Ask Our Doctors – Archive
Our Medical Directors are outstanding physicians that you will find to be very personable and compassionate, who take care to ensure that you have the most cutting-edge fertility treatments at your disposal. This is your outlet to ask your questions to the doctors.
I am trying to conceive since 4 years but not succeeded yet. Since last may 2018, I am undergoing fertility treatment 3 cycles of letroz 1 clomid, ovulation successful, still no conception. Dr. recommended laparoscopy everything is normal except, delayed spill on left tube. I had PCOD, so ovarian drilling also done. Biopsy of endometrial tissue resulted in mycobacterium tuberclosis detection.
My question is, I am very scared, is it dangerous or cureable?
Will I ever get pregnant?
Will it affect my partner (through intercourse)
Tuberculosis is caused by a bacterium known as mycobacterium tuberculosis. It is primarily an infectious process that involves the lungs it is capable of spreading elsewhere (extra-pulmonary TB) It can spread to the woman’s reproductive tract and cause infertility. The commonest site is the Fallopian tubes. From there it can spread to uterine lining (endometrium) and to the ovaries. The lower genital tract (cervix, vagina and vulva can also be affected but this is very rare.
Contrary to popular belief, TB does not spread by surface contact (sharing of utensils or clothes or through touch). Rather it spreads by droplet contamination when you come into contact with an individual who has pulmonary disease, who coughs, spits or sneezes and you come in contact with mycobacterium Tuberculosis. There is a rare form of TB caused by mycobacterium tuberculosis bovis, that spreads through ingestion of infected milk but this usually affects bowel and bone, not the reproductive tract.
While pelvic tuberculosis is a very common cause of infertility in developing countries and in Asia (India in particular), it so rarely causes of infertility in the United States, that the diagnosis is often overlooked here. However, there is good reason to believe that the condition is on the rise in the United States as a result of the influx of immigrants from Asia and other third world countries where tuberculosis is rampant.
Pelvic tuberculosis is often a master of disguise….a silent disease. It may be present for 10 to 20 years without producing any symptoms – the woman remaining in apparent excellent health. Infertility is often one, and sometimes the only, reason that women investigate for the presence of the condition.
Pelvic tuberculosis usually presents with one or more of the following signs and symptoms:
•Pelvic pain, dysmenorrhea (pain with menstruation), dyspareunia (pain with intercourse), chronic lower abdominal pain or discomfort, and chronic back pain
•Absent or irregular menstruation,
•Abdominal distention, usually due to ascites (collection of free fluid in the abdominal-pelvic cavity
•Tuberculosis-related infertility is most commonly due to tuberculous salpingitis (tubal inflammation) which occurs in 75% of cases, ovulation dysfunction that often presents with absent, excessive or non-cyclical menstruation, largely attributable to ovarian involvement (40% of cases) and uterine (endometrial) tuberculosis (30%)
•Sometimes (albeit rarely), local tuberculous lesions may appear on the external genitalia, cervix, and/or vagina.
Diagnosis:
The diagnosis is usually based upon a multitude of signs, symptoms and special tests, there being no magic bullet for diagnosing pelvic tuberculosis.
•Clinical suspicion: Evidence of concomitant, pulmonary tuberculosis, the detection of calcifications on pelvic X-rays, a typical tubal pattern on hysterosalpingogram (dye X-ray test)
•Findings at laparoscopy or laparotomy and the subsequent pathologic examination of biopsy material obtained during these procedures
•Blood tests such as a differential blood count and erythrocyte sedimentation rate
•Microscopic and bacteriologic examination is the primary method for diagnosing pelvic tuberculosis:
•Polymerase chain reaction (PCR) done on biopsied material (usually from a defined tuberculous lesion or from uterine curettings.
1.Most commonly a dilatation and curettage (D&C) of the uterus is performed a few days prior to menstruation. The surgeon takes care to avoid using an antiseptic to clean the vagina and cervix while preparing for the D&C;, lest the antiseptic kill any tuberculous bacilli present in the specimen thereby rendering a falsely negative culture result. Instead a physiologic salt solution is used to cleanse the operative field. Upon collection, the specimen of uterine curetings is immediately divided into two parts. The first is placed in a physiologic salt solution and expeditiously delivered to the bacteriologic lab for culturing. A specialized culture medium (e.g., Loewenstein Jensen medium) is used for this purpose. Some of the curettings are also used for Guinea pig inoculation. While menstrual products can also be cultured, this approach is less effective. The second portion of the specimen is fixed and then stained for the detection of the acid-fast Bacillus, mycobacterium tuberculosis. The Ziel Nielsen stain is one of the methods used.
2.Biopsy specimens of local lesions and endometrial curettings can of can also be subjected to histopathologic examination, culture and guinea pig inoculation
3.PCR: analysis: . PCR is a molecular test, which”
Even in the presence of established tuberculosis, histopathologic examination will only be positive about 50% of the time. Cultures, although more reliable, can also yield false-negative results. And while PCR analysis, conducted under ideal conditions is a highly sensitive and specific method for the detection of the target genes specific to Mycobacterium tuberculosis and has a high positive predictive value, “false positive” results can occur Accordingly, it is often necessary to repeat such tests several times if the diagnosis is strongly suspected.
Treatment
Treatment of TB primarily directed towards the eradication of the infection by means of specific chemotherapeutics such as Para-amino-salicylic acid (PAS), isoniazid (INH), rifampicin (Rifampin) and streptomycin derivatives.
Given the severity and intractability of fallopian tube-TB, natural conception is very unlikely. Pelvic surgery (other than to remove distended or infected lesions and damaged fallopian tubes) has little therapeutic benefit. Provided that the tuberculous inflammatory process has not totally destroyed the basal uterine endometrium (lining) , leaving it capable of responding adequately to estrogen and progesterone, , in vitro fertilization (IVF) following protracted successful anti-bacterial treatment is the only rational method of treating infertility associated with pelvic tuberculosis.
Geoff Sher
Dr. Sher,
I am reaching out for guidance.
I have just miscarried my fourth PGS normal IVF transfer.
I have Hashimoto’s, positive Lupus antibodies, Factor II clotting antibodies, and MTHFR.
For this FET I did an autoimmune protocol
Prednisone 10 mg bid
Lovenox 30 bid
LDN daily
Plaquenil 200 bid
Intralipids weekly
This was my last embryo and at 40 years old I am not sure if I should do this again.
I miscarry from 6 to 10 weeks.
This past one right at six weeks.
What else can be done ?
We need to talk!
When it comes to reproduction, humans are the poorest performers of all mammals. In fact we are so inefficient that up to 75% of fertilized eggs do not produce live births, and up to 30% of pregnancies end up being lost within 10 weeks of conception (in the first trimester). RPL is defined as two (2) or more failed pregnancies. Less than 5% of women will experience two (2) consecutive miscarriages, and only 1% experience three or more.
Pregnancy loss can be classified by the stage of pregnancy when the loss occurs:
•Early pregnancy loss (first trimester)
•Late pregnancy loss (after the first trimester)
•Occult “hidden” and not clinically recognized, (chemical) pregnancy loss (occurs prior to ultrasound confirmation of pregnancy)
•Early pregnancy losses usually occur sporadically (are not repetitive).
In more than 70% of cases the loss is due to embryo aneuploidy (where there are more or less than the normal quota of 46 chromosomes). Conversely, repeated losses (RPL), with isolated exceptions where the cause is structural (e.g., unbalanced translocations), are seldom attributable to numerical chromosomal abnormalities (aneuploidy). In fact, the vast majority of cases of RPL are attributable to non-chromosomal causes such as anatomical uterine abnormalities or Immunologic Implantation Dysfunction (IID).
Since most sporadic early pregnancy losses are induced by chromosomal factors and thus are non-repetitive, having had a single miscarriage the likelihood of a second one occurring is no greater than average. However, once having had two losses the chance of a third one occurring is double (35-40%) and after having had three losses the chance of a fourth miscarriage increases to about 60%. The reason for this is that the more miscarriages a woman has, the greater is the likelihood of this being due to a non-chromosomal (repetitive) cause such as IID. It follows that if numerical chromosomal analysis (karyotyping) of embryonic/fetal products derived from a miscarriage tests karyotypically normal, then by a process of elimination, there would be a strong likelihood of a miscarriage repeating in subsequent pregnancies and one would not have to wait for the disaster to recur before taking action. This is precisely why we strongly advocate that all miscarriage specimens be karyotyped.
There is however one caveat to be taken into consideration. That is that the laboratory performing the karyotyping might unwittingly be testing the mother’s cells rather than that of the conceptus. That is why it is not possible to confidently exclude aneuploidy in cases where karyotyping of products suggests a “chromosomally normal” (euploid) female.
Late pregnancy losses (occurring after completion of the 1st trimester/12th week) occur far less frequently (1%) than early pregnancy losses. They are most commonly due to anatomical abnormalities of the uterus and/or cervix. Weakness of the neck of the cervix rendering it able to act as an effective valve that retains the pregnancy (i.e., cervical incompetence) is in fact one of the commonest causes of late pregnancy loss. So also are developmental (congenital) abnormalities of the uterus (e.g., a uterine septum) and uterine fibroid tumors. In some cases intrauterine growth retardation, premature separation of the placenta (placental abruption), premature rupture of the membranes and premature labor can also causes of late pregnancy loss.
Much progress has been made in understanding the mechanisms involved in RPL. There are two broad categories:
1.Problems involving the uterine environment in which a normal embryo is prohibited from properly implanting and developing. Possible causes include:
•Inadequate thickening of the uterine lining
•Irregularity in the contour of the uterine cavity (polyps, fibroid tumors in the uterine wall, intra-uterine scarring and adenomyosis)
•Hormonal imbalances (progesterone deficiency or luteal phase defects). This most commonly results in occult RPL.
•Deficient blood flow to the uterine lining (thin uterine lining).
•Immunologic implantation dysfunction (IID). A major cause of RPL. Plays a role in 75% of cases where chromosomally normal preimplantation embryos fail to implant.
•Interference of blood supply to the developing conceptus can occur due to a hereditary clotting disorder known as Thrombophilia.
2.Genetic and/or structural chromosomal abnormality of the embryo.Genetic abnormalities are rare causes of RPL. Structural chromosomal abnormalities are slightly more common but are also occur infrequently (1%). These are referred to as unbalanced translocation and they result from part of one chromosome detaching and then fusing with another chromosome. Additionally, a number of studies suggest the existence of paternal (sperm derived) effect on human embryo quality and pregnancy outcome that are not reflected as a chromosomal abnormality. Damaged sperm DNA can have a negative impact on fetal development and present clinically as occult or early clinical miscarriage. The Sperm Chromatin Structure Assay (SCSA) which measures the same endpoints are newer and possibly improved methods for evaluating.
IMMUNOLOGIC IMPLANTATION DYSFUNCTION
Autoimmune IID: Here an immunologic reaction is produced by the individual to his/her body’s own cellular components. The most common antibodies that form in such situations are APA and antithyroid antibodies (ATA).
But it is only when specialized immune cells in the uterine lining, known as cytotoxic lymphocytes (CTL) and natural killer (NK) cells, become activated and start to release an excessive/disproportionate amount of TH-1 cytokines that attack the root system of the embryo, that implantation potential is jeopardized. Diagnosis of such activation requires highly specialized blood test for cytokine activity that can only be performed by a handful of reproductive immunology reference laboratories in the United States.
Alloimmune IID, i.e., where antibodies are formed against antigens derived from another member of the same species, is believed to be a relatively common immunologic cause of recurrent pregnancy loss.
Autoimmune IID is often genetically transmitted. Thus it should not be surprising to learn that it is more likely to exist in women who have a family (or personal) history of primary autoimmune diseases such as lupus erythematosus (LE), scleroderma or autoimmune hypothyroidism (Hashimoto’s disease), autoimmune hyperthyroidism (Grave’s disease), rheumatoid arthritis, etc. Reactionary (secondary) autoimmunity can occur in conjunction with any medical condition associated with widespread tissue damage. One such gynecologic condition is endometriosis. Since autoimmune IID is usually associated with activated NK and T-cells from the outset, it usually results in such very early destruction of the embryo’s root system that the patient does not even recognize that she is pregnant. Accordingly the condition usually presents as “unexplained infertility” or “unexplained IVF failure” rather than as a miscarriage.
Alloimmune IID, on the other hand, usually starts off presenting as unexplained miscarriages (often manifesting as RPL). Over time as NK/T cell activation builds and eventually becomes permanently established the patient often goes from RPL to “infertility” due to failed implantation. RPL is more commonly the consequence of alloimmune rather than autoimmune implantation dysfunction.
However, regardless, of whether miscarriage is due to autoimmune or alloimmune implantation dysfunction the final blow to the pregnancy is the result of activated NK cells and CTL in the uterine lining that damage the developing embryo’s “root system” (trophoblast) so that it can no longer sustain the growing conceptus. This having been said, it is important to note that autoimmune IID is readily amenable to reversal through timely, appropriately administered, selective immunotherapy, and alloimmune IID is not. It is much more difficult to treat successfully, even with the use of immunotherapy. In fact, in some cases the only solution will be to revert to selective immunotherapy plus using donor sperm (provided there is no “match” between the donor’s DQa profile and that of the female recipient) or alternatively to resort to gestational surrogacy.
DIAGNOSING THE CAUSE OF RPL
In the past, women who miscarried were not evaluated thoroughly until they had lost several pregnancies in a row. This was because sporadic miscarriages are most commonly the result of embryo numerical chromosomal irregularities (aneuploidy) and thus not treatable. However, a consecutive series of miscarriages points to a repetitive cause that is non-chromosomal and is potentially remediable. Since RPL is most commonly due to a uterine pathology or immunologic causes that are potentially treatable, it follows that early chromosomal evaluation of products of conception could point to a potentially treatable situation. Thus I strongly recommend that such testing be done in most cases of miscarriage. Doing so will avoid a great deal of unnecessary heartache for many patients.
Establishing the correct diagnosis is the first step toward determining effective treatment for couples with RPL. It results from a problem within the pregnancy itself or within the uterine environment where the pregnancy implants and grows. Diagnostic tests useful in identifying individuals at greater risk for a problem within the pregnancy itself include:
•Karyotyping (chromosome analysis) both prospective parents
•Assessment of the karyotype of products of conception derived from previous miscarriage specimens
•Ultrasound examination of the uterine cavity after sterile water is injected or sonohysterogram, fluid ultrasound, etc.)
•Hysterosalpingogram (dye X-ray test)
•Hysteroscopic evaluation of the uterine cavity
•Full hormonal evaluation (estrogen, progesterone, adrenal steroid hormones, thyroid hormones, FSH/LH, etc.)
•Immunologic testing to include:
a)Antiphospholipid antibody (APA) panel
b)Antinuclear antibody (ANA) panel
c)Antithyroid antibody panel (i.e., antithyroglobulin and antimicrosomal antibodies)
d)Reproductive immunophenotype
e)Natural killer cell activity (NKa) assay (i.e., K562 target cell test)
f)Alloimmune testing of both the male and female partners
TREATMENT OF RPL
Treatment for Anatomic Abnormalities of the Uterus: This involves restoration through removal of local lesions such as fibroids, scar tissue, and endometrial polyps or timely insertion of a cervical cerclage (a stitch placed around the neck of the weakened cervix) or the excision of a uterine septum when indicated.
Treatment of Thin Uterine Lining: A thin uterine lining has been shown to correlate with compromised pregnancy outcome. Often this will be associated with reduced blood flow to the endometrium. Such decreased blood flow to the uterus can be improved through treatment with sildenafil and possibly aspirin.
Sildenafil (Viagra) Therapy. Viagra has been used successfully to increase uterine blood flow. However, to be effective it must be administered starting as soon as the period stops up until the day of ovulation and it must be administered vaginally (not orally). Viagra in the form of vaginal suppositories given in the dosage of 25 mg four times a day has been shown to increase uterine blood flow as well as thickness of the uterine lining. To date, we have seen significant improvement of the thickness of the uterine lining in about 70% of women treated. Successful pregnancy resulted in 42% of women who responded to the Viagra. It should be remembered that most of these women had previously experienced repeated IVF failures.
Use of Aspirin: This is an anti-prostaglandin that improves blood flow to the endometrium. It is administered at a dosage of 81 mg orally, daily from the beginning of the cycle until ovulation.
Treating Immunologic Implantation Dysfunction with Selective Immunotherapy: Modalities such as IL/IVIg, heparinoids (Lovenox/Clexane), and corticosteroids (dexamethasone, prednisone, prednisolone) can be used in select cases depending on autoimmune or alloimmune dysfunction.
The Use of IVF in the Treatment of RPL
In the following circumstances, IVF is the preferred option:
1.When in addition to a history of RPL, another standard indication for IVF (e.g., tubal factor, endometriosis, and male factor infertility) is superimposed.
2.In cases where selective immunotherapy is needed to treat an immunologic implantation dysfunction.
The reason for IVF being a preferred approach in such cases is that in order to be effective, the immunotherapy needs to be initiated well before spontaneous or induced ovulation. Given the fact that the anticipated birthrate per cycle of COS with or without IUI is at best about 15%, it follows that short of IVF, to have even a reasonable chance of a live birth, most women with immunologic causes of RPL would need to undergo immunotherapy repeatedly, over consecutive cycles. Conversely, with IVF, the chance of a successful outcome in a single cycle of treatment is several times greater and, because of the attenuated and concentrated time period required for treatment, IVF is far safer and thus represents a more practicable alternative
Since embryo aneuploidy is a common cause of miscarriage, the use of preimplantation genetic diagnosis (PGD), with tests such as CGH, can provide a valuable diagnostic and therapeutic advantage in cases of RPL. PGD requires IVF to provide access to embryos for testing.
There are a few cases of intractable alloimmune dysfunction due to absolute DQ alpha matching where Gestational Surrogacy or use of donor sperm could represent the only viable recourse, other than abandoning treatment altogether and/or resorting to adoption. Other non-immunologic factors such as an intractably thin uterine lining or severe uterine pathology might also warrant that last resort consideration be given to gestational surrogacy.
The good news is that if a couple with RPL is open to all of the diagnostic and treatment options referred to above, a live birthrate of 70%–80% is ultimately achievable.
I strongly recommend that you visit www. SherIVF.com. Then go to my Blog and access the “search bar”. Type in the titles of any/all of the articles listed below, one by one. “Click” and you will immediately be taken to those you select. Please also take the time to post any questions or comments with the full expectation that I will (as always) respond promptly.
•The IVF Journey: The importance of “Planning the Trip” Before Taking the Ride”
•Controlled Ovarian Stimulation (COS) for IVF: Selecting the ideal protocol
•IVF: Factors Affecting Egg/Embryo “competency” during Controlled Ovarian Stimulation(COS)
•The Fundamental Requirements For Achieving Optimal IVF Success
•Ovarian Stimulation for IVF using GnRH Antagonists: Comparing the Agonist/Antagonist Conversion Protocol.(A/ACP) With the “Conventional” Antagonist Approach
•Ovarian Stimulation in Women Who have Diminished Ovarian Reserve (DOR): Introducing the Agonist/Antagonist Conversion protocol
•Anti Mullerian Hormone (AMH) Measurement to Assess Ovarian Reserve and Design the Optimal Protocol for Controlled Ovarian Stimulation (COS) in IVF.
•Human Growth Hormone Administration in IVF: Does it Enhances Egg/Embryo Quality and Outcome?
•The BCP: Does Launching a Cycle of Controlled Ovarian Stimulation (COS). Coming off the BCP Compromise Response?
•Blastocyst Embryo Transfers Should be the Standard of Care in IVF
•IVF: How Many Attempts should be considered before Stopping?
•“Unexplained” Infertility: Often a matter of the Diagnosis Being Overlooked!
•IVF Failure and Implantation Dysfunction:
•The Role of Immunologic Implantation Dysfunction (IID) & Infertility (IID):PART 1-Background
•Immunologic Implantation Dysfunction (IID) & Infertility (IID):PART 2- Making a Diagnosis
•Immunologic Dysfunction (IID) & Infertility (IID):PART 3-Treatment
•Thyroid autoantibodies and Immunologic Implantation Dysfunction (IID)
•Immunologic Implantation Dysfunction: Importance of Meticulous Evaluation and Strategic Management:(Case Report
•Intralipid and IVIG therapy: Understanding the Basis for its use in the Treatment of Immunologic Implantation Dysfunction (IID)
•Intralipid (IL) Administration in IVF: It’s Composition; How it Works; Administration; Side-effects; Reactions and Precautions
•Natural Killer Cell Activation (NKa) and Immunologic Implantation Dysfunction in IVF: The Controversy!
•Endometrial Thickness, Uterine Pathology and Immunologic Factors
•Vaginally Administered Viagra is Often a Highly Effective Treatment to Help Thicken a Thin Uterine Lining
•Treating Out-of-State and Out-of-Country Patients at Sher-IVF in Las Vegas:
•A personalized, stepwise approach to IVF
•How Many Embryos should be transferred: A Critical Decision in IVF.
•The Role of Nutritional Supplements in Preparing for IVF
If you are interested in my advice or medical services, I urge you to contact my patient concierge, ASAP to set up a Skype or an in-person consultation with me. You can also set this up by emailing concierge@sherivf.com or by calling 702-533-2691 and/or 800-780-743. You can also enroll for a consultation with me, online at http://www.SherIVF.com.
Also, my book, “In Vitro Fertilization, the ART of Making Babies” is available as a down-load through http://www.Amazon.com .
Geoffrey Sher MD
I had a 5 day transfer and am currently 6 weeks pregnant. I am prediabetic and my last pregnancy I had gestational diabetes as well. I know the doctors can’t test for gestational diabetes this soon but I also know that spiking my blood pressure is very bad for a developing fetus. Because I am so nauseous it is very hard for me to eat the healthy way I should, I am trying my best but sometimes all I can eat are crackers and bread. I have my old glucose monitor and know my numbers spike when I don’t eat well. So far it has only happened a few times. What can I do? What does this actually mean for my baby?
Hi Natalie,
I am afraid this falls in the domain of your treating OB. Please discuss this with him/her ASAP.
Good luck and congratulations!
Geoff Sher
Hello Doctor! I had a 15mm follicle with reasonable estradiol levels. Yesterday the follicle was 19mm but estradiol came down. I don’t know if this means ovulation or whether this has turned into a cyst. Will taking Ovidrel now help this cyst/follicle to ovulate? If I already ovulated but the follicle turned into a cyst-will taking Ovidrel hurt?
Hi Glafki. This is not a good sign and could suggest premature luteinization (premature LH surge). If correct this would limit the chance of a successful cycle quite dramatically.
Sorry!
Geoff Sher
Testing