Insomnia more common in teens whose mums had postnatal depression

insomnia
More than a third (36%) of teenagers whose mothers suffered from postnatal depression experienced sleep problems at the age of 18, compared to only one in five (22%) teenagers whose mothers didn’t suffer from postnatal depression.

Insomnia affects between one in two and one in 10 people worldwide and can be debilitating. It can lead to memory problems and fatigue, and raises the risk of developing high blood pressure and heart disease.

Such health problems have a high economic cost, both direct (healthcare, drugs, tests and research) and indirect (absenteeism, lack of productivity).

Now, for the first time, researchers have looked to see if postnatal depression in women could contribute to their children having sleep problems in adolescence. It is already well established that postnatal depression can affect a child’s mental health and how well they do at school but the impact of it on sleep has not been examined before.

By looking at Children of the 90s (University of Bristol), a unique 25-year-long study of 14,500 mothers and their children (born in 1991 or 1992), researchers were able to ask teenagers when they were 16 and 18 about their sleep problems and compare their answers to the information more than 10,000 mothers had provided years before about postnatal depression. The study is based at the University of Bristol.

By assessing the problem so many years after the children were born, the researchers were able to rule out sleepless nights during infancy as the cause of the postnatal depression and ask the teenagers themselves about their sleep problems rather than rely on what their mothers said (which may have been affected by their depression).

What they found is that more than a third (36%) of teenagers whose mothers suffered from postnatal depression experienced sleep problems at the age of 18, compared to only one in five (22%) teenagers whose mothers didn’t suffer from postnatal depression.

This was the case even after a number of important factors were taken into account:

  • Whether the teenager suffered from depression when they were aged 16
  • Whether the teenager had experienced sleep problems as a young child (measured at the ages of 6, 18 and 26 months)
  • The mother’s education, her age when the child was born, and the number of other children in the family
  • Whether the mother smoked or experienced depression when pregnant

Although a mother’s depression increases the likelihood that her child will have sleep problems, the reasons for this are not clear.

Dr Rebecca Pearson from the University of Bristol, who supervised the research, suggests three possible reasons:

  • Shared genes between the mother and child can affect sleeping patterns
  • Antenatal depression which precedes postnatal depression can have a biological effect on the child while it is still in the womb
  • Postnatal depression can make it more difficult for mothers to help regulate their baby’s emotions and their ability to establish regular and calm sleeping patterns. Continued depressive symptoms in the mother during her child’s early years (up to age 12) were also found to play a role.

Speaking about the findings, she said:

“Postnatal depression can make it more difficult for mothers to interact with their babies and this could make it particularly hard to establish a regular sleeping routine and help babies to learn to regulate their emotions and settle themselves to sleep. A noisy, disruptive house can also make it difficult for children to sleep and such environments can be linked to maternal depression.

Depressed mothers are increasingly offered support to improve their mood and to promote positive interactions with their babies and we would advocate that such support also considers the child’s sleeping pattern. As we’ve shown here, maternal depression can potentially have serious long-term implications for the health and wellbeing of both the mother and her child.

There is substantial evidence that postnatal depression is linked with a broad range of child difficulties. Individual risks are often small but because depression in mothers can influence so many aspects of their child’s development, in total it is very costly.”

Anna Taylor, a medical undergraduate student at the University of Bristol who led the research, explained that:

“Poor sleep affects school performance as well as physical and mental health, all of which can have significant impact on the child’s life and what they are able to achieve, so preventing sleep problems is really important. The cost of supporting depressed mothers is far smaller than the longer-term costs of dealing with multiple problems later in life.”

Dr Pearson added:

“As far as we’re aware, no one has ever looked at the long-term effects of postnatal depression on a child’s sleeping habits as reported by the children themselves as teenagers. Luckily, Children of the 90s, with its 25-year dataset, allows us to go back in time and examine these issues in great detail.”

via University of Bristol – ALSPAC – Insomnia more common in teens whose mums had postnatal depression

The full paper, The association between maternal postnatal depressive symptoms and offspring sleep problems in adolescence has been published Open Access in Psychological Medicine, and can be viewed here.

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Explore the online archive of AGMG

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Cambridge University Press and Twin Research and Human Genetics (TRHG) are proud to announce the release of the online archive of AGMG, the predecessor journal to TRHG. AGMG was the official journal of the International Society for Twin Studies (ISTS) from 1952-1998 when TRHG took over this role. However, both journals have always had a wider interest in the field of human genetics.

Twins can provide unique and powerful opportunities to study genetic and environmental factors that make people differ in how they look, behave and how healthy they are. Monozygotic [identical] twins share all their genetic variation and dizygotic [non-identical] twin pairs, on average, share about 50% of their genetic variation. Both types of twin pairs often but not always share similar pre- and post-natal environments as well. Having twins participate in these studies helps to continue important research for common human conditions such as diseases, health, and behaviors, leading to advances in science, medicine and future potential therapies.

Much effort has gone into creating this digitised archive and making it available online to the research community because we believe that many of the classic papers published in AGMG reveal the academic foundations of the subject and still have relevance today. Below is a link to the 20 most cited papers from the AGMG archive to demonstrate the wide scope of interest. We encourage you to explore and enjoy this fascinating resource.

View the 20 most-cited papers from the AGMG archive here .

The papers cover a wide spectrum of topics and include the following articles:

  • Population-Based Twin Registries: Illustrative Applications in Genetic Epidemiology and Behavioral Genetics from the Finnish Twin Cohort Study (1990)
  • Resting Metabolic Rate in Monozygotic and Dizygotic Twins (1985)
  • Causes of Variation in Drinking Habits in a Large Twin Sample (1984)
  • The Vanishing Twin (1982)

 

Sociology, Stigma and Innovation – Sam Rowlands on editing a book about abortion

Abortion Care Cover

After last month’s article about the journey of a medical book from an author’s perspective, this month we hear from Sam Rowlands, editor of Abortion Care, about editing a book which boasts more than 40 contributors – and which is about a particularly emotive topic…

There aren’t many medical books dedicated to abortion care. I felt there was a gap in the market for a smaller book that could be easily carried around. I wanted to produce a book that had all the conventional ingredients such as the methods of abortion, complications and so on but also looked at abortion from a wider perspective.

I drew up a list of around 30 chapters and identified potential authors for each. Cambridge were keen for the book to have international appeal so I endeavoured to select recognised specialists from around the world. I am fortunate to have met many of these personally through my career in sexual and reproductive health but still I was delighted (and surprised) that most of the colleagues I chose readily agreed despite their very busy schedules. I was then intrigued by how many chapter authors (15) asked to collaborate with their selected colleagues. This has resulted in an even richer authorship.

I had originally thought I might ask a couple of collaborators to co-edit with me but on reflection decided to edit the book on my own. The advantage of this was that I could be in control and do things my way, especially as I had by now a clear view of how the book would look. The downside was that when more than 20 chapter manuscripts arrived in a rather short space of time, I felt a bit overwhelmed! The lead chapter authors are all authorities in their fields. Some are academics and some are skilled practical clinicians, some both. Some are neither of these, just incredibly knowledgeable and wise. All authors developed their chapters in their own way; I encouraged them but tried not to steer them in any particular direction.

Although the book is mainly for readers with a medical bent, I have tried to include chapters to stretch their minds on topics that they might not necessarily otherwise tackle. Sociological topics are included but the authors of these were banned from using inaccessible terminology! There are two chapters with an epidemiological flavour which are not too daunting even to the numerically-challenged. There are two chapters written by lawyers which really flow, despite references to statute and case law.

Although the book is about a controversial subject and is bound to be serious in most of its content it is written in language that I hope is accessible and uses a lighter touch at times, for example a quote from Monty Python in the ethics chapter. The historical chapter provides a wonderful backdrop, painting a vivid picture of days gone by with some poignant examples of tragic cases. Stigma is a theme that runs through the book. Half a chapter is dedicated to this but reference is also made elsewhere, particularly in the chapter on staff. Although we all know that abortion is stigmatised, it’s only quite recently that it’s been written about and even measured.

I tried to include some innovations in the book and two chapters come up trumps in this respect. One covers abortion care provided by personnel other than doctors, showing that all the evidence points to this being not only safe but actually preferred by many women. The other looks to the future and shows how telemedicine can be applied to facilitate communication and treatment when the clinician and the woman are not in the same place, which has potential to improve access in more rural areas or in those parts of the world with restrictive regimes.

I’ve found it very rewarding to head up this project but don’t claim it is perfect. I invite anyone to make suggestions for a second edition.

Sam Rowlands MBBS, MD, LLM, FRCGP, FFSRH, Clinical Lead in Community Sexual and Reproductive Health, Dorset HealthCare and Visiting Professor, School of Health & Social Care, Bournemouth University

Sam Rowlands is the editor of Abortion Care (out now).

Biomarkers for early detection of postpartum depression

On the basis of molecule levels in the blood, researchers can predict the risk of developing postpartum depression at an early stage.

Not every pregnancy and birth of a child leads to feelings of happiness. Some new mothers develop postpartum depression which can extensively influence the health of both, mother and child. Often the illness remains untreated because young mothers misinterpret the symptoms or cannot afford professional care. Scientists of the Max Planck Institute of Psychiatry in Munich have now discovered biomarkers, which allow detection of at risk patients before birth and early treatment. Apparently, the hormone estrogen plays a key role in postpartum depression since some of the biomarkers control the system of estrogen in the body.

Michael Greiner, Max Planck Institute of Psychiatry

About 70% of all women suffer from depression shortly after birth – the so-called “baby blues”. Instead of expected happiness, they experience sadness, tension and tiredness. Presumably the changes of hormonal levels can cause these emotions. After several days, the symptoms of baby blues subside and hormonal levels become rebalanced.

But about 13% of all women develop further symptoms within 6 to 12 weeks after delivery – the so-called postpartum depression. The symptoms include anxiety, aggression, despair, and the inability to build a secure mother-infant attachment. In some extreme cases women engage in substance abuse and experience suicidal thoughts. Children of postpartum depressed women often suffer from sleep disturbances, poor growth rates or malnutrition. They have a higher risk of developing depression or respiratory and bowel diseases and more often show social withdrawal and internalizing behaviour.

“Despite the severity of possible consequences, postpartum depression frequently remains untreated. Women may misinterpret the symptoms as to be related to stress of childbirth and changed life conditions.” states Elisabeth Binder, director of the Translational Research Department at the Max Planck Institute of Psychiatry in Munich. “Moreover, women at risk may fail to seek help due to lack of resources, social stigma or inadequate social support.” The scientific team of Elisabeth Binder therefore aimed at discovering biomarkers for detection of at risk patients before birth to allow early treatment or prevention.

In particular biological, psychological and social factors including hormonal changes, substance abuse, stress, marital disharmony or family violence have been associated with postpartum depression. Additionally, several genetic factors also appear to influence the risk of developing this disorder.

In collaboration with scientists of the Emory University School of Medicine (Atlanta, USA) blood samples of 45 women were taken during the first and third trimester of pregnancy. These women were classified as high-risk patients according to their clinical or social history. Indeed, 17 women developed postpartum depression after delivery and 28 remained unaffected. Comparing the blood samples, more than 100 genes appeared to be differently regulated in subsequently affected women. Applying those biomarkers, scientists were able to predict postpartum onset depression with 88% accuracy from blood samples taken in the third trimester of pregnancy.

A further test involving another group of 24 pregnant women in their third trimester of pregnancy came to the same result.

“Surprisingly, about 34% of the detected genes were related to mechanisms linked to the female sex-hormone estrogen”, explains Divya Mehta, associate scientist at the Max Planck Institute of Psychiatry and first author of the study. “All women displayed comparable levels of estrogen in the blood samples, but subsequently affected women appeared more sensitive to estrogen signalling.”

Earlier studies already indicated the influence of estrogen on mood symptoms via effects on the level of serotonin in the brain. Serotonin is thought to be a contributor to feelings of well-being and happiness. In women displaying increased sensitivity, the drop of estrogen after childbirth might lead to reduced levels of serotonin in the brain, affecting the mood in a negative way.

Thanks to the discoveries of the scientific team around Elisabeth Binder, medical practitioners may predict a woman’s risk of suffering from postpartum depression even before childbirth.

The full paper “Early predictive biomarkers for postpartum depression point to a role for estrogen receptor signaling” can be viewed free of charge for a limited time here.

Vitamin D deficiency in pregnant women and newborn infants

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Pregnant women, in Germany, are not sufficiently supplied with Vitamin D – and not just in winter.

This is the result of a study, published in British Journal of Nutrition, by Prof. Clemens Kunz and his research group at the Institute of Nutritional Science, Justus-Liebig University Giessen (JLU); together with Dr. Peter Gilbert and his team from the St. Josefs Hospital Giessen Hospital. The research, carried out on 261 pregnant women and 328 newborns, showed that during the winter months 98 percent of the pregnant women had a Vitamin D status lower than that recommended by the German Nutrition Society (DGE). However, in the summer months when Vitamin D can be formed by sunlight in the skin, the levels were often still too low.

The DGE and other professional societies, such as The German Society of Pediatrics and Adolescent Medicine recommend 105 to 30 minutes of outdoor exposure in order to stimulate Vitamin D production in the skin. Due to the generally poor Vitamin D status of the population in Germany the DGE has recently increased the Vitamin D intake recommendations for pregnant women from 5 micrograms (200 International Units, IU) to 20 micrograms (800 IU) per day but only if no endogenous Vitamin D synthesis occurs in the skin.

In Germany, there has been no reliable data to assess the supply of Vitamin D in pregnancy because investigation on its levels in the blood is required and this research is expensive and not routinely performed.

An adequate supply of Vitamin D is important for both mother and child as many studies suggest a link between poor Vitamin D status in pregnancy and the occurrence of complications during pregnancy, which can include: diabetes mellitus, hypertension, infection and preterm birth. The risks for newborns relate to an insufficient bone structure, lung disease and also diabetes mellitus.

Due to the alarming data revealed in the Giessen study, Prof. Kunz argues for a routine examination of the Vitamin D status in pregnant woman. This should be done by measuring 25-hydroxyvitamin D in the blood, the form in which Vitamin D is stored, and the status of this is the best way to determine the presence of the vitamin. Prof. Kunz states that once the insufficiency is diagnosed pregnant women should take supplements containing Vitamin D. Furthermore, based on the results of the study, he recommends pregnant women should take these precautions particularly in the winter months.

The International Osteoporosis Foundation, the Canadian Osteoporosis Society and the Endocrine Society defines 25-hydroxyvitamin D levels of less than 50 nanomoles per liter (nmol /l) or less than 20 nanograms per milliliter (ng/ml)  as a Vitamin D deficiency. The Giessen study shows that around 50 percent of the women had a classified Vitamin D deficiency in the summer.

The most important factor influencing the Vitamin D status of the women was thought to be the time of year, as the supply of Vitamin D through diet is very low and the greater part is produced by  UV-B rays of the sun in the skin, from October to March. However, the intensity of sunlight in Germany is too weak to provide enough Vitamin D for the body. Therefore, it is necessary to increase the intake of Vitamin D via supplements. The implementation of this in everyday life is not easy, as packaging inserts in Vitamin D tablets often warns against an excessive intake while pregnant. Prof. Kunz believes that the relevant regulatory authorities need to intervene: “Without changing the rules, a better Vitamin D status and thus a lower risk for pregnant women and their children is hard to achieve. An overdose is not likely as the Vitamin D supplied, either as a tablet or produced in the skin, is not effective as such. The active form is produced by the body in the kidney – but only if there is a need and if it is not needed then Vitamin D remains inactive and is broken down and excreted “.

The research will now move on to an observation study in pregnant women that have been medically diagnosed with Vitamin D deficiency and whether the daily intake of 1,000 IU of Vitamin D during pregnancy is sufficient to ensure the required supply

Publication

Wuertz C, Gilbert P, Baier W, Kunz C (2013):

Cross-sectional study of factors did influence the 25-hydroxyvitamin D status in pregnant women and in cord blood in Germany, British Journal of Nutrition

This paper is freely available online for 2 weeks after publication via the following link

http://journals.cambridge.org/bjn/giessen

Notes:

Involved in this study, gynecological surgeries are Sabine Fink, Kerstin Schröder, Klaus-Dieter Fleck, Peter Gilbert (St. Josefs Hospital, Giessen) and Prof. Dr. Dr.hc. Hans-Rudolf Tinneberg (Obstetrics and Gynecology, University Hospital Giessen and Marburg).

Contact

Prof. Dr. Clemens Kunz

E-mail: clemens.kunz(at)uni-giessen.de

via Vitamin D deficiency in pregnant women and Newborn infants « Journals in the News « Cambridge Journals Blog.

AUB-L – When is the leiomyoma the culprit?

Blog Post by Malcolm G. Munro MD, FACOG, FRCS(c), Professor, Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Director of Gynecologic Services, Kaiser Permanante, Los Angeles Medical Center, Los Angeles, CA, USA

I frequently am approached by surgically ambitious residents (registrars) with a pitch that goes something like this:

“I have a 47 year old patient with menometrorrhagia from a 13 week size symptomatic fibroid uterus who wants a hysterectomy. When can we do it?”

Typically the patient hasn’t been adequately investigated as the assumption is that the leiomyomas (fibroids), detected with some combination of manual examination and ultrasound are indeed the cause of the abnormal bleeding – this, coupled with an irrational exuberance for surgery, results in a patient who “wants” a hysterectomy. So what is wrong with this story?

In the United States, at least, by the age of 50, leiomyomas are present in almost 70 per cent of Caucasians and more than 80 per cent of women of African ancestry. (1) Since most of these women don’t have any symptoms, an astute observer should conclude that most “fibroids” are asymptomatic. So when the symptom of abnormal uterine bleeding (AUB) occurs in a woman who can be demonstrated to have leiomyomas, the clinician should be challenged to distinguish AUB that is caused by the myomas from that which occurs for other reasons. Those familiar with the varied causes of AUB in the reproductive years, detailed in FIGOs new classification system, will recognize that there are a large number of potential entities, both structural, and those unrelated to visible pathology, that could coexist with asymptomatic leiomyomas and be the actual cause of the abnormal bleeding.(2) So, you might ask, if that is the case, which leiomyomas contribute to AUB and which do not?

To answer this, we should look to the FIGO system, which has a subclassification for leiomyomas. When a woman presents with AUB and is found to have one or more submucous leiomyomas (Types 0, 1, & 2), she is categorized as having AUB-Lsm; if the endometrial cavity is normal, meaning that none of the leiomyomas distort the cavity by deviating the endometrium (Types 3-8), she is categorized as having AUB-Lo (“o” standing for other leiomyomas or those outside the endometrial cavity). While we need more well-designed studies, the present hypothesis is that the leiomyoma likely must directly contact the endometrium for the lesion to contribute to the AUB; in other words, the leiomyoma must be submucous in location, a circumstance that can be noted in the FIGO system as “AUB-Lsm”.

What is the evidence for such a relationship? Until recently, most of the evidence was indirect, with studies showing that removal of submucous leiomyomas resulted in the predictable improvement in the symptom of heavy menstrual bleeding. However, more recently, we are beginning to assemble the molecular puzzle, as it is apparent that leiomyomas manufacture factors such as TGF-Beta3 that can impact the endometrium, if it is nearby, by interfering with the action of the unlikely substance bone morphogenetic protein (BMP), that adversely impacts some of the mechanisms involved in local control of menstrual bleeding.(3) It takes little imagination to see that if the leiomyoma is remote from the endometrium, such an impact would be reduced or eliminated altogether.

So when we interview the resident’s patient with a structured history, we frequently find that indeed the patient has the irregular bleeding typically associated with an ovulatory disorder (AUB-O) and, despite the presence of Type 4 and 5 leiomyomas, evaluation with office hysteroscopy, contrast sonography or MRI, demonstrates a normal endometrial cavity. In such instances, the endocrine etiology of the problem is amenable to a host of medical interventions including combination oral contraceptives and cyclical or continuous progestins – and, such patients may even have a discernable and treatable cause of the anovulation, ranging from hypothyroidism, obesity or personal stress. Alternatively, the hysteroscopy or contrast sonography might identify a polyp or smaller Type 0 or 1 lesion that can be removed easily, often in the office. So the patient’s options are frequently are far more numerous than hysterectomy, and often safer and relatively painless. So just because you find leiomyomas in a woman with AUB, doesn’t mean that the two are related – taking the time to critically evaluate all the potential contributors to the symptom of AUB may relieve your patient from the unlikely notion of “wanting” a hysterectomy.

More about AUB-L can be found in the book Abnormal Uterine Bleeding, from Cambridge Medical Press.(4)

1. Day Baird D, Dunson DB, Hill MC, Cousins D, Schectman JM. High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. Am J Obstet Gynecol. 2003;188:100-7.
2. Munro MG, Critchley HO, Broder MS, Fraser IS. FIGO classification system (PALM-COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age. Int J Gynaecol Obstet. 2011;113:3-13.
3. Sinclair DC, Mastroyannis A, Taylor HS. Leiomyoma simultaneously impair endometrial BMP-2-mediated decidualization and anticoagulant expression through secretion of TGF-beta3. The Journal of clinical endocrinology and metabolism. 2011;96:412-21.
4. Munro MG. Abnormal Uterine Bleeding. Cambridge: Cambridge University Press; 2010.

How Common is AUB-C?

Blog Post by Malcolm G. Munro MD, FACOG, FRCS(c), Professor, Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Director of Gynecologic Services, Kaiser Permanante, Los Angeles Medical Center, Los Angeles, CA, USA

Among the varied causes of the symptom of heavy menstrual bleeding (HMB) in reproductive aged women are congenital disorders of hemostasis, commonly called coagulopathies. In the new FIGO PALM-COEIN classification system for causes of AUB in the reproductive years, such women are categorized as having AUB-C.(1) While there exist a number of such entities, by far, the most common is von Willebrand disease (vWD), a disorder that has a mean prevalence of about 13% in women of all ages with HMB.(2) There exist three recognized variants of vWD; the majority has the mild Type 1 form that can only be diagnosed with certainty using specific testing for von Willebrand factor (vWF). Type 2 vWD is a quantitative deficiency where vWF levels are typically 10-45% of normal while Type 3 is a serious deficiency that adversely impacts hemostasis even in the face mild injury or menses. Other less common factor-based coagulopathies are caused by deficiencies in Factors II, V, VII, VIII, IX, X, XI and XII. Of course, AUB-C can be also caused by iatrogenic means secondary to the use of anticoagulants. Because it is not clear to what degree the mild variants of inherited coagulopathies contribute to symptom of HMB in a given woman it is important to always perform a complete evaluation considering all of the elements in FIGO’s PALM-COEIN classification system.

AUB-C may present initially at menarche, when the adolescent, perhaps for the first time, has to attain satisfactory hemostasis over a large bleeding surface – the endometrium. The problem can be compounded because at menarche, many, if not most, such bleeds are anovulatory, where the endometrium is already deficient in endometrial vasoconstrictors such as PG F2-α and endothelin-1 that are largely dependent on the production of progesterone. When added to the delay in presentation fostered by the embarrassment and immaturity of the typical adolescent, menarcheal girls with von Willebrand disease and other disorders of systemic hemostasis are at great risk for a serious episode of HMB. Indeed, one study has reported that almost 20% of young girls who presented in the emergency department with acute HMB have AUB-C. (3)

So how does one diagnose AUB-C? The first step is to have a high index of suspicion. So when an adolescent presents around menarche with acute HMB, steps should be taken to evaluate for a systemic disorder of hemostasis. For other women, there is evidence that a structured history can identify about 90% of the women with laboratory evidence of von Willebrand disease. Any woman with lifelong heavy menstrual bleeding is at risk, as are those with a family history, or with a personal history of frequent bruising, bleeding with brushing teeth or unexplained bleeding associated with childbirth or surgical procedures.(4, 5) For women who fail the screen, the process should start with non-specific assays including prothrombin time (PT), partial thromboplastin time (PTT), ABO blood type and Ivy bleeding time as well as more specific assays measuring vWF, Ristocetin co-factor and Factor VIII . Other assays such as those for platelet aggregation or more rare factor deficiencies can be obtained as appropriate, depending on the clinical situation, and the advice of a consulting hematologist. Of course, the evaluation of any individual with AUB, including HMB, should be performed considering focal lesions of the lower genital tract as well as the other potential contributors to the bleeding categorized in FIGO’s PALM-COEIN system, two of which (AUB-E and AUB-O) have been discussed in previous editions of this blog.

Treatment of women with AUB-C will vary according to the severity of the disorder, the desires regarding current and future fertility, and the response to simple interventions such as tranexamic acid and local or systemic progestin-containing regimens. More about AUB-C can be found in the book Abnormal Uterine Bleeding, from Cambridge Medical Press.(6)

1. Munro MG, Critchley HO, Broder MS, Fraser IS. FIGO classification system (PALM-COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age. Int J Gynaecol Obstet. 2011;113:3-13.
2. Shankar M, Lee CA, Sabin CA, Economides DL, Kadir RA. von Willebrand disease in women with menorrhagia: a systematic review. BJOG. 2004;111:734-40.
3. Claessens EA, Cowell CA. Acute adolescent menorrhagia. American journal of obstetrics and gynecology. 1981;139:277-80.
4. Kadir RA, Economides DL, Sabin CA, Owens D, Lee CA. Frequency of inherited bleeding disorders in women with menorrhagia. Lancet. 1998;351:485-9.
5. Kouides PA, Conard J, Peyvandi F, Lukes A, Kadir R. Hemostasis and menstruation: appropriate investigation for underlying disorders of hemostasis in women with excessive menstrual bleeding. Fertil Steril. 2005;84:1345-51.
6. Munro MG. Abnormal Uterine Bleeding. Cambridge: Cambridge University Press; 2010.

Munro MG. Abnormal Uterine Bleeding. Cambridge: Cambridge University Press; 2010.

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