Controversial issues in obstetric management of women with novel coronavirus disease covid-19 during pregnancy and childbirth

Introduction

Coronavirus infection as a causative agent of community-acquired pneumonia with an “atypical” course became relevant in the XXI century. Over the past 20 years, coronaviruses (CoV) have caused the third outbreak of the disease:

• 2002 – SARS (severe acute respiratory syndrome), its causative agent was SARS-CoV, mortality among pregnant women was up to 25%;
• 2012 – MERS (Middle East respiratory syndrome), its causative agent was MERS-CoV, mortality among pregnant women was up to 37%;
• 2019 – COVID-19 (coronavirus disease 2019), its causative agent is SARS-CoV-2.

The new coronavirus infection, which was identified in Wuhan (Hubei province, China) in late 2019, caused an outbreak of severe pneumonia. The disease quickly spread throughout China and was followed by a dramatic increase in number of new cases in other countries of the world. In February 2020, the World Health Organization (WHO) introduced the disease nomenclature, COVID-19. On 11 March 2020, the WHO declared a pandemic of the disease which was caused by a new coronavirus. The Coronavirus Study Group of the International Committee on Taxonomy of Viruses has proposed to call the virus as severe acute respiratory syndrome coronavirus 2 (SARSCoV-2). SARS-CoV-2 is a single-stranded RNA virus belonging to the family Coronaviridae. After identifying its pathogenicity, it was referred to group II, like other representatives of this family (SARS-CoV, MERSCoV). Whole genome sequencing and phylogenetic analysis have shown that the causative agent of COVID19 is a betacoronavirus which is similar to the virus of severe acute respiratory syndrome (SARS-CoV), as well as several bat coronaviruses [1–4, 5].

Currently, limited information on predisposition of pregnant women to COVID-19 is available in the published scientific reports. Immunological and physiological changes that occur during pregnancy may increase susceptibility to COVID-19. However, the data of a systematic review published by Elshafeey F. et al. (n=385) indicate that pregnant women have a lighter course of COVID-19 (95.6%), and a lower percentage of critical forms (0.8%). The authors associate these results with the possible protective effect of general immunological changes in pregnancy due to Th1 inhibition of the proinflammatory pathway by progesterone and human chorionic gonadotropin (HCG); it decreases the likelihood of a cytokine storm, which may cause mortality and extreme severity of COVID-19 manifestations [6]. At the same time, according to the data of American researchers (Breslin N. et al., n=43), the distribution of the severe COVID19 cases in pregnant women does not differ from one in the general population and is 86% of light cases versus 4.7% of extremely severe cases [7]. According to the WHO publication on the assessment of the course of the COVID-19 outbreak in China, pregnant women are not at risk for severe infection. Out of 147 people, 8% of patients had a severe form and 1% of cases were extremely severe [8]. Nevertheless, current information is not sufficient to perform a complete assessment of the risks and course of this infectious disease in pregnant women. There have been several reports on preterm births in mothers infected with COVID-19 during pregnancy. It remains unclear how this can be related to the maternal infection.

The severity of COVID-19 infection depends on the degree of severity of respiratory distress syndrome and pneumonia. Community-acquired pneumonia (CAP) is one of the most common acute infectious diseases, the second most common cause of hospitalization, and the most common infectious cause of death. According to foreign epidemiological studies, the incidence of CAP in adults (≥18 years) ranges widely: it is 1–11.6% in young and middle-aged people; it is 25–44% in older age groups [9, 10]. In the USA, 5–6 million cases of CAP occur each year with >1.5 of those cases requiring hospitalization [11, 12].

The estimated incidence of CAP in Russia is 14–15% per year (about 1 million people). In 2017 the incidence of CAP in the Russian Federation was 412.3 per 100,000 population which was lower by 1.4% in comparison with its incidence in 2016. The highest incidence rates were observed in the Far Eastern and Volga Federal districts (565.3 and 510.2 per 100,000 population, respectively) [13]. In 2017 pneumonia accounted for 42% of deaths from respiratory diseases in the Russian Federation; death rate was 17.3 per 100,000 population in 2017 [13].

In 2018 the incidence of CAP in St. Petersburg was 281.7 per 100,000 population which was 10.3% lower than in 2017 and 1.0% lower compared to the average annual rate. The maximum incidence rates were registered in children aged 3-6 years, namely 657.3 per 100,000. Among adults, 129 deaths were registered. Laboratory tests for influenza were monitored weekly in 82.1% of people hospitalized with CAP diagnosis. Detection rate of influenza virus was 27.9% [14]. During a one-week period from April 1, 2019 to April 7, 2019 the proportion of influenza viruses in the pattern of positive findings was 15.8%, and proportion of viral infections of non-influenza etiology (respiratory syndrome, metapneumovirus, coronavirus, etc.) was 84.2% in St. Petersburg. The number of hospitalized patients ranged from 194 to 266 people per day, that is 1.5% to 13.0% of cases [5].

Any infectious pneumonia is the most common socalled non-obstetric infection in pregnant women. Adverse outcomes are associated primarily with maternal mortality and, secondly, with perinatal complications. According to one study, pneumonia is the third-leading indirect cause of maternal death: one in four pregnant patients with pneumonia requires hospitalization in the intensive care unit (ICU) with respiratory support. Viral pneumonia in comparison with bacterial one has higher morbidity and mortality rates. During the period of 1918–1919, the rate of death from influenza in pregnancy was 27% (especially in the third trimester) and it was 50% due to pneumonia; during the flu epidemic in Asia in 1957–1958, the mortality rate among pregnant women was 10%, which was twice higher than the mortality rate among nonpregnant women. The most common obstetric complications of pneumonia in pregnant women are premature rupture of membranes, premature birth, intrauterine growth retardation (IUGR), perinatal mortality [15].

Perinatal risks for pregnant women with CAP

The current SARS-CoV-2 is closer to the SARS virus which caused an outbreak in 2002-2003. The virus had a lower ability to spread, but a higher lethality. In pregnant women outcomes were worse in comparison with the rest of the population. The SARS-CoV-1 outbreak in 2002-2003 was associated with a high maternal mortality rate (the mortality rate was 25%), spontaneous miscarriages in the first trimester, and IUGR in the second and third trimesters [16]. There have been no cases of vertical transmission of SARSCoV from mother to fetus. No new patients with SARSCoV have been registered since 2003.

The following changes in the placenta were noted in acute SARS-CoV infection: excessive fibrin deposits in subchorial and interstitial space, which may be associated with impaired blood flow in the placenta. In some cases, thrombotic vasculopathy with avascular areas was found in the placenta. IUGR was detected in these pregnancies. No histological signs of hematogenic infections (including villitis) transmitted to the fetus through the placenta were revealed in SARS-CoV.

Similarly, several cases of MERS-CoV infection were reported in 2012, maternal mortality rate was 35% and neonatal mortality rate was 27% [16]. There were no cases of vertical transmission of the virus from mother to fetus, but a comprehensive study with the analysis of all necessary biological fluids for the content of the virus was not conducted. However, according to the recommendations on monitoring pregnancies with COVID-19, it is necessary to analyze the data obtained during the current epidemic, rather than limited experience of previous outbreaks, since their epidemiology, clinical course, and response to treatment may be different [17].

It has not been proved that coronaviruses which are able to cause colds can be transmitted transplacentally or during childbirth [16]. Genital tract infections are significantly associated with preterm birth. Some infections that do not affect the genitals, such as pyelonephritis, pneumonia, and appendicitis, can also lead to an increased risk of premature birth. These risks can occur due to bacteremia with transplacental transfer. In this case, the myometrium changes its activity from the so-called “static” to “contractile” status which is accompanied by the change in the anti-inflammatory to proinflammatory signaling pathway, including the production of chemokines (IL-8), cytokines (IL-1 and IL-6) and contraction-associated proteins (oxytocin receptor expression, connexin 43, prostaglandin receptors). Infected women presenting with premature birth have intrauterine infectious process that causes immune response, increased production of variety of cytokines, prostaglandins, and metalloproteinases (MMP-8 and MMP-9) which result in uterine activity, cervical ripening, rupture of membranes, and finally to premature birth [18].

In comparison with the bacterial infection, the association of viral disease with preterm birth in pregnant women is largely unknown. However, there is a risk of premature birth in case of severe course of the disease, such as severe acute respiratory syndrome.

Due to the fact that there is no data on the possibility of transplacental transfer of the virus in SARS-CoV, the risks of premature birth are unlikely to be associated with intrauterine infection. The most likely cause is severe respiratory failure in mother with hypoxemia, which can impair the utero-placental blood flow and cause premature birth [19].

Since there are no studies that have detected the virus in the amniotic fluid, placenta, and membranes, there is no reason to assume that the infectious process itself can lead to premature birth in pregnant women with SARSCoV-2. During the severe course of the infection which is followed by the development of acute respiratory distress syndrome, hypoxemia is most likely to cause circulatory disorders in the placenta.

Perinatal risks affecting obstetric management of patients with CAP and COVID-19

Among the controversial issues in the management of pregnant women with COVID-19, the tactics of prolonging pregnancy is the most noteworthy. According to many clinical guidelines, such as those of the RCOG and the Ministry of Health, it is necessary to prolong pregnancy in the condition of the mother and fetus is not life-threatening, as interruption of pregnancy and delivery during the peak of the disease are related to high maternal mortality and complications, namely the progression of respiratory failure, obstetric hemorrhage, intrapartum fetal death, purulent-inflammatory complications after birth [20, 21]. There is an increased risk of septic complications and severity of systemic inflammatory response. Therefore, the need for tocolytic therapy in premature birth is not indicated in any of the available clinical guidelines. However, there are some references to the tactics of early delivery due to the obstetric situation.

Most of the studies also provide evidence that there are no risks of vertical transmission of infection, which justifies necessity of prolonging pregnancy in case if there is no risk for the fetus and his condition is satisfactory but the mother is infected. To date, according to the information from literature, there is no convincing evidence of vertical transmission of the coronavirus infection. There were two registered cases of positive reverse transcription-polymerase chain reaction (RT-PCR) tests for the RNA of COVID-19. For these tests nasopharyngeal samples were obtained from newborns 30 hours after delivery, previous tests were negative. However, these findings do not contain information about the isolation of the child, which increases the probability of infection in the neonatal period [22, 23].

In one review it has been shown that 1 in 75 newborns had a positive test for SARS-CoV-2 infection. This child had transient lymphocytopenia and impaired liver function [24]. Out of 10 cases (SARS-CoV-2 atypical pneumonia test is negative in all children) reported by Zhu H. et al. (2020), two children developed disseminated intravascular coagulation and recovered; one child died due to multiple organ failure, [25]. Fan C. et al. (2020) reported that two newborns with mild lymphocytopenia and radiological evidence of pneumonia but without any clinical manifestations of the disease fully recovered. Based on these data, we cannot rule out that the fetus and newborn may have a reaction (often subclinical) to the mother’s infection, and thus vertical transmission from mother to fetus cannot be ruled out [26]. This view was supported by a recently published study in which three babies delivered by caesarean section had a positive test for SARSCoV-2 two days after birth [27]. However, Schwartz D. et al. (2020) found no evidence of intrauterine transmission in their analysis of 38 infected pregnant women [28]. Lymphocytopenia and thrombocytopenia as well as X-ray findings have been frequently revealed in newborns without any clinical picture, infants were born to women infected with SARS-CoV2. Therefore, it is necessary to conduct thorough clinical monitoring of newborns from mothers with COVID-19.

In a clinical situation described by Alzamora M. et al. (British American Hospital, Lima, Peru) [29], a 41-year-old multiparous woman with gestational diabetes mellitus and remarkable obstetric history (presence of a scar on the uterus after two cesarean sections) presented at 33 weeks gestation with general malaise, fatigue, and subfebrile temperature. On day 4, after the onset of catarrhal symptoms, there was difficulty breathing, which required emergency medical assistance. In hospital, the diagnosis of coronavirus infection was confirmed by a positive real-time PCR test of samples from nasopharynx for the COVID-19 virus and a typical computer tomography (CT) image. Due to the worsening respiratory failure, at 33+4 weeks gestation caesarean section was performed, and a live premature baby weighing 2970 g was born, 6/8 points according to Apgar scale. After clamping the umbilical cord, the child was immediately isolated, and an initial examination was carried out in the neonatology intensive care unit. Chest X-ray examination did not reveal any pathology, a real-time PCR test of the sample from nasopharynx for the COVID-19 virus was negative, titers of IgM and IgG antibodies in the newborn’s blood were negative. Laboratory parameters were subsequently monitored in dynamics: 16 hours after delivery, a repeated PCR test was taken from nasopharynx of the newborn for the COVID-19 virus, the result was positive. During daily analysis of the serological response, a negative reaction persisted; only on the 5th day of life, IgM antibodies were detected in the child’s blood. This clinical case demonstrates that an infant can be infected postnatally at the stage of cesarean section, but the sterile conditions in the operating room and compliance with the isolation precautions of the newborn in the above case prevent possible infection. Therefore, vertical transmission should be regarded with some concern.

Dong L., Tian J. et al. reported that two hours after delivery infants born to mothers infected with COVID19 were found to have IgM antibodies (45.83 IU/ml) with an expected serological response 3-7 days after infection. The result of the PCR test of a swab from the nasopharynx showed a negative response two hours after birth and on the 16th day of life. It is known that IgM antibodies do not cross the placental barrier due to their molecular weight and large size. Thus, it is possible that these antibodies are produced in the fetus in response to vertical transmission of infection. However, such information is not the final evidence, since such findings may be associated with changes in the placenta leading to its permeability, or false positive testing [30].

Research performed by Zhang L. et al. failed to prove fetal infection of 46 newborns with coronavirus; clinicians received negative test results of amniotic fluid, cord blood, breast milk, and smear test of the mother during the whole period of hospitalization [25, 31–35]. According to Zhu H., there were negative PCR tests of the swabs from the nasopharynx taken from day 1 to day 9 of life in children born to nine pregnant women with confirmed COVID-19 diagnosis [25]. Zeng et al. showed that the low expression of angiotensinconverting enzyme 2 (ACE-2 is described as a receptor for SARS-CO-2 in people) is present in almost all placental barrier cells, suggesting that the placenta practically has no cells susceptible to virus [27].

Prolonged respiratory failure in a pregnant woman with COVID-19 increases the risks of IUGR due to maternal hypoxia resulting in the release of powerful vasoconstrictors such as endothelin-1 and hypoxiainduced factor, which lead to placental hypoperfusion and decreased fetal oxygen delivery [36]. Dashraath P. and co-authors (National Hospital of Singapore) state that IUGR complicates approximately 10% of pregnancies with coronavirus infection, and fetal monitoring is performed by ultrasound evaluation of fetal growth. After sonographic examination of high-risk patients, ultrasound transducers must be disinfected in accordance with the manufacturer’s instructions. According to the tactics proposed by Dashraath P., monitoring of the fetal condition during natural childbirth in women infected with COVID-19 includes continuous registration of cardiotocography, which is currently consistent with all leading clinical recommendations for the management of labor in patients with SARS-CoV-2 [22].

Nowadays, the clinical guidelines present the common ideas on the need for the use of glucocorticosteroids to prevent respiratory distress syndrome (RDS) of the fetus and newborn when there is a risk of premature birth or early delivery. However, there are clarifications when tocolytic therapy should not be administered for preventing RDS of the fetus and newborn in a condition that threatens the life of the mother or fetus. Critical condition of the mother or the fetus is a restriction for the prevention of fetal RDS and urgent delivery is required. [21, 37].

Thus, there is no convincing evidence that prolonging pregnancy poses risks of infection in the fetus. Tocolysis is indicated for prolonging pregnancy and reducing the risks of prematurity; it is also possible to complete the necessary treatment and to stabilize woman’s condition before delivery. At the same time, the issue of prolonging pregnancy in the patient with severe obstetric complications, life-threatening severity of somatic pathology of the mother is not discussed. Tocolysis is indicated in a satisfactory condition of the fetus and the absence of a direct threat to the mother’s life and clinical manifestations of preterm birth. The assessment of the fetal condition in RDS is complex and not fully understood. If respiratory support is necessary for a pregnant woman, the question arises about the criteria for evaluating CTG. There are no indications of how to interpret CTG results in the sources of information available to us. In such circumstances, a generally accepted standard method for interpreting CTG results can be applied. Similarly, reviews describing clinical cases do not provide data on the severity of the mother’s condition, CTG data, indications for delivery, and other fundamental points that would allow us to develop a balanced strategy for managing such patients, and evaluate the experience of foreign colleagues.

The issues of labor induction and mode of delivery remain controversial, since the suggestions on management tactics in the clinical guidelines differ from actual clinical practice. A positive test result for COVID-19 in a pregnant woman without clinical manifestations and signs of fetal distress is not an indication for preinduction and induction of labor. Induction of labor is associated with an increased risk of complications and a longer period of hospital stay than in spontaneous delivery. The decision on preinduction and induction of labor should be taken after evaluating the benefits and all possible risks; it can be performed if the woman is ready for birth and in case of IUGR according to fetometry [21].

To date, there is no single expert opinion on the mode of delivery of patients with suspected or confirmed COVID-19 infection. According to the data presented in the clinical guidelines of the Royal College of Obstetricians and Gynecologists, there is no evidence that cesarean section has advantages and is preferable to spontaneous vaginal delivery. The mode of delivery should not depend on the presence of COVID-19, unless the woman’s condition (respiratory failure) requires urgent intervention.

The decision on time and mode of delivery is made individually by an interdisciplinary team of specialists and depends mainly on the patient’s clinical status, gestational age and fetal condition [20, 36]. In case if an infected woman spontaneously goes into labor, the delivery should be conducted using conservative methods, provided that the pregnant woman and the fetus are in a satisfactory condition. Monitoring of a woman in childbirth is carried out in accordance with the standard method. In addition, it is necessary to monitor the oxygen saturation hourly and keep it at a level of more than 94%; when it decreases, oxygen inhalation is required [21]. Given the frequency of fetal complications reported in two Chinese reviews [23, 25], continuous monitoring of the fetal condition during delivery is also recommended. Mehreen Zaigham and Ola Andersson in their review analyzed the delivery outcomes of 108 pregnant patients with confirmed COVID-19 and demonstrated that spontaneous vaginal delivery was not associated with poorer outcomes [17]. Management of the second stage of labor does not differ from one of somatically healthy patients, performing instrumental or operative delivery is indicated only for the certain obstetric situations. It should be noted that a number of specialists consider that the second stage of labor can be shortened by operative or instrumental delivery due to a woman’s insufficient strength for pushing when wearing a surgical mask [37].

As for pain relief, there is no evidence that epidural or spinal analgesia or anesthesia is contraindicated in patients with the coronavirus infection. Therefore, it is recommended to perform epidural analgesia in women with suspected or confirmed COVID-19 infection during childbirth to minimize the need for general anesthesia if urgent surgery is required. At the same time, few cases of spontaneous vaginal delivery of pregnant women with COVID-19 have been described. According to the Italian researchers [38], among 50 patients, 96% of the pregnant women were delivered by cesarean section, the indications are not clearly described. In 39% of cases, it was a premature birth; the median gestational age during the delivery was 36.5 weeks. The authors note that in most cases the intervention was elective and probably it was not justified, but they do not exclude that the choice of mode of delivery was influenced by the presence of respiratory failure in the mother. The interval between admission and delivery in all cases was from 1 to 7 days (median is 2 days). The pregnant women under study did not suffer from concomitant diseases such as hypertension or diabetes. Among these patients, one had gestational hypertension and one had preeclampsia, in both cases after the diagnosis of COVID-19. Four women had a scar on the uterus, one patient had complete placenta previa. Two women had vaginal delivery at 34 and 31 weeks’ gestation. At least 26% out of 48 patients had a premature rupture of membranes. Spontaneous preterm birth was noted in 6 patients. The authors state that the decision on the mode of delivery might be made due to the risk of the potential consequences of this viral infection.

According to another review of 108 pregnant women from Korea, China, Honduras, Sweden and the United States, cesarean section was also performed in the majority of cases, 92% of patients were delivered by cesarean section. Successful vaginal delivery was detected in 8% of the cases. The most common indication described in the review was fetal distress [17]. However, according to the study of Elshafeey F. et al., the incidence of fetal distress was 7.8% [6].

In spite of the fact that all domestic and foreign guidelines recommend to choose the mode of delivery according to the obstetric situation with the priority given to vaginal delivery and emergency caesarean section should be done in critical situations, some recommendations indicate that the threshold of making a decision on emergency caesarean section in a woman with COVID-19 is lower compared to the general population, taking into account the signs of fetal distress, poor progress of labor, deterioration in the mother’s condition.

Thus, the issue of the most optimal tactics for managing such pregnant women remains controversial. On the one hand, the most sparing mode of delivery for a patient with the progressing infectious process remains natural birth in terms of the course and risks of complications of the postpartum period. On the other hand, if the mother experiences maternal hypoxemia, hypoxia may start developing in the fetus, as well as blood circulation disorders in the placenta due to the ongoing infectious process. Moreover, the possibility of active participation of a woman with COVID-19 in the second stage of labor may be limited because of the patient’s general condition and use of personal protective equipment.

Chinese colleagues indicate that cesarean section was performed in all cases to prevent intrauterine, perinatal and postnatal transmission of SARS-CoV-2 to the fetus and newborn, except for patients who were admitted urgently in the active phase of labor [35]. They also note that the risk of transmission of infection to the fetus in childbirth is not significant. According to the morphological analysis of the placentas from mothers with COVID-19, there were no signs of an infectious process, as well as viral RNA in the studied samples. Different severity of fibrin deposits in the villi and around the villi with locally enlarged syncytial nodules was found, which can be interpreted as a sign and may be suggestive of circulatory disorders in the placenta [34, 39].

It appears that the percentage of cesarean section deliveries is only partially related to medical indications such as the condition of the fetus, other obstetric indications, and the severity of the mother’s condition. In most cases, in our opinion and in the opinion of some foreign colleagues, cesarean section was performed due to epidemic indications. It is widely believed that cesarean section contributes to respiratory failure, however, we present the data from experts in the field of anesthesiology and resuscitation on this issue.

So, abdominal delivery of a pregnant woman with COVID-19 infection, who has moderate or severe respiratory failure, may be accompanied by additional risks for both woman and medical staff, which are usually underestimated by obstetricians and gynecologists, anesthesiologists and resuscitators. According to the guidelines of the Russian Federation of Anesthesiologists and Resuscitators, operative delivery in patients with respiratory failure should be performed under general anesthesia and the patient should be put to mechanical ventilation. Currently, it has been shown that mechanism of lung damage in COVID-19 involves microcirculatory impairment with the formation of thrombosis, increased resistance of the pulmonary blood circulation and the development of right ventricular dysfunction. In such conditions, the use of ventilation with an increase in intrathoracic pressure should be considered as a risk factor for decompensation of right ventricular failure. In addition, it is well known that immediately after operative delivery, there is a risk for developing hypervolemia, which is caused by the cessation of aortocaval compression and contraction of the uterus. This dramatic increase in circulating blood volume is an additional depressing factor for the right ventricle of a pregnant woman with COVID-19, which increases the risk of decompensation of heart and respiratory failure.

The use of ventilation in the patient with COVID19 significantly increases the risk of contamination of the personnel in the operating room due to the generation of infected aerosol during tracheal intubation and respiratory support with positive airway pressure. This extremely important circumstance should also be taken into consideration when determining the mode of delivery in COVID-19 pregnant women with respiratory failure. If there are any indications, elective cesarean section can be postponed until the general condition of the pregnant woman improves. Emergency delivery is indicated only in the case of a life-threatening condition of the mother or for obstetric indications, and should be performed with the prevention of coagulopathic and hypotonic bleeding.

In the postpartum period, all women need to assess the risk of hypotonic bleeding. If the risks are minimal, it is recommended to start again taking low molecular weight heparin as soon as possible for the prevention of venous thromboembolic complications, given that these patients are at high risk of complications in the postpartum period. The first dose of low molecular weight heparin should be administered as soon as possible after delivery, provided that there is reliable hemostasis. If regional analgesia was given in childbirth, low molecular weight heparin can be administered four hours after removal of the epidural catheter [21].

Conclusion

Nowadays, the world has faced another and probably not the last epidemic of viral infection. Researchers and practical healthcare specialists have more questions than answers due to the limited time and number of studies, lack of evidence of vertically transmitted infection from mother to fetus, absence of clear understanding of viral pathogenesis during pregnancy, as well as the level and degree of initiation of SARS-CoV-2 pathological processes in the mother and fetus that can have a negative influence on the perinatal outcome. However, it is noteworthy that elective operative delivery (cesarean section or operative vaginal delivery) should not be used as the main tool for solving the problem of minimizing both obstetric and perinatal risks under the conditions of inactive viral infection process. Further study of the pathological processes affecting the single functional system “mother-placenta-fetus” under the conditions of SARS-CoV-2 infection will resolve many issues of theoretical and practical significance in obstetrics.