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FERTILITY
UPDATE
F ERTILITY U PDATE
August 2008 Vol 10 No 2
Alterations of the Y-Chromosome
and Male Infertility
Management of Prostate Pathology
Recurrent Implantation Failure:
The Therapeuatic Approach
Ovarian Hyperstimulation Syndrome (OHSS)
Are there predictive factors?
Rubella Virus: An Underestimated Pathogen in
Nigeria?
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FERTILITY
UPDATE
THE BRIDGE CLINIC PROFILE
T
he Bridge Clinic is Nigeria’s first focused assisted conception clinic. It was set up in collaboration with consultants from
the prestigious King’s College Hospital, London, in 1999 to make assisted conception treatment available in Nigeria.
We batched patients for treatment between 1999 and 2000 and during this period, the team from UK would come to Nigeria
and treat the batches. At the same time, we sent some staff to The King’s College Hospital to receive requisite training. The
team from King’s College was able to hand over to the Nigerian team by April 2001. Since then, the day-to-day operations of
the clinic have been run by the Nigerian team.
The science of reproduction is a rapidly advancing subject and in addition to the hands-on training received, we register our
embryologists in particular for the M.Sc programme at the University of Leeds. We have to date successfully trained 2
embryologists to M.Sc level and have a third in the programme
Furthermore, we have maintained our relationship with the King’s College Hospital and they attend regularly to audit the
activities of the clinic.
The Mission of The Bridge Clinic is to use our knowledge of the science of reproduction to provide hope for couples that
desire children.
God has supported our mission and to date; 756 babies have been born following treatment at the Lagos clinic. We have also
had the birth of 111 babies at our Port Harcourt clinic.
The first conception and live birth following Intracytoplasmic Sperm Injection (ICSI);
The first conception and live birth following ICSI with surgically collected sperms;
The first birth following in vitro Fertilisation (IVF) and gestational surrogacy;
The birth of a child of the desired sex for family balancing, following ICSI with ‘sorted’ sperm; and
The first clinic in West Africa to recieve a Certificate for implementing the ISO 9001: 2000 Quality Management System.
The Bridge Clinic, Lagos
Clinical Staff
Consultant Gynaecologists
Dr R A Ajayi
Dr A I Arilesere
Dr O Adeyemi-Bero
Board of Directors
Chief (Dr) O A Finnih - Chairman
Dr R A Ajayi - Managing Director
Dr F A B Coker
Dr (Mrs) P I Ajayi
Chief G K Animashawun
Mr Biodun Dabiri
The Bridge Clinic, Port Harcourt
Clinical Staff
Consultant Gynaecologists
Dr R A Ajayi
Dr P Feibai
Editorial Committee
Embryologists
Femi Akinrinola
Dayo Yussuf
Omonigho Osemeikhian
Lauretta Mbaeze
Segun Babatunde
Olajide Wilson
Client Coordinators
2
Simisola Akintujoye
Sandra Ahmed
Promise Ubali
Ebele Onwuagbaizu
China Mereghini
Patricia Ekechukwu
Abidemi Adesanya
Anita Uzowuru-Ajayi
Mary Olasore
Vol 10 No 2
Dayo Yusuf
Ebele Onwuagbaizu
Dr Femi-Adebayo
Embryologist (P.H)
Obianuju Ukoha
Client Coordinators (P.H)
Rachel Oga
Queen Ahiwe
Fortune Mgbekei
FERTILITY
UPDATE
Editorial
T
his is the first edition of Fertility Update which is completely electronic. We believe
we will have a wider coverage through this media.
If you will like to be on our mailing list, kindly send your e-mail address to
[email protected].
In this issue we discuss chromosomal abnormalities and male infertility. Another
topical issue is the management of prostate pathology and we talk about the latest
techniques available for this.
The success rates for IVF treatment is 25 – 30% and implantation failure contributes to
the high failure rate; the third article discuses this in detail.
The fourth article examines Ovarian Hyper-Stimulation Syndrome,
acomplication of IVF treatment which can be quite severe.
Earlier this year, there was an outbreak of Rubella in Northern Nigeria, the final article
discusses preventive measures for this disease.
Have an exciting read.
The Editor
P O R T HARCOURT
L AGOS
41A Evo Road, G.R.A. Phase II, Port Harcourt.
Plot 1397A Tiamiyu Savage Street, Victoria Island, Lagos.
TEL: +234 - 1 - 461 9006
TEL: +234 - 84 - 763 975, 793 531, 764 664, 465 003-5, 0702 814 2295
FAX: +234 - 84 - 231627
FAX: +234 - 1 - 461 2807
E --M
M A I L: [email protected]
W EBSITE: www.thebridgeclinic.com
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FERTILITY
UPDATE
Alterations of the Y-Chromosome
and Male Infertility
Omonigho Omolara OSEMEIKHIAN
Trainee Embryologist
THE BRIDGE CLINIC, LAGOS
Introduction
The human Y chromosome plays an essential role in human biology. The presence or
absence of this chromosome determines gender of an individual. Therefore,
mammalian embryos with the Y chromosome develop testis (male) while those without
it develop ovaries (females). 1 The Y chromosome is one of the smallest chromosomes
in the human genome and is divided into many portions as a result of cytogenetic
observations based on chromosome banding studies.2
Structure of the Y Chromosome
The Y chromosome (Fig.1) is divided into two arms
by a centromere, the short arm (p) and the long arm
(q). The terminals of both arms are referred to as
pseudoautosomal regions. These regions pair and also
exchange genetic materials with the pseudoautosomal
regions of the X chromosome during male meiosis.
Fig.1. The Human Y chromosome
Following the pseudoautosomal region of the long
arm is the heterochromatic region. This region is
assumed to be genetically inert and polymorphic in
length in different male populations. It is also the
portion that retains a record of mutational events that
have occurred along the male lineage throughout
evolution. This is because it is holoandrically
transmitted from father to son without recombination
during meiosis. All the other portions of the Ychromosome, apart from the pseudoautosomal regions
and the heterochromatic region are referred to as the
euchromatic region. This region consists of numerous
highly repeated gene sequences and also contains genes
responsible for male fertility.
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The Y Chromosome And Male Infertility
The occurrence of grossly cytogenetically detectable
and unexplained deletions in six azoospermic individuals, describing for the first time the role of the Y
chromosome in spermatogenesis, was reported in
1976.2 These observations led to the postulation of
the existence of a locus, called Azoospermic factor
(AZF), on the long arm of the Y chromosome (Yq), required for complete spermatogenesis since the seminal fluid of these
patients did not contain mature spermatozoa. The location of AZF in Yq was further
confirmed by numerous studies at cytogenetic and molecular level.3 4 5
The original AZF region was further
subdivided into three different non-overlapping sub
regions on Yq, all associated with male infertility.6
They were named AZFa, AZFb, and AZFc regions. Each
of these regions contains several genes proposed as
candidate genes involved in male factor infertility.
The AZFa region is located in the proximal Yq.
Several genes have been identified in this region and
only the Drosophila Fats Facets Related Y (DFFRY)
gene or Ubiquitin-specific protease (USP9Y) gene has
been proposed to play a role in gametogenesis. It
encodes a protein involved in deubiquitination (the
process by which proteins are tagged for degradation)
and mutations in Drosophila homologue of the gene
cause a sterile phenotype. 7 8
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The AZFb region follows immediately after the
AZFa region and has been estimated to be of the same
molecular extension as the AZFa region (1-3Mb). Five
genes have been described within this region among
which only three are related to male infertility. The
RNA binding motif gene (RBM gene) encodes germ
cell specific nuclear proteins containing RNA-binding motif and it is present in multiple copies along
the Y chromosome. However, not all of these copies
are functional and most may be pseudo genes. It has
been strongly proposed as a candidate infertility gene
since its expression is testis-specific, it is recurrently
deleted in azoospermic men and it seems to be specifically expressed in spermatogonia and primary
spermatocytes. 9 10 The two other genes expressed
specifically in adult testis which are also recurrently
deleted in infertile males are the Chromodomain Y
(CDY) gene and the XK Related Y (XKRY) gene.
The AZFc region is located in the proximity of the
heterochromatin region and its molecular extension
is about 500Kb.11 The Deleted in Azoospermia (DAZ)
gene cluster is located in this region and encodes a
testis specific RNA binding protein.11 There are at least
six to nine copies of the DAZ gene in this region and
although it has been proposed as the cause of the
AZFc phenotype, other genes must be involved since
deletions within AZFc region without including DAZ
have been recently reported. 12 13 14
The other genes identified within this region, PTPBL Related Y (PRY) gene, Basic Protein Y2 (BPY2) gene,
and Testis Transcript Y2 (TTY2) gene, also present a
testis-specific expression and are present in multiple
copies on the Y chromosome.
Although the exact interrelationship between spermatogenesis and the coding sequence for these
Deleted Region
(Genotype)
AZFa
AZFb
AZFc
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particular regions remain ambiguous, research has
linked particular AZF deletions with observable
changes in the spermatogenetic process (Table 1)
Additional genes affecting spermatogenesis both
within the Y chromosome and along other
chromosomes are possible, further complicating the
etiology. Genetic screening of male infertility patients
and their offspring demonstrated the heritability of
micro-deletions in their Y-chromosomes.
Further research has substantiated that all males
with micro-deletions will either pass on those same
micro-deletions or even larger mutations to their male
children.6 This can be as a result of either aberrant
crossover events or unbalanced sister chromatid
exchange during meiosis. These deletions can in rare
cases be passed on through sexual intercourse and
can certainly be passed on using assisted reproductive
techniques, such as intrauterine insemination (IUI),
in vitro fertilization (IVF), and intracytoplasmic sperm
injection (ICSI). 15 16 17
Clinical Implications of Y Chromosome Deletions
There is currently no treatment to improve fertility
in men with Y-chromosome deletions. However,
knowledge of a Y-chromosome micro deletion is
useful for several reasons. First, detection of a Ychromosome deletion provides a diagnosis for
infertility, and patients usually want to know why they
are infertile. Second, a diagnosis of a Y-chromosome
micro deletion allows the physician to forego
empirical treatments and to direct the patient to
assisted reproduction or adoption.
Perhaps the knowledge of Y-chromosome micro deletions will allow couples that go on to conceive by
assisted reproduction techniques inform their male
children of their potential fertility
challenges. This is because there is a
Table 1
high possibility that at a later age, they
might experience infertility. With
Effect
prior knowledge of a Y-chromosome
(Phenotype)
micro deletion, the child’s male factor
Oligozoospermia or spermatogenic
infertility need not be a surprise, as it
arrest
probably was from his father, but
Azoospermia, Oligozoospermia or
rather an expected problem for which
normal sperm counts with
appropriate counselling and planning
teratozoospermia
may be done in advance.
Azoospermia or Oligozoospermia
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Conclusion
Research into male infertility remains productive and
continuous. Investigations to determine the origin and
transmission of mutations, as well as the refinement
of the epidemiological parameters related to infertility should be encouraged. In the nearest future, researchers should eventually be able to correct
congenital birth defects. Although the exact etiology
remains highly complex, the replacement of mutated
strands of the Y-chromosome through advanced gene
therapy may prove to be useful in the restoration of
male fertilization potential at the genetic level.
References
1. Polani, P.E. (1981) Experiments on chiasmata and
nondisjunction in mice. Hum Genet Suppl., 2, 145-146.
2. Tiepolo, L., Zuffardi, O. (1976) Localization of factors controlling spermatogenesis in the nonflourescent
portion of the human Y chromosome long arm. Hum
Genet. 34, 119-124.
3. Ferguson-Smith, M.A., Affara, N.A., Magenis, R.E.
(1987) Ordering of Y-specific sequences by deletion
mapping and analysis of X-Y interchange males and
females. Development Suppl., 101:41–50.
4. Anderson, M., Page, D.C., Pettay, D. et al. (1988)
Y autosome translocations and mosaicism in the
etiology of 45, X maleness: assignment of fertility
factor to distal Yq11. Hum Genet., 79:2–7.
5. Bardoni, B., Zuffardi, O., Guioli, S. et al. (1991) A
deletion map of the human Yq11 region: implications
for the evolution of the Y chromosome and tentative
mapping of a locus involved in spermatogenesis.
Genomics., 11:443–451.
6. Vogt, P.H., Edelmann, A., Kirsh S. et al. (1996)
Human Y chromosome azoospermia factors (AZF)
mapped to different subregions in Yq11. Hum Mol
Genet., 5:933–943.
7. Fischer-Vize, J.A., Rubin, G.M., Lehmann, R. (1992)
The fat facets gene is required for Drosophila eye
and embryo development. Development. 116:985–
1000.
8. Brown, G.M., Furlong, R.A., Sargent, C.A. et al.
(1998) Characterisation of the coding sequence and
fine mapping of the human DFFRY gene and
comparative expression analysis and mapping to the
Sxrb interval of the mouse Y chromosome of the
DFFRY gene. Hum Mol Genet. 7:97-107.
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9. Ma, K., Inglis, J.D., Sharkey, A. et al. (1993) A Y
chromosome gene family with RNA-binding protein
homology: candidates for the azoospermia factor AZF
controlling spermatogenesis. Cell., 75:1287–1295.
10. Eliott, D.J., Millar, M.R., Oghene, K. et al. (1997)
Expression of RBM in the nuclei of human germ cells
is dependent on a critical region of the Y chromosome
long arm. Proc Natl Acad Sci USA., 94:3848–3853.
11. Reijo, R., Lee, T.Y., Salo, P. et al. (1995) Diverse
spermatogenic defects in humans caused by Y chromosome deletions encompassing a novel RNA-binding protein gene. Nat Genet., 10:383–395.
12. Stuppia, L., Mastroprimiano, G., Calabrese, G. et
al. (1996) Microdeletions in interval 6 of the Y chromosome detected by STS-PCR in 6 of 33 patients with
idiopathic oligoand azoospermia. Cytogenet Cell
Genet., 72:155–158.
13. Najmabadi, H., Huang, V., Yen, P. et al. (1996)
Substantial prevalence of micro deletions of the Ychromosome in infertile men with idiopathic
azoospermia and oligospermia detected using a
sequence tagged site based mapping strategy. J Clin
Endocrinol Metabol., 81:1347–1352.
14. Foresta, C., Ferlin, A., Garolla, A. et al. (1997) Ychromosome deletions in idiopathic severe
testiculopathies. J Clin Endocrinol Metabol., 82:1075–
1080.
15. Kent-First, M.G., Kol, S., Muallem, A., Ofir, R.,
Manor, D., Blazer, S., First N. and Itskovitz-Eldor, J.
(1996b) The incidence and possible relevance of Ylinked microdeletions in babies born after intracytoplasmic-sperm injection and their infertile fathers.
Mol Hum Reprod., 2:943-950.
16. Mulhall, J.R., Reijo, R., Alagappan, R., Brown, L.,
Page, D., Carson, R. and Oates, R.D. (1997)
Azoospermic men with deletion of the DAZ gene cluster are capable of completing spermatogenesis-fertilization. normal embryonic development and pregnancy occur when retrieved testicular spermatozoa
are used for intracytoplasmic sperm injection. Hum
Reprod., 12:503-508.
17. Pryor, J.L., Kent-First, M., Muallem, A., Van
Bergen, A., Nolten, W.E., Meisner, L. and Roberts,
K.P. (1997) Microdeletions in the Y chromosome of
infertile men. N Eng J Med., 336:534-539.
FERTILITY
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Management of Prostate
Pathology
Mr. Adeleye AJAYI MBBS (Lond) MD (Eng) FRCS (Eng) FRCS (Urol)
CONSULTANT UROLOGICAL SURGEON
ROYAL FREE HOSPITAL, LONDON
Epidemology of Prostate Cancer
Prostate cancer is the second commonest cause of death from cancer in the western
world with 198,000 new cases and 31,500 deaths in the USA in 2001 with a 16.6%
lifetime risk of the disease and a 3.4% lifetime risk of death. The exact incidence of
prostate cancer in Nigeria is unknown as no epidemiological data is available.
However, anecdotal evidence suggests that prostate cancer is common in Nigeria
with a high mortality rate. Patients often present with incurable metastatic disease
as there is no national screening program and public awareness is limited.
Diagnosis and Staging of Prostate cancer
Patients may present with obstructive lower urinary tract
symptoms in the form of hesitancy, poor urinary stream,
frequency of urine or heamaturia. A large percentage
of patients present with features suggestive of metastatic disease with lower lumbar back pain or caudia
equina nerve route compression causing lower limb paralysis, urinary retention, priapism or constipation.
A patient undergoing investigation for suspected
prostate cancer requires a Digital Rectal Examination (DRE) to assess the size and consistency of the
prostate gland and a Prostate Specific Antigen (PSA)
blood test. PSA is useful in the detection, staging and
monitoring of prostate cancer. A normal serum PSA
level is <4mg/l. Although PSA is prostate specific, it
is not cancer specific and its value can be elevated in
patients with Benign Prostatic Hyperplasia (BPH),
Prostatitis, and Urinary retention.
There is an ongoing quest to find a tumour marker
which has a high sensitivity and specificity. A
promising marker is urinary PCA3 gene test. A new
test in which the higher the urinary PCA3 Score, the
greater the likelihood of prostate cancer. Although
this test is available in clinical practice, its exact role
is yet to be defined.
A transrectal ultrasound guided prostate biopsy
under local anaesthetic is required in order to obtain
histological diagnosis of prostate cancer. A metastatic
search is performed using Bone scan. This is indicated
if the PSA >20mg/l. A CT Scan & MRI Scan is useful
to exclude extraprostatic capsular disease.
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Treatment options for localized prostate cancer
There are a number of treatment options available to
a patient with prostate cancer and appropriate
informed discussion is required in order to tailor the
treatment to the patient. These range from observation
or active monitoring of the patient to more aggressive
treatment options such as external beam radiotherapy
and radical prostatectomy (retropubic or perineal).
These treatment options produce satisfactory
outcomes with high cancer specific survival rates.
However, the potential complications (blood
transfusion, rectal injury) and long term side effects
such as impotence and incontinence makes these
treatments difficult for the patients to accept. There
are now minimally invasive treatment options such
as Brachytherapy, High Intensity Focused Ultrasound,
Laparoscopic or Robotic Prostatectomy which have
encouraging results with lower long term
complications.
Dietary Prevention of prostate cancer
Patients often enquire about dietary measures to
reduce their risk of developing prostate cancer.
Dietary suggestions include Soya beans
(phytoestrogens), Green Tea, Selenium-protects cell
from oxidative damage, Vitamin E an intracellular
antioxidant and agents high in Lycopenes (Tomato &
watermelon).
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X-ray of radioactive Brachytherapy seeds in the prostate
Benign Prostatic Hyperplasia (BPH)
The prostate is one of four accessory sex glands in a
male weighing an average of 18grams. BPH is a histological diagnosis with increased prostatic epithelial
and stromal cells in the periurethral area. Patients
present with storage (frequency, urgency, nocturia,
incontinence) or voiding (hesitancy, poor stream and
post micturition dribbling) lower urinary tract symptoms. Occasionally they present with heamaturia and
acute retention of urine
The evaluation of a patient includes a focused
history and a targeted examination including a Digital
Rectal Examination to assess the size of the prostate
and identify any suspicious prostatic mass. Serum PSA
to assess for prostate cancer and creatinine blood test
to ensure the patient has not developed obstructive
uropathy. An International Prostatic Symptom Score
(IPSS) is completed by the patient to assess the severity of their symptoms. A urine dipstix is done to
exclude a urinary tract infection. The patient is then
invited to perform a Uroflowmetry to obtain objective
evidence of the patients urinary flow rate together
with a post void bladder scan to assess the post void
residual volume.
Medical Treatment
Medical treatment involves the use of a1 Alpha
blockers (Alfuzosin, Tamsulosin or Doxazosin)- This
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Schematic diagram illustrating HIFU treatment
for Prostate cancer
group of medications improve symptoms and increase
urinary flow rate by relaxing prostatic and bladderneck smooth muscle through sympathetic activity
blockade. Potential side effects include postural hypotension, dizziness, blurred vision and retrograde
ejaculation. Another class of medication are 5-a
reductase inhibitors (Dutesteride and Finasteride)
which increase urinary flow rate and prevent BPH
progression by reducing prostate growth through
The da Vinci Robot used to perform
radical prostatectomy for cancer
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Green light laser used to treat patients with BPH
hormonal mechanisms.
Erectile dysfunction is reported in -5% of patients,
therefore it is important the patient is aware of this
potential side effect, which is reversible by stopping
the drug. These two classes of drugs can be used in
isolation or in combination. The current trend is to
use them in combination. the role of Phytotherapy is
yet to be determined.
Surgical Treatment
Transurethral Resection of the Prostate (TURP) has
been the Gold standard for over 25 years. This
procedure is often performed under spinal anaesthetic
with the patient fully awake. A retrospective study of
5,000 cases published as the British National
Prostatectomy Audit revealed satisfactory results with
65% patients reporting a 13 point drop in their IPSS
score, all patients reported an improvement in flow
rate with 90% of patients reporting that they are
satisfied with the outcome. However, 70% of patients
reported retrograde ejaculation, 10% impotence and
a blood transfusion rate of 5%.
These side effects are not acceptable to the patient:
therefore, there are continued efforts to develop
equipment which can reduce these side effects. One
such mechanism is the use of the Green light laser
photoselective vaporisation of prostate (PVP). The Laser light is produced by Nd YAG laser and fired
through KTP crystal which doubles the frequency of
the light. The green colour of the laser is rapidly
absorbed by Heamoglobin which is extremely
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Animated picture showing the residual cavity
of the prostate following Green light laser
prostatectomy.
valuable as the Prostate has an excellent blood supply
and allows for prostatic tissue to vaporise with little
bleeding as vessels are sealed at the time of vaporisation.
This technique allows patients to be treated and
discharged on the same day. A significant percentage of patients are catheter free within 24hrs. Very
large prostates can be vapourised preventing the need
for the old fashion open Millin’s retropubic prostatectomy. The side effects are much less than TURP with
1% impotence, 36% retrograde ejaculation and no
blood transfusion. With increasing use of this
technique, one can predict the Green light laser will
be the Platinum standard for treating patients with
BPH.
FERTILITY
UPDATE
Recurrent Implantation Failure:
The Therapeuatic Approach
Rachel Oga
Senior Fertility Nurse
The Bridge Clinic, PORT HARCOURT
INTRODUCTION:
Recurrent Implantation Failure is an issue of concern to In-vitro fertilisation (IVF)
practice and also to the patient concerned. For many couples with infertility issues,
IVF constitutes the last resort in the line of infertility management. Over 70% of the
treated cases will not be successful, with implantation failure being touted as a
major contributory factor. The reasons for IVF cycle failure could be very complex,
and it has been difficult to find a lasting solution despite extensive ongoing research.
The underlying cause for IVF failure has been attributed to problems with the embryos,
the uterine environment, or the patient’s immune system˙.
The Embryos and Age
As women advance with age, the quality of their eggs
begins to decline. The overall effect is on the resulting
embryo, which at that stage is associated with high
incidence of chromosomal abnormalities. Embryos
with such abnormal chromosomal components are
thus likely to be lost soon after transfer or do not
implant at all. In addition, women with diminished
ovarian reserve (high FSH level on cycle day 3 etc.)
are more likely to produce fewer eggs of poor quality,
which is eventually transferred to the developing
embryos. One of the associated characteristics of
clients with recurrent IVF failure is a thick zona
pellucida, which is a common feature in women with
advanced age, high FSH level, and recurrent
implantation failure history.
To overcome this potential problem, a technique
known as assisted hatching has been developed and
applied in-vitro, prior to embryo transfer procedure
to trim or reduce the zona thickness with a view to
aiding implantation. With this same technique, skilled
embryologists can also remove fragments (cellular
debris between the cells) from “poor quality”
embryos, thus improving their potential for
implantation.1
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Problems within the Uterus
Problems within the uterine environment that inhibits
the embryo from implanting have been classified as
anatomic, hormonal and immunologic.
A. Anatomic abnormalities are lesions inside the
uterus that mechanically inhibit implantation. These
anatomic abnormalities act like an intrauterine device
to prevent implantation of the embryo. These include:
Endometrial polyps— benign outgrowths of the
uterine lining that protrude into the uterine cavity)
Submucous fibroids – benign tumors of the uterine
wall that protrude into the uterine cavity
Uterine synechia - scarring or adhesions inside the
uterine cavity
Evaluation of the uterine cavity to rule out fibroids,
polyps or scar tissue is a routine practice by most
assisted conception units. Uterine evaluation is usually
accomplished with a hysterosalpingogram (HSG) or
a saline infusion ultrasound (sonohysterography).
Patients with good quality embryos that fail to
conceive would require a more thorough evaluation
of the uterine cavity to rule out any uterine factors
FERTILITY
UPDATE
that might be responsible. Recent studies have shown
that hysteroscopy often provides significant findings
in this group of patients.˙
B. Hormonal responses of the lining of the uterus to
both estrogen and progesterone are necessary for the
uterus to be receptive to the embryo. Mutations in
some of the genes encoding for the progesterone
receptor have been associated with recurrent
implantation failure.
C. Immunologic mechanisms involved in implantation
are being identified. The uterus as well as the embryo
has to be made amenable to implantation. Uterine
receptivity requires continuous interactions between
the embryo and the mother. These interactions are
communicated through proteins known as cytokines.
The cells within the uterine lining including the
immune cell secrete cytokines. During the preimplantation period preparation of the uterine lining
for implantation involves stimulation expression of
adhesion systems that hold the embryo to the uterus.
If the immune cells do not send proper signals through
secretion of appropriate cytokines to the embryo or
if these cells do not respond to signals from the
embryo, then adhesion and thus subsequent
implantation will not occur.
This immunological interaction during
implantation has been implicated as a cause of
recurrent implantation failure˝.
Preferred Therapeutic Approach
PGD (Pre Implantation Genetic Diagnosis) and
PGAS (Pre implantation Genetic Aneuploidy
Screening)
N PGAS enables the assessment of the numerical
chromosomal constitution of cleavage stage embryos
through the of fluorescence in-situ hybridization
(FISH). Theoretically, the selection of euploid embryos
for transfer would result in a higher implantation and
pregnancy rate and a reduced miscarriage rate .
Recent advances in reproductive medicine and
molecular cytogenetics have changed the approach
to the management of infertile couples. The
introduction of FISH has enabled the chromosomal
assessment of embryos. The initial application of pre
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implantation genetic diagnosis (PGD) to prevent xlinked recessive diseases and the unbalanced
transmission of parental balanced translocations has
widened to improve IVF results in repetitive
implantation failure.
PGD for aneuploidy screening has also been
investigated in patients with unexplained recurrent
spontaneous pregnancy loss. It is theorized that PGD
could improve the possibility of successful pregnancy
in this population, as a large proportion of embryos
about 50%-70% are chromosomally abnormal. In a
pilot study, Wilding and colleagues reported that in
patients with a history of recurrent abortion, IVF
outcomes were better with the analysis of 5
chromosomes as opposed to 3 chromosomes, although
no control group was available for comparison.
The authors state in their analysis that it is not
clear from the limited sample of patients whether the
protocol described can be applied to all patient
groups. They call for a larger, prospective,
randomized, controlled, multicenter trial comparing
PGD with other IVF protocols to determine the
accuracy of their data.
Platteau and colleagues reported on a group of
49 patients, divided by age into two groups, those
<37 years and those 37 or older. They reported that
although the aneuploidy rate was relatively high in
the younger population, PGD did not improve the
selection of transferred embryos and did not seem to
improve the pregnancy rate compared to their general
IVF population.
Live births were not reported, but the authors
suggested that the expected live birth rate in this
population would have been the same without any
treatment. Results in the older patient cohort were
disappointing, and the authors stated that PGD
brought no benefit, apart from being diagnostic and
redirecting treatment to other options.
In general, they concluded there was no
therapeutic evidence to prescribe IVF, with or without
PGD, for patients with recurrent miscarriages.
In a study published in the May 2007 issue of the
medical journal Fertility and Sterility, researchers set
out to determine if couples that failed to achieve
pregnancy with IVF after multiple transfers had a
higher incidence of chromosome abnormalities than
other patients.
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They looked at data from PGD screening using
CGH (comparative genomic hybridization) a second
type of PGD. (During CGH, a labeled identical copy
of each chromosome in a cell is created. This DNA
copy is then hybridized with a labeled copy of DNA
from a cell that is known to be normal).
This was done on analysis on 176 embryos from
28 women. Twenty-two women had a history of
recurrent implantation failure (RIF), and six did not.
Women were classified as having RIF when 10 or more
embryos had been transferred previously without
achieving a pregnancy. The average number of
previously transferred embryos in this group was 16.5.
The authors created a category of abnormalities
that they referred to as “complex”. An embryo was
considered to have a complex abnormality if there
were 3 or more chromosomes that were not present
in correct numbers. Seventy-six (45%) embryos tested
normally and were suitable for transfer, 46 (27%)
showed aneuploidy for one or two chromosomes, 4%
showed partial aneuploidy, and 49 (29%) had complex
abnormalities involving three or more chromosome.
its constituent glycoproteins has been implicated in
reduced hatching rates.
AH probably enhances clinical pregnancy, especially
in women with previous failure of assisted conception
treatment. Assisted hatching is achieved by zona
dissection, drilling or thinning, making use of acid
solutions, proteinases, piezon vibrators and laser. It
is said that hatched embryos implant one day earlier
than unhatched embryos. The procedure is
increasingly offered to older women, those with high
FSH levels, higher risk of zona hardening and
following repeated implantation failure.
In a 2005 study in Reproductive Biomedicine, a
sample of 150 people with previous implantation
failure were treated with intracytoplasmic sperm
injection and divided into two groups, one with only
one previous implantation failure, and the second,
with several implantation failures. For group two,
those patients who had had laser assisted hatching
had a significantly higher rate of pregnancy than those
who didn’t (10.9% for those who had laser treatment
as opposed to 2.6% for those who didn’t).
Blastocyst Transfer
Another strategy involves culture to blastocyst stage,
thereby allowing self-selection of those embryos
capable of proceeding to blastulation and exclusion
of less viable embryos showing developmental arrest.
The transfer of as many as two blastocysts has been
shown on the average to be effective in reducing the
number of multiple gestations in patients with good
ovarian response and capable of establishing
pregnancies in women with previous IVF failures.
Generally, a good quality blastocyst contains a well
–expanded blastocoelic cavity, homogenous
trophoblast with multiple cell-cell contacts and
distinct nuclei, and an inner cell mass that is clearly
visible and intact. A large number of studies attest to
excellent success rates following blastocyst transfer
with implantation rates of 67%
The Role Of Human Leukocyte Antigens (HLA)
Studies have shown that parental Human Leukocyte
Antigens lead to implantation failure. Maternal
recognition of paternally derived fetal antigens occurs
during normal pregnancy and may be beneficial for
implantation and maintenance of gestation. Studies
have shown that couples with more than 3
implantation failures after IVF have more than 2
shared HLAS. If so, it would be worthwhile to screen
couples for HLA compatibility who fail to concieve
after multiple IVF attempts.
Gamete or embryo donation would be a
therapeutic alternative in this case in order to provide
the wide Antigen difference between the mother and
foetus necessary for successful implantation.
Monserrat et al, 1998. Noteworthy though is the fact
that these researchers could not identify any specific
HLA associated with failure of implantation after ET,
but it is still advisable to screen the couple.
Assisted Hatching (AH)
Cultured embryos develop slowly and poorly in vitro.
Many fail to achieve blastocyst stage or hatch, and
implant at lower rates than occur naturally. Hardening
of the zona pellucida resulting from cross-linking of
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Conclusion
The management of recurrent implantation is still
evolving, but it would seem like an act of God for
pregnancy to occur in the end having exhausted all
options available. The issues to critically examine are:
how involving are infections of the vagina, cervix and
endometrium, and should they not be treated before
commencement of treatment? What about the role
of mucus aspiration and washing of the cervix on
transfer, the role of catheter guidance for a correct
transfer and portion of embryos, the effect of mock
transfer and the role of hysteroscopy and its timing
before embryo transfer procedures. All these put
together form the basis for the skilled to be better
equipped to improve implantation success.
References
1. Claudio Benadiva, MD. Center for Advanced
Reproductive Services, Department of Ob/Gyn,
University of Connecticut Health Center
2. SHER Institute For Reproductive Medicine
3. P.Donoso et al. Current value of pre implantation
genetic aneuploidy screening in IVF, Hum. Rep update
(electronic version).
4. Platteau P, Staessen C, Michiels A et al.
Preimplantation genetic diagnosis for aneuploidy
screening in patients with unexplained recurrent
miscarriages. Fertil Steril 2005;83(2):393-7
5. Wilding M, Forman R, Hogewind G.
Preimplantation genetic diagnosis for the treatment
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of failed in vitro fertilization-embryo transfer and
habitual abortion. Fertil Steril 2004;81(5):1302-7
6-7.
Platteau P, Staessen C, Michiels A et al.
Preimplantation genetic diagnosis foraneuploidy
screening in patients with unexplained recurrent
miscarriages. Fertil Steril 2005;83(2):393-7
8. Gardener DK,Lane,Stevens J et al. Blastocyst score
affects implantation and pregnancy outcome: Towards
a single blastocyst transfer. Fertil Steril 2000;73:115558
9. Toledo AA.Wright G.Jones et al. Blastocyst
transfer: a useful tool for reduction of high-order
multiple gestations in assisted reproduction
programme. Am J obstet Gynecol 2000;183:377-79
10. Langley DT,Marek DM et al. Extended embryo
culture in human assisted reproduction treatment,
Hum Reprod 2001:16-902-8.
11. Rijnders PM,Jansen CAM The predictive value of
day 3 embryo morphology regarding blastocyst
formation,pregnancy and implantation rate after day
5 transfer following in-vitro fert or ICSI. Hum Reprod
1998;13:2869-73
12. Edmond Edi-Osagie et al. The impact of assisted
hatching on live birth rates and outcomes of assited
conception:a systematic review, Hum.Rep.2003
13. Reproductive BioMedicine Online, Volume 10,
Number 2, February 2005 , pp. 224-22
14. Montserrat et al. Dept of Obs & Gyn, Immunology
Center, University of Barcelona. Hum. Rep,
publication,vol 13,no.1,pp39-43,1998.
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Ovarian Hyperstimulation Syndrome (OHSS)
Are there predictive factors?
Queen AHIWE
Fertility Nurse
THE BRIDGE CLINIC PORT HARCOURT
Introduction
Ovarian Hyper stimulation Syndrome (OHSS) is a systemic disease resulting from
vasoactive products released by hyper stimulated ovaries; often triggered by the
administration of hCG. The syndrome is characterised by increased capillary permeability, leading to leakage of fluid from the vascular compartment, with third space
fluid accumulation and intravascular dehydration.
The symptoms usually begin 4-5 days after egg collection. The majority of women
have a mild or moderate form of the syndrome and invariably resolve within a few
days unless pregnancy occurs, which may delay recovery. OHSS is rarely severe,
and as the ovaries are swollen, the woman can experience a pronounced degree of
discomfort. Severe OHSS is, perhaps, the most serious complication of IVF.
Incidence
The incidence of OHSS varies between treatments
and patient groups, and accurate estimates from the
literature are difficult owing to different definitions
of the grades of severity, different criteria for prevention, and the variety of classification schemes
used. The incidence at The Bridge Clinic (2003 -2007)
averaged 7%.
The majority of cases of severe OHSS are seen
following IVF treatment. Mild OHSS occurs after any
form of supraphysiological ovarian stimulation,
including clomiphene and gonadotrophin ovulation
induction in a small proportion of women.
Further Classification
A division of OHSS into ‘early’ and ‘late’, depending
on the time of onset, may be useful in determining
the prognosis. OHSS presenting within 9 days after
the ovulatory dose of hCG is likely to reflect excessive ovarian response and the precipitating effect of
exogenous hCG administered for follicular maturation.
OHSS presenting after this period reflects endogenous hCG stimulation from an early pregnancy. Late
OHSS is more likely to be severe and to last longer
than early OHSS.
Classification
GRADE
Mild OHSS
Moderate OHSS
Severe OHSS
Critical OHSS
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SYMPTOMS
Abdominal bloating, mild abdominal pain, slight
discomfort, ovaries usually <8cm
Moderate abdominal pain, nausea, vomiting, ascites,
ovaries 8-12cm.
Clinical ascites (occasionally hydrothorax), oliguria,
haemoconcentration (haematocrit>45%),
hypoproteinaemia,
Ovaries >12cm
Tense ascites or large hydrothorax, oligo/anuria,
thromboembolism, acute respiratory distress,
haematocrit >55%.
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Pathophysiology
The initial pathophysiological event in severe OHSS
is an increased permeability, especially in the enlarged
ovaries, due to the local production of prostaglandin, histamine, and the activation of the follicular
renin-angiotensin system, leading to the extravasation of fluid into the abdominal cavity.
The extravasation of fluid into the abdominal
cavity can cause ascites, a contraction of circulatory
blood volume, arterial hypotension and a compensatory increase in heart rate and cardiac output,
haemoconcentration, and renal sodium and water
retention. Renal failure is an expression of an extreme
diminution of intravascular volume.
Are There Predictive Factors For OHSS?
Prediction of OHSS is difficult as the predictive value
of most tests is low, although some risk factors may
point to the possibility of its occurrence. As such,
preventive measures should be considered when
treatment is started in high-risk individuals. However,
the risk factors include Young Age
Occurrence is higher in women <34 years of age
Polycystic Ovarian Syndrome (PCOS)
Increases risk of occurrence of OHSS because of the
increased number of primordial follicles on the
ovaries at the resting phase. Polycystic ovaries tend
to over respond when they are being stimulated.
Low Body Mass Index
Women with body mass index of <25kg/m2 are more
predisposed to OHSS.
Hypogonadotropic Hypogonadism
Some women, on investigation, have their basal LH
higher than the FSH. This is a reflection of
hypogonadotropic hypogonadism, and most at times,
a resultant PCOS. These patients have been found to
over respond to ovarian stimulation.
Previous History Of OHSS
OHSS tends to re-occur in subsequent cycles of
ovarian stimulation.
Response During Stimulation
Monitoring of response in high-risk individuals may
indicate possibility of OHSS occurring.
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High Oestradiol level (>3000 pg/ml) pre hCG and
during treatment.
Oestradiol levels of 3000pg/ml and above, before the
administration of hCG and during treatment, should
warn the clinician that the client is at a higher risk of
OHSS.
Use of GnRH agonists and hMG vs FSH
Rizk and Smitz reviewed the world literature concerning OHSS after the use of different GnRHa for
superovulation in IVF and other related ARTs showed
that the use of GnRHa leads to significantly higher
preovulatory Oestradiol concentrations, and more frequently to severe OHSS. This may be related to the
action of the agonist on the ovary, or to the increased
FSH and LH levels as a result of increased exogenous
gonadotropin. They reported high affinity GnRH
receptors in human granulosa cells at a late stage of
follicular maturation. Therefore, it is suggested that
the use of FSH offers a safe treatment compared with
GnRHa and hMG, resulting in higher pregnancy rates
and lower OHSS rates.
Excessive follicular development on egg scan
Women who develop more than 20 follicles at egg
scan stand a higher risk of developing OHSS.
Exposure to hCG
The preovulatory hCG dose plays an important role
in the initiation of OHSS. The role of hCG generated
by the presence of a pregnancy may therefore,
essentially augment the prevailing condition, initiated
by the preovulatory hCG administration.
Prevention Of OHSS
Prevention of OHSS is always the best strategy.
This syndrome can best be avoided by individualized
judicious use of fertility medications.
Endocrine and ultrasound follicular monitoring to
determine patients at risk pre hCG.
Reducing or withholding the preovulatory hCG
administration, although this could be at the expense
of losing the cycle.
Luteal phase support with progesterone
Cryopreservation of embryos and subsequent
replacement
Intravenous albumin administration during oocyte
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retrieval may increase oncotic pressure and subsequently reverse the leakage of fluids from the intravascular space.
Management
Mild OHSS usually resolves within 1-3 weeks. The
treatment is conservative, with observation and follow
up. On the other hand, severe OHSS requires hospital
admission and active monitoring.
Strict monitoring of fluid and electrolyte balance
is necessary. Fluid replacement therapy and intake
and output recording is also needed.
Relief of pain and discomfort with analgesics and
antacids. NSAIDS should not be used.
Ultrasonographic examination provides accurate
assessment of ovarian size and the presence of ascites,
as well as pleural or pericardial effusions. Chest Xray will provide information on the latter.
Paracenthesis is appropriate in women who are
distressed due to ascites, and women who are oliguric
despite adequate fluid replacement. Transabdominal aspiration is likely to be better tolerated than a vaginal approach.
Biochemical monitoring include serum proteins
and electrolyte, renal and liver function tests, a
cagulation profile, and a blood count.
In cases of hypovolaemia, efforts are directed
towards a normal intravascular volume and preserving adequate renal function, using colloid plasma
expanders or human albumin.
Anticoagulant therapy is indicated if there is
clinical evidence of thromboembolic complications
or laboratory evidence of hypercoagulability.
Diuretics should be avoided as they deplete intra-
vascular volume.
Complications
Thromboembolism
Miscarriage
Pleural Effusion
Renal Failure
Adnexal torsion
Congenital malformations (as a result of drug
administration)
Summary
Ovarian Hyperstimulation is the most serious complication of ovulation induction. PCOS appears to be
the major predisposing factor: it is documented in at
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least 50% of the major series of OHSS. The combination of GnRHa and hMG is associated with a higher
incidence of OHSS. OHSS is more frequent in
pregnancy than in non-pregnancy cycles.
The most effective management of OHSS is its
accurate prediction and active prevention. Combined
sonography and endocrine monitoring should improve
the prediction compared to either method used alone.
The presence of 20 or more follicles and a high serum
oestradiol >3000 pg/ml should alert the clinician.
Delaying hCG will decrease the risk of OHSS,
withholding hCG will also reduce OHSS, but at the
expense of getting immature eggs. Cryopreservation
of embryos and replacement in subsequent cycles is
a useful option in IVF programme but does not prevent
OHSS completely.
In PCOS patients, titration of hMG, or FSH dosage
administered gradually and slowly should be used to
prevent OHSS. Luteal-phase support using progesterone intravaginally or intramuscularly should be used
in cycles at risk of OHSS.
References
1. Aboulghar M A, Mansour R T. Ovarian
hyperstimulation in the treatment of infertility. Fertil
Steril 1989;51: 834-836.
2. Schenker J G, Ezra y. Complications of assisted
reproduction techniques. Fertil Steril 1999; 61:411422.
3. Schenker J G, Weinsten D. Ovarian
hyperstimulation syndrome: a current survey. Fertil
Steril 1987; 30:255-268.
4. Phillips L L, Glanstone W, Van de Wiele R. Studies
of hyperstimulation syndrome after administration of
human gonadotropins. J Reprod Med 1995; 14:138
5. Kaaja R, Sieberg R, Titinen A,. Severe ovarian
hyperstimulation syndrome. Lancet 1998; ii:1043.
6. Smith B H, Cooke I D. Ovarian hyperstimulation: actual
and theoritical risks. Br Med J 1991; 298:127-128
7. Ong A C M, Eisen V, Rennie D P et al. The
pathogenesis of the ovarian hyperstimulation syndrome. Clin Endocrinol (Oxf) 1991; 34:43-49.
8. Forman R G, Frydman R, Barlow D. Severe OHSS
using GnRHa in IVF: a proposal for prevention. Fertil
Steril 1990; 53:938-943.
9. Rizk B, Aboulghar M. Complications of ART. 1994
(in press).
10. Rizk B, Smitz J. Ovarian hyperstimulation syndrome after superovulation for IVF and related
procedures. Hum Reprod 1992; 7:320-327.
FERTILITY
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Rubella Virus: An Underestimated
Pathogen in Nigeria?
Dr Folasade T. Ogunsola (MBCHB, FMC Path, FWACP, Ph.D)
Department of Medical Microbiology and Parasitology
COLLEGE OF MEDICINE, UNIVERSITY OF LAGOS
Introducton
The Rubella virus is the aetiological agent of Rubella (“German measles”, “3-Day
measles”) and Congenital Rubella Syndrome. It is an enveloped RNA virus that belongs to the family Togaviridae. There is only one serotype and humans are the only
known host. It does not cross react with any other virus. It is transmitted by the
respiratory route and replicates in the nasopharyngeal mucosa and local lymph nodes
prior to a generalised viraemia. In pregnant women the virus directly infects the
placenta and the developing fetus.
Epidemiology
Rubella is a contagious viral infection characterized
by a distinctive red rash. It has an Incubation period
of 12 to 23 days, and it is infectious from one week
before the onset of the rash until about two weeks
after the rash disappears. It has a worldwide distribution and in endemic areas, epidemics occur every 59 years. In endemic areas children are infected
between the ages of 6-12 years in industrialized areas
and 2-8 years in urban areas of developing countries.
World wide, the extent of susceptibility in women of
childbearing age varies considerably from <5% in
Kuwait to 30% in Nigeria and 60% in rural Panama.
Immune Response
Infection usually confers permanent immunity.
Antibodies are first detectable about 14-18 days after
onset of infection which tends to coincide with the
appearance of the rash. There is an initial IgM
response that wanes rapidly and may be undetectable
by 4-8 weeks. This is followed by an IgG response
which may be persistent. Rubella-specific cell-mediated lymphocyte response begins a week after the
humoral response and appears to persist for a lifetime. Babies born to immune mothers are protected
by maternal antibodies for the first 6-9 months of life
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Clinical Features
Most infections are subclinical and the signs and
symptoms are often very mild and difficult to notice
and last about 2-3 days. They may include mild fever
≤ 38.9oC (102oF), headache, Stuffy or runny nose,
inflamed, red eyes, enlarged, tender lymph nodes
characteristically at the base of the skull, back of the
neck and behind the ears. A fine, pink rash that begins
on the face and quickly spreads to the trunk and then
the arms and legs, before disappearing in the same
sequence is sometimes reported. Complications are
usually few and include arthritis in the fingers, wrists
and knees, otitis media or encephalitis. However,
infection in early pregnancy (from just before
conception and first 8-10 weeks of gestation) are
associated with multiple fetal defects in up to 90% of
cases and many of these pregnancies will result in
miscarriage or stillbirth. Fetal defects are rare with
maternal rubella after the 16th week of pregnancy.
Clinical features of Congenital Rubella Syndrome
The major signs are congenital heart disease , ocular
defects and sensorineural hearing loss. Other important signs and symptoms considered minor include
failure to thrive, developmental delays, microcephaly,
mental retardation, thrombocytopaenia, purpuric
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rash, radiolucent bones on x-ray, hepatosplenomegaly,
meningoencephalitis, hepatitis and jaundice that
begins within 24 hours after birth.
Diagnosis
Rubella infection requires laboratory confirmation,
particularly under non-epidemic conditions but there
are criteria for clinical confirmation of CRS:, an infant
with either 2 major signs or 1 major and 1 minor
sign. A probable CRS is an infant with heart disease,
suspected hearing impairment, or at least 1 eye sign
consistent with a diagnosis of Congenital Rubella
Syndrome.
Serology is the preferred method for routine laboratory diagnosis and is usually by ELISA. A laboratory-confirmed CRS is an infant with positive serology
for rubella IgM and clinical signs consistent with a
diagnosis of CRS. Samples should be taken within
28days of onset of rash for the demonstration of IgM.
If this is not possible, a significant rise in rubella IgG
from paired acute and convalescent sera also provides evidence of ongoing or recent rubella infection.
Viral isolation is labour-intensive and costly and is
not routinely used for diagnosis though the virus can
be isolated from the pharynx or urine of an infant
with CRS for one year or more.
Antenatal screening for Rubella: Pregnant women
should be screened within 4-6 weeks of a rash
especially in the first trimester to detect IgM
antibodies. Routine screening is usually done at about
12-20 wks of gestation for IgG. The laboratory reports
are usually qualitative for IgG titre and are reported
as “immune” (> 15 IU/mL) or “nonimmune”. A
limitation is that routine tests cannot detect
substantial rises in IgG levels (indicating possible
infection) nor can they differentiate between vaccineinduced immunity and infection acquired in early
pregnancy. They also cannot detect low or borderline IgG levels (re-infection resulting in Congenital
Rubella Syndrome has occurred at low levels of immunity).
Treatment
Infected persons should be isolated from others,
especially pregnant women. Pregnant women who
contract rubella may have to terminate the pregnancy
or use hyperimmune globulin, which can reduce
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symptoms but does not eliminate the possibility of
the baby developing CRS.
Prevention
Most common is the trivalent MMR (Mumps-MeaslesRubella) based on the live attenuated RA 27/3 strain
of the virus grown in Human diploid cells. The first
dose is given at 12 - 15 months of age and the 2nd
dose is given at 4 - 6 years (before entering school). It
is safe and efficacious.
It is important that girls receive the vaccine to
prevent rubella during future pregnancies. Vaccine
should not be given to pregnant women or to a woman
who may become pregnant within one month of
receiving the vaccine. Women thinking about becoming pregnant, should receive the vaccine at least one
month before becoming pregnant. Usually babies are
passively protected from rubella for 6-8 months after
birth
Most people experience no side effects from the
vaccine and there is no scientific evidence to link the
MMR vaccine and autism.
Key points
Rubella is endemic in Nigeria as about 30% of
women of child bearing age are susceptible. Therefore all young women should be vaccinated against
Rubella.
Children with any of the major and minor signs
should be investigated for presence of Rubella IgM.
Women should be screened for rubella susceptibility at each pregnancy.
Women with a low positive IgG titre (e.g., 10– 15
IU/mL) before pregnancy may benefit from (repeat)
rubella vaccination.
Pregnant women with a low positive IgG titre, who
have recently been exposed to rubella, should be
screened for Rubella IgM to help distinguish between
new infection and immunity.
All pregnant women found to be negative for
Rubella should be Vaccinated in the immediate Postpartum period.
There is a need for Nigeria to join other Nations
in introducing the MMR into the National Programme
on Immunisation.