|Proton pump inhibitors and pregnancy outcomes

Use of Proton-Pump Inhibitors in Early Pregnancy and the Risk of Birth Defects
Björn Pasternak, M.D., Ph.D., and Anders Hviid, Dr.Med.Sci.
N Engl J Med 2010; 363:2114-2123November 25, 2010

DISCUSSION
This nationwide cohort study showed that there were no significant associations between the use of PPIs during the first trimester and the risk of major birth defects. In subgroup analyses, estimates of risk were similar across the individual PPIs, with the exception of rabeprazole, for which there were limited data. In secondary analyses, we found no significant associations between the use of PPIs during the first trimester and subgroups of major birth defects according to organ system.
Our initial analysis defined exposure to PPIs as the filling of a prescription at some time between 4 weeks before conception and the end of the first trimester, since we wanted to include data from women who had started taking PPIs before conception and continued taking them during early pregnancy. When exposure within 4 weeks before conception was included in the main analysis, there was a significant association between exposure to PPIs and major birth defects. When separate analyses were performed on data from women who filled prescriptions within 4 weeks before conception and from those who filled prescriptions in the first trimester, only women who received PPIs within 4 weeks before conception were at increased risk for having infants with birth defects. Furthermore, when the analyses accounted for the daily doses of PPIs in prescriptions filled before conception, only infants whose mothers took PPIs before the estimated date of conception but did not receive enough doses to have a theoretical chance of continued exposure beyond conception were at increased risk for birth defects. Analyses of data from alternative exposure-time windows supported the main results. Although some misclassification of the timing of exposure is possible17 given the uncertainty regarding the dates of conception, the results of analyses focusing on exposures during weeks 3 to 8 after presumed conception were consistent with the main results involving exposure during the 12 weeks after presumed conception.
The observed association between exposure to PPIs within the month before conception and major birth defects may represent unmeasured confounding or may have been due to chance. The plasma half-lives of PPIs range between 1 and 2 hours; therefore, it is unlikely that there was a carryover effect from exposure before conception into early pregnancy.
Our results with respect to the effect of exposure to PPIs during the first trimester are consistent with findings from previous research involving various types of cohorts, including registry-based historical cohorts, prospective cohorts of mothers seeking advice from teratology services, and cohorts identified from pregnancy registries.7-9,11,23,24 A meta-analysis of these studies, which was based on 1530 women exposed to PPIs in early pregnancy, showed that there was no significant increase in the risk of birth defects associated with exposure to PPIs (odds ratio, 1.12; 95% CI, 0.86 to 1.45).6 Our study, which had a substantially larger cohort than the samples in all the previous reports collectively, confirms the findings from previous reports regarding omeprazole and extends those findings to other PPIs.
Our study covered a period of 13 years and involved a nationwide population and independent ascertainment of exposure and outcome. Several previous studies7,8,23 did not follow children beyond the immediate neonatal period, and defects diagnosed later would not have been included in the analyses, whereas our study had a 1-year follow-up period for birth defects. Although we adjusted for several potential confounders, it is possible that there were confounding factors that we did not identify. Our primary concern would be factors that could have masked a risk of birth defects associated with the use of PPIs. Given the size of the cohort, such factors would have had to be common or would have had to be strongly associated with both the use of PPIs and a reduced risk of defects. We consider it unlikely that there were unmeasured confounding factors that met these criteria.
We used a registry-based case-finding strategy for the identification of birth defects, and the outcome may have been subject to minor misclassification.18 Although any misclassification was probably random, it could bias the results toward no effect. We used filled prescriptions as proxies for exposure to PPIs. If women did not take the dispensed PPIs, however, the results would be biased toward no effect, and teratogenic effects, if present, could be obscured. Omeprazole and lansoprazole became available as over-the-counter drugs during the last years of the study. Misclassification of exposure on the basis of the use of over-the-counter preparations by women who were classified as not having been exposed to PPIs could similarly bias the results toward no effect. However, the analysis that was restricted to the period when PPIs were available by prescription only provides further reassurance that misclassification of exposure was not an important source of bias.
The main outcome measure — all major birth defects combined — may have some shortcomings. Teratogens typically cause specific defects or groups of defects and do not necessarily increase the rate of birth defects overall.25 Nevertheless, composite outcomes are often used in studies of birth defects26,27 and offer opportunities to identify previously unknown or unsuspected associations. A limitation of cohort studies of births defects is that specific defects are uncommon, and therefore the power to detect associations with individual defects is limited.25 Our analyses of subgroups of birth defects should therefore be interpreted with caution. Large case–control studies28,29 may provide opportunities to investigate specific defects with sufficient power.
Most studies of the safety of PPIs during pregnancy have involved women exposed to omeprazole. The results of our study add to the data supporting the safety of this drug with regard to birth defects. Moreover, research that showed no increase in the risk of spontaneous abortions or preterm births associated with the use of PPIs was also based largely on exposure to omeprazole.6 Further study is needed to address the safety of PPIs with regard to perinatal outcomes, as well as the outcomes when PPIs are taken during lactation, and to address specific birth defects and potential long-term risks associated with individual PPIs.30
In conclusion, in this nationwide cohort study, we found no significant association between the use of PPIs during the first trimester of pregnancy and the risk of major birth defects. These results provide reassurance that PPIs, and omeprazole in particular, can be used relatively safely during the first trimester.

Previous preterm birth and future management

Risk facotrs : The primary risk factors for recurrent spontaneous preterm birth (SPTB) are a history of SPTB and a short cervical length (CL) found on second trimester transvaginal ultrasound (TVU).


In women with prior SPTB or a short CL, the most frequently used interventions to prevent preterm birth (PTB) are cerclage and progesterone supplementation.

1.200 mg of daily vaginal/rectal  progesterone beginning as early as 16 weeks' gestation and continuing  through 36 weeks.

2.The best evidence that progesterone reduces the risk of prematurity among women with a short cervix comes from the trial of Fonseca et al, in which women with a CL of 15 mm or less in the midtrimester were randomly allocated to receive 200 mg of daily vaginal progesterone or matching placebo from 24 to 34 weeks' gestation. In this trial, the 125 women allocated to progesterone had a significantly reduced risk of prematurity before 34 weeks (the primary study outcome) than the 125 allocated to placebo, 19% versus 34%.

3. For women with a prior SPTB (spontaneous preterm birth), regardless of their CL (cervix length), 17P is indicated. Furthermore, 17P should not be withheld from women who undergo cerclage for a history of prior SPTB and a short cervix

Ref : 17-Alpha-Hydroxyprogesterone Caproate for the Prevention of Preterm Birth in Women With Prior Preterm Birth and a Short Cervical Length, Obstet.Gynaecol Survey 2010 Nov

Communication

Communication in military combat is essential to successfully execute a plan. It ensures safety, keeps everyone focused on their responsibilities, and builds awareness in rapidly changing environments.

In the heat of battle, where effective communication is critical, fighter pilots:

Brief the mission in order to establish objectives, delegate responsibilities, analyze threats, and review contingency plans.
Establish a communication ("comm") game plan which confirms when and where to change frequencies.
Ensure positive two-way communication is established during critical elements of a mission.
Brief a back-up plan in case communication fails (known as "radio-out" procedures).
Debrief every mission to review lessons learned and reinforce training.

As a business leader, do you have a "comm plan" with your employees and colleagues? Are you taking the time to brief your missions to ensure all your wingmen are on the same wave length and understand their roles, responsibilities, and objectives? Finally, are you aware of those who might be on the wrong frequency or off course? What's your plan to get them back on target?
Checking in with your wingmen, listening to their questions, and understanding their challenges are fundamental components of teamwork and leadership. They are the cornerstones in building an environment of mutual support and trust.
.
Here are several communication "wingtips" gleaned from my experience as a fighter pilot that can apply to you as a business leader:

Have a mass briefing at least once a month. Gather your troops and communicate the latest trends, organizational goals, sales updates, and product upgrades etc. Your wingmen need to hear important news — whether good or bad — from you first. This is also a great time to publicly recognize your top performers.
Conduct feedback sessions on a regular basis. Sit down with your wingmen and let them know how they are doing. Are they meeting your expectations? Ask them about their goals and challenges and how you can help. Then solicit feedback on you as a leader. What would they like to see from you? Avoid letting your ego get in the way of their feedback.
Walk the flight line. Get your hands dirty with your wingmen. Spend time with them on the job and observe how they do business. Ask questions. Show them your appreciation by connecting with them as people first and employees second.
De-brief your missions. Remove your 'rank' and conduct a nameless, blameless, and rank-less de-brief after every critical mission. Find out if objectives were met, and analyze why they weren't. Search for trends and communicate these to the rest of your organization.
Your aim should be to listen as much as possible in order to build what we call situational awareness — a comprehensive understanding of the mission. The greater your situational awareness, the better your ability to handle contingencies and adapt to change. As the flight lead of your team, it's very important that you create an environment where others can come to you for help. This inspires a culture of trust which is mission critical in business.




http://blogs.hbr.org/frontline-leadership/2010/10/a-fighter-pilots-guide-to-effe.html?cm_mmc=email-_-newsletter-_-weekly_hotlist-_-hotlist110110&referral=00202&utm_source=newsletter_weekly_hotlist&utm_medium=email&utm_campaign=hotlist110110

Severe SPD

Today I met up with a lady at 40+1/40 weeks who had such a severe SPD that she could not lie on her back to listen to the fetus. I have to listen to the fetus in the chair only. Obviously my concern was how are we going to induce, how are we going to monitor the foetus etc.

Finally I decided to speak to senior consultant who agreed with my queries and we told her she may be better of having caesarean section even though it was a soft indication.

Recurrent pregnancy losses

Management of previous stillbirth

-The overall recurrence risk for stillbirth is increased 2 to 10 folds in the next pregnancy, depending on the circumstances. Understanding the circumstances of the previous stillbirth is important for counseling about stillbirth recurrence risk.

- In a significant number of cases, either the evaluation was incomplete or the prior stillbirth remains unexplained despite a complete work-up.

-- factors that have been associated with an increased overall risk of stillbirth include previous pregnancy outcomes, nulliparity, maternal age >=35 years, black race, maternal obesity (prepregnancy body mass index >30 kg/m²), smoking, maternal medical disease, fetal growth impairment, postterm and assisted reproductive technology, specifically in vitro fertilization/intracytoplasmic sperm injection. Obesity and smoking are the most modifiable risk factors for stillbirth. Women who quit smoking from their first to second pregnancy have been shown to reduce their risk of stillbirth to the same level as nonsmokers in the second pregnancy.

Predictive Markers: Biochemical Markers

The first trimester screen [nuchal translucency, pregnancy-associated plasma protein A (PAPP-A), and the beta subunit human chorionic gonadotropin ([beta]-hCG)] used for Down syndrome risk assessment may be useful for stillbirth risk assessment. PAPP-A is a protease for insulin-like growth factor (IGF) binding proteins 4 and 5. Low PAPP-A will lead to decreased free IGF. IGFs are crucial for regulation of fetal growth and trophoblast function. In a cohort of 7934 pregnancies, PAPP-A, defined as <5th class="fulltext-RA" href="http://ovidsp.tx.ovid.com.ezproxy.galter.northwestern.edu/sp-3.2.4b/ovidweb.cgi?&S=FFAEFPFFLFDDDDNFNCDLFBJCLMOKAA00&Link+Set=S.sh.15.17.19%7c24%7csl_10#59" style="margin-top: 0px; margin-right: 0px; margin-bottom: 0px; margin-left: 0px; padding-top: 0px; padding-right: 0px; padding-bottom: 0px; padding-left: 0px; font-weight: normal; text-decoration: none; color: rgb(7, 104, 169); ">7 The role of second trimester serum screening using [alpha]-fetoprotein, hCG, uE3, and inhibin-A, in stillbirth prediction has been studied. Unexplained elevated maternal serum alpha-fetoprotein (in the absence of neural tube defect or ventral wall defect) has been associated with stillbirth via a defect in placentation. The role of second trimester serum screening using [alpha]-fetoprotein, hCG, uE3, and inhibin-A, in stillbirth prediction has been studied. Unexplained elevated maternal serum alpha-fetoprotein (in the absence of neural tube defect or ventral wall defect) has been associated with stillbirth via a defect in placentation. In a large study of first and second trimester biomarkers, low PAPP-A was not associated with high AFP, suggesting they reflect different aspects of placental dysfunction. *****The OR for antepartum stillbirth for women with a high AFP was 2.5, for women with a low PAPP-A was 2.2, and for women with both low PAPP-A and high AFP was 36.7. Thus, women with low PAPP-A and high AFP had a synergistic increase in stillbirth risk.10 Predictive Markers: Uterine Artery Doppler During pregnancy the spiral arteries undergo a series of vascular transformations to ensure a more than 10-fold increase in the blood supply to the intervillous space. In conditions associated with failure of trophoblastic invasion of the spiral arteries, Doppler studies demonstrate that impedance to flow in the uterine arteries is increased. A review of Doppler studies performed in unselected populations found that abnormal uterine artery studies at 22 to 24 weeks was associated with increased rates of development of preeclampsia, fetal growth restriction, and perinatal death.11In pooled analyses of 4 studies, the likelihood of fetal or perinatal death in those with an abnormal Doppler result was about 2.4 times higher than the background risk. Predictive Markers: Ultrasound and fetal growth Fetal growth restriction is the single largest category of conditions associated with stillbirth and is found in the majority of the cases previously considered unexplained. mproved antenatal detection of fetal growth restriction is crucial to having a positive impact on stillbirth prevention. In up to one-third of pregnancies, fetal growth restriction may be missed and is incorrectly diagnosed about 50% of the time.14Without the correct diagnosis of fetal growth restriction, antenatal surveillance may not be performed and timely delivery of the fetus at risk for stillbirth from an unfavorable intrauterine environment will not occur. The authors proposed initiating antepartum surveillance at 32 weeks or later, acknowledging that a rare patient with earlier fetal compromise may be missed.16 American Congress of Obstetricians and Gynecologists (ACOG) supports this conclusion and states that starting antepartum testing at 32 to 34 weeks is appropriate in healthy pregnant women with a history of stillbirth. In pregnancies with multiple or particularly worrisome high-risk conditions (eg, chronic hypertension with suspected fetal growth restriction), testing may begin as early as 26 to 28 weeks of gestation.17 Fetal kick count t is customary to recommend that women with prior stillbirth be instructed on fetal movement assessment and women who report decreased fetal movement undergo follow-up fetal surveillance. Because stillbirths may be preceded by a reduction or cessation of fetal movements, recognition of decreased fetal movement, followed by testing to confirm fetal compromise and expedite delivery, may prevent such deaths. This observation is the basis for fetal movement assessment by the mother (“kick counts”) as a means of antepartum fetal surveillance. Reviews of stillbirth indicate that almost half of it occurs in low-risk pregnant women with structurally normal fetuses, women who are not candidates for traditional antepartum surveillance. The recommendation is that all women with a prior stillbirth should be instructed to begin fetal movement assessment from 26 to 28 weeks of gestation and those who report decreased fetal movement should have follow-up fetal surveillance.16 THERAPY FOR PREVENTION OF RECURRENT STILLBIRTH Improved treatment of maternal medical disorders such as diabetes and hypertension has clearly decreased the risk of stillbirth in these situations. The risk of stillbirth associated with antiphospholipid antibody syndrome is decreased with treatment with prophylactic heparin or low molecular weight heparin and low-dose aspirin. ASPIRIN THERAPY There has been a growing interest in the use of low-dose aspirin to improve subsequent pregnancy after fetal death. Low-dose aspirin is an antiplatelet agent, which irreversibly inhibits platelet cyclo-oxgenase thereby decreasing the production of thromboxane A2, a potent vasoconstrictor. Aspirin use was promoted by the recognition that thrombosis was central to the pathophysiology of antiphospholipid syndrome and was first used to treat recurrent pregnancy loss in women with antiphospholipid syndrome. There is speculation that low-dose aspirin may improve the uteroplacental circulation by decreasing placental thrombosis, infarction, and insufficiency, which are associated with fetal death. Management of the Subsequent Pregnancy During the preconception or initial visit, the obstetric provider should obtain a detailed medical and obstetrical history; review the evaluation of the prior stillbirth; determine recurrence risk based on available information; and discuss the risk of other obstetrical complications such as placental abruption, preterm delivery, and cesarean delivery. Counseling should be individualized to the woman's particular circumstances. For example, if a couple experienced a previous second trimester stillbirth as a result of a cystic hygroma and nonimmune hydrops due to Turner syndrome, they can be reassured that it is a sporadic condition and is not associated with advanced maternal age. However, in the subsequent pregnancy one can offer nuchal translucency ultrasound to provide reassurance. First trimester sonogram should be performed for accurate dating. Although the predictive value for maternal serum screening in the first trimester is low, performing maternal serum PAPP-A may provide some reassurance regarding the recurrence risk of stillbirth from “placental causes.” In the second trimester, fetal anatomic survey may be performed at 18 to 20 weeks. Similar to the first trimester screen, the predictive value of second trimester analytes for stillbirth (MSAFP, hCG, estriol, and inhibin-A) is poor but may provide additional information. MSAFP testing may be associated with the presence of a placental abnormality if it is elevated in a chromosomally normal fetus. Likewise, an abnormally elevated [beta]-hCG may be associated with an increased risk of stillbirth but has poor predictive value. Women with a prior stillbirth should be already counseled and monitored clinically based on their previous history of stillbirth. Although there is no evidence to support further alteration in the management plan based on abnormal serum screening, the clinician may consider increasing the frequency of antepartum surveillance. Because nearly half of all stillbirths are associated with fetal growth restriction, serial ultrasounds for fetal growth may be performed, starting at 28 weeks. If there is evidence of fetal growth restriction then the frequency of ultrasound to monitor fetal growth may be increased, usually to every 2 to 4 weeks and Doppler studies and antepartum fetal testing performed. The ACOG technical bulletin on intrauterine growth restriction outlines management strategies. In all women with a previous stillbirth, maternal assessment of fetal movement or fetal kick counts may be started at 28 weeks of gestation. Antepartum fetal testing such as twice weekly nonstress tests and amniotic fluid index or biophysical profiles may be initiated at 32 weeks or 1 to 2 weeks before the gestational age of the previous stillbirth. In women with especially high-risk medical or obstetric conditions, testing should be initiated at 26 to 28 weeks.17 Caution should be used when interpreting the antepartum fetal surveillance of a fetus below 32 weeks of gestation. he delivery plan should be discussed with the couple well in advance of the third trimester. The timing of the delivery depends on maternal anxiety, cervical ripeness, and the cause of the previous stillbirth. In most cases, if the pregnancy is uncomplicated, elective induction at 39 weeks of gestation may be appropriate. In summary, there is limited information to support each step of the management schema outlined in Table 2. The key for the clinician is to gather as much information regarding the circumstances of the previous stillbirth, individualize management of the subsequent pregnancy, be compulsive in monitoring the development of obstetric complications, and to provide support and reassurance to a couple likely to be anxious during their next pregnancy.

Not all elevated ALT and bile acids are cases of OC

I learnt from a patient who was having hence pt has had bile acids done which showed upward trend. Initially it was 30 went up to 70 and then to 90 at 30 weeks of gestation.

Similar story with AST, went from 50 to 120 to 240 to 600.

After two weeks all these levels start falling and pt started feeling better.

Looking backwards, it appears that pt probably suffered viral infection and accordingly levels went up and with slow recovery the levels of AST and Bile acides declined.

So do not panick to deliver based on the levels

diabetic ketosis (DK) and Diabetic ketoacidosis (DKA)

Today , I came to knwo the difference between between DK and DKA.

In DK you will have hyperglycaemia and ketonuira. In DKA apart from hyperglycemia and ketonuria, on blood gas analysis, you will have base excess of -10 or more.

If untreated DK will pead to DKA.

Intrapartum tachycardia and hypoxia

Today, I had a lady who developed tachycardia of 142-160 beats per minute, immediately she started shwoing hypoxia of (pulse oximetry opf 92%), but temperature was normal 36.5. I suspected intrapartum sepsis and expedited delivery by ventouse and sent placental swab and gave Ceph + Met and follwing delivery her tachcyardia reduced to 102/min but her temperature rose to 38.6. This case highlights two things, one tachycardia may be the first sign of sepsis follwoed by hypoxia and hyperthermia may be the last to set in.

I think once sepsis is suspected expedition of delivery is the key, otherwise mum and baby are giong to get more and more infected and become septic.

Perform, ECG, CXR, ABG, U&Es and Ca and Mg levels

Recurrent Miscarriage

N Engl J Med 2010; 363:1740-1747, 28/10/2010

A 32-year-old woman presents for evaluation after three consecutive miscarriages. Before these miscarriages, she had one successful pregnancy. The patient reports no medical problems or previous surgeries. In her first miscarriage, uterine bleeding and cramping started in the 7th week of gestation, and an ultrasonographic evaluation showed an empty gestational sac of 6 weeks' size. In her next pregnancy, she presented with a miscarriage in the 8th week. The third miscarriage was identified by ultrasonographic testing as a dead embryo measuring 7.5 weeks' size. How should her case be evaluated and managed?

The Clinical Problem

Miscarriage is the spontaneous loss of the conceptus before 20 weeks' gestation. In 10% of pregnancies, miscarriage is a clinically recognized event, and in another 20% of pregnancies, it is manifested only as a transient elevation of the level of human chorionic gonadotropin before or near menses.1

A majority of miscarriages that occur before 10 weeks' gestation are due to chromosomal aneuploidies arising from noninherited, new nondisjunctional events; these events are more frequent in very early miscarriages.2 The rate of miscarriage increases with a maternal age of less than 18 years or an age of 35 years or more, an increasing number of previous miscarriages, and increasing parity.3 The sharp increase in the rate of miscarriage in women 35 years of age or older is due in part to increasing rates of aneuploidy in association with older oocytes.2,3

Recurrent miscarriage, defined as the loss of three or more consecutive pregnancies, occurs in approximately 1% of couples attempting to bear children.4 This rate is higher than would be expected if recurrences were due solely to chance, suggesting an underlying predisposition in some couples. Many experts consider two consecutive losses as sufficient for the diagnosis of recurrent miscarriage5,6 because the recurrence rate is similar to that after three losses. Two consecutive miscarriages occur in up to 5% of reproductively active couples and an even higher proportion of women 35 years of age or older. For many couples, evaluation does not reveal a cause, and in some cases, it leads to an unrelated finding or unnecessary treatment.

Most women with recurrent miscarriage have recurrent early miscarriage — either the failure of the development of an ultrasonographically recognizable embryo or embryonic death before 10 weeks' gestation; however, signs and symptoms of the miscarriage (uterine bleeding and cramping) may appear after 10 weeks. A substantial proportion of recurrent early miscarriages are due to conceptus aneuploidy, although it is less common than with sporadic miscarriage.7 A smaller proportion of women with recurrent miscarriage have late miscarriage (death of the conceptus at or after 10 weeks' gestation), usually before 15 to 16 weeks.8 Causes and recurrence rates for late miscarriage may differ from those for early miscarriage.

Recurrent miscarriage is a distressing problem. Frequently, the cause is elusive or multifactorial, and misinformation abounds, giving rise to frustration for the couple and the physician.

Strategies and Evidence

Evaluation

The physician should determine the

1. nature of previous pregnancy losses, especially with regard to the actual gestational age at the time of the demise of the conceptus (rather than the onset of symptoms).

2.The medical and obstetrical history should cover any features suggestive of the antiphospholipid syndrome (e.g., thrombosis or fetal death)

3.or possible uterine malformation (e.g., breech presentation).

4.Poorly controlled diabetes9

5.or thyroid disease10 in early pregnancy is associated with miscarriage, but well-controlled disease is not; testing for these conditions is not recommended for the sole indication of recurrent miscarriage.

6. Obesity,11 cigarette smoking,12 alcohol use,13 and moderate-to-heavy caffeine use14 may be associated with sporadic miscarriage, but relationships between these conditions and recurrent miscarriage have not been extensively studied and are uncertain. There is no good evidence that physical activity, including sexual activity and exercise, causes miscarriage.

Five to 15% of women with recurrent miscarriage have clinically significant antiphospholipid antibody titers, as compared with 2 to 5% of unselected obstetrical patients.15

****Because results may be transiently positive after infection, the antiphospholipid syndrome should be diagnosed only when two tests performed 12 or more weeks apart are positive.

7. It also has become common to screen patients with recurrent miscarriage for thrombophilias, although it is uncertain whether this screening is warranted. Case–control studies have shown a modest association (odds ratios of 2 to 3) between recurrent miscarriage and thrombophilias such as the factor V Leiden mutation and the prothrombin G20210A mutation.16 However, associations have tended to be stronger for fetal deaths, such as stillbirths after 20 weeks' gestation, than for recurrent early losses, and several large, prospective cohort studies have not shown significant associations between thrombophilias and sporadic pregnancy loss.17-19 Furthermore, many thrombophilias are common in the general population, and the vast majority of women with thrombophilias have normal pregnancies.

8. Uterine malformations, most commonly arcuate and septate uteruses are detected in 10 to25% of women with recurrent miscarriage but in only 5% of controls,20 and evaluation of the uterine cavity (primarily to look for a septum) is recommended by professional organizations in women with recurrent miscarriage (Table 1Table 1Evaluation of a Woman with Recurrent Miscarriage.). Vascular insufficiency is thought to underlie miscarriage in the case of septate uterus.

8.One partner (more often the woman) has a balanced chromosomal rearrangement in 3 to 6% of cases of recurrent miscarriage.2,21 The most common abnormality is a translocation, either reciprocal or robertsonian (involving two homologous or nonhomologous acrocentric chromosomes [chromosomes 13, 14, 15, 21, and 22]) Parental karyotyping is expensive. Because available treatment (in vitro fertilization [IVF] with preimplantation genetic diagnosis) has not been shown to improve the outcome, as compared with that of spontaneous conception (see below), some couples may choose to forgo parental karyotype testing.

Though controversial,

9.some experts recommend karytoype analysis of the conceptus in couples with recurrent miscarriage to avoid unnecessary evaluation and treatment and because an aneuploid conceptus indicates a somewhat greater likelihood of success with a subsequent pregnancy.22 If karyotype analysis is not possible because of cell-culture failure, array comparative genomic hybridization may be considered. This test provides most of the information provided by cytogenetic analysis, as well as data regarding smaller regions of chromosomes than those identified by traditional karyotype analysis. Array comparative genomic hybridization cannot identify balanced translocations.

Although any bacterial or viral infections that spread to the uterus may cause sporadic miscarriage, there is no proven infectious cause of recurrent miscarriage. Thus, screening tests for ureaplasma, chlamydia, and other infectious agents are not recommended in the evaluation of recurrent miscarriage.

Similarly, although a deficiency of progesterone during the luteal phase (resulting in inadequate endometrial preparation) has been proposed as a cause of miscarriage, screening for a deficiency would be problematic, because there is no clear threshold for normal progesterone values, which vary considerably from one person to another, and progesterone measurements are not closely correlated with other markers of endometrial function.23,24 Thus, diagnosis of this putative disorder by means of timed endometrial histologic analysis or measurement of progesterone levels is not recommended.

Immunologic testing such as HLA typing tests for immune reactivity in the mother against the father or determination of leukocyte populations has been recommended by some clinicians on the basis of the hypothesis that recurrent miscarriage may be caused by maternal immunologic rejection of the conceptus as a semi-allograft.

10.However, most experts do not support such testing, since unequivocal evidence of an alloimmune cause of recurrent miscarriage in humans is lacking, and there is no good evidence that screening for alloimmunization, with treatment in identified cases, improves clinical outcomes.5,6,25

Management

The prognosis for women with a history of recurrent miscarriage is often favorable, even without intervention. In one of the largest treatment trials involving women with idiopathic recurrent miscarriage,26 which included women with 4.2 consecutive miscarriages and an average age of 32.7 years, the placebo group had a live-birth rate of 65%. Other studies suggest even better outcomes with frequent prenatal visits and visualization of the pregnancy on ultrasonographic examination, beginning early in pregnancy and extending throughout the first trimester,25,27 perhaps owing to maternal reassurance.

Anticoagulant Therapy

1. Repeatedly positive antiphospolipid antibody tests need,

prophylactic doses of unfractionated heparin (e.g., 5000 U subcutaneously twice daily) and low-dose aspirin, as compared with aspirin alone.28,29 , two clinical trials showed improved live-birth rates with the use of

This strategy has become standard treatment for recurrent miscarriage due to the antiphospholipid syndrome, yet two more recent randomized trials involving women with this syndrome showed no significant improvement in the live-birth rate with the use of prophylactic doses of low-molecular-weight heparin and low-dose aspirin, as compared with aspirin alone.30,31 Unlike the earlier positive studies, the negative studies included women with low levels of antibodies, used low-molecular-weight heparin (rather than unfractionated heparin), and showed high rates of live births among women who received only low-dose aspirin. Improved live-birth rates were also reported in some32 but not other33 studies of heparin thromboprophylaxis (with or without aspirin) in women with a heritable thrombophilia and recurrent miscarriage or fetal death. Thus, the role of this treatment specifically for the prevention of recurrent miscarriage remains controversial. Women with a history of thrombosis in whom the antiphospholipid syndrome or a heritable thrombophilia is diagnosed should receive an appropriate dose of unfractionated heparin or low-molecular-weight heparin.34

For women with unexplained recurrent miscarriage, it has become common practice to provide empirical treatment with low-dose aspirin, prophylactic doses of low-molecular-weight heparin, or both. However, two recent controlled, randomized trials involving women with unexplained recurrent miscarriage showed no improvement in live-birth rates with the use of low-dose aspirin alone35 or low-molecular-weight heparin and low-dose aspirin.35,36, Thus, this approach is not recommended outside of clinical trials.

Treatment of Uterine Anomalies

Most experts recommend hysteroscopic resection of a uterine septum in women with recurrent miscarriage; this recommendation is based on retrospective and uncontrolled observational studies and case series.37,38 However, data from well-designed trials supporting this practice are lacking, and septa are also detected among women with normal pregnancies.39 The high likelihood of successful pregnancy outcomes in nulliparous women with septa, as well as good outcomes without surgery, weigh against surgical correction of a uterine septum in nulligravid women.40 Since most women with bicornuate or unicornuate uteruses have good obstetrical outcomes, and surgical repair of these abnormalities is more invasive than septum resection and associated with a higher risk of complications, repair of these abnormalities is not generally advised.

Management of Genetic Abnormalities

Although the prognosis varies depending on the abnormality, pregnancy outcomes among couples with a balanced translocation are better than one might anticipate. Overall, there is up to a 70% chance of a live birth with no interventions.41 The risk of a live-born infant with a translocation trisomy is low, generally less than 1%. IVF with preimplantation genetic diagnosis has been used in an attempt to avert such outcomes. However, the high likelihood of a karyotypically normal or balanced offspring in the absence of this intervention41,42 makes its usefulness questionable.

To increase the likelihood of successful pregnancy, preimplantation genetic screening of biopsied blastomeres during IVF has been recommended in order to prevent the transfer of karyotypically abnormal embryos in couples with normal karyotypes. However, this approach is not supported by appropriately conducted randomized trials. Also, in a randomized trial involving women undergoing IVF who were at increased risk for miscarriage because of their age, the use of IVF with preimplantation genetic screening did not significantly increase the likelihood of successful live birth.43 This finding may be explained in part by chromosomal mosaicism in early embryos, with discordance between the chromosomes in a biopsied blastomere and those in the resulting fetus. Given these data, and in the absence of convincing evidence of a benefit, preimplantation genetic screening in couples with idiopathic recurrent miscarriage is not recommended.44 The use of array comparative genomic hybridization, which has finer resolution, with biopsied polar bodies and assessment of the karyotype contribution from the oocyte may potentially improve the success of preimplantation genetic screening of blastomeres, but trials are needed to evaluate its use in couples with recurrent miscarriage.

Immunologic Intervention

Although alloimmunity has been hypothesized to be a possible cause of recurrent miscarriage, a randomized trial of paternal leukocyte immunization showed no improvement in the rate of live births,26 and the Food and Drug Administration now requires investigational-drug approval for the use of this biologic product. In addition, a Cochrane review of seven trials showed that intravenous immune globulin had no significant benefit with regard to the live-birth rate among couples with recurrent miscarriage.45

Areas of Uncertainty

Some experts have questioned the association of recurrent miscarriage with antiphospholipid antibodies, and a recent international task force concluded that further studies using standardized antiphospholipid-antibody testing with confirmation in a central laboratory would be informative.46 Anticoagulant therapy is commonly prescribed for women with a history of recurrent miscarriage and antiphospholipid antibodies, and it is recommended in published guidelines, although discrepant results of recent trials have raised controversy in the field.

The treatment of women with recurrent miscarriage who also carry a heritable thrombophilia has not been adequately studied, and thus no recommendations regarding treatment efficacy can be made; results of a completed treatment trial (Low Molecular Weight Heparin and/or Aspirin in Prevention of Habitual Abortion; ClinicalTrials.gov number, NCT009596211) that included women with recurrent miscarriage and heritable thrombophilias are awaited. Recent studies did not show that treatment with low-molecular-weight heparin and low-dose aspirin in women with recurrent miscarriage was beneficial.35,36 Additional trials of low-molecular-weight heparin that include women with unexplained recurrent miscarriage are currently under way (Prevention of Unexplained Recurrent Abortion by Enoxaparine [NCT00740545] and Effectiveness of Dalteparin Therapy as Intervention in Recurrent Pregnancy Loss [NCT00400387]).

It is likely that genetic abnormalities that are not detectable by karyotype testing play a role in some cases of sporadic or recurrent miscarriage. Several single-gene disorders are associated with both sporadic and recurrent miscarriage. Genetic abnormalities that are reported to be associated with recurrent miscarriage include skewed X-chromosome inactivation, confined placental mosaicism, abnormalities in sperm DNA, and small deletions or additions detected by means of array comparative genomic hybridization (see Figure 1 in the Supplementary Appendix, available with the full text of this article at NEJM.org).47,48

Multiple intramural and submucosal fibroids are associated with an increased risk of pregnancies ending in miscarriage.49,50 The benefits of myomectomy are uncertain and supported only by reports of better outcomes after surgery than before surgery. More extensive surgery to remove uterine myomas involving laparoscopy or laparotomy poses hazards for subsequent pregnancies (e.g., a risk of uterine rupture), and its effect on the likelihood of subsequent miscarriage is uncertain.49,50

The risk of recurrent miscarriage may be increased among women with the polycystic ovary syndrome.51 However, the rate of subsequent miscarriage among women with recurrent miscarriage and polycystic ovaries detected on ultrasonographic examination is not higher than that among women with recurrent miscarriage who do not have polycystic ovaries,52 and rates of miscarriage after ovulation induction are not consistently higher among women with the polycystic ovary syndrome than among other women.53 Suppression of luteinizing hormone with long-acting agonists of gonadotropin-releasing hormone in women with the polycystic ovary syndrome, recurrent miscarriage, and luteinizing hormone hypersecretion did not improve the rate of successful pregnancy in a randomized, controlled trial.51 Some studies have shown greater insulin resistance in women with recurrent miscarriage than in women with a similar body-mass index and successful pregnancies, even in the absence of the polycystic ovary syndrome.54 Although data are lacking regarding the use of metformin in women with recurrent miscarriage, its use has not been shown to reduce the risk of miscarriage among women with the polycystic ovary syndrome.55

Guidelines

The American College of Obstetricians and Gynecologists,5 the Royal College of Obstetricians and Gynaecologists,25 and the American Society for Reproductive Medicine6 have published guidelines for the evaluation and management of recurrent miscarriage. The recommendations provided here are generally consistent with these guidelines (Table 1).

Conclusions and Recommendations

For a patient with recurrent miscarriage such as the woman described in the vignette, we recommend a medical history taking (with attention to a personal or family history of thrombosis, autoimmune disease, or clinically overt diabetes or thyroid disease) and testing for antiphospholipid antibodies, uterine abnormalities, and possibly parental karyotype abnormalities. We recommend the administration of heparin at a prophylactic dose and low-dose aspirin during the next pregnancy in women with the antiphospholipid syndrome, though we acknowledge that recent trials have raised questions regarding the need for heparin in women who do not have a history of thrombosis. Given recent trials showing no benefit of anticoagulant therapy in women with idiopathic recurrent miscarriage, we do not currently recommend anticoagulant therapy in other women with recurrent miscarriage. Most experts recommend that a uterine septum or intrauterine abnormalities be treated by means of hysteroscopy before a next pregnancy is attempted, but data from randomized trials are lacking to show that this strategy improves outcomes. Some experts recommend IVF with preimplantation genetic diagnosis for couples in whom one or both persons is a carrier of a balanced translocation, but this procedure is expensive and may not improve the live-birth rate, as compared with spontaneous conception. Obtaining karyotypes of the conceptus from subsequent miscarriages may have an emotional benefit and modest prognostic usefulness, but the effect of this information on clinical decision making is uncertain. Couples should be informed that good evidence is lacking to support several commonly used interventions for recurrent miscarriage and that observation is a reasonable strategy, since without intervention, a subsequent pregnancy will result in a live birth for about two thirds of couples.

An audio version of this article is available at NEJM.org.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

No potential conflict of interest relevant to this article was reported.

Source Information

From the University of Utah Health Sciences Center (D.W.B., M.G., R.M.S.) and Intermountain Healthcare (D.W.B.) — both in Salt Lake City.

Address reprint requests to Dr. Branch at the University of Utah Health Sciences Center, 30 N. 1900 East, 2B200 SOM, Salt Lake City, UT 84132, or at ware.branch@hsc.utah.edu.

Pyrexia of unknown origin during pregnancy tests to be done

Malaria blood film

Hepatitis B C E serology

Parvovirus B19

ASO titre

Syphilis serology

CMV,EBV and Toxoplasma IgM and IgG

Viral throat swab (Pink transport mer=dium)

CXR with abdo shield

Quantiferon gold test

Undergraduate Obstetrics

Undergraduate Obstetrics

favourite websites

Dr.Tucker_Australian Gynaecologist_http://www.youtube.com/watch?v=6AM6wDwTjmc

skype in labour ward : http://www.healthcaresuccess.com/blog/hospital-advertising-public-relations/skype-from-maternity-ward-a-winning-concept-for-healthcare-and-hospital-public-relations/

My notes

1st April 2010

Today, Thursday, I got a phonecall from Mr.Yoong asking any news about my shrotlisting. I said no, he phoned Miss.Subba, and said He is sorry, I am not shortlisted.

Obviously this is shocking to me. I felt my character has been assassinated by people like Subba, Govind and Okolo. Wheere they have used me liberally when needed and when it came to shrotlisting me they are in a sorry state for me. This is shame for them.

I am lost to think how I have been made to feel low. But, I am going to take thbis as a challenge and it take from.


14th May 2010

Today, I gave a talk on Medical Management of Postpartum Hemorrhage at Cumbran, Newport, Wales. It was well appreciated by everybody. At the end clinical director Miss.Anju Kumari came and said to she would like to offer a Consultant post at Newport from Jan.2011. She asked me to send a copy of my CV.

I also met Mr.David Newman, who suggested he will speak to Daffyd to include me in NATA.

I alos had a discussion with Louis, about short and longterm plans,

Short term plans include, to register for
1.Diploma in Clinical Risk Management,
2.Work for Safety in Obstetrics, And also
3.Blood less surgery in Obstetrics (Go to America as a viewer and see what things they do differntly)
4. Develop special skills in Management of Adherent placenta and I have been accepted for 6 weeks Study Programme in Buenos Aires, Argentina.

5.Develop effective strategies to reduce blood transfusion.

6.

Correction of Levo- rotation to effect normal delivery

Avoiding instrumental delivery with correction of levorotation abdominally and manual correction vaginally

1. Situation

Multip pushing for >1hour and not delivered

1. Correction of levorotation abdominally with hands and stabilisation of the same with 2-3 contractions.

2. V/E - Correction of LOA to OA manually and maintainance of manula correction with pushing

Encourage pushing ----- Spontaneous vaginal delivery