Cardiomyopathy :: Postpartum Cardiopulmonary a dangerous compl-A nightmare for all of us,. Comes suddenly like a thunder or atonic PPH.

PQ.1 . What is the definition of Peripartum cardiomyopathy-Ans;-Postpartum cardiomyopathy, also known as peripartum cardiomyopathy (PPCM), is defined as new onset of heart failure between the last month of pregnancy and 5 months post delivery with no determinable cause. First described in a case series in 1937. Postpartum cardiomyopathy is a rare cause of heart failure.

Q.2: How severe is this uncommon compl  ? Ans:-Postpartum cardiomyopathy is a
dreaded complication of pregnancy  and if left untreated there  will be 100% mortality. May be we have missed some cases in our lifetime and written as amniotic Fluid embolism or Pulm embolism in death certificate

Q,. 3. What are the symptoms?? Ans . Such features are exhibited clinically by unexplained tachycardia, breathless, low O2 saturation, and basal crepitations (all were present in this case)   
. Q. 4. Time of onset of PPCM Ans:-Most patients present soon after delivery especially in the first week postpartum. The symptoms as mentioned earlier are suggestive of heart failure, for example, orthopnea and paroxysmal nocturnal dyspnea.  In antenatal period (not in this case) these symptoms are usually attributed to normal pregnancy and that is why a diagnosis of postpartum cardiomyopathy can be easily missed.

Q.5: What are the signs?? Ans:- There will be sudden  onset of tachycardia, elevated jugular venous pressure, bilateral pulmonary crackles due to pulmonary edema, third heart sound (S3) and displaced apical pulse. Severe cases may present with acute respiratory failure( as was typical in this case)  or cardiogenic shock and a need for close monitoring in the intensive care unit. 

Q.6:-What are the risk Factors??

·         1) Advanced maternal age (more cases reported in both extremes of age) 

·        2)  High parity (71% of women diagnosed with PPCM had three or more prior pregnancies) 3) ·         Twin pregnancy (more endemic in women with twin pregnancies)

·          4) Use of tocolytic therapy (greater than 4 weeks can cause silent ischemia)-a great warning to all of us.

·         

5)        Poverty 6)      Hypertension 7) such cardiomyopathy is more prevalent in association with mild PIH. & 8) in cases with increased liquor  for reasons not clear to us 9) PGF2alpha

·         

Q. 7:-What about ECG?? ECG may show non-specific changes like sinus tachycardia, interventricular delay and sometimes, LBBB pattern and Echocardiography suffices to differentiate it from other causes and usually shows left ventricle dilatation of variable degrees, left ventricle systolic dysfunction, right ventricular and bi-atrial enlargement, mitral and tricuspid regurgitation, and pulmonary hypertension..

Q. 8: What about Echo?  Echocardiography criteria to diagnose PPCM includes ejection fraction less than 45%,(this was however present in this case) , end-diastolic diameter greater than 2.7 cm/m2 and/or M-mode fractional shortening less than 30%.

 used to diagnose when an accurate estimation of the ejection fraction (EF) is required.

Q. 9 . What should be the ideal Treatment??

Treatment is usually supportive and directed toward the management of the heart failure symptoms. Standard heart failure therapy is used to optimize the patient's volume status. Beta-blockers and ACEIs are the most commonly used drugs and have shown to lower the mortality. The caveat is ACEI is contraindicated in pregnant patients. Diuretics are often used to ease symptoms related to heart failure(this life saving agent was very rightly used in this case) . Novel anti-heart failure medications, such as sacubitril/valsartan have been reported to improve heart failure symptoms in pregnancy-related cardiomyopathy but the decision to prescribe such modern agents are best left to Internist/In charge of ICU..

 Q. 8. What is the presumed etiology?? Ans:-Recent data suggest that an increase in oxidative stress during the peripartum period increases the formation of abnormal 16-kDa prolactin which induces toxic effects on cardiac myocyte. Bromocriptine, a dopamine receptor agonist with prolactin-blocking properties, decreases the effect of 16-kDa prolactin on cardiac myocyte and has been associated with better outcomes in small studies. Cardiac resynchronization therapy has also shown to improve ejection fraction and outcomes when medical therapy alone is ineffective. 

Relevance of normal loci in Yq11 position( q means long arm of chromosome) & normal Spermatogenesis ??

Relevance of  normal loci in Yq11 position( q means long  arm   of chromosome) & normal Spermatogenesis ?? Spermatogenesis  is governed by long arm of the Y chromosome AS such if there is changes in Y chromosome i.e. in the form of Yq11Microdeletion of the azoospermia factor (AZF) region located on the long arm of the Y chromosome (Yq11) is considered the most common genetic cause of male infertility . However, Y microdeletions can be transmitted from infertile fathers to their male offspring, who could also experience infertility, through the procedure of ICSI. Thus, it is important to evaluate Y microdeletions in male infertility before assisted reproduction in order to provide appropriate information to patients.The AZF region is divided into three nonoverlapping subregions called AZFa, AZFb, and AZFc, all of which are required for normal spermatogenesis. Microdeletions in these three regions are associated with various spermatogenetic alterations including Sertoli cell-only syndrome (SCOS), maturation arrest, and hypospermatogenesis. Specifically, microdeletion of AZFa is relevant to complete SCOS and azoospermia. The absence of AZFb is associated with maturation arrest at meiosis, whereas microdeletion of AZFc results in variable clinical and histologic phenotypes, ranging from oligozoospermia to SCOS . Extensive studies have been carried on Y microdeletions in non-obstructive azoospermic and severely oligozoospermic patients, with a reported incidence ranging from 3% to 28%. Therefore, disruption of AZF can be viewed as the most common molecularly diagnosable cause of spermatogenic failure in the setting of non-obstructive azoospermia or severe oligozoospermia .

Recently, the techniques of testicular sperm extraction (TESE) and intracytoplasmic sperm injection (ICSI) have made it possible to help men with azoospermia or severe oligozoospermia to achieve successful fertilizations and pregnancies . However, Y microdeletions can be transmitted from infertile fathers to their male offspring, who could also experience infertility, through the procedure of ICSI. Thus, it is important to evaluate Y microdeletions in male infertility before assisted reproduction in order to provide appropriate information to patients.

Micro Deletin of genes rsponsible for sperm production with rsulatant azoospermia

Y chromosome: Deletion of one particular  segment of Y chromosome i.e., long arm of the Y chromosome (Yq11) is considered the most common genetic cause of male infertility .

 : How relevant to us?? It will be prudent to do for genetic test ( Micro deletion of a particular segment in Y chromosome ) of those  male partner who are being selected for ICSI due to a)  azoospermia  or b) NOA i.e. nonobstructive azoospermia. Lets view briefly  how prevalent is  Y chromosome Microdeletions in Infertile Men with Non-obstructive Azoospermia and Severe Oligozoospermia. Y chromosome microdeletion is a major genetic cause of primary male azoospermia. Detection of Y chromosome microdeletions is of great use for guiding clinical diagnosis, helping selecting treatment schemes, and reducing the incidence of genetic diseases. In the following Post New Year day discussions  the importance of Y chromosome microdeletion screening and genetic counseling is strongly emphasized for infertile men prior to employment of assisted reproduction techniques.

 Many research works were carried out by andrologist to investigate the frequencies and types of Y chromosome microdeletions in infertile men and to analyze the relationship between the levels of reproductive hormones and Y microdeletions. The most commonly cited  study summary is as follows:-

A total of 1,226 infertile men were screened for A)  Y chromosome microdeletions using multiplex PCR assay..Further,  B) Karyotype analysis was also  performed on peripheral blood lymphocytes with standard G-banding. C) Serum reproductive hormone levels were measured. Out of 1226 such men as many as 11% had Y microdeletions To put in other way round, as  many as 14% of NOA and 20% of Oligozoospermia men had such Y microdeletions in particular segment .The portion of Y chromosome which regulates sperm production is called AZF(Azoospermic Factor) segment / portion of Y chromosome ,It contains several genes which are again located in different loci in that segment  . The most frequent microdeletions were detected in the AZFc region, followed by AZFbc, AZFb, AZFa, AZF abc(Yq), Yp(SRY)+Yq, and partial AZF c regions. Levels of FSH and LH in patients with AZFc microdeletion were significantly lower, Out of all azoospermic men & OAT as many as 28% had sex chromosomal, abnormalities. There is a need for Y chromosome microdeletion screening prior to ICSI or any there ART (where there is Azoospermia or severe OAT)  for correct diagnosis of male infertility. Obtaining reliable genetic information for assisted reproductive techniques can prevent unnecessary treatment and vertical transmission of genetic defects to offspring. Microdeletion of the azoospermia factor (AZF) region: It is a genetic diseases  Microdeletions of the azoospermia factor (AZF) region located on the long arm of the Y chromosome (Yq11) is considered the most common genetic cause of male infertility .

The AZF region is divided into three nonoverlapping subregions called AZFa, AZFb, and AZFc, all of which are required for normal spermatogenesis.

Y Chromosome Microdeletions in Infertile Men with Non-obstructive Azoospermia and Severe Oligozoospermia is an important issue to geneticists prior to ART in case of azoospermia as important a is with Cong Vas Obstruction (cystic fibrosis).

Can microdeletion of Y chromosome be a cause of Rec Preg Losss ??

Microdeletion of sperm producing Y chromosome –as a cause of RPL  --- Is is a dream or reality??

It is worth remembering that Different   micro deletions have deleterious  effects  in different  aspects   of male fertility More informations  on Microdeletion of  a segment of long arm of Y chromosome . That particular segment i.e. –the long arm segment contains many loci (full of genes ) whose duty  is entrusted for  sperm production,.  Micro deletions of the chromosome Y long arm are the most frequent molecular   genetics of severe   male infertility , mainly   by presence of   severe oligozoospermia and non obstructive azoospermia . Nowadays   these genetic    alterations could be screened   as routine   which is important since  they are present  in approximately in 9% of the oligo azoospermia males.

At the molecular   level   Y chromosome  micro deletions affect at least three regions known   as azoospermia factor    these  three regions  are essential   for a   successful spermatogenesis.. It is of note though   the AFZ cv 2/64   deletions since men carrying   them produce    a higher percentage   of nullisomy for the sex    chromosome   and NY   disomy  .

Query to learned members: Can there be   a link between male   carriers of Y  chromosome    deletions and RPL(Rec Preg losses) ?? I don’t know. Any member like to volunteer pl??    . In fact Dewan et al in 2006  observed that in couples  with RPL  a significant percentage   of the  males   had chromosome Y  micro deletions . Another   study   carried out by Agarwal et al in 2015   stated that in couples suffering  RPL  32.5% of males  were carriers of chromosome Y  micro deletions  and after excluding  the female  factor  in 13. 5%   of the cases. Interestingly the most  frequent   micro deletion was the AZFc.  The incidence of    chromosome Y   micro deletion   is different in different  population    since is linked  to chromosome  Y  haplogroups  . In fact Venkatesh et al   did not  detect   any micro deletion  in a population of RPL  in New Delhi.

Nevertheless taking  in account  the population  that one is dealing the prevalence of microdeletion as an cause of RPL may vary . Is that also the members opinion. PL share your views This will be a later date which will offer a relationship of AZF deletions and its etiology as RPL besides cong thrombophilia and  other genetic causes of Post embryonic growth & development aberrations. A day may come when we the treating gynecologist  may ask cases of RPL for AZF deletion in male partner . Till then let’s hope that that micro deletions in chromosome Y   may not be a  cause  of RPL  so that

The unfortunate male is exempted from study    of such    chromosomal   abnormalities   in cases of RPL & idiopathic abortion

Prevalence of male subfertility ? Prevalence of Y chromosome micro deletion amongst azospermic men,

Prevalence of male subfertility ? Infertility is defined as failure to conceive after one year of unprotected sexual intercourse .This problem affects approximately 10%–15% of couples worldwide, and male-related factors are responsible for half of this case . Several factors have been implicated in male infertility such as  Cause :1) hormonal abnormalities, Cause :2 ) erectile dysfunction, Cause :3) infections, Cause :4 )  antisperm antibodies, Cause :5) exposure to chemical agents and radiations, Cause :6)  testicular cancer, Cause :7) varicocele, Cause :8) genetic factors, and Cause :9) others .Thus, male infertility is a multifactorial syndrome encompassing a wide variety of disorders. However, in about 30%–50% of male cases, the etiology of infertility is still unknown.

Sertoli cell-only syndrome (SCOS), maturation arrest, and hypospermatogenesis à The main culprit is “Microdeletion of the azoospermia factor (AZF) region located on the long arm of the Y chromosome (Yq11)”. This is  considered the most common genetic cause of male infertility .The AZF region is divided into three nonoverlapping subregions called AZFa, AZFb, and AZFc, all of which are required for normal spermatogenesis. Microdeletions in these three regions are associated with various spermatogenetic alterations including Sertoli cell-only syndrome (SCOS), maturation arrest, and hypospermatogenesis. Specifically, microdeletion of AZFa is relevant to complete SCOS and azoospermia. The absence of AZFb is associated with maturation arrest at meiosis, whereas microdeletion of AZFc results in variable clinical and histologic phenotypes, ranging from oligozoospermia to SCOS Extensive studies have been carried on Y microdeletions in non-obstructive azoospermic and severely oligozoospermic patients, with a reported incidence ranging from 3% to 28% Therefore, disruption of AZF can be viewed as the most common molecularly diagnosable cause of spermatogenic failure in the setting of non-obstructive azoospermia or severe oligozoospermia Recently, the techniques of testicular sperm extraction (TESE) and intracytoplasmic sperm injection (ICSI) have made it possible to help men with azoospermia or severe oligozoospermia to achieve successful fertilizations and pregnancies .However, Y microdeletions can be transmitted from infertile fathers to their male offspring, who could also experience infertility, through the procedure of ICSI. Thus, it is important to evaluate Y microdeletions in male infertility before assisted reproduction in order to provide appropriate information to patients.

Y chromosome microdeletions can be detected by using multiplex polymerase chain reaction (PCR) in infertile men. Moreover, the relationship between the levels of reproductive hormones and Y chromosome microdeletions has to be analyzed.

Male Factor subfertility

History of a male parner in an infertile couple   

Duration of infertility.

1.     Erectile and ejaculatory function along with coital frequency and timing are important. Awareness about the ovulation time, can significantly affect fertility outcomes.

2.     Surgery for hernia, or other surgery which may affect ejaculation, like orchidopexy, hernia repair, testicular torsion, testicular trauma, retroperitoneal lymph node dissection for testicular tumours and bladder neck surgery should be noted.

3.     Neurological and psychological conditions could also affect the ability to ejaculate. Infections like mumps related orchids and smallpox are associated with impaired spermatogenesis. Any infection or febrile illness is also associated with abnormal semen analysis, for up to 6 months.

4.      Delayed onset of puberty and gynecomastia may be associated with endocrine and chromosomal abnormalities and should be asked for.

Examination

1.      Detailed general examination, to identify develop­ment of secondary sexual characteristics, is important.

2.      Genetic and hormonal causes may be identified by physical features unique to them.

3.      Examination of the genitalia

•      Assessing the size and the consistency of the testes, including measurement using an orchidometer, gives an idea about possible atrophy, indicating that the seminiferous tubules are inadequate.

•      Palpation of the epididymis and the vas deferens helps in establishing any obstruction to the passage of sperms from the testes

•      Examination of the spermatic cords will identify the presence and grade of varicocoele.

4.      Digital rectal examination

•      It identifies any cystic dilatation of the seminal vesicles and ejaculatory ducts

•      Tenderness in this area helps to identify prostatic infections.

Male chromosome defect may be the cause of Recurrent abortion: Microdeletion

  Y  micro deletions  ::Do you believe if I say that couples suffering RPL 32.5% of males were carriers of chromosome Y  micro deletions  and after excluding  the female  factor  in 13. 5%   of the cases. Y Micro deletions : Do U honestly believe that there is a link between RPL and male   carriers of   Y  chromosome    deletions ??  What is your view??

What is meant by azoospermia factor    ?    Molecular   genetics of severe   male infertility, % of the oligo azoospermia males. Can    Y  chromosome    deletions  may lead to  RPL that in couples suffering RPL 32.5% of males were carriers of chromosome Y  micro deletions  and after excluding  the female  factor  in 13. 5%   of the cases .

Male Carriers of Chromosome Y Micro deletions

Severe   male infertility: can it be  due to micro deletions of the chromosome of Y long arm?? Ans: Yes.  It is quite possible. Microdeletion of Y arm of a male are the most frequent abnormal molecular   genetics of severe   male infertility . Such are  mainly exhibited    by the presence of   severe oligozoospermia and non obstructive azoospermia  Nowadays   these genetic    alterations could be screened   as routine   which is important since  they are present  in approximately in 9% of the oligo azoospermia males(OAT) .

At the molecular   level   Y chromosome microdeletions affect at least three regions known   as azoospermia factor     regions. All these three regions of Y chromosome are important in sperm production. Therefore to sumarize these three regions  are essential   for a   successful spermatogenesis. Different   micro deletions have deleterious effects  in different  aspects   of male fertility . It is of note though   the AFZ cv 2/64   deletions since men carrying   them produce    a higher percentage   of nullisomy for the sex    chromosome   and NY   disomy  . There is a link between male   carriers of   Y  chromosome    deletions and RPL   was suggested  . It has been observed that in couples  with RPL  a significant percentage   of the  males   had chromosome Y  micro deletions . Another   study   carried out by Agarwal et al in 2015   stated that in couples suffering RPL 32.5% of males were carriers of chromosome Y  micro deletions  and after excluding  the female  factor  in 13. 5%   of the cases. Interestingly the most  frequent   micro deletion was the AZFc The incidence of    chromosome Y   micro deletion   is different in different  population    since is linked  to chromosome  Y  haplogroups  .But another study carried out at Delhi by  venkatesh et al   did not  detect   any micro deletion  in a population of RPL  in New Delhi.

Nevertheless taking  in account  the population  that we are  working  with  this novel data    suggests   that micro deletions in chromosome Y   could be the cause  of RPL  so the study    of these   chromosomal   abnormalities   could be offered to couples with idiopathic abortion .

De novo  Duplications / Deletions from Couples with Normal  Karyotype

Sporadic early  pregnancy loss    occurs  in   10-15%  clinically recognized  gestations. As  we have  mentioned   earlier  must of the cases of miscarriages are    due to full chromosomal   trisomies  or monosomies. Nevertheless  in some cases   the  cause of these   abortions could be submicroscopic  chromosomal changes like    duplications and / or   deletions  . The problems is that these structural  abnormalities  could  appear    de novo. This    mens that even though   parents   have a perfectly normal karyotype the embryos could carry   a dup/ del. In these cases the recurrence  risk would be  similar   to general    population  With   the introduction  by pre implantations genetic  testing  for aneuploidies for aneuploidy   screening   also in couples  with normal    karyotype  small dup /del   have been  indentified   in per implantation   embryos  also/ The introduction  of more accurate  techniques like array comparative genomic hybridization and Next   Generation seque3ncing enable the clinicians   the possibility  of  detecting   these small changes in the embryo  before    transfer   in IVF   couples