Introduction
Nausea and vomiting of pregnancy (NVP) are extremely common. Up to 90% of women experience nausea during pregnancy. Studies showed that approximately 27 to 30 percent of women experienced only nausea, while vomiting could be seen in 28 to 52% of all pregnancies (1). However, 0.3-3.6% of pregnant patients suffer from the most severe form of NVP known as hyperemesis gravidarum (HG) (2). HG refers to intractable vomiting during pregnancy, leading to weight loss, electrolyte imbalances, dehydration, and volume depletion, resulting in ketonuria (3). There is no consensus on specific diagnostic criteria, but it generally refers to the severe end of the spectrum regarding NVP (4).
The etiology of HG is unknown, but several theories exist. Levels of human chorionic gonadotropin (hCG) levels peak during the first trimester, corresponding to the typical onset of hyperemesis symptoms (5). Estradiol levels increase in early pregnancy and decrease later, mirroring NVP symptoms. Additionally, nausea and vomiting are side effects of estrogen-containing medications (6).
In patients with severe HG, complications including vitamin deficiency, dehydration, and malnutrition may occur if not treated appropriately. Wernicke encephalopathy, caused by vitamin-B1 deficiency, can lead to death and permanent disability if left untreated (7). Additionally, there have been case reports of injuries secondary to forceful and frequent vomiting, including esophageal rupture and pneumothorax (8). Electrolyte abnormalities such as hypokalemia can also cause significant morbidity and mortality (9).
No single measure can easily define, quantify or evaluate the treatment of HG. An English pregnancy-specific questionnaire, Pregnancy-Unique Quantification of Emesis (PUQE), has been developed to assess the severity of emesis in pregnancy. This questionnaire contains three questions regarding the time-span of nausea, vomiting, and retching, respectively, as well as one question assessing the global psychological and physical quality of life.
To our knowledge, there is a large body of research on the relationship between first-trimester uterine artery Doppler findings and pregnancy complications. However, there is limited research on the use of first-trimester uterine artery Doppler to predict placental abnormalities in cases of HG. Therefore, this study aimed to evaluate the relationship between first-trimester uterine artery Doppler measurements and biochemical markers and PUQE test scores in pregnant women who attended first-trimester prenatal screening.
Methods
This prospective observational study was conducted at the Department of Obstetrics and Gynecology of a Tertiary University Hospital, between December 2016 and March 2017 and comprised singleton pregnant women who attended first trimester prenatal screening. The study was in line with the Helsinki Decleration and approved the Ethics Committee of the Bezmialem Vakıf University (decision no: 17/22, date: 07.12.2016). All participants were informed regarding the study and they gave informed consent prior participation.
Inclusion criteria were: singleton pregnancies between 11-13.6 weeks of gestation, absence of any gastrointestinal, audiovestibular, endocrinological, infectious, and psychological disorders that might cause nausea and vomiting, except pregnancy-induced vomiting, and agreed to participate to the study. Exclusion criteria were: multiple pregnancy, molar pregnancy, fetal structural anormality, and abnormal nuchal fold thickness.
A total of 207 consecutive patients who met the inclusion and exclusion criteria were included in the study. Sociodemographic, clinical characteristics, obstetric and medical histories, and anthropometric measurements were collected. Then, PUQE scores, biochemical blood, and urine sample results were collected. Next, pregnant women underwent first trimester screening and uterine arter doppler ultrasonography using Philips HD11 XE device with 3.5 mHz curvilinear probe. The screening consisted of nuchal translucency (NT) and serum free b-human chorionic gonadotrophin (free b-hCG) and pregnancy-associated plasma protein A (PAPP-A) measurements. Gestational age was determined according to the head-rump distance (CRL) measured in the sagittal plane on abdominal ultrasonography. During the Doppler ultrasonography examination, the probe was placed in the iliac fossa above the level of the inguinal ligament. The uterine artery was detected where it crossed the external iliac artery by color Doppler imaging. A pulsed Doppler was used to determine the waveform. A resistance-index (RI) and pulsatility-index (PI) were calculated from each uterine artery and the presence or absence of a notch were noted. The same procedure was repeated for the contralateral uterine artery. The urine analysis test was classified according to ketones positivity and urinary tract infection. Those with leukocyte positivity, bacteriuria, or leukocyte esterase positivity were included in the urinary tract infection group.
The 24 h PUQE (10,11) is a self-reported measure of the duration of nausea, episodes of vomiting, and episodes of retching in the last 24 hours on a 5-point scale. A higher score indicates more severe NVP. NVP was evaluated as mild in those with <6 points, moderate in those with 7-12 points, and severe in those with 13 points and above (12). The patients in the mild group were classified as group I, and the patients in the moderate and severe groups were classified as group II.
Statistical Analysis
IBM SPSS 21.0 (Statistical Package for Social Sciences Chicago, USA) was employed to analyze the collected data. When the numerical data fit the normal distribution, analysis between groups was performed using the Student or ANOVA test. The Mann-Whitney test was applied when the data did not conform to the normal distribution. Categorical data were analyzed using the chi-square test. A p-value of <0.05 was considered statistically significant.
Results
A total 207 pregnant women enrolled in this study. Of the patients, 131 were in group I and 76 in group II.
The mean age of the patients was 29.9±4.9 (range: 18-44 years). The mean age of group I patients was 29.7±5.0 and 30.4±4.8 years in group II. The body mass index (BMI) values of all patients ranged from 15.4 to 34.8, with a mean of 24.6±3.7. The mean BMI of the patients in group I was 24.6±3.7 and in group II was 24.5±3.7 kg/m2. No significant difference was found in demographic and obstetric variables between the two groups. The demographic information and obstetric characteristics of the patients are presented in Table 1.
The mean CRL value of patients in group I was 63.3±7.2 and in group II was 61.8±6.5 mm. There was no significant difference between the two groups in CRL measurements (p=0.1). NT measurements varied between 1.1 and 3.0, with a mean of 1.4±0.2 mm. The mean NT value of the patients in group I was 63.3±7.2 and in group II was 61.8±6.5. There was no statistically significant difference between the two groups in terms of CRL measurements (p=0.1). No significant difference was observed in terms of first trimester screening serum markers, and doppler ultrasonography findings between the two groups. There was no statistically significant difference between the patients in group I and group II in terms of the presence of urinary tract infections. Ketonuria was detected in three patients (2.4%) in group I and 11 patients (17.2%) in group II (p<0.01) (Table 2).
No statistically significant difference was observed between sociodemographic, first-trimester uterine artery Doppler measurements and first-trimester screening ultrasonographic and serum markers between mild NVP, moderate NVP, and severe NVP groups (Table 3).
Discussion
The results of the present study indicated that there was no association between the first trimester uterine artery doppler parameters, biochemical markers of the first trimester antenatal screening test and severity of HG according to PUQE score.
Prior research revealed that high levels of HCG was associated with placentation abnormalities such as preeclampsia, small for gestational age or HG. A population based cohort study involving over one million pregnant women in Sweden also reported that an elevated risk of placentation dysfunction disorders in women with HG. Therefore, uterin artery doppler ultrasonography examination has been suggested in this patient group (13). In a study evaluating first-trimester Doppler ultrasonography findings in pregnant women with HG, it was found that there was no difference in uterine artery Doppler values, except for uterine artery notch (14).
The literature shows contradictory results between HG and first-trimester biochemical markers. Derbent et al. (15) demonstrated that HG was associated with elevated levels of serum maternal PAPP-A and free b-hCG levels. Similarly, Yildiz et al. (16) demonstrated that higher levels of free b-hCG was related to increased risk for HG. However, researchers also noted that no significant relationship was found in uterin artery doppler findings or serum PAPP-A levels. On the contrary, Madendağ et al. (17) found that serum PAPP-A value was significantly decreased in women with HG. But, they also noted that severe HG had no significant effect on free b-hCG levels (17). In this context, we believe that more research needs to be undertaken on this subject in order to better understand the relationship between HG and PAPP-A, and free b-hCG levels.
Another important finding was that this study showed no link between HG and NT. This finding was in line with the suggestion of Yildiz et al. (16), who suggested that there was no relationship between HG and NT.
There are controversies about the association between first trimester uterine artery doppler values and HG. The findings of the current study were consistent with those of Biyik et al. (14) who also found no association between doppler RI, PI, standard deviation (SD) values and HG. In contrast, a recent study by Kartal et al. (18) demonstrated an association between RI, PI, and SD values of the uterine artery Doppler waveform and HG. A possible explanation for this might be that our cohort consisted of outpatients, Doppler and biochemistry values did not differ significantly between groups.
Study Limitations
One of the limitations of the study was the small number of severe HG patients in the study. We believe that the relationship between Doppler and first trimester parameters and HG severity may be elucidated in future large, multi-center studies. To the best of our knowledge, there are many studies on the relationship between first-trimester uterine artery Doppler findings and pregnancy complications, however, there are only a few studies aimed at predicting placentation abnormalities with first trimester uterine artery Doppler in cases with HG.
Conclusion
In our study, no significant relationship was found between the first-trimester uterine artery doppler parameters, biochemical markers and the severity of HG, which was measured according to PUQE scoring system. However, we did find that PUQE test was an effective test in the detection of patients with ketonuria. Further research is needed to better understand the significance of uterine artery Doppler measurements and biochemical markers in cases with HG.
Ethics
Ethics Committee Approval: The study was in line with the Helsinki Decleration and approved the Ethics Committee of the Bezmialem Vakıf University (decision no: 17/22, date: 07.12.2016).
Informed Consent: All participants were informed regarding the study and they gave informed consent prior participation.
Authorship Contributions
Surgical and Medical Practices: M.M., Concept: M.M., İ.A., B.D., Design: M.M., İ.A., B.D., Data Collection or Processing: M.M., E.K., P.Y., M.M.K., R.B.B., E.M., G.Y., İ.A., B.D., Analysis or Interpretation: M.M., E.K., P.Y., M.M.K., R.B.B., E.M., G.Y., İ.A., B.D., Literature Search: M.M., E.K., P.Y., M.M.K., R.B.B., İ.A., B.D., Writing: M.M., E.K., P.Y., M.M.K., R.B.B., E.M., G.Y., İ.A., B.D.
Conflict of Interest: No conflict of interest was declared by the authors.
Financial Disclosure: The authors declared that this study received no financial support.