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EARLY PREGNANCY: Biology and Medicine Editor-in-Chief: Eytan R. Barnea MD, FACOG

THREE MONTHS IN REVIEW

S. M. Stemmer, M.D.

Current Clinical Progress In Early Pregnancy Investigation

Sonographic Spectrum of the Corpus Luteum in Early Pregnancy: Gray-Scale, Color, and Pulsed Doppler Appearance

The corpus luteum of pregnancy is considered essential for the maintenance of the early pregnancy. It produces progesterone, which sustains the pregnancy until the placenta is formed. Recognition of the corpus luteum as a physiologic structure is important to prevent confusion with true ovarian abnormalities. Using transvaginal sonography, the ovaries of 160 patients with spontaneous singleton intrauterine gestations were prospectively evaluated. Only patients with a singleton intrauterine pregnancies between 5 and 8 weeks menstrual age were included.

The corpus luteum was identified in 157 (98%) of 160 patients. The mean diameter was 1.9± 0.6 cm. The corpus luteum had a wide range of sonographic appearances. The most common appearance was a round hypoechoic structure, found in 54 patients (34%). Other appearances included a cyst with a thick wall and anechoic center (43 patients, 27%), a cyst containing internal debris (36 patients, 23%), and a thin-walled simple cyst (24 patients, 15%). Color Doppler imaging typically revealed a circumferential rim surrounding part or all of the corpus luteum. Blood flow around the corpus luteum was visualized with color doppler imaging in 145 (92%) of the 157 patients in whom the corpus luteum was found. Low-resistance blood flow was seen with pulsed Doppler interrogation, with a mean resistance index of 0.49± 0.08 and mean peak systolic velocity of 17± 10 cm/sec.

The American institute of Ultrasound in Medicine recommend the evaluation of both ovaries in early pregnancy. By recognizing the various appearances of the corpus luteum during pregnancy, transvaginal sonography can be used routinely to identify the corpus luteum in early pregnancy and distinguish them from true ovarian abnormalities.

Congenital Malformations After the Use of Inhaled Budesonide in Early Pregnancy

Asthma is relatively common among pregnant women. Treatment with inhaled glucocorticoids are occasionally used in early pregnancy. In the United States, budesonide an inhaled glucocorticoid, is classified as category C, indicating a teratogenic risk in animal experiments and a lack of sufficient human data. The teratogenic risks with use of an inhaled glucocorticoid, budesonide, in early pregnancy was studied using the Swedish Medical Birth Registry. The incidence of congenital malformations were studied in 2014 infants whose mothers stated the use of inhaled budesonide in early pregnancy. Standardization for maternal age, parity, or smoking was not done since these variables have minimal affect on the rate of malformations.

Seventy five infants had malformation out of 2014 infants born to mothers who used budesonide during pregnancy (3.8%, 95% CI 2.9,4.6). This rate is similar to the general population rate. In Sweden among all infants born between 1995 to 1997, the corresponding congenital malformation rate was 3.5%. Animal experiments showed that with exposure to budesonide the most common malformation is orofacial clefting. There were only four infants in the study group that had orofacial clefts. This is less than the rate in the general population which is estimated at 3.3. Eighteen infants had a diagnosis of congenital cardiac defect which is similar to the expected number in the general population. Two somewhat unusual malformations were observed, Poland syndrome and unilateral jaw malformation. It appears that this two malformations are probably coincidental.

Although it can not entirely be ruled out that a specific teratogenic effect may occur with the use of budesonide in pregnancy. This study could not identify any teratogenic effects from the use of budesonide for the treatment of asthma during pregnancy.

Absence of Teratogenicity of Oral Ganciclovir Used During Early Pregnancy in a Liver Transplant Recipient

Cytomegalovirus (CMV) is recognized as the most common viral perinatal infectious agent in humans. In immunocompromised patients CMV infection can lead to serious morbidity and even mortality. In immunocompromised patients such as organ transplant patients Ganciclovir (GCV) is effective in prevention of CMV disease. The teratogenic effect of GCV on the human fetus is mostly unknown. In animals, extremely high levels of the drug can cause teratogenicity, however this does not occur in clinically relevant lower doses. The medical record of a pregnant liver transplant patient who received GCV as well as world literature were reviewed.

A 29 year-old mother underwent liver transplant for hepatitis C cirrhosis complicated by membranous nephropathy. The donor liver was CMV positive and the recipient was CMV negative. The patient was discharged taking a regimen which included GCV 1 gm three times daily. Five months after the liver transplant she had unprotected intercourse. Three months later she was admitted to the hospital with a bacterial pneumonia and pregnancy was confirmed. Oral GCV was stopped. At 30 week gestation the patient was delivered via cesarean section secondary to worsening preeclampsia and non-reassuring fetal heart rate tracing. Physical examination of the baby, except for the small size, was normal with no evidence of malformations.

This reported case and other cases reported elsewhere (4) suggest that GCV use in pregnancy does not cause teratogenicity. The long term effect of GCV on the infant are however unknown, therefore the use of GCV in pregnancy must be weighed against the risk of CMV disease in the immunocompromised patient and the possible development of congenital CMV in the fetus.

Maternal Thyroid Deficiency During Pregnancy and Subsequent Neuropsychological Development of The Child

The connection between iodine deficiency causing maternal hypothyroidism and mental retardation in the offspring has been known for about 100 years. Iodine deficiency may cause thyroid deficiency in the mother and the fetus. Whether developmental problem are due to maternal hypothyroidism or both maternal and fetal hypothyroidism is not known. The aim if this study was to determine if maternal hypothyroidism is associated with lower IQ in the offspring.

Serum thyrotropin were measured from 25,216 serum samples collected from pregnant woman between 1987 and 1990. Hypothyroidism was determined by high levels of serum thyrotropin concentration without regard to treatment status. For each patient with hypothyroidism, control subjects were matched based on mother’s age at time of delivery, number of year of education of the mother, gestational age, duration of storage of serum sample, and sex of the child. Neuropsychological testing of the women’s children included assessment of intelligence, attention, language, reading ability, school performance, and visual-motor performance.

Sixty two women with hypothyroidism during pregnancy were identified. The children of these women performed in all 15 tests slightly below the controls. Their IQ scores averaged 4 point lower than those of the children of the 124 matched control women (p=0.06). Fifteen percent of the children born to mothers with hypothyroidism during pregnancy had IQ score of 85 or less compared to 5 percent of the control children. Forty eight women out of the 62 women with hypothyroidism in pregnancy were not treated for the condition during the pregnancy. Their children had an average IQ score 7 point less than the matched control and 19 percent had a score of 85 or less.

This study demonstrate that maternal hypothyroidism may adversely affect the neuropsychological development of their offspring. Decrease in performance in neuropsychological tests may occur even when maternal hypothyroidism is mild and probably asymptomatic. Routine screening for hypothyroidism during pregnancy preferably at the first prenatal visit may be beneficial so treatment can be initiated as early in the pregnancy as possible.

Mononuclear-Cell Immunization in Prevention of Recurrent Miscarriages: A Randomized Trial

Recurrent miscarriages defined as woman who had three or more spontaneous abortions occurs in 0.5-1.0% of couples. Most of the women who experience recurrent miscarriages, the cause remains unknown. A possible explanation to idiopathic recurrent miscarriage is an alloimmune abnormalities that prevents the mother from developing immune responses essential for the survival of the genetically foreign conceptus. Immunization with paternal white cells is offered by many medical centers, however it efficacy is controversial. This double-blind multicenter randomized clinical trial investigates whether paternal mononuclear cell immunization improves the rate of successful pregnancies.

Patients with idiopathic recurrent pregnancy loss were recruited at six centers between 1992 to 1997. The criteria for inclusion were: three or more recurrent miscarriages that were not ectopic pregnancies or chromosomally abnormal fetuses, age 40 or younger, no more than one liveborn with the current partner, not pregnant at the time of immunization, and no anti-HLA antibodies. Ninety one women were randomized to treatment with immunization with paternal mononuclear cells and 92 women were given sterile saline (control). Success was defined as pregnancy of 28 or more weeks of gestation.

In the treated group eighty six women completed the trial and the success rate was 31/86 (36%). In the control group eighty five women completed the trial and the success rate was 41/85 (48%). The total number of pregnancies in the trial was 131. The analysis of pregnant women only showed a success rate of 31/68 (46%) in the treatment group and 41/85 (65%) in the control group.

This study showed that despite a history of unexplained miscarriages, 65% of control patient who became pregnant had a successful outcome. Immunization with paternal mononuclear cells did not improve the success rate of carrying a pregnancy to or beyond 28 weeks gestation and indeed the miscarriage rate was higher than the control. Therefore, immunization with paternal mononuclear cells is not recommended for the treatment of idiopathic recurrent miscarriages.

Lack of Sensitivity of Endometrial Thickness in Predicting the Presence of an Ectopic Pregnancy

Ectopic pregnancy is the leading cause of first trimester pregnancy related death in the United States. Evaluation of clinically suspected ectopic pregnancy includes transvaginal ultrasonography and measurement of serum HCG. Spandorfer and Barnhart (6) evaluated patients with a clinical suspicion of ectopic pregnancy who had HCG levels less than 1500 mIU/ml. They found a statistically significant difference in endometrial thickness between patients with a normal intrauterine pregnancy (IUP), spontaneous abortion (SAB) and ectopic pregnancy, with ectopic pregnancy associated with the thinnest enometrium of all groups. Anecdotal impression was that the group with spontaneous abortion had the thinnest endometrium. The purpose of this study was to evaluate endometrial thickness of patients with a clinical suspicion of an ectopic pregnancy, including patients with HCG levels of greater or less than 2000mIU/ml.

Patients with a clinical suspicion of ectopic pregnancy between January 1,1994 and December 31, 1995 were included in the study. Static ultrasound images of 676 patients were reviewed by the authors without knowledge of pregnancy outcome. The patients in the study were divided into three groups based on the outcome: Ectopic pregnancy, SAB, and IUP. The groups were further divided by HCG values of less or greater than 2000 mIU/ml.

A total of 676 women were evaluated for clinical suspicion of an ectopic pregnancy. From these women 128 had an initial sonogram without evidence of an IUP. Follow-up examination of the 128 women revealed that 42 (33%) had an ectopic pregnancy, 52 (40%) had SAB, and 34 (27%) had a normal IUP. The mean endometrial thickness measurements for the ectopic pregnancy group was 9.0mm (range 2-20mm), for the SAB group 8.4mm (range 2-18mm), and for the IUP group 11.4 (range of 2-22). There was no statistically significant difference in this measurements between the three groups. When the three groups were subdivided by HCG values of less than or greater than 2000 mIU/ml, again no statistically significant differences was found in the measurement of endometrial thickness.

This study found no difference in the endometrial thickness in women evaluated for clinical suspicion of an ectopic pregnancy who on follow-up were found to have either an early IUP, spontaneous abortion or an ectopic pregnancy. No threshold for endometrial thickness was found that may be helpful in the evaluation of patients suspected of having an ectopic pregnancy.

The Effectiveness of Non-Surgical Management of Early Interstitial Pregnancy: A Report of Ten Cases and Review of the Literature

Implantation of the fertilized ovum in the interstitial portion of the fallopian tube occurs in 1.1-6.3% of all ectopic pregnancies. In the past, diagnosis and treatment of an interstitial pregnancy required laparotomy and at times hysterectomy due to tubal rupture and major hemorrhage. The increased use of ultrasound for diagnosis of early pregnancy complications allows now for non-invasive diagnosis and treatment of interstitial pregnancy. In this report ten cases of interstitial pregnancies which were treated non surgically are presented.

Women with suspected early pregnancy complications were examined by transvaginal ultrasound. The diagnosis of interstitial pregnancy was made by ultrasound alone. The main criteria for diagnosis of an interstitial pregnancy was visualization of products of conception in the upper lateral aspect of the uterus, outside the uterine cavity, and at least partially surrounded by myometrium. All patients diagnosed with an intact interstitial pregnancy were offered medical therapy. Methotrexate was given either systemically or by local injection under ultrasound guidance.

A total of 6112 women were evaluated for early pregnancy complication. Ectopic pregnancy was diagnosed in 241 (3.9%) cases, and out of those, interstitial pregnancy was detected in 11 women (4.6%). One patient opted for surgery and the remaining ten women opted for conservative therapy. Five women received local injection which was successful in all. Five women were treated with systemic methotrexate and four were cured (80%). One patient failed systemic methotraxate therapy and developed increased in abdominal pain and serum HCG. She underwent laparotomy and cornual resection.

Medical treatment of interstitial pregnancy appears safe and effective. Local injection of methotraxate under ultrasound guidance appears more successful and better tolerated.

Ruptured Tubal Ectopic Pregnancy: Risk Factors and Reproductive Outcome: Results of a Population-Based Study in France

Early diagnosis of ectopic pregnancy has reduced the incidence of tubal rupture, however the proportion of ectopic pregnancies resulting in tubal rupture is still large estimated at 22% to 34 %. It is the largest cause of death in women from ectopic pregnancies. Treatment of a ruptured ectopic pregnancy may requires laparotomy and salpingectomy. There are very few studies on the subsequent effect on fertility in these women. The aim of this study was to investigate the principal characteristic of women with ectopic pregnancy and tubal rupture, and to describe its treatment and future fertility.

The data was obtained from a population-based register in France. Women aged 25 to 45 treated for an ectopic pregnancy were registered and than followed until age of 45. Between January, 1992 and December, 1996, 849 women with tubal ectopic pregnancy were registered. All women were interviewed by a trained investigator during their stay in the hospital. Follow-up involved telephone interview every six months to find out if they were trying to conceive again. Women with tubal rupture were compared to women without rupture. Risk factors for tubal rupture were identified by calculating crude and adjusted odds ratios. Future fertility rates were determined by calculating cumulative intrauterine pregnancy rates.

There were 153 women with ruptured tubal wall (18%) compared to 696 women in which no tubal rupture occurred. Four risks factors for tubal rupture were found: history of infertility and prior tubal damage, no prior use of contraception, induction of ovulation, and HCG levels of at least 10,000 when ectopic pregnancy was suspected. The 1-year cumulative frequency of intrauterine pregnancy was not significantly lower after tubal rupture (adjusted risk ratio 0.85[0.53 to 1.38]).

This study shows that ectopic pregnancy complicated by tubal rupture does not seem to have an independent effect on the long term prognosis for subsequent pregnancies. Women with suspected ectopic pregnancy and with risk factor for tubal rupture should undergo laparoscopy sooner rather than later as medical treatment is unlikely to be of value.

The Contribution of Maternal Serum Markers in the Early Prenatal Diagnosis of Molar Pregnancies

Molar pregnancies are classified as complete (classical) and partial hydatiform moles. Complete hydatiform moles are recognized by the presence of diffuse trophoblastic hyperplasia, swelling of villous tissue, and absence of embryonic or fetal parts. A normal diploid karyotype of paternal origin is present. Following uterine evacuation, 18-29% of patients with a complete mole will develop a persistent trophoblastic tumor. Partial hydatiform moles consists of both placenta and fetus. Morphologically they are characterized by focal swelling of the villous tissue, focal trophoblastic hyperplasia and embryonic or fetal tissue. They usually have a triploid karyotype with one maternal and two paternal sets of chromosomes. Following evacuation, patients with a partial mole are 1-10% at risk of developing non-metastatic and metastatic forms of gestational trophoblastic disease. Diagnosis of molar pregnancy in utero is based on ultrasonographic findings. However, ultrasound provides no information on trophoblastic activity. Since the outcome is different, it is important to differentiate between partial mole and complete mole with a co-existing fetus and from benign hydropic degeneration of the placenta. The aim of this study was to investigate the usefulness of maternal serum protein markers in the diagnosis and management of molar pregnancies detected by ultrasound in early pregnancy.

Ten cases of molar pregnancies diagnosed at 11 to 13 weeks of which maternal serum has been stored were reviewed retrospectively. Serum markers concentration: Human chorionic gonadotropin (HCG), alpha fetoprotein (AFP), pregnancy-associated plasma protein A (PAPP-A) and pregnancy-specific B1-glycoprotein (SP1) were compared to normal ranges for unaffected pregnancies.

There were six pregnancies with complete moles which consisted of three singleton euploid complete mole and three cases of multiple pregnancy combining a complete mole and a normal gestational sac. There were four pregnancies with a partial mole which included two cases of triploidy and two cases of euploidy. Free B-HCG and intact HCG concentrations were very high in al cases. AFP concentration were extremely low in all cases of singleton complete moles and high in one case of twin complete mole and in three cases of partial moles. SP1 levels were high in complete moles as well as PAPP-A except one case of partial triploid mole. In euploid partial moles at 17-20 weeks, HCG concentrations were within normal ranges, and AFP levels were more than 3.5 MoM, in contrast with the twin and triplet complete moles where HCG levels were over 9.0 and AFP was in the normal range.

In ongoing pregnancies with a complete mole coexisting with a normal fetus and placenta the combined used of ultrasound findings, fetal karyotype and maternal HCG and AFP concentrations may aid in the early perinatal diagnosis and subsequent management of the pregnancy.

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