dutch Hunger Winter

Epigenetic Effects on Metabolic and Heart Health

By Kuei-Chiu Chen

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In this interrupted case study, students learn about the influence of early fetal nutritional conditions on the expression of genes related to metabolism and growth. Beginning with the true event of a food and fuel embargo that led to famine in the western Netherlands toward the end of World War II, students learn about the historical background of the Dutch Hunger Winter and its social impact. Using real data from the study conducted by Heijmans and coauthors (2008), students then compare the methylation level of a specific gene between individuals conceived during the famine and their unaffected siblings, and how changes in the expression of this metabolically important gene may impact the risk of developing type 2 diabetes. Supported by other studies on mice and in humans, students conclude that in utero events may impact the health of individuals later in life through epigenetic mechanisms. The case is ideally suited for a molecular or cell biology course, but is also appropriate for an introductory biology course in which students have an understanding of descriptive statistics, interpretation of statistical test results, eukaryotic gene structure, and regulation of gene expression.

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• Explain how a historical event served as a valuable research subject for understanding the impact of gestational undernutrition to human health.
• Distinguish major types of diabetes.
• Demonstrate general understanding of genomic imprinting in mammals.
• Explain the role of methylation at specific DNA sites and how it influences chromatin remodeling.
• Explain how maternal diet during early gestation may impact the level of expression of metabolism-related genes in the fetus.
• Explain how epigenetic influences on certain metabolically important genes may last a lifetime.
• Use significance levels to interpret study results.
• Evaluate advantages and disadvantages of presenting raw and processed data in graphs.

Dutch hunger winter; Dutch famine; eukaryotic gene expression; epigenetic; thrifty genotype hypothesis; thrifty phenotype hypothesis; thrifty epigenotype hypothesis; methylation; CpG; prenatal exposure

Subject Headings

EDUCATIONAL LEVEL

Undergraduate lower division, Undergraduate upper division

TOPICAL AREAS

History of science

TYPE/METHODS

Teaching Notes & Answer Key

Teaching notes.

Case teaching notes are protected and access to them is limited to paid subscribed instructors. To become a paid subscriber, purchase a subscription here .

Teaching notes are intended to help teachers select and adopt a case. They typically include a summary of the case, teaching objectives, information about the intended audience, details about how the case may be taught, and a list of references and resources.

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Answer Keys are protected and access to them is limited to paid subscribed instructors. To become a paid subscriber, purchase a subscription here .

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Materials & Media

Supplemental materials.

The preparation assignment below focuses on the basics of diabetes. The optional PowerPoint presentation contains images from the case handout and can be used to help guide classroom discussion.

• Preparation Assignment
• PowerPoint Presentation (~2.8 MB)
• What Is Diabetes? This is an excellent, basic video focusing on type 1 diabetes in children. Running time: 4:11 min. Produced by Phoenix Children’s Hospital, 2018.
• Pathophysiology – Type II Diabetes This animation from Khan Academy explains diabetes in general with a focus on type 2 diabetes and covers the concept of insulin resistance. Running time: 7:43 min. Produced by Matthew McPheeters for Khan Academy, 2015.

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The dutch famine birth cohort, lessons learned from 25 years of research into long-term consequences of prenatal exposure to the 1944-1945 dutch famine.

Journal : International Journal of Environmental Health Research      Date: May 2021

The Dutch famine, also known as the Dutch Hunger Winter, occurred in The Netherlands at the end of World War II. The Nazis had cut off food supplies to the western part of The Netherlands in retaliation for the exiled Dutch government supporting the Allies. Some twenty thousand people died and 4.5 million were affected by the direct and indirect consequences of the famine, which took place from November 1944 through May 1945. In addition to an exceptionally harsh winter, bad crops, and four years of brutal war, the population was forced to live on rations of 400-800 calories per day. People had to eat grass and tulip bulbs to survive.

This article reports on the lessons learned from 25 years of research into the long-term health effects the famine has had on those who were in utero during the time it occurred. This group is called the Dutch Famine Birth Cohort. Studies have also focused on the children of this cohort, and their grandchildren.

 Several factors allowed researchers to study the effects of this tragic event in great detail:

• There was a sudden onset and rapid relief from the famine (well defined time period).
• It was imposed on a previously well-nourished population.
• Food availability was registered accurately throughout the famine.
• Midwives and doctors continued to provide obstetric care and kept detailed medical records throughout the famine, some of which have been kept for decades – allowing long-term, follow-up studies.

Summary Prenatal exposure to the famine had permanent effects on health outcomes that emerged later in life among the offspring.  People who were in utero during the famine suffered a variety of physical and mental health issues as adults. The two main lessons reported out in this journal article were:

1) There were effects of prenatal famine exposure in the absence of effects on body size at birth. In other words, in spite of adaptations that enable the fetus to grow to a normal size during famine, undernutrition still had adverse, long-term health consequences.

2) The effects of undernutrition in the womb depended on the timing of when organs and systems were developing.

• The effects on health later in life were most pronounced among those exposed to famine in early gestation . This may not be surprising considering the fact that all organs are laid down in early pregnancy. An insufficient food supply in early gestation interferes with basic organ development.  
• Exposure to famine in mid gestation was linked to an increase in micro-albuminuria in adulthood (an early sign of vascular disease) and a decrease in creatinine clearance (waste filtered from the blood by the kidneys and excreted in urine). These are both factors that signify an elevated risk for heart and kidney disease. Mid gestation is when the number of filtering units (nephrons) in the kidney rapidly increase, and exposure to famine in mid-gestation prevented robust kidney development. Mid gestation is also the time when lungs are developing and the bronchial tree grows most rapidly. Those exposed to famine in mid gestation had an increased prevalence of obstructive airways disease. Studies of the Dutch hunger winter provide another layer of evidence that undernutrition in the womb permanently affects the structure and physiology of the lungs and kidneys.

Other findings (not exhaustive)

• Males and females exposed at any stage in utero put them at higher risk for type 2 diabetes and heart disease.
• Exposed females grew up to have more children, give birth to twins more often, be less likely to remain childless and start having children at a younger age than unexposed females.
• Females exposed in early gestation had an increased prevalence of breast cancer, higher cardiovascular mortality, cancer mortality and breast cancer mortality.
• At age 63, women (but not men) exposed to the famine in early gestation had an overall higher mortality rate compared to unexposed 63-year-old women.
• Children whose mothers were in utero during the famine were heavier at birth, while those whose fathers were exposed in utero were heavier in adult life – suggesting different epigenetic influences according to the sex of the parent. 
• At age 58, both men and women exposed to famine in early gestation had poorer cognitive function.
• Males exposed to famine in early gestation had a higher risk for neurodegenerative diseases.
• Males exposed to famine in early gestation reported more symptoms of anxiety and depression.

Key takeaways/Why this is important: This paper provides a long-term view of the consequences of undernutrition during pregnancy by studying the effects of the Dutch famine for decades. The findings can be used to provide guidance on preventive strategies and remedial actions today. The authors argue we should prioritize a more equal distribution of food across the world so that the consequences of poor diets due to both undernutrition and overnutrition will be prevented, and that priority should be given to women of reproductive age. Based on the findings presented in this review, the authors expect that adequately feeding women before and during pregnancy will allow future generations to reach their potential and lead healthier and more productive lives - ultimately leading to a healthier and more equitable future.

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The OHSU Bob and Charlee Moore Institute for Nutrition & Wellness supports human research that seeks to find the links between maternal stresses, including poor nutrition, and elevated disease risks for babies as they become adolescents and adults.

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De Rooij, SR, Bleker, LS, Painter, RC, Ravelli, AC, & Roseboom, TJ (2021). Lessons learned from 25 Years of Research into Long term Consequences of Prenatal Exposure to the Dutch famine 1944–45: The Dutch famine Birth Cohort. International Journal of Environmental Health Research , Retrieved online DOI: 10.1080/09603123.2021.1888894

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Dutch Famine Affected Regulation of Growth Genes

May have helped these individuals to adjust to conditions.

Individuals conceived in the severe Dutch Famine, also called the Hunger Winter, may have adjusted to this horrendous period of World War II by making adaptations to how active their DNA is. Genes involved in growth and development were differentially regulated, according to researchers at the Leiden University Medical Center, Harvard University, and Columbia University’s Mailman School of Public Health. Findings are published in the journal Nature Communications .

Decades later growth genes seemed different

“The different setting of the growth genes may have helped the Hunger Winter children to withstand the Famine conditions as compared with their unexposed siblings, but these changes may likewise be unfavorable for their metabolism as adults,” said Leiden University principal investigator Dr. Bas Heijmans. For example, the altered settings were associated with LDL cholesterol at age 60, according to the authors. The research team in Leiden compared the DNA of the Hunger Winter children, now aged 60, at 1.2 million CpG methylation sites comparing them with same-sex siblings not exposed to famine. They were able to see how the genes were differentially regulated in the Hunger Winter children, as compared with their siblings with a similar genetic and familial background.  Groups of genes involved in growth and development showed a different gene activity setting. The Hunger Winter children were all approximately 60 years of age when they gave blood for DNA research. It was at this point in time that their growth genes seem altered for life. “The potential for a gene to become active is mainly determined in the crucial weeks after fertilization. This master regulatory system that determines which genes are on and which are off is called epigenetics and can be compared to a sound technician making adjustments during a recording to get that perfect sound. Environmental factors during development can make a lasting imprint on this system,” noted Dr. Heijmans. The authors point out that a wealth of past epidemiological studies suggests that early development is important for later health. “Thanks to the willingness of the Hunger Winter children and their families to contribute to our studies, we can pin- point which phases of development are especially sensitive to the environment. We are currently extending our inquiries not only to those conceived during the famine, but also to those exposed during other gestation periods. A lot of important things are happening in the womb about which we know quite little in humans”, says co-author Dr. Elmar W. Tobi. “These findings are exciting and provide tremendous opportunities for epidemiologists,” said L.H. Lumey, MD, PhD, associate professor of Epidemiology at Columbia University’s Mailman School of Public Health and senior author who collected the analyzed blood samples.   “Looking at the human genome we see systematic changes in gene regulation during early human development in response to the environment. The epigenetic revolution has given us the tools to investigate these changes and look at the impact for later life.” The study was supported by the National Institute of Aging [R01AG042190] and National Heart, Lung, and Blood Institute [R01-HL067914], National Institutes of Health; Netherlands Genomics Initiative/Netherlands Organization for Scientific Research [93518027], European Union-funded Network of Excellence LifeSpan [FP6 036894], and the Netherlands Consortium for Healthy Aging [05060810].

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Beyond DNA: Epigenetics

Deciphering the link between nature and nurture.

Photographed during the Dutch Hunger Winter, which lasted from the start of November 1944 to the late spring of 1945, a Dutch boy waits at a restaurant with a spoon tucked into his waistband. Epidemiologists have been able to follow the long-term effects of the famine on those who lived through it, and have even seen its effects in the next generation.

Excerpted from The Epigenetics Revolution: How Modern Biology Is Rewriting Our Understanding of Genetics, Disease, and Inheritance, by Nessa Carey (Columbia University Press, 2012). Copyright © 2012 Nessa Carey.

We talk about DNA as if it’s a template , like a mold for a car part in a factory. In the factory, molten metal or plastic gets poured into the mold thousands of times, and, unless something goes wrong in the process, out pop thousands of identical car parts.

But DNA isn’t really like that. It’s more like a script. Think of Romeo and Juliet , for example. In 1936 George Cukor directed Leslie Howard and Norma Shearer in a film version. Sixty years later Baz Luhrmann directed Leonardo DiCaprio and Claire Danes in another movie version of this play. Both productions used Shakespeare’s script, yet the two movies are entirely different. Identical starting points, different outcomes.

That’s what happens when cells read the genetic code that’s in DNA. The same script can result in different productions. The implications of this for human health are very wide-ranging, as we will see from the case studies we are going to look at in a moment. In all these case studies it’s really important to remember that nothing happened to the DNA blueprint of the people in these case studies. Their DNA didn’t change (mutate), and yet their life histories altered irrevocably in response to their environments.

Audrey Hepburn was one of the twentieth century’s greatest movie stars. Stylish, elegant, and with a delicately lovely, almost fragile bone structure, she became an icon in her role as Holly Golightly in Breakfast at Tiffany’s , even to those who have never seen the movie. It’s startling to think that this wonderful beauty was created by terrible hardship. Audrey Hepburn was a survivor of an event in World War II known as the Dutch Hunger Winter. This ended when she was sixteen years old, but the aftereffects of that period, including poor physical health, stayed with her for the rest of her life.

The Dutch Hunger Winter lasted from the start of November 1944 to the late spring of 1945. That was a bitterly cold period in Western Europe, creating further hardship on a continent that had been devastated by four years of brutal war. Nowhere was this worse than in the western Netherlands, which at this stage was still under German control. A German blockade resulted in a catastrophic drop in the availability of food to the Dutch population. At one point the population was try­ing to survive on only about 30 percent of the normal daily calorie intake. People ate grass and tulip bulbs, and burned every scrap of furniture they could get their hands on, in a desperate effort to stay alive. More than 20,000 people had died by the time food supplies were restored in May 1945.

The dreadful privations of that time also created a remarkable scientific study population. The Dutch sur­vivors were a well-defined group of individuals all of whom suffered just one period of malnutrition, all of them at exactly the same time. Because of the excellent health-care infrastructure and record-keeping in the Netherlands, epidemiologists have been able to follow the long-term effects of the famine. Their findings were completely unexpected.

One of the first aspects they studied was the effect of the famine on the birth weights of children who had been in the womb during that terrible period. If a mother was well fed around the time of conception and malnourished only for the last few months of the pregnancy, her baby was likely to be born small. If, on the other hand, the mother suffered malnutrition only for the first three months of the pregnancy (because the baby was conceived toward the end of the terrible episode), but then was well fed, she was likely to have anormal-size baby. The fetus “caught up” in body weight.

That all seems quite straightforward, as we are all used to the idea that fetuses do most of their growing in the last few months of pregnancy. But epi­demiologists were able to study these groups of babies for decades, and what they found was really surprising. The babies who were born small stayed small all their lives, with lower obesity rates than the general popula­tion. For forty or more years, those people had access to as much food as they wanted, and yet their bodies never got over the early period of malnutrition. Why not? How did their early life experiences affect these individuals for decades? Why weren’t they able to go back to normal once their environment reverted to the way it should be?

More unexpectedly, the children whose mothers had been malnourished only early in pregnancy had higher obesity rates than normal. Recent reports have shown a greater incidence of other health problems as well, including effects on certain measures of mental health. Even though those individuals had seemed perfectly healthy at birth, something had happened to their devel­opment in the womb that affected them for decades after. And it wasn’t just the fact that something had happened that mattered, it was when it happened. Events that take place in the first three months of gestation, a stage when the fetus is really very small and developing very rapidly, can affect an individual for the rest of his or her life.

Even more extraordinarily, some of these effects seem to be present in the children of this group, that is, in the grandchildren of the women who were malnour­ished during the first three months of their pregnancy. So something that happened in one pregnant population affected their children’s children. That raised the really puzzling question of how those effects were passed on to subsequent generations.

Let’s consider a different human story . Schizo­phrenia is a dreadful mental illness, which, if un­treated, can completely overwhelm and disable an affected person. Patients may present with a range of symptoms including delusions, hallucinations, and enormous difficulties focusing mentally. People with schizophrenia may become completely incapable of dis­tinguishing between the “real world” and their own hallucinatory and delusional realm. Normal cogni­tive, emotional, and societal responses are lost. There is a terrible misconception, however, that people with schizophrenia are likely to be violent and dangerous. For the great majority of patients that isn’t the case at all, and the people most likely to suffer harm because of this illness are the patients themselves. Individuals with schizophrenia are fifty times as likely to attempt suicide as healthy individuals.

Schizophrenia is tragically common. It affects between 0.5 and 1 percent of the population in most countries and cultures, which means that there may be more than 50 million people alive today who are suffering from this condition. Scientists have known for some time that genetics plays a strong role in determining if a person will develop this illness. We know this because if one of a pair of identical twins has schizophrenia, there is a 50 percent chance that their twin will also have the condition. That is much higher than the 1 percent risk in the general population or even the 15 percent risk for fraternal twins. Identical twins have exactly the same genetic code as each other. They share the same womb, and usually they are brought up in very similar environments. When we consider this, it doesn’t seem surprising that if one of the twins develops schizophrenia, the chance that his or her twin will also develop the illness is very high. In fact, we have to start wondering why it isn’t higher. Why isn’t the figure 100 percent? How is it that two apparently identical individuals can become so very different? An individual has a devastating mental illness, but will his or her identical twin suffer from it too? Flip a coin—heads they win, tails they lose. Variations in the environment are unlikely to account for this, and even if they did, how would those environmental effects have such profoundly different impacts on two genetically identical people?

Here’s a third case study. A small child, less than three years old, is abused and neglected by his or her parents. Eventually, the state intervenes, and the child is taken away from the biological parents and placed with foster or adoptive parents. These new caregivers love and cherish the child, doing everything they can to create a secure home, full of affection. The child stays with these new parents throughout the rest of his or her childhood and adolescence, and into young adulthood.

Sometimes everything works out well for such chil­dren. They grow up into happy, stable individuals indistinguishable from all their peers who had normal, non-abusive childhoods. But often, tragically, it doesn’t work out this way. Children who have suffered from abuse or neglect in their early years grow up with a substantially higher risk of adult mental health problems than the gen­eral population. All too often such a child grows up into an adult at high risk of depression, self-harm, drug abuse, and suicide.

Once again, we have to ask ourselves why. Why is it so difficult to override the effects of early childhood exposure to neglect or abuse? Why should something that happened early in life have effects on mental health that may still be obvious decades later? In some cases, the adult may have absolutely no recollection of the traumat­ic events, and yet he or she may suffer the consequences mentally and emotionally for the rest of life.

These three case studies seem very different on the surface. The first is mainly about nutrition, especially of the unborn child. The second is about the differences that arise between genetically identical individuals. The third is about long-term psychological damage as a result of childhood abuse.

But these stories are linked at a very fundamental bio­logical level. They are all examples of epigenetics. Epigenetics is the new discipline that is revolutionizing biol­ogy. Whenever two genetically identical individuals are nonidentical in some way we can measure, this is called epigenetics. When a change in environment has biological consequences that last long after the event itself has vanished into distant memory, we are seeing an epigenetic effect in action.

When scientists talk about epigenetics they are referring to all the cases in which the genetic code alone isn’t enough to describe what’s happening—there must be something else going on as well. That is one of the ways that epigenetics is described scientifically: where things that are genetically identical can actually appear quite different from one another. But there has to be a mechanism that brings out this mismatch between the genetic script and the final outcome. Epigenetic effects must be caused by some sort of physical change, some alterations in the vast array of molecules that make up the cells of every living organ­ism. That leads us to the other scientific way of viewing epigenetics—the molecular description. In this model, epigenetics can be defined as the set of chemical modifications surrounding and attaching to our genetic material that change the ways genes are switched on or off, but don’t alter the genes themselves.

Although it may seem confusing that the word “epigenetics” can have two different meanings, it’s just because we are describing the same event at two different levels. It’s a bit like looking at the pictures in old news­papers with a magnifying glass, and seeing that they are made up of dots. If we didn’t have a magnifying glass we might have thought that each picture was just made in one solid piece, and we’d probably never have been able to work out how so many new images could be created each day. On the other hand, if all we ever did was look through the magnifying glass, all we would see would be dots, and we’d never see the incredible image that they formed together and that we’d see if we could only step back and look at the big picture.

The revolution that has happened very recently in biology is that for the first time we are actually starting to understand how amazing epigenetic phenomena are caused. We’re no longer just seeing the large image, we can now also analyze the individual dots that created it. Crucially, this means that we are finally starting to unravel the missing link between nature and nurture: how our environment talks to us and alters us, sometimes forever.

The “epi” in epigenetics is derived from Greek and means at, on, to, upon, over, or beside. The DNA in our cells is not some pure, unadulterated molecule. Small chemical groups can be added at specific regions of DNA. Our DNA is also smothered in special proteins. These proteins can themselves be covered with additional small chemicals. None of these molecular amendments—which I will explore in the next issue of Natural History —changes the underlying genetic code. But adding these chemical groups to the DNA, or to the associated proteins, or removing Scientists in both the academic and commercial sectors are also waking up to the enormous impact them, changes the expression of nearby genes. These changes in gene expression alter the functions of cells, and the very nature of the cells themselves. Sometimes, if these patterns of chemical modifications are put on or taken off at a critical period in development, the pattern can be set for the rest of our lives, even if we live to be over a 100 years of age. 

There’s no debate that the DNA blueprint is the starting point—a very important starting point and absolutely necessary, without a doubt. But it isn’t a sufficient explanation for all the sometimes wonderful, sometimes awful complexity of life. If the DNA sequence were all that mattered, identical twins would always be absolutely identical in every way. Babies born to malnourished mothers would gain weight as easily as other babies who had a healthier start in life. And we would all look like big amorphous blobs, because all the cells in our bodies would be completely identical. That’s because epigenetics is the mechanism by which cells with the same genetic code express different parts of it during development, becoming liver, muscle, brain, or any of the hundreds other cell types in the human body.

Huge areas of biology are influenced by epigenetic mechanisms, and the revolution in our thinking is spreading further and further into unexpected frontiers of life on our planet. Why can’t we make a baby from two sperm or two eggs, but must have one of each? What makes cloning possible? Why is cloning so difficult? Why do some plants need a period of cold before they can flower? Since queen bees and worker bees are genetically identical, why are they completely different in form and function? Why are virtually all tortoiseshell cats female? Why is it that humans contain trillions of cells in hundreds of complex organs, and microscopic worms contain about a thousand cells and only rudimentary organs, but we and the worm have the same number of genes?

Scientists in both the academic and commercial sectors are also waking up to the enormous impact that epigenetics has on human health. It’s implicated in diseases from schizophrenia to rheumatoid arthritis, from cancer to chronic pain. There are already two types of drugs that successfully treat certain cancers by interfering with epigenetic processes. Pharmaceutical companies are spending hundreds of millions of dollars in a race to develop the next generation of epigenetic drugs to treat some of the most serious illnesses afflicting the industrialized world. Epigenetic therapies are the new frontier of drug discovery.

In biology, Darwin and Mendel came to define the nineteenth century as the era of evolution and genetics. Watson and Crick defined the twentieth century as the era of DNA, and the functional understanding of how genetics and evolution interact. But in the twenty-first century, it is the new scientific discipline of epigenetics that is deconstructing so much of what we took as dogma and rebuilding it in an infinitely more varied, more complex, and even more beautiful fashion.

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Article Contents

How did the study come about, who set it up, and how is it funded, what does the study cover, who is in the sample, how often have they been followed up, what has been measured, what is attrition like, what has it found so far, strengths and weaknesses, can i get hold of the data where can i find out more about the study, acknowledgements.

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Cohort Profile: The Dutch Hunger Winter Families Study

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LH Lumey, Aryeh D Stein, Henry S Kahn, Karin M van der Pal-de Bruin, GJ Blauw, Patricia A Zybert, Ezra S Susser, Cohort Profile: The Dutch Hunger Winter Families Study, International Journal of Epidemiology , Volume 36, Issue 6, December 2007, Pages 1196–1204, https://doi.org/10.1093/ije/dym126

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Historical setting

The winter of 1944–45 is known as the ‘Hunger Winter’ in The Netherlands, which was occupied by the Germans in May 1940. Beginning in September 1944, Allied troops had liberated most of the South of the country, but their advance towards the North came to a stop at the Waal and Rhine rivers and the battle of Arnhem. In support of the Allied war effort, the Dutch government in exile in London called for a national railway strike to hinder German military initiatives. In retaliation, in October 1944, the German authorities blocked all food supplies to the occupied West of the country.

Despite the war, nutrition in The Netherlands had generally been adequate up to October 1944. 1 Thereafter, food supplies became increasingly scarce. By November 26, 1944, official rations, which eventually consisted of little more than bread and potatoes, had fallen below 1000 kcal per day, and by April 1945, they were as low as 500 kcal per day. Widespread starvation was seen especially in the cities of the western Netherlands. 1–5 Food supplies were restored immediately after liberation on May 5, 1945. On the basis of these historical data it is possible to accurately define the beginning and the end of the famine period. The famine affected fertility, weight gain during pregnancy, maternal blood pressure, infant size at birth and central nervous system development. 6–11 The reduction in fertility was greater among manual workers than among those in other occupations. 2 A decline in mean birth weight of 300 g was seen among those exposed to maternal undernutrition during the third trimester. 2 , ,6 ,7 ,9 ,12 After liberation and the restoration of food supplies, birth weights and other measures of infant size rapidly rebounded to pre-famine levels. 12 Because the Dutch population was typically well fed before and after the Hunger Winter, the circumstances of the famine created what can be regarded as a ‘natural experiment’ in which exposure to famine is assigned based on an individual's time and place of birth. This design was used to examine how maternal undernutrition during specific gestational time windows may affect the subsequent life course of offspring who experienced the famine in-utero .

Previous follow-up studies of people with prenatal famine exposure

The first investigators to study a possible association between prenatal exposure to famine and health outcomes at age 18 analysed records from over 400 000 men examined at conscription for military service. 2 , ,13 These studies, conducted in the 1970s, used the Dutch Famine to analyse adult health outcomes in relation to specific periods of gestation. Exposure to the famine was defined by place and date of birth in relation to distributed food rations. Exposure during gestation was not associated with altered performance on the Raven's Progressive Matrices test of intelligence, 13 but exposure to famine in early and mid-gestation was associated with a doubling of the then low prevalence of obesity. 14 While benefiting from the large sample provided by a national birth cohort, these studies were limited to men, as women were never conscripted in The Netherlands, and the available data do not include birth records.

These investigators also adopted a number of complementary approaches. For subgroups in the population, data on births were analysed in relation to birth weight, length, placental weight and the post-partum body weight of the mother. 15 , ,16 In the general population, periconceptional and early gestational exposures were related to fertility and fecundity, 8 and to births with congenital neural defects (mainly neural tube defects). 17 Available data on vital statistics provided information on mortality rates by age of death up to early adulthood for those exposed in utero. 18

A second approach used the information in the national Dutch psychiatric registries to examine adult psychiatric outcomes among persons exposed to famine at specific times during gestation. The best known finding from these studies is the increased risk of schizophrenia among the birth cohort conceived at the height of the famine, 19–21 a finding subsequently replicated in a study based on the Chinese famine of 1959–61. 22 There was also some evidence of an increased risk of affective disorders after prenatal exposure. 23 These findings prompted investigators to also return to the data on military conscripts, in which the results of psychiatric examinations were recorded, to examine the relation of prenatal famine to schizophrenia spectrum and to antisocial personality disorders. 24–26

A third approach was developed through a series of studies based on infants identified at birth from hospital records, who were sampled according to exposure to prenatal famine and traced to their current address through the Dutch population registration system and examined as adults. The first such study included 1067 singleton girls born between August 1, 1944 and April 15, 1946 in the former Wilhelmina Gasthuis hospital in Amsterdam. This study, conducted in the early 1990s when the famine-exposed cohort was aged 43 years, established that it was possible to identify, trace and interview a large group of famine-born infants after a long follow-up period. Excluding deaths (16% of cohort) and emigrations from The Netherlands (8%), losses to follow-up were minimal and participation in face-to-face interviews was high. In all, >700 women were interviewed. 10 This study confirmed the clear decline in birth weight after third- trimester exposure, and showed an increase in birth weight following exposure in the first-trimester.

The availability of prenatal and birth records also provided the opportunity to study the course of pregnancy itself. Maternal weight gain up to 0.5 kg/week was strongly associated with infant size at birth. 9 There was a 2–5% increase in the ratio of placental weight to infant birth weight among births with first trimester famine exposure, suggesting that placental growth may be related to the nutritional status of women at the beginning of pregnancy. 27 At least four indicators of reproductive performance, including age at first birth, completed family size, birth spacing and probability of not having any children by age 40, were not related to exposure. 28 The normal increase in birth weights of offspring with increasing birth order was not seen, however, among women who themselves were exposed to famine in the first trimester of pregnancy. 29 An overview of this series of studies is given elsewhere. 30

In a fourth series of studies, male births from the same institution were added, resulting in a birth series of 2414 singleton men and women. From this group, ∼740 men and women were successfully examined at age 50 years. Selected outcomes include the glucose and insulin profile, 31 blood pressure 32 and body mass index (wt/ht 2 ). 33 An overview of this fourth series of studies is given elsewhere. 34 The series has subsequently been resurveyed at age 58 years. 35

The Dutch Hunger Winter Families study thus represents the fifth in the series of Dutch famine birth cohort studies and includes 3307 singleton births in three clinics in cities affected by the famine. 12 Endpoints are similar to those selected for the third and fourth series, with some measures of cardiovascular disease risk and hand morphology added. To avoid potential biases related to the clustering of health outcomes across the generations, we examined whenever possible an unexposed same-sex sibling of each clinic birth as a family control. The survivors in this study were interviewed and examined at the age of 59 years.

Additional studies have focused on the health outcomes of persons who experienced the famine as young adults 36–39 but these will not be further discussed here.

The study was set up by L.H.Lumey, in collaboration with Ana Diez-Roux at Columbia University, New York, NY (current affiliation: University of Michigan), Ezra Susser at Columbia University, New York, NY, Aryeh D. Stein at Emory University, Atlanta, GA, Henry S. Kahn at the Division of Diabetes Translation, Centers for Disease Control and Prevention, Atlanta, GA, and executed with S.P.Verloove-Vanhorick, A.L. den Ouden, M. van de Bor and K. van der Pal- de Bruin at the Institute for Preventive Health (TNO-PG), Leiden, The Netherlands and G.J. Blauw at the Study Center for Gerontology and Geriatrics, Leiden University Medical Center (LUMC). Study funding was provided by the National Heart Lung and Blood Institute, US National Institutes of Health (RO-1 HL87914; Principal Investigator: LHL).

The primary aims of the study are (i) to examine whether changes in maternal nutrition in pregnancy affect the risk among offspring for metabolic and cardiovascular disease in adulthood; (ii) to identify critical time windows of pregnancy at which fetal programming might occur; (iii) to document to what extent the time windows of prenatal programming might differ with respect to the adult risk of Type 2 diabetes mellitus, blood pressure and obesity and (iv) to validate the performance of selected morphological measures of the hand (e.g. fingertip ridge-count differences and digit-length ratios) as specific markers of disturbances in early gestation. The study also included measures of other outcomes of interest such as cognitive status and depressive symptoms.

We identified 3307 live-born singleton births at three institutions in famine-exposed cities (the midwifery training schools in Amsterdam and Rotterdam and the university hospital in Leiden). We selected (i) all 2417 births between February 1, 1945 and March 31, 1946 (infants whose mothers were exposed to the famine during or immediately preceding that pregnancy) and (ii) a sample of 890 births from 1943 and 1947 as time controls (infants whose mothers did not experience famine during this pregnancy). The sample of controls included an equal number of births for each month, allocated across the three institutions according to their size. At the time the large majority of deliveries (70% or more) were scheduled to occur at home. The client mix at the two midwifery schools consisted of low-risk pregnancies to women of lower socioeconomic status whose home environment was unsuitable for delivery. The client mix in Leiden also included higher-risk pregnancies identified during prenatal care and emergency admissions following complications of labour or delivery.

Whenever possible, we also enrolled a same-sex sibling of each member of the birth series as controls. For participants recruited as siblings, no information from prenatal or delivery records is available, as they were not members of the primary birth cohort and were generally delivered at home or in other institutions.

Members of the study population were traced to their current address in 2003. A telephone interview and medical examination were conducted in 2003–05.

Birth records

We extracted the following information from the pregnancy and delivery medical records: mother's and infant's names; address; age at delivery; occupation; religion; last menstrual period (LMP); gravidity and parity; lifetime number of spontaneous abortions; date of first prenatal visit; weight, height and blood pressure at prenatal visits; date and time of delivery; maternal postpartum weight (two clinics only): obstetrical presentation; mode of delivery; sex; birth weight; crown-to-heel length; head circumference; placental weight (two clinics only) and vital status at discharge. Abstraction of records of the 3307 birth records was completed in May 2003.

We submitted the names and addresses at birth to the local population registers with a request to provide a current address. We then invited by mail all traced members of the birth cohort to participate in the study. Initially, we enrolled only traced people along with a same-sex sibling; later we revisited the selection criteria and enrolled all available members of the birth cohort, regardless of the availability of a sibling.

We conducted a telephone interview, followed by a clinical examination at the Leiden University Medical Center. All study protocols and materials for data collection were approved by the human subjects committees of all the participating institutions. Participants provided oral consent at the start of the interview and written informed consent at the start of the clinical examination for all study procedures.

Telephone Interview

The telephone interview included questions on sociodemographic characteristics and socioeconomic status. In addition, we collected information on health and reproductive history, on current health status, on prevalent medical conditions such as stroke and cardiac problems (including the Rose angina questionnaire), on high blood pressure and on diabetes. We also collected information on smoking and drinking habits. For selected conditions, participants were asked for information on their parents and siblings. After the telephone interview, an appointment was made with participants for a medical examination in the study clinic at Leiden University Medical Center. This examination was usually completed within 6 weeks of the telephone interview. In all, 1031 telephone interviews were completed, including 718 participants from the hospital series and 313 same-sex siblings.

Clinical examinations

Participants were asked to fast overnight before a morning appointment; over 95% complied with this request. On their arrival at the clinic, we first obtained written informed consents for study examinations and blood collection and storage, including consent for later study of DNA. We then measured blood pressure with an automated blood pressure monitor with digital readout, recorded three successive electrocardiogram (ECG) readings and drew a blood sample to obtain fasting measures of lipids, glucose and insulin. We administered a standard oral glucose tolerance test with blood samples obtained at 30 and 120 min after a 75 gm glucose load.

Measures of adult weight, height (standing and seated), lengths (leg and arm), circumferences (waist, hip and right midthigh), skinfold thicknesses (right subscapular, right triceps and right anterior midthigh) and the supine sagittal abdominal diameter (SAD) were collected. Participants were asked to recall their body weight at ages 20 and 30 years. Current hand preference (right vs left) was assessed 40 and rolled fingerprints were obtained from all 10 digits using conventional ink-and-paper methods. In addition, the lengths of the second and fourth fingers on each hand were measured using a sliding caliper with digital readout. 41

During the clinical examination, several questionnaires were completed by the participants: a standardized food frequency questionnaire 42 ; a physical activity questionnaire 43 ; a neuropsychological test battery for cognitive function [Mini-Mental State Examination (MMSE)], visual verbal learning, colour scale performance (Stroop), letter digit coding, and verbal fluency 44–47 ; a quality-of-life assessment [Short Form 36 (SF-36)] 48 ; a sleep questionnaire 49 ; and an assessment of depressive symptomatology (Centers for Epidemiologic Studies Depression Scale [CES-D]) 50 and perceived anger (Spielberger State-Trait Anger Scale) 51 with versions adapted for use in The Netherlands. Whenever possible, we used validated questionnaires for which normative data are available from large study samples from The Netherlands.

Upon completion, all questionnaires were checked by study staff and participants were asked to provide missing information where necessary.

All collected study information was entered twice into a database (double entry keypunching) and any discrepancies were resolved by re-checking against the original coding sheets. In all, we completed the clinical examination in 94% (971/1031) of the people interviewed by telephone. Full details of causes of attrition for eligible participants to interview and clinical examinations, together with comparisons of perinatal characteristics between those who were included in these follow-up data collections and those who could not be are provided below.

Defining exposure to the famine

To define exposure to the famine for all selected participants, we have used an ecological measure to classify stage of gestation in relation to the available food rations. Several approaches have been developed in the past. Here, for the first time, we provide an overview of all definitions of exposure that have been used in studies of the Dutch famine and compare the degree to which these overlap.

Although maternal nutrition in pregnancy cannot be ascertained at the individual level, evidence for the impact of the famine on morbidity and mortality at the population level is abundant. 4 , ,5 With regard to nutrition in pregnancy, we have shown that many women actually lost weight in pregnancy. 9

Exposure by date of last menstrual period

We used the date of last menstrual period (LMP) listed on the birth record to define the start of gestation unless it was missing or implausible (12%). In those cases we inferred the LMP date from the date of birth, annotations of estimated gestation made at delivery, and estimated gestational age from birth weight and date of birth, using cutpoints from published tables of sex-, parity- and gestation-specific birth weights from the combined birth records of the Amsterdam midwives school (1948–57) and the University of Amsterdam obstetrics department (1931–65). 52 For each infant the most consistent and plausible estimate of gestation was selected and used together with date of birth to infer the LMP.

We have characterized exposure to famine during gestation by determining the gestational ages (in weeks after the LMP) during which the mother was exposed to an official ration of <900 kcal/day between November 26, 1944, and May 12, 1945. We considered the mother exposed in gestational weeks 1–10, 11–20, 21–30 or 31–delivery if these gestational time windows were entirely included in this period. Thus, pregnancies with LMP's between November 26, 1944, and March 4, 1945, were exposed in weeks 1–10; between September 18, 1944, and December 24, 1944, in weeks 11–20; between July 10, 1944, and October 15, 1944, in weeks 21–30; and between May 2, 1944, and August 24, 1944, in weeks 31 through delivery.

By these definitions, participants could have been exposed to famine during at most two 10-week periods. A limitation of this approach is that persons conceived towards the end of the famine—when it was most severe—can only be included among the exposed if they had 10 weeks of exposure before liberation.

We also quantified exposure to famine in the 6 months preceding conception by assigning a weight of one to any week during which the ration was 900–1500 kcal/day (October 1–November 25, 1944, and May 13–May 20, 1945; 9 weeks), and a weight of two to any week in which the ration was <900 kcal/day (November 26, 1944–May 12, 1945; 24 weeks). The score ranges from zero for births without any reduction in rations before conception to 57 for conceptions at the end of the famine period.

Exposure by date of birth

In contrast to this prospective approach, in most studies of the Dutch famine to date, prenatal exposure to famine has been defined relative to date of birth and an assumed gestation of 40 weeks for each pregnancy. For convenience and ease of comparison of current and future studies, these studies are summarized subsequently.

Stein et al . 13 in their report on mental performance at age 18 in relation to prenatal exposure to famine and in a subsequent monograph on the Dutch famine 2 arrayed the study population by week of birth and defined groupings based on ‘the criterion of stage of gestation in relation to famine exposure’. This approach was modified slightly with a smaller mid-pregnancy exposure group by Ravelli et al . 14 for the analysis of anthropometric data from military records.

It was formalized by Lumey et al . 10 and by Susser et al . 21 as an average ration of <1000 kcal/day during a trimester. Lumey et al . 10 used this approach for the analyses of reproductive outcomes among women born in the Wilhelmina Gasthuis hospital in Amsterdam. The approach results in partially overlapping windows of 5 months’ duration. 10 In subsequent studies of schizophrenia related outcomes, E. Susser and colleagues defined exposure in early gestation at the height of the famine by combining the following criteria: (i) low food rations of <1000 kcal/day during the first trimester of gestation; (ii) conception at the height of the famine as indicated by adverse health effects in the general population and (iii) a detectable excess of congenital neural defects. 19

In the studies carried out by Ravelli et al . of men and women born in the Wilhelmina Gasthuis in Amsterdam, ‘[b]abies were considered to be exposed to famine in utero if the average maternal ration during any 13-week period of gestation provided <1000 kcal. Babies born between 7 January, 1945, and 8 December, 1945, were thus exposed’. 31 Subsequently, three non-overlapping periods of 16 weeks were used to distinguish between babies who were exposed primarily during late-, mid- and early-gestation.

As shown in Table 1 and Figure 1 , the approaches based on date of birth show a substantial overlap in the assignment of broad categories of exposure and no gross misclassification comparing exposures in early and late pregnancy. Moderate misclassification remains a concern however, particularly for those exposed in mid-gestation by most definitions. Comparison of a recent date of birth based approach with the LMP based approach for the 3307 births in our hospital series ( Table 2 ) shows that the LMP approach appears to be more precise in categorizing participants with early exposure. As noted earlier, our definition will exclude participants with exposure of less than 10 weeks during early gestation and like other approaches it therefore has its advantages and disadvantages. We feel that on balance the LMP approach is well tailored, however, to the particular sample and questions of this study.

Classification of prenatal famine exposure categories by date of birth in the studies of Stein et al ., 2 G.P. Ravelli et al ., 14 Lumey et al ., 10 Susser et al ., 19 and A.C. Ravelli et al . 31 Category names are taken from the original publications

Categorization of exposure to the Dutch famine in different pregnancy periods based on date of birth, by various authors

Cross-classification of famine exposure based on LMP date and partially overlapping exposure windows by exposure based on date of birth and non-overlapping exposure windows. Study cohort births in three institutions (Amsterdam, Rotterdam and Leiden) in the western Netherlands, 1943–47

a Count for categories weeks 1–10 to weeks 31–delivery combined may exceed count for exposure at any time in pregnancy because of partial overlap of exposure categories.

Here we provide information on (i) the tracing from birth to current address; (ii) the response to letters of invitation sent to current address; (iii) participants enrolled for interview and medical examination; (iv) characteristics of traced and untraced persons; (v) characteristics of responders and non-responders to the letter of invitation and (vi) characteristics of infants enrolled for study and non-enrolled infants from the eligible birth cohort.

Tracing from birth to current address

The name and address for 3307 births were provided to the population register in the municipality of birth with a request for tracing to their current address. Of them, 308 (9%) were reported to have died in The Netherlands (10% of men and 8% of women) and 275 (8%) to have migrated (7% of men and 10% of women). The population registry in Rotterdam declined to trace 130 persons born out of wedlock (4%) and for 294 subjects (9%) a current address could not be located. Address information was therefore obtained for 2300 offspring (70% of the birth cohort).

Response to the letter of invitation

A letter of invitation signed by the current director of the institution in which they were born was sent to the 2300 traced persons, together with a brochure describing the study and a response card. We mailed one reminder letter to non-responders. Initially, our study design called for the recruitment of same-sex sibling pairs, and the lack of an available sibling was a reason for ineligibility. We received some reply to 58% of the initial letters and to 44% of the reminder letters; 347 persons (20% of 1767 respondents) expressed willingness to participate together with a sibling. Among the 1415 who declined, 951 (67%) reported not having a same-sex sibling available for study. To increase the number of participants, we recontacted these 951 offspring, 381 of whom expressed willingness to participate, for a grand total of 1075 positive responses. This number includes 751 births from the hospital series and 324 of their siblings. The higher positive response to our letters in women than in men (36% vs 29% overall) was consistent across all exposure categories. Individuals who indicated they were not able to travel to the site of the clinical examination were enrolled for a telephone interview where possible.

Study subjects enrolled for interview and medical examination

We completed the study telephone interview in 96% (1031/1075) of those with an initial positive response and a clinical examination for 971 among this group (437 men, 534 women). This latter group includes 359 offspring with prenatal exposure to famine and 299 offspring without prenatal famine exposure born in the study hospitals as well as 313 siblings. We examined two siblings whose matching proband did not attend the clinical examination. The resulting sample size by (overlapping) periods of exposure was 74, 127, 145 and 133 for gestational weeks 1–10, 11–20, 21–30 and 31–delivery, respectively. There were no differences across periods of exposure in the proportion of probands who had siblings available for study.

Selected characteristics of traced and untraced offspring

We found no clinically significant differences in mean birth weight (3350 vs 3315 g), length (50.4 vs 50.2 cm), placental weight (601 vs 593 g), maternal age at delivery (28.2 vs 27.4 years) or birth order (2.3 vs 2.3) comparing the 2300 study subjects from the birth series who had been traced to their current address to the 1007 subjects who had died, emigrated or could not be located. The proportion of deceased offspring was somewhat higher among probands born in 1943 (10%) than in 1947 (6%) and was higher in men than in women (10 vs 8%). Emigration status or other reasons why a current address was not found did not differ by year of birth. Emigration was more common in women than in men (10 vs 7%).

Selected characteristics of respondents and non-respondents to letter

We found no clinically significant differences in mean birth weight (3372 vs 3339 g) or length (50.5 vs 50.3 cm), placental weight (600 vs 601 g), maternal age at delivery (28.6 vs 28.1 y) or birth order (2.4 vs 2.2) when we compared the 751 positive responders from the birth series to the 1549 who did not respond to our letter. The response was somewhat lower for the 646 persons born in 1943 or 1947 (30%) compared with the other birth years (34%). With respect to distance between current address and the examination centre, 11% of those who were interviewed lived within 5 km (3 miles) of Leiden, as compared with 10% of those who were not interviewed, and 34% of the interviewed lived >45 km (28 miles) from Leiden as compared with 29% of those not interviewed. The median 1998 post-tax incomes were somewhat higher for postal district catchments of the interviewed (Euro 23 116) than for those not interviewed (Euro 22 919).

Selected characteristics at birth of study participants and non-participants from the eligible birth cohort

We found only marginal increases in birth weight [43 gram; 95% confidence interval (CI): −0.3–85], crown to heel length (0.25 cm; CI: 0.04–0.45), placental weight (2 gram; CI: −10–14), maternal age at delivery (0.9 years; CI: 0.4–1.4), or infant birth order 0.13 (0.03–0.30) when we compared the birth characteristics of the 751 study participants of the hospital series with those of the remaining 2556 infants of the eligible birth cohort. These differences did not change with statistical adjustment for date of birth and follow-up status (died, emigrated, current address found and no current address available).

Based on birth records, we have shown to date that except for birth weight following exposure in late pregnancy, measures of newborn weight, length and head circumference, taken alone or as any of their ratios, are poor indicators of maternal nutrition in pregnancy, even under the extreme conditions of the Dutch famine. 12 This makes their use as indicators of prenatal nutrition in studies of adult disease problematic. We also established that exposure to the famine was not associated with the proportion of boys and girls at birth (sex-ratio). 53

With respect to outcomes measured at age 59, we found significant changes in anthropometric measures indicative of the deposition of fat at several tissue sites in exposed women but not in men, 54 a modest association between prenatal exposure and current blood pressure, 55 and an association between the early pregnancy environment and a dermatoglyphic characteristic based on fingertip ridge-count differences. 56 Further reports are in preparation.

The circumstances of the Dutch famine provide a natural experiment to directly examine the long-term health effects of profound nutritional changes at different stages in pregnancy. With archived records of the weekly food rations distributed in the affected areas, there is no need to use birth weight as a proxy measure of maternal nutrition in pregnancy.

In this study, we assigned exposure based on the date of mothers’ LMP from the birth record, adjudicated where necessary, In contrast, previous studies of birth cohorts from the Dutch famine have used date of birth, assuming a gestation of 40 weeks for all participants across all exposure categories. Although both approaches have their strengths and weaknesses, we believe that the use of LMP rather than date of birth is preferable for the long-term follow-up of exposures in specific periods of pregnancy.

Study population

We have traced and examined a new birth cohort series from three institutions in the western Netherlands for which this information was previously not available. This allows for an independent assessment of birth cohort observations from other institutions. Our study group also adds to the number of persons in birth cohorts drawn from the famine. This is important because individual studies have limited study power for the detection of the long-term effect of the exposure, especially for discrete outcomes such as incidence of cardiovascular disease incidence or deaths. Statistical power may be somewhat less of an issue for continuous outcomes such as weight, blood pressure or metabolic measures when they are compared across exposure categories.

We and others have shown that normally the loss to follow-up is low (11% or less) when infants are traced from their famine birth records to their current address in The Netherlands some 50 years later. 10 , ,31 In this study the loss to follow-up was 9% when we exclude the 130 infants (4% of the cohort) who were not traced by the Rotterdam registry as they had been born out of wedlock. Other local registries did not object to tracing for this reason. Subsequent study enrolment of the majority of traced people can be more of a problem, however, depending on study protocol.

The proportion of eligible participants among those alive and resident in The Netherlands who were enrolled for study was 84% in 1992 when only home interviews were conducted, 10 36% in 1998, when clinical examinations were carried out in men and women of the Amsterdam birth cohort, 31 and 28% for the present study with a clinical examination between 2003 and 2005. Although we wished to enrol a larger proportion of those eligible for clinical examinations, we found that this was not possible with the current study protocol that included a clinical examination in a central study hospital. There is no evidence for follow-up bias in the current study, however, when we compare selected birth characteristics of the study participants with those of other eligible cohort members who did not participate because of death, emigration, loss to follow-up or refusal.

To maximize participation in future studies of the cohort, it will be important to consider the use of telephone or home interviews whenever possible and to simplify and shorten clinical study protocols. This will also be helpful in future studies of subsets of the current study population. An optimal enrolment strategy will depend on the study question and on available funds.

Sibling controls

Our use of sibling controls in this area of research is novel. These controls were chosen to reduce the potential for bias related to family-level factors with an effect on health outcomes that is independent of the exposure of interest. This is important in light of the strong associations between socioeconomic status of the family and fertility during the famine, with stronger declines in fertility among manual vs non-manual occupations. 8 We will analyse the effects of having such controls in a future publication.

Intermediary variables over the life course

Although extensive recorded information is available from the time of birth and from the time of examination at age 59 years, there is no source for intermediary data points except for the individual interview, in which we ascertained recalled weight at age 20 and 30 and collected a medical history.

Within The Netherlands health care system, well baby clinic records were collected for all study participants 57 and reports from annual school health examinations were collected through adolescence that included height, weight and selected medical problems. Both these sets of data are no longer available for study, however, as they have been discarded by the local health authorities. Military examination records are not routinely available for analysis in The Netherlands. For the studies of mental performance and body size among Dutch recruits mentioned earlier 13 , ,14 an anonymized computer data file was prepared by the military authorities with information on these research questions.

Study outcomes

Although the primary study focus is on risk factors for offspring cardiovascular and metabolic disease among offspring in relation to prenatal nutrition, we also collected measures of hand morphology (fingerprint ridge-count differences and digit-length ratios) as potential markers of early pregnancy circumstances as they are formed in early pregnancy and are unlikely to change thereafter. Our first analyses suggest that these measures may indeed be useful in epidemiological studies of fetal programming where specific prenatal exposures may not be well defined. In addition, we collected some measures in other domains (e.g. cognition and mental health) to provide a basis for further studies in these areas. Future analyses of biological specimens collected from the participants (including DNA) may point to other metabolic or to epigenetic effects of changes in the prenatal environment.

Specific proposals for collaborations are welcome. Further information about the study can be obtained from the Principal Investigator (LHL) who can be contacted through e-mail at [email protected] .

We thank the Vroedvrouwenscholen of Amsterdam (mrs M.van der Meijde) and Rotterdam (mrs M.C.W. van den Boogaard) and the Obstetrics Department of the Leiden University Medical Center in Leiden (J. van Roosmalen) for their help in accessing the archived delivery and birth records and the population registers in The Netherlands for tracing of the offspring from births to current address.

We thank our study consultants H.A. Delemarre-van de Waal, Department of Paediatric Endocrinology, Free University, Amsterdam; J.A. Romijn, Department of Medicine, Leiden University Medical Center and J. van Roosmalen, Department of Obstetrics, Leiden University Medical Center; for their advice on study design and logistics.

We thank R.J. Prineas, Wake Forest University School of Medicine, Winston Salem North Carolina, USA for his training of the local study staff in ECG acquisition and transmission methods; R.A. Bausch-Goldbohm of the TNO Quality of Life Institute in Zeist for the design of the food frequency questionnaire; J. Jolles of the University of Maastricht for the design of the neuropsychological test battery and B.J.M. Delemarre, Department of Cardiology, Leyenburg Hospital, the Hague, for the clinical review of all ECG results.

The study External Advisory Board included George Davey Smith, University of Bristol, England; Leiv S. Bakketeig, University of Southern Denmark, Odense, Denmark and Mervyn W. Susser, Columbia University, New York, NY, USA.

Finally, we thank Z.A. Stein for reviewing the manuscript and all participants for their involvement in the study.

The funding of the study was supported by grant RO1 HL067914 (Principal Investigator: LHL), National Institutes of Health, USA.

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• factor v leiden
• birth weight
• netherlands
• relationship - sibling
• prenatal care
• prenatal exposure

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