Causes of hyperemesis gravidarum

What Is Hyperemesis Gravidarum?

Women with prolonged hyperemesis gravidarum have a greater risk of preterm labor and preeclampsia.

Morning sickness is a common symptom of pregnancy, with 70 to 80 percent of pregnant women experiencing some form of it, according to the American Pregnancy Association (APA).

However, when the sickness is so extreme that it causes severe nausea, vomiting, and weight loss during pregnancy, it may be diagnosed as hyperemesis gravidarum.

Hyperemesis gravidarum usually continues beyond the first trimester and may stop by 21 weeks of pregnancy, but it can last the entire pregnancy in some women who experience the condition, according to the Hyperemesis Education & Research (HER) Foundation.

According to the APA, around 60,000 cases of hyperemesis gravidarum are treated in U.S. hospitals each year. But the number of diagnosed cases could be even higher, since some women may be treated at home or in a doctor’s office.

Causes

While there is no proven cause of hyperemesis gravidarum, there are new theories that emerge each year.

Possible causes or contributing factors include the following:

  • Rising levels of hormones, such as human chorionic gonadotropin (HCG), estrogen, and progesterone early in pregnancy
  • Increase in blood thyroxine levels, which has been documented in 70 percent of hyperemesis gravidarum cases, according to the HER Foundation
  • A multiple pregnancy (twins, triplets, etc.)
  • Abnormal tissue growth in the uterus, called a hydatidiform mole
  • Regurgitation of the contents of the duodenum (upper small intestine) back into the stomach
  • Abnormalities of peristalsis (the way the gastrointestinal tract moves content along)
  • Liver abnormalities
  • Abnormalities of fat in the blood
  • Inner ear problems
  • Infection with Helicobacter pylori, or H. pylori (the organism that causes stomach ulcers)
  • Deficiency of the nutrients pyridoxine and zinc

Hyperemesis gravidarum may lead to the following symptoms and conditions:

  • Severe nausea and vomiting
  • Dizziness, lightheadedness, and fainting
  • Increased salivation
  • Anemia
  • Headaches
  • Confusion
  • Yellowing of the skin and eyes (jaundice)
  • Low blood pressure
  • Rapid heart rate
  • Overactive thyroid or parathyroid
  • Dehydration and production of ketones (sometimes leading to breath that smells “fruity”)
  • Nutritional deficiencies
  • Metabolic imbalances
  • Increased sense of smell
  • Distorted sense of taste
  • Loss of skin elasticity
  • Loss of over 5 percent, and usually over 10 percent, of pre-pregnancy body weight
  • Difficulty with daily activities
  • Psychological issues — many women with hyperemesis gravidarum also experience depression, mood changes, anxiety, or irritability

Risk Factors

The following factors may increase your chances of getting hyperemesis gravidarum:

  • Having the condition during a previous pregnancy
  • Being overweight
  • Having a multiple pregnancy
  • Being pregnant for the first time
  • Having trophoblastic disease (abnormal growth of cells inside the uterus)
  • Family history of other women developing the condition

Treatment

If you have severe symptoms of hyperemesis gravidarum, you may need to be hospitalized. Otherwise, you may be able to seek treatment at home or at a doctor’s office.

While the course of treatment for hyperemesis gravidarum varies from person to person, your doctor may recommend one or more of the following:

  • Preventive measures, such as vitamin B6, ginger, peppermint, or a pressure-point wristband to help with nausea
  • Small, frequent meals that include dry, bland foods such as crackers
  • Intravenous fluids to help with dehydration
  • For severe cases, total parenteral nutrition, in which an intravenous (IV) solution of nutrients is given as a substitute for food
  • Medicine to prevent nausea, such as Phenergan (promethazine), Antivert (meclizine), or Inapsine (droperidol), doxylamine-pyridoxine (Diclegis), or metoclopramide (Reglan) which may be taken orally, by IV, or as a suppository
  • Complementary and alternative therapies, such as massage, acupuncture, acupressure, and hypnosis

Complications

The main risks to women with hyperemesis gravidarum are dehydration and electrolyte imbalances.

Women with prolonged hyperemesis gravidarum are at greater risk for preterm labor and preeclampsia, according to the HER Foundation.

Long-term complications to the baby may occur if the condition is left untreated, if the mother does not gain sufficient weight during the second half of pregnancy, and if the baby becomes malnourished.

Less common but severe complications of hyperemesis gravidarum include:

  • Ruptured esophagus from forceful vomiting
  • Collapsed lung
  • Liver disease
  • Blindness
  • Brain swelling from malnutrition
  • Kidney failure
  • Blood clots
  • Seizures
  • Coma
  • Death

Most women experience some type of morning sickness during pregnancy, but some women develop a far more serious condition.

Hyperemesis gravidarum (HG), which causes severe nausea and vomiting during pregnancy, affects as many as 3 percent of pregnancies, leading to over 167,000 emergency department visits each year in the U.S.

Until intravenous hydration was introduced in the 1950s, it was the leading cause of maternal death. Now, it is the second leading cause, after preterm labor, of hospitalization during pregnancy.

And yet, the disease is neither well-understood nor well-known, even with the flurry of headlines when it was announced that the Duchess of Cambridge during her pregnancies suffered from the condition.

I decided to start researching HG in 1999 after losing a baby at 15 weeks of gestation due to constant violent vomiting. I found that there was surprisingly little research on this disease.

To date, I’ve been contacted by over 4,400 pregnant women worldwide and have collected extensive survey data and saliva samples from women with HG and their unaffected friends. Analysis of these data has enabled me to answer some of the most pressing questions about the disease.

How is this different from morning sickness?

Even though HG is prevalent, many women don’t know about it until they experience it themselves. Symptoms can include extreme nausea and vomiting, as well as rapid weight loss, dehydration, electrolyte imbalance, dizziness and excessive saliva. Some women may start to vomit blood or bile and may require intravenous fluids and medication.

Some of the women I have encountered in my research on HG experience vomiting so violent that their retinas have detached, their ribs have fractured, their eardrums have burst, their esophagi have torn, their fingernails have fallen off and in rare cases, they can suffer from brain damage from malnutrition.

HG cannot be controlled by small frequent meals and saltine crackers – common recommendations for women with morning sickness. HG can also last for much longer than morning sickness.

HG can have consequences for mother and child. Pregnant women ultrasound image via www..com.

The old wives’ tale that the baby gets everything it needs from the mother even if she is unable to eat or drink or take vitamins is false.

Population studies of neural tube defects and animal studies, as well as studies of human offspring born during famine, in addition to those exposed to HG, now prove that malnutrition in early pregnancy can be linked to long-term health consequences in the exposed fetus.

Children exposed to HG in utero have a three-fold increased risk of neurodevelopmental delay. Research shows early symptoms of HG were linked to delay, which suggests early vitamin and nutrient deficiencies may be at play.

For women with HG there is a four-fold increased risk of adverse outcomes, such as preterm birth, and a 3.6-fold increased lifetime risk of emotional disorders, such as depression and anxiety.

The effects of HG can last long after birth. In one survey we found a significant increased risk of chronic postpartum symptoms in women with HG including reflux, anxiety, depression, insomnia, fatigue and muscle pain, and 18 percent experienced the full criteria of post-traumatic stress symptoms.

And HG can also lead to Wernicke’s Encephalopathy (WE), a severe neurological condition caused by a deficiency in thiamin (vitamin B1). Over a dozen cases were published in the medical literature between 2012-2014, and recently maternal deaths caused by complications from HG including Wernicke’s Encephalopathy have been documented in the U.S., England and Africa.

In a survey of over 800 women with HG, more than one in seven women with HG decided to terminate the pregnancy, primarily because they had no hope for relief from the condition.

How is HG treated?

Accurate data about what drugs can treat HG effectively and safely are hard to come by. This is due, in part, to the thalidomide disaster of the 1950s, when the drug was prescribed to women with HG to relieve symptoms of nausea and babies were born with limb deformities. This led to difficulty in developing and testing medications on pregnant women.

So what do the limited available data say? A study I conducted with colleagues found that antihistamine use to treat HG has been linked to preterm birth. We also found that Ondansetron (Zofran) is effective in treating HG symptoms for more than 50 percent of the women in our studies. We have also found that potentially serious side effects in women taking the drug, such as intestinal obstructions, are rare. In recent research, we found between ondansetron and birth defects.

But we do know this: Women with HG who are losing weight in pregnancy, and are unable to tolerate food or vitamins for more than a week, should be treated not only with fluids but also with thiamin to avoid the rare but preventable progression to WE, as well as maternal or fetal death.

Caretakers, family members and patients themselves may lean toward termination of a wanted pregnancy rather than try a medication of unknown safety. So for women with HG, seeking treatment can be a fraught experience.

A centralized, national database to document cases of HG, treatments and medications and their effectiveness, and maternal and child outcomes could help us figure out which medications are safe and effective in treating HG. This would increase patient and provider confidence about using treatments during pregnancy. It would also reduce the risk of malpractice or class action suits, which make drug companies and doctors hesitant to test and prescribe new treatments.

We need more – and better – research to treat HG. Pregnant woman via www..com.

We need to know what causes HG to treat it

Years of research, primarily focusing on hormones, have failed to identify what causes HG, and consequently, a clinically proven safe and effective treatment has yet to be found.

Currently, the leading hypothesis is that pregnancy hormones cause nausea and vomiting, and genetic and environmental factors that influence susceptibility to nausea and vomiting may turn normal pregnancy nausea into hyperemesis.

Increasing evidence suggests a genetic component to HG. If a woman has HG during one pregnancy there is about an 80 percent risk of recurrence in a subsequent pregnancy. The risk of recurrence is not affected by change in partner or psychiatric factors. The greatest risk factor for HG (besides having a previous HG pregnancy) is having a sister with HG, which constitutes a 17-fold increased risk.

A common misconception is that if a woman is the only one in her family with HG, it is not genetic. However, our research suggests the gene or genes responsible are equally likely to be passed from the paternal line as the maternal line. In a recent study of five families with a history of HG, we found a gene that signals vomiting in two of them. In addition, HG may be caused by a combination of several genes. A woman with HG may be the only one in her family with a pregnancy history that carries a particular combination of predisposing genes.

Once we identify the genetic and associated biological causes of HG, further research will likely help us develop therapies that target these causes of the condition, rather than blindly and rather ineffectively treating symptoms.

Hyperemesis Gravidarum (Severe Nausea & Vomiting During Pregnancy)

What is hyperemesis gravidarum?

Hyperemesis gravidarum is an uncommon disorder in which extreme, persistent nausea and vomiting occur during pregnancy. This condition might lead to dehydration.

What causes hyperemesis gravidarum?

The condition might be caused by rapidly rising serum levels of hormones such as HCG (human chorionic gonadotropin) and estrogen. Extreme nausea and vomiting during pregnancy might indicate a multiple pregnancy (the woman is carrying more than one baby) or hydatidiform mole (abnormal tissue growth that is not a true pregnancy).

What are the symptoms of hyperemesis gravidarum?

Hyperemesis gravidarum usually occurs during the first trimester of pregnancy. A woman might have hyperemesis gravidarum if she is pregnant and she vomits:

  • More than three to four times per day
  • So much that she loses more than 10 pounds
  • So much that she feels dizzy and lightheaded
  • So much that she is becoming dehydrated

What are the risk factors for hyperemesis gravidarum?

A risk factor is something that increases a person’s chance of getting a disease or condition. Risk factors do not necessarily mean that a person will develop a condition.

In the case of hyperemesis gravidarum, the following are risk factors:

  • Hyperemesis gravidarum during an earlier pregnancy
  • Being overweight
  • Having a multiple pregnancy
  • Being a first-time mother
  • The presence of trophoblastic disease, which involves the abnormal growth of cells inside the uterus

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Severe Morning Sickness (Hyperemesis Gravidarum)

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During the first trimester of pregnancy, many women experience the bouts of nausea and vomiting known as morning sickness.

Despite its name, morning sickness can occur at any time, day or night. It usually begins around the 6th week of pregnancy, peaks around week 9, and disappears by weeks 16 to 18. Although unpleasant, morning sickness is considered a normal part of a healthy pregnancy.

But what’s not normal is when morning sickness becomes so severe that a woman persistently vomits several times a day, loses weight, and becomes dehydrated or at risk for dehydration.

When this rare pregnancy-related condition is left untreated, it can interfere with a woman’s health and her baby’s ability to thrive.

About Severe Morning Sickness

The medical term for severe morning sickness is “hyperemesis gravidarum” (which means “excessive vomiting during pregnancy”). It usually follows a timeline that is similar to morning sickness; however, it often begins earlier in the pregnancy, between weeks 4 and 5, and lasts longer.

Although some women with severe morning sickness feel better about halfway through their pregnancy (around week 20), some continue to experience it throughout the entire pregnancy. Often, the symptoms become less severe as the pregnancy progresses.

Most of the time, hyperemesis gravidarum occurs during a woman’s first pregnancy. Unfortunately, women who experience it in one pregnancy are more likely to experience it again in later pregnancies.

The cause of severe morning sickness is unknown. Research suggests that it might be related to hormonal changes that occur during pregnancy. Specifically, a hormone called human chorionic gonadotropin, or HCG, might be to blame because the condition primarily occurs when HCG is at its highest levels in a pregnant woman’s body.

Severe morning sickness also might be hereditary because it is more common in women whose close family members (such as mothers and sisters) have had it.

Certain factors can increase a woman’s chances of having severe morning sickness during pregnancy. In addition to having a personal or family history of the condition, the following can put a woman at risk:

  • carrying multiples (twins, triplets, etc.)
  • history of motion sickness
  • migraine headaches with nausea or vomiting

Effects

The nausea and vomiting that happens in a case of severe morning sickness are so extreme that they can have harmful effects on both the mother and baby. The inability to keep down food makes it difficult for a woman to meet her nutritional needs. As a result, she might lose weight. And a loss of fluids, combined with the loss of stomach acid that occurs during vomiting, also can cause dehydration and electrolyte imbalances.

If a woman does not receive treatment, it can cause many complications, including organ failure and the premature birth of her baby.

When to Call the Doctor

It’s important to call the doctor right away if a pregnant woman has any of the following symptoms:

  • nausea that persists throughout the day, making it impossible to eat or drink
  • vomiting that occurs three to four times per day or an inability to keep anything in the stomach
  • vomit that is a brownish color or has blood or streaks of blood in it
  • weight loss
  • fainting or dizziness
  • decreased urination
  • a rapid heart rate
  • recurrent headaches
  • unpleasant, fruity mouth or body odor
  • extreme fatigue
  • confusion

Although treatments that are commonly used for morning sickness, such as eating dry crackers in the morning or consuming a bland diet, may be recommended for women with extreme morning sickness, they may not be effective on their own because of the severity of the condition.

Medical treatment may include:

  • a short period of not eating by mouth to rest the gastrointestinal system
  • intravenous (IV) fluids
  • vitamin and nutritional supplements

If necessary, the woman might also receive medicine to stop the vomiting, either by mouth or through an IV. The doctor might recommend eating foods with ginger or taking vitamin B6 supplements to help alleviate nausea. The following can also help:

  • consuming a bland diet
  • eating frequent small meals
  • drinking plenty of fluids when not feeling nauseated
  • avoiding spicy and fatty foods
  • eating high-protein snacks
  • avoiding sensory stimuli that can act as triggers

Additionally, if a woman is feeling anxious or depressed as a result of her condition, talking to a therapist or counselor might help her cope with her feelings.

Outlook

With treatment, a woman with a case of severe morning sickness can feel better and receive the nourishment she needs to help her and her baby thrive. And lifestyle changes can help to minimize nausea and vomiting and make the pregnancy more enjoyable.

With time, symptoms usually do improve, and — of course — resolve completely by the beginning of a woman’s next miraculous journey: parenthood./p>

Reviewed by: Elana Pearl Ben-Joseph, MD Date reviewed: April 2014

Two genes likely play key role in extreme nausea and vomiting during pregnancy

Sometimes the symptoms are so serious that hospitalization is required. Known as hyperemesis gravidarum, the condition is the same one that Kate Middleton, the Duchess of Cambridge, endured in her pregnancies.

A new study led by researchers at UCLA and published in the journal Nature Communications has identified two genes associated with hyperemesis gravidarum, whose cause has not been determined in previous studies. The genes, known as GDF15 and IGFBP7, are both involved in the development of the placenta and play important roles in early pregnancy and appetite regulation.

“It has long been assumed that the pregnancy hormones, human chorionic gonadotropin or estrogen, were the likely culprits of extreme nausea and vomiting, but our study found no evidence to support this,” Marlena Fejzo, the study’s first author, said. She is an associate researcher at the David Geffen School of Medicine at UCLA. The two genes, she added, coincidentally are linked to cachexia, a weight loss and muscle wasting condition that leads to death in about 20 percent of cancer patients and has similar symptoms to hyperemesis gravidarum.

Fejzo herself had hyperemesis gravidarum and lost a pregnancy to the condition in 1999. The debilitating symptoms can include rapid weight loss, malnutrition and dehydration due to persistent nausea and/or vomiting.

Current medications to treat the condition are largely ineffective and can lead to serious health consequences for both mother and baby. The condition is the second leading cause of hospitalization during pregnancy. Women often require intravenous fluids and, in the most severe cases, feeding tubes.

Previous research has shown that severe nausea and vomiting during pregnancy often runs in families, suggesting that genetics plays a role. For this study, the team compared the variation in DNA from pregnant women with no nausea and vomiting to those with hyperemesis gravidarum to see what the differences were between the two groups. DNA variation around the genes GDF15 and IGFBP7 was associated with hyperemesis gravidarum. The findings were then confirmed in an independent study of women with hyperemesis gravidarum.

In a separate follow-up study, researchers then proved the proteins GDF15 and IGFBP7 are abnormally high in women with hyperemesis gravidarum. They presented these findings at the International Colloquium on Hyperemesis Gravidarum in 2017.

The next step is to determine whether GDF15 and IGFBP7 protein levels can be altered safely in pregnancy to minimize nausea and vomiting.

The findings help to suggest a new avenue of research into a condition for which treatments have progressed little in the past.

“It is my hope that one day a medication that affects this pathway will be used to successfully treat and possibly cure hyperemesis gravidarum,” Fejzo said.

Hyperemesis gravidarum

Morning sickness can most often be managed by avoiding triggering foods that trigger the problem and drinking plenty of fluids when the symptoms let up in order to stay hydrated.

If your nausea and vomiting causes you to become dehydrated, you will receive fluids through an IV. You also may be given anti-nausea medicine. If nausea and vomiting is so severe that you and your baby might be in danger, you will be admitted to the hospital for treatment. If you can’t eat enough to get the nutrients you and your baby need, you may get extra nutrients either through an IV or a tube placed into your stomach.

To help manage symptoms at home, try these tips.

Avoid triggers. You may notice that certain things can trigger nausea and vomiting. These may include:

  • Certain noises and sounds, even the radio or TV
  • Bright or blinking lights
  • Toothpaste
  • Smells such as perfume and scented bathing and grooming products
  • Pressure on your stomach (wear loose-fitting clothes)
  • Riding in a car
  • Taking showers

Eat and drink when you are able. Take advantage of the times you feel better to eat and drink. Eat small, frequent meals. Try dry, bland foods such as crackers or potatoes. Try eating any foods that appeal to you. See if you can tolerate nutritious smoothies with fruits or vegetables.

Increase fluids during times of the day when you feel least nauseated. Seltzer, ginger ale, or other sparkling drinks may help. You can also try using low-dose ginger supplements or acupressure wrist bands to ease symptoms.

Vitamin B6 (no more than 100 mg daily) has been shown to decrease nausea in early pregnancy. Ask your provider if this vitamin might help you. Another medicine called doxylamine (Unisom) has been shown to be very effective and safe when combined with Vitamin B6 for nausea in pregnancy. You can buy this medicine without a prescription.

Extreme nausea and relentless vomiting strike many pregnant women, endangering them and their babies.

Vesna Andjic/ISTOCKPHOTO.COM

After paralyzing nausea and intrac­table vomiting caused her to lose the baby she was carrying in 1999, Marlena Fejzo decided to use her professional skills to understand her personal tragedy. A geneticist at the University of California, Los Angeles, Fejzo began to research hyperemesis gravidarum (HG), an extreme form of the “morning sick­ness” that afflicts most pregnant women. Jeopardizing the health of mother and fetus with dehydration and malnourishment, the little-studied condition hospitalizes at least 60,000 U.S. women a year.

Now, two studies, one led by Fejzo, sug­gest that an excess of a blood-borne protein, growth differentiation factor 15 (GDF15), is a cause of HG, and perhaps other cases of nausea and vomiting in pregnancy. The finding “finally gives some answers … and validates what women have been experienc­ing,” says Caitlin Dean, a U.K. nurse who became chair of a patient advocacy group after enduring unrelenting vomiting and nausea when pregnant multiple times. In the past, some doctors asserted that women exaggerated their symptoms, and even to­day, women with hyperemesis report that medical staff brush off the severity of their symptoms as a routine part of pregnancy.

Dean, who now studies HG as part of a Ph.D. program at the University of Plym­outh in the United Kingdom, calls the GDF15 discovery “an incredibly exciting breakthrough” that proves HG is a physical, not a psychological, condition. The finding “also points to potential therapeutic intervention,” says biochemist Stephen O’Rahilly of the University of Cambridge in the United Kingdom, who led the second study, which independently highlighted GDF15.

Unable to keep food and liquids down as early as 4 weeks into a pregnancy, women with HG can lose more than 5% of their normal body weight. They suffer electro­lyte imbalances, vitamin deficiencies, and other symptoms of starvation that can lead to blood clotting dysfunction and brain atrophy. Violent vomiting can produce com­plications such as esophageal rupture and retinal detachment. Symptoms peak around 9 weeks’ gestation, but can persist until birth. The traumatic experience can lead women to end a pregnancy or decide not to have more children.

Some studies have implicated estrogen and pregnancy hormones in HG. Fejzo, whose initial research focused on cancer genetics, has slowly built a case that genes play a role in the condition. In 2007, she persuaded the consumer genetic testing company 23andMe to incorporate questions about pregnancy sickness into its surveys, enabling her and her colleagues to scan the genomes of thou­sands of the company’s customers for DNA variations associated with hyperemesis.

That partnership paid off. In Nature Com­munications this week, Fejzo’s team reports two genome-wide association scans. One compares the genomes of 1306 women who received intravenous (IV) fluid therapy for nausea and vomiting during pregnancy—a proxy for HG—to those of 15,756 who did not report any nausea or vomiting while expecting. Two variants stood out, the most significant associated with the gene for GDF15 and the second with a gene for a protein called IGFBP7. Previous animal studies suggest that both molecules influence pla­centa development and appetite.

In the second analysis, the team scruti­nized the genomes of pregnant women re­porting a gradient of nausea and vomiting symptoms, from none to very severe. The same DNA variants stood out. Finally, Fejzo confirmed the results in a non-23andMe co­hort of hundreds of women with hypereme­sis who required IV fluid therapy or a feeding tube. The genome scans didn’t implicate estrogen or other hormones. Fejzo’s study shows “very clearly that genetic variation close to GDF15 is the single, strongest genetic signal for hyperemesis,” O’Rahilly says.

Last year, O’Rahilly’s team reported in a preprint that women who reported vomiting during the second trimester had more GDF15 in their blood at 12 to 18 weeks of gestation than those who reported no nausea and vomiting or only feeling nau­seated. That finding, he suggests, connects GDF15 to more typical pregnancy sickness, and perhaps to HG as well.

The molecular link makes sense to Samuel Breit, an immunologist and physi­cian at St. Vincent’s Hospital in Sydney, Australia. His team has previously found cancer patients with an anorexic and muscle-wasting syndrome called cachexia also have high blood levels of GDF15. Such patients experience persistent nausea and extreme vomiting as well. Last year, another group found that knocking out GDF15’s re­ceptor in the brain made mice resistant to chemotherapy-induced nausea.

These clues have sparked interest in blocking the actions of GDF15 for therapy, O’Rahilly says. Fejzo and other researchers caution that it’s too soon to consider testing such a strategy in expectant women, given how little is known about the protein’s role in pregnancy. Reduced serum levels of GDF15 are associated with miscarriage, so the molecule may confer some protec­tive effect—perhaps by keeping the mother from consuming potentially toxic foods. But Dean is optimistic. “At least there is hope now for the future,” she says.

Take a look at the Recent articles

Abstract

Objective: Previously we reported on the increased risk of adverse neurodevelopmental outcomes in children exposed in utero to hyperemesis gravidarum. The purpose of this study is to determine the frequency of non-neurodevelopmental long-term health effects in children exposed in utero to hyperemesis gravidarum and to identify prognostic factors for these disorders.

Study design: Long-term outcomes of 312 children from 203 mothers with hyperemesis gravidarum were compared to outcomes from 169 children from 89 unaffected mothers. The clinical profiles of patients having a child with an adverse outcome were then compared to the clinical profiles of patients having a child with a normal outcome to identify prognostic factors. Proportion tests were used to compare outcomes between variables with binary responses. Continuous responses were analyzed using a t-test.

Results: Children exposed in utero to hyperemesis gravidarum have a 3.82-fold increase in odds of being diagnosed with a long-term health effect including allergies, chronic constipation, gastroesophageal reflux disease, growth restriction (height and weight below 20th percentile), lactose intolerance, chronic respiratory or ear infections, or sleep difficulties (p< 0.0005). Among hyperemesis gravidarum patients, women who took promethazine during pregnancy or began gaining weight later in their pregnancy (after 20 weeks) were more likely to have a child that was diagnosed with allergies (p=0.037 for promethazine and p=0.004 for late weight gain). Those who took antidepressants while pregnant were more likely to have a child with chronic constipation (p=0.029). Metoclopramide use during pregnancy was protective against having a child diagnosed with gastroesophageal reflux disease (p=0.014). Preterm delivery was significantly linked to growth restriction in a child (p=0.003). Both herbal medicine and homeopathics were also significantly linked to growth restriction (p=0.006 for herbal medicine and p=0.001 for homeopathics), as well as to sleep difficulties (p=0.017for herbal medicine and p=0.013 for homeopathics). Peripherally inserted central catheter and Dolasetron use were linked to having a child with respiratory or ear infections (p=0.006 for PICC and p=0.038 for Dolasetron).

Conclusion: Women with hyperemesis gravidarum are at a significantly higher risk of having a child with long-term health effects. This study demonstrates the need for further analyses to address whether hyperemesis gravidarum itself or certain herbal and prescribed medications taken during pregnancy are responsible for the increased risk.

Key words

allergies, hyperemesis gravidarum, nausea, pregnancy, health effects

Introduction

Hyperemesis Gravidarum is defined as persistent and debilitating nausea and vomiting during pregnancy that results in more than a 5% body weight loss, abnormal fluid and nutritional intake, electrolyte imbalance, dehydration, and ketonuria.Symptoms often extend beyond the first trimester and can last throughout the entire pregnancy in as many as one-third of cases, leading to extreme weight loss and a state of malnutrition with prolonged dehydration during pregnancy.

Hyperemesis Gravidarum (HG) is associated with over 285,000 admissions/hospitalizations in the U.S. annually .Estimates of severe Nausea and Vomiting of Pregnancy (NVP) vary greatly and range from 0.3% in a Swedish registry to as high as 10.8% in a Chinese registry of pregnant women, with most authors reporting an incidence of approximately 0.5%. HG can be associated with serious maternal and fetal morbidity such as Wernicke’s encephalopathy,fetal growth restriction, and even maternal and fetal death.

Published data has demonstrated perinatal complications associated with HG. Two systematic reviews showed HG is significantly associated with low birth weight, small for gestational age infants, and preterm birth.There is less information, however, on outcomes of children exposed to HG in utero.Previously, we found a 3.6-fold increased risk of neurodevelopmental disorders in adults exposed to HG in utero .In a more recent study we found that children exposed to HG in utero show a 3.28-fold increase in odds of having a neurodevelopmental diagnosis including attention disorders, learning delay, sensory disorders, and speech and language delay .Herein, we determine the risk for non-neurodevelopmental long-term health effects in children from well-defined cases of HG compared to well-defined controls. Factors including pregnancy characteristics, treatments, and medications taken during pregnancy were also evaluated for having any association with adverse outcomes in children exposed to HG in utero.

Materials and methods

This study is part of a larger investigation evaluating the genetics and epidemiology of HG. Eligible patients were recruited through the Hyperemesis Education and Research Foundation (HER Foundation) web site at www.HelpHer.org beginning in 2007. Each potential participant was asked a series of eligibility questions. They were included in the study if they 1) were currently living in the United States, 2) had severe nausea and vomiting in a singleton pregnancy, 3) were treated with Intravenous (IV) Fluids and/or Total Parenteral Nutrition (TPN) or other form of feeding tube in the pregnancy due to nausea and vomiting, and 4) were between 18 and 50 years-old. Each participant was asked to submit a medical record of HG diagnosis and IV fluid treatment/tube feeding if available. However, a submitted medical record was not required to participate in the study. Each case was asked to recruit an acquaintance with at least two pregnancies to participate as a control. If a case was unable to successfully recruit a control or the control did not complete the study or update their contact information for follow-up, the case was still included in the study. Controls were eligible if they experienced either no NVP or normal NVP that did not interfere with their daily routine, they did not have any weight loss due to NVP, and they did not require medical attention in any pregnancy due to NVP. To ensure outcomes amongst subjects were independent of one another, relatives of participants in the study were not included. Minors (under 18 years old) were excluded because few teens are expected to fit the study criteria for controls having had two pregnancies. Multiple gestations and pregnancies complicated by a chromosome abnormality were also excluded because each may be associated with HG due to unique physiological pathways. Participants who have no children were excluded because child outcomes were the focus of this study. There were 203 HG patients and 89 control patients enrolled in the study. This study was approved by the Institutional Review Board at University of California at Los Angeles, IRB # 09-08-122-01A.

Study procedures

Participants with HG submitted medical records and completed an online survey to obtain information regarding demographics, pre-existing medical conditions, family history, pregnancy symptoms, medication use, and maternal, fetal, and child outcomes .Low Socioeconomic Status (SES) was defined as anything below a household income of $35k. Medium SES included a household income between $35k and $75k, while high SES was an income above $75k. The sites http://zipwho.com/ and http://www.zipdatamaps.com/ were used to estimate yearly household income based on zip code.In 2013, participants who met the study criteria were administered a follow-up survey to report on the diagnosis of childhood long-term health outcomes. Childhood outcomes of interest were determined by a diagnosis made by a medical professional and reported by the mother in the survey. There were 203 HG patients reporting on the physical outcomes of 312 children exposed to HG in utero and 89 control participants reporting on 169 children not exposed to HG in utero (Figure 1).

Figure 1. Schematic of study participants. A) 203 women with HG (HG Moms/Families) reported on diagnoses in B) their 312 children exposed to HG in utero. These women were compared to A) 89 women who did not have HG in their pregnancies (Control Moms/Families) who reported on B) diagnoses in their 169 children who were NOT exposed to HG in utero (Control children). C) Then children exposed in utero to HG who had a significant diagnosis (eg. Allergies) were compared to children exposed in utero to HG who did not have that particular diagnosis (ie No Allergies).

Statistical analyses

Maternal and child characteristics were compared between children who were exposed to HG in utero and those who were not (Table 1). To account for genetic or familial traits, individual variables would only be counted once per family. To evaluate differences amongst the groups, proportion tests were conducted for categorical variables and t-tests were used for numerical variables. Logistic regression was performed in order to derive estimated odds ratios and confidence intervals corresponding to various diagnoses found in families (Table 2).

Table 1. Maternal and child characteristics

1Hyperemesis Gravidarum

2Socio-Economic Status

Table 2. Increased risk of adverse physical outcomes (diagnosis in at least one child reported per family) in children exposed to HG.

1Hyperemesis Gravidarum

2Gastroesophageal reflux/acid disease

In children exposed to HG in utero, pregnancy characteristics, hospitalization data, preterm birth, treatments, and medications taken during pregnancy were compared between those who had a child with a long-term health effect versus those who had a healthy child outcome (Figure 1C, Table 3). Within the HG group, we examined potential factors linked to adverse outcomes such as treatments and medications received during pregnancy, NVP characteristics, and preterm births. To see if a treatment, medication, or symptom affected the probability of having a child with an adverse outcome, a proportion test on the presence of each long-term effect was performed.

Table 3. Medications and treatments significantly associated with specific childhood diagnosis.

1 Gastroesophageal reflux/acid disease

2 Intravenous

3 Peripherally inserted central catheter

4 Diagnosis

Results

Demographic characteristics

Cases and controls were matched for mean maternal age, race, Socioeconomic Status (SES), spontaneous labor, delivery method, and use of assisted reproduction (Table 1). The children of both groups were also matched for gender and age, with the average age being between 8 and 9 years old. HG patients tended to have fewer children (1.54 on average for cases with HG compared to 1.9 for the control group; p=0.0015) and were more likely to have a child born before 37 weeks (p=0.0502).

Outcome

HG patients were significantly more likely to report a child that had a diagnosis of allergies (p=0.02), chronic constipation (p=0.0116), gastroesophageal reflux/acid reflux disease (p=0.0007), growth restriction (p=0.0273), lactose intolerance (p=0.0178), chronic respiratory or ear infections (p=0.0322), or chronic sleep difficulty (p=0.0023) in at least one of their children (Table 2). There were no significant differences in the reported rates of other non-neurodevelopmental issues between the cases and controls.

Preterm birth, though not statistically significant (p = 0.07), was more common among HG families. Overall, 84% of HG patients reported at least one child with a long-term health effect, compared to 57% of women without HG. This corresponds to a combined 3.82-fold increase in odds of having a child diagnosed with an adverse physical condition from pregnancies complicated by HG (OR 3.82, 95% CI = ).

Antenatal characteristics associated with adverse physical outcomes in children exposed to HG in utero

The maternal pregnancy characteristics that were found to be significantly associated with each childhood diagnosis are shown in Table 3. Later maternal pregnancy weight gain was significantly associated with having a child diagnosed with allergies (p=.004), preterm birth was significantly associated with having a child with growth retardation (p=.003), and herbal medicine and homeopathics were significantly associated with having a child with chronic sleep difficulties (p=.017, p=.013). Finally, maternal weight gain beginning after 20 weeks gestation was significantly associated with having at least one of the significant adverse outcomes when compared to children with none of the significant adverse outcomes listed in Table 3.

Medications/Treatments and outcome

Thirty-seven different treatments and medications were explored for possible links to individual adverse outcomes. Our sample included 232 children that were exposed to HG with a long-term health effect and 80 children who were exposed to HG with a good outcome. Only the medications and treatments that were found to be significantly associated with specific childhood diagnoses are shown in Table 3.

Comment

This study focuses on the most extreme end of NVP in which symptoms are prolonged and intractable. Women affected with HG show a 3.82-fold increase in odds of having a child diagnosed with an adverse physical outcome later in life. Failure to gain enough weight during pregnancy puts the child at risk for intrauterine growth restriction, which then may put the child at greater risk for other neurodevelopmental and physical problems later in life compared to infants of normal weight. Our data supports this, showing that HG mothers have a 3.14-fold increase in odds of having a child who suffers from growth failure.

The specific mechanism linking exposure to HG and abnormal physical development is unknown, however several studies have shown significant associations between HG and physical developmental problems in children. Higher rates of undescended testicles and hip dysplasia were reported as associated with HG according to a cohort study done in Sweden.In utero, vitamin D deficiency has recently been linked to an increased risk of asthma, allergy, and acute lower respiratory infections in early childhood.Neonatal vitamin A deficiency has been associated with an increased risk of ear and respiratory infections .Herbal medicine was found to be linked to higher rates of growth failure and chronic sleep difficulties in our study, and some herbal medicines, specifically huanglian and An-Tai-Yin, have been found to be significantly associated with congenital malformations .

In more than a quarter of HG pregnancies, patients experience at least a 15% loss in body weight, and HG symptoms persist until the end of the pregnancy in over 20% of cases. This lack of nutrition and hydration suggests HG can be a form of prolonged starvation.The Dutch Famine of 1944 demonstrated the detrimental effects of prenatal exposure to undernutrition. The Dutch Famine Birth Cohort Study not only found that the children whose mothers were pregnant during the famine were at higher risk for health problems, but the children of these children were thought to be smaller than average, suggesting a possible epigenetic characteristic was passed down to the next generation .

There are limitations to the study. Participants were not assessed for common factors associated with adverse or delayed physical outcomes such as maternal smoking, alcohol consumption, and recreational drug use during pregnancy.However, given that maternal smoking is inversely associated with HG, if cases and controls were not well matched for these characteristics, the results would likely bias toward the null.

An online survey was used to collect data for this study. Medical diagnoses were reported by the mother and there was no review of the child’s medical records. Inaccuracies in the diagnoses are a possibility and there is also the potential for recall bias. However, rates of diagnoses in our control population are consistent with rates reported in the published literature. In our sample 35.96% of control mothers reported that at least one of their children had allergies. According to the American Academy of Allergy, Asthma, and Immunology the population proportion of school children who are reactive to common allergens is approximately 40% .In March 2015 the American Academy of Otolaryngology reported an estimated 5-8% of adolescent children have GERD, which is consistent with the 7.87% of our controls that reported at least one child with GERD .

Our small sample size is also another limitation. We examined as a response variable the collection of all significant adverse outcomes in order to search for potential predictors and found significantly higher rates of adverse physical outcomes amongst those who took anti-motion medications, had IV fluid treatment, were home health care patients, and began gaining weight after week 20. However, for particular individual response variables, especially rarely observed outcomes such as chronic sleep difficulties or chronic constipation, our study may have insufficient power to detect significant predictors. Further, in this study we performed numerous simultaneous tests in order to investigate potential links between HG and associated treatments with a variety of outcomes. We reported individual p-values and these should be interpreted qualitatively as summaries of the strength of the observed correlation, but further study is needed to determine if these associations definitively exist in the overall population. In addition, we certainly cannot infer causal links between treatments and adverse consequences based on the observed associations from this observational study.

One of the strengths of this study comes from the long-standing collaboration with the HER Foundation that provided a unique opportunity to involve a large group of women affected with HG to contribute important data. In addition, the design allowed for a significantly well-matched study sample. By limiting the second part of our analysis to HG patients only, we were able to control for potential confounding factors contributing to HG that could possibly also contribute to adverse child outcomes. In addition, our finding that preterm birth is linked to childhood growth retardation, which is already a well-known predictor of poor child growth, suggests at least some of the novel associations identified in this study are likely to be validated with further study.

Adverse physical outcomes are significantly associated with children who were exposed to HG in utero. This suggests that such exposure could have long-term effects on a child. The cause for the association is unknown, but may be related to certain medications/treatments, maternal stress, abnormal hormone levels during fetal development, malnutrition, or vitamin deficiency. HG is an under-studied and under-treated condition of pregnancy that not only results in maternal physical and mental health problems, but also potentially results in long term physical and mental health consequences to the exposed fetus.

Acknowledgment

This work was supported, in part, by the Hyperemesis Education and Research Foundation and the Paul and Janis Plotkin Family Foundation

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Consider neurodevelopmental impacts of hyperemesis gravidarum

Hyperemesis gravidarum (HG) affects just 1%-2% of pregnant women, but it’s clinical consequences are significant, with excess vomiting and dehydration, hospitalization, and the need for intravenous fluids being common in that group. In extreme cases, repeated vomiting has led to tears in the esophagus and severe dehydration has caused acute renal failure. All of that leaves aside the obvious suffering and distress it causes for women with the condition.

While studies continue to support the long-held theory that mild-to-moderate nausea and vomiting has a protective effect in pregnancy, that does not appear to be true for HG. Rather, the medical literature shows that HG is associated with small-for-gestational-age neonates, low birth weight, higher rates of preterm birth, and lower Apgar scores at 5 minutes.

Dr. Gideon Koren

What is even more concerning is what is happening to these children developmentally. In the last few years, controlled studies have emerged looking at long-term neurological development following pregnancy with HG.

I was one of the investigators on a study that prospectively followed more than 200 women with nausea and vomiting in pregnancy from 2006 to 2012. We found that children whose mothers were hospitalized for their symptoms – 22 in all – had significantly lower IQ scores at 3.5 years to 7 years, compared with children whose mothers were not hospitalized. Verbal IQ scores were 107.2 points vs. 112.7 (P = .04), performance IQ scores were 105.6 vs. 112.3 (P = .03), and full scale IQ was 108.7 vs. 114.2 (P = .05).

The study cohort included three groups: women treated with more than four tablets per day of doxylamine/pyridoxine (Diclegis); women treated with up to four tablets per day of the drug; and women who did not receive pharmacotherapy (Obstet Gynecol. 2015. doi: 10.1097/01.AOG.0000463229.81803.1a).

Hospitalized women in the study received antiemetics about a week later, experienced more severe symptoms, and were more likely to report depression. Overall, we found that duration of hospitalization, maternal depression, and maternal IQ all were significant predictors for these outcomes. However, daily antiemetic therapy was not associated with adverse outcomes.

©monkeybusinessimages/thinkstockphotos.com These findings led my colleagues and I to conclude that timely preventive antiemetics and depression control could help prevent hospitalization and the associated worsened outcomes in child neurodevelopment.

Another study, published the same year, found that children exposed to HG had a more than three times increased risk for a neurodevelopmental diagnosis, including attention disorders, speech and language delays, and sensory disorders. The changes were more prevalent when women experienced symptoms early in pregnancy – prior to 5 weeks of gestation (Eur J Obstet Gynecol Reprod Biol. 2015 Jun;189:79-84).

The study compared neurodevelopmental outcomes for 312 children from 203 women with HG, with 169 children from 89 unaffected mothers. The findings are similar to those of our study, despite the differences in methodologies. Both studies found that the antiemetics were not associated with adverse outcomes, but the symptoms of HG appear to be the culprit.

While more research is needed to confirm these findings, it makes sense that the nutritional deficiencies created by excess vomiting and inability to eat are having an impact on the fetus.

It also raises an important question for the ob.gyn. about when to intervene in these women. Often, clinicians take a wait-and-see approach to nausea and vomiting in pregnancy, but the developing research suggests that earlier intervention would lead to better outcomes for mother and baby. One guide to determining that preventive antiemetics are necessary is to consider whether your patient has had HG in a previous pregnancy or if her mother or sister has experienced HG.

Another consideration is treating the nutritional deficiency that develops in women whose HG symptoms persist. These women are not simply in need of fluids and electrolytes but are missing essential vitamins and proteins. This is an area where much more research is needed, but clinicians can take a proactive approach by providing team care that includes consultation with a dietitians or nutritionist.

Finally, we cannot forget that maternal depression also appears to be significant predictor of poor fetal outcomes, so providing appropriate psychiatric treatment is essential.

Dr. Koren is professor of physiology/pharmacology and pediatrics at Western University in Ontario. He is the founder of the Motherisk Program. Dr. Koren was a principal investigator in the U.S. study that resulted in the approval of Diclegis, marketed by Duchesnay USA, and has served as a consultant to Duchesnay.

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